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Answers and Critiques Item 1 Answer: C Bibliography Hillengass J, Usnrani S, Rajkumrr SV et rl. lntcrnational Myekrma Wrrrking Educational Objective: Evaluate smoldering myeloma Croup consensus reconlnlendrtions on imaging in monoclonal plasmir with whole-body MRL cell disorders. Lancet Oncol. 2019;20:eii02 eill2. IPMID: 31162104] doi:10.1016151470 2045(t9)3O:]O9 2 Whole body MRI is the most appropriate imaging test to perfirrm next in this patient (Option C). Smolderir.rg rrultiple myekrml (MM) is characterized by a serum M pnrtein level Item 2 Answer: C UI ot'3 grdL (:10 gi L) or greater (or >500 n'rg,/24 hr <tf urinary Educational Objective: Treat pure red cell aplasia in an c, r.nonoclonal lree light chains) or bone nlarrow plasnra clonal immunocompromised patient. ET cells of lO'X, to 59',1, and no evidence of r.uyekrma related L signs or syntptoms. All patients with MM should be assessed The most appropriate treatment for this patient is intra (., tbr skeletal lesions at diagnosis, periodically there:rfler. and venous immune gkrbulir.r (IVIC) (Option C). She has pure =, E when new symptoms occur. Skeletal survey fbllowing a red cell aplasia (PRCA) characterized by normocytic ane tli' Ut negative low dose CT scan would not provicle any value. mia with decreased reticukrcytes and absent or decreased (l, Low close CT and PE'l CT scan are recomntencled as the ini erythrocyte precursors in the bone marrow and with giant proerythroblasts with intranuclear viral inclusions vt = tial inraging procedure because of increasecl sensitivity. CT E is lrref'erred because of its relatively high sensitivity, speed, characteristic of parvovirus Bl9 infection. Several condi ancl patient convenience. If initial imaging with rvhole body tions have beer.r implicatecl in the pathogenesis of PRCA, krw dose CT is negative, whole body MRI is recontntencled. and chief among thern are parvovirus B19 infection, thy MRI has been fbund to be more sensitive in iclentilying moma, autoimmune disease (systemic lupus erythemato myeloma related bone lesions and soft tissue lesions fron-r sus), and lymphoid leukemias and lymphomas. Because plasnracytoma but is more inconvenient fbr the patient. tf' of her recent chemotherlpy, she is immunocompromised nrore than one lesion greater than 5 mm is discovered, the and vulnerable to viral inlections such as parvovirus Bl9, patient should be considered to have MM requirir.rg therapy. which she may have been exposed to as a kindergarten In this patient with smoldering MM. negative finclings r-rn teacher. Parvovirus infection in adults may be asymptom w,hole body low dose CT scan does not exclude skeletal :rtic or associated with tever, coryza, headache, nausea, lesions, and MRI is needed for further evaluation. and diarrhea. fbtlowed by a rash. ln adults, the classic Although bone scans are useful in detecting bone "slapped cheek" rash may not be apparent but other cuta nletilstases fiom underlying cancer, the bone lesions in MM neous manifestations mily occur. Parvovirus infection is are otten purely lytic and lack the enhanced osteoblast activ usually transient ar.rd rarely causes clinically significant ity that is shown by bone scan imaging. Bonc scans should anemia in healthy patients. llowever, parvovirus is cyto not be used to assess bone involvement in MM (Option A). toxic to erythrocyte precursors, and significant anemia In the evaluation of MM, advanced cross sectional can develop in patients witl'r chronic hemolysis (such as imagir.rg with whole-body low dose CT, PET CT scan, or sickle cell anemia) whri depencl on increased erythrcr wholc body MRI is preferred to a radiographic skeletal sur cyte production to m:rintair.r hernoglobin levels. lmmuno vey because advanced cross sectional imaging is signifi compromised patients can have sustained viremia leading cantly nrore sensitive and better able to classify the patient's to proionged anenria requiring lVlC treatment to hasten disease and thereby guide therapy (Option B). viral cleararrce. 'lhe presence or absence of local skeletal lesions on Acyckivir has no benefit in treating parvovirus infec whole body MRI wiil determine the pl:rn of carc ftrr patients tion, and empiric use of tl.ris antiviral agent will not hasten with sntoldering MM. Perfbrming no turther irnrrging places the resolution olthis patient's PRCA (Option A). the patient at risk of missing a diagnosis of early MM and Erythropoietin is aplrropriate to treat anemia in certain appropriate treatment (Option D). patients u'ith myelodysplastic syndrome (MDS) or end stage kidney disease (Option B). 'lhis patient has a normal plate r(EY P0t 1{TS let count and leukocyte cour.rt, which would be unlikely in . Low dose CT (preferred) and PET CT are recom MDS, and no history of chronic kidney disease, so erythro n.rended as the initial imaging procedure fbr patients poietin is not indicated. with a monoclonal gammopathy because of increased Prednisone would be indicated with signs or symp sensitivity for the detection of lytic lesions. toms of hemolytic ancrnia (Option D). However, the r A whole body low dose CT scan negative fbr sn.rolder low reticulocyte coullt and normal serum lactate dehy drogenase, haptoglobir.r, and bilirubin levels exclude ing myeloma should be followed by a whole body MRI. hemolvtic anemia.

Answers and Critiques Item 1 Answer: C Bibliography Hillengass J, Usnrani S, Rajkumrr SV et rl. lntcrnational Myekrma Wrrrking Educational Objective: Evaluate smoldering myeloma Croup consensus reconlnlendrtions on imaging in monoclonal plasmir with whole-body MRL cell disorders. Lancet Oncol. 2019;20:eii02 eill2. IPMID: 31162104] doi:10.1016151470 2045(t9)3O:]O9 2 Whole body MRI is the most appropriate imaging test to perfirrm next in this patient (Option C). Smolderir.rg rrultiple myekrml (MM) is characterized by a serum M pnrtein level Item 2 Answer: C UI ot'3 grdL (:10 gi L) or greater (or >500 n'rg,/24 hr <tf urinary Educational Objective: Treat pure red cell aplasia in an c, r.nonoclonal lree light chains) or bone nlarrow plasnra clonal immunocompromised patient. ET cells of lO'X, to 59',1, and no evidence of r.uyekrma related L signs or syntptoms. All patients with MM should be assessed The most appropriate treatment for this patient is intra (., tbr skeletal lesions at diagnosis, periodically there:rfler. and venous immune gkrbulir.r (IVIC) (Option C). She has pure =, E when new symptoms occur. Skeletal survey fbllowing a red cell aplasia (PRCA) characterized by normocytic ane tli' Ut negative low dose CT scan would not provicle any value. mia with decreased reticukrcytes and absent or decreased (l, Low close CT and PE'l CT scan are recomntencled as the ini erythrocyte precursors in the bone marrow and with giant proerythroblasts with intranuclear viral inclusions vt = tial inraging procedure because of increasecl sensitivity. CT E is lrref'erred because of its relatively high sensitivity, speed, characteristic of parvovirus Bl9 infection. Several condi ancl patient convenience. If initial imaging with rvhole body tions have beer.r implicatecl in the pathogenesis of PRCA, krw dose CT is negative, whole body MRI is recontntencled. and chief among thern are parvovirus B19 infection, thy MRI has been fbund to be more sensitive in iclentilying moma, autoimmune disease (systemic lupus erythemato myeloma related bone lesions and soft tissue lesions fron-r sus), and lymphoid leukemias and lymphomas. Because plasnracytoma but is more inconvenient fbr the patient. tf' of her recent chemotherlpy, she is immunocompromised nrore than one lesion greater than 5 mm is discovered, the and vulnerable to viral inlections such as parvovirus Bl9, patient should be considered to have MM requirir.rg therapy. which she may have been exposed to as a kindergarten In this patient with smoldering MM. negative finclings r-rn teacher. Parvovirus infection in adults may be asymptom w,hole body low dose CT scan does not exclude skeletal :rtic or associated with tever, coryza, headache, nausea, lesions, and MRI is needed for further evaluation. and diarrhea. fbtlowed by a rash. ln adults, the classic Although bone scans are useful in detecting bone "slapped cheek" rash may not be apparent but other cuta nletilstases fiom underlying cancer, the bone lesions in MM neous manifestations mily occur. Parvovirus infection is are otten purely lytic and lack the enhanced osteoblast activ usually transient ar.rd rarely causes clinically significant ity that is shown by bone scan imaging. Bonc scans should anemia in healthy patients. llowever, parvovirus is cyto not be used to assess bone involvement in MM (Option A). toxic to erythrocyte precursors, and significant anemia In the evaluation of MM, advanced cross sectional can develop in patients witl'r chronic hemolysis (such as imagir.rg with whole-body low dose CT, PET CT scan, or sickle cell anemia) whri depencl on increased erythrcr wholc body MRI is preferred to a radiographic skeletal sur cyte production to m:rintair.r hernoglobin levels. lmmuno vey because advanced cross sectional imaging is signifi compromised patients can have sustained viremia leading cantly nrore sensitive and better able to classify the patient's to proionged anenria requiring lVlC treatment to hasten disease and thereby guide therapy (Option B). viral cleararrce. 'lhe presence or absence of local skeletal lesions on Acyckivir has no benefit in treating parvovirus infec whole body MRI wiil determine the pl:rn of carc ftrr patients tion, and empiric use of tl.ris antiviral agent will not hasten with sntoldering MM. Perfbrming no turther irnrrging places the resolution olthis patient's PRCA (Option A). the patient at risk of missing a diagnosis of early MM and Erythropoietin is aplrropriate to treat anemia in certain appropriate treatment (Option D). patients u'ith myelodysplastic syndrome (MDS) or end stage kidney disease (Option B). 'lhis patient has a normal plate r(EY P0t 1{TS let count and leukocyte cour.rt, which would be unlikely in . Low dose CT (preferred) and PET CT are recom MDS, and no history of chronic kidney disease, so erythro n.rended as the initial imaging procedure fbr patients poietin is not indicated. with a monoclonal gammopathy because of increased Prednisone would be indicated with signs or symp sensitivity for the detection of lytic lesions. toms of hemolytic ancrnia (Option D). However, the r A whole body low dose CT scan negative fbr sn.rolder low reticulocyte coullt and normal serum lactate dehy drogenase, haptoglobir.r, and bilirubin levels exclude ing myeloma should be followed by a whole body MRI. hemolvtic anemia. 89

Answers and Critiques t(tY p0tilIs TEY POIXTS r Pure red cell aplasia is characterized by normocytic or . Pregnancy is associated with elevated D dimer meas- macrocytic anemia with decreased reticulocy.tes and urement. absent or decreased er5rthrocyte precursors in the o The pregnancy-adapted YEARS criteria along with bone marrow. D dimer measurement can help determine the risk . Immunocompromised patients can have sustained for pulmonary embolism and avoid unnecessary radi parvovirus viremia, leading to acquired pure red cell ation exposure. aplasia and prolonged anemia requiring intravenous immune globulin to hasten viral clearance. Bibliography van der Pol LM. Tromeur C, Bistervels lM, et al: Anemis Studl lnvesligators. Pregnancy adapted YEARS algorithm fbr diagnosis ofsuspected pulmo Bibliography nary embolism. N Engl J Med. 20l9rll80:1139 1149. IPMII): 3089353.1] Means RT Jr. Pure red cell aplasia. Hematolos/ Am Soc Hematol Educ doi: I O. lO56/NFlJMorl8l3865 tt Program. 2016;2016:51 56. [PMID: 27913462] € .D U! !, Item 3 Answer: E Item 4 Answer: D IL Educational Objective: Evaluate a pregnant patient for Educational Objective: Prevent herpes zoster virus r.t pulmonary embolism. reactivation during multiple myeloma treatment.

t(tY p0tilIs TEY POIXTS r Pure red cell aplasia is characterized by normocytic or . Pregnancy is associated with elevated D dimer meas- macrocytic anemia with decreased reticulocy.tes and urement. absent or decreased er5rthrocyte precursors in the o The pregnancy-adapted YEARS criteria along with bone marrow. D dimer measurement can help determine the risk . Immunocompromised patients can have sustained for pulmonary embolism and avoid unnecessary radi parvovirus viremia, leading to acquired pure red cell ation exposure. aplasia and prolonged anemia requiring intravenous immune globulin to hasten viral clearance. Bibliography van der Pol LM. Tromeur C, Bistervels lM, et al: Anemis Studl lnvesligators. Pregnancy adapted YEARS algorithm fbr diagnosis ofsuspected pulmo Bibliography nary embolism. N Engl J Med. 20l9rll80:1139 1149. IPMII): 3089353.1] Means RT Jr. Pure red cell aplasia. Hematolos/ Am Soc Hematol Educ doi: I O. lO56/NFlJMorl8l3865 tt Program. 2016;2016:51 56. [PMID: 27913462] € .D U! !, Item 3 Answer: E Item 4 Answer: D IL Educational Objective: Evaluate a pregnant patient for Educational Objective: Prevent herpes zoster virus r.t pulmonary embolism. reactivation during multiple myeloma treatment. tt No further evaluation is needed (Option E). According to In addition to chemotherapy, this patient should receive pro the pregnancy-adapted YEARS algorithm, this patient has a phylactic therapy with valacyclovir to prevent herpes zoster o UI very low probability of having a pulmonary embolism (PE). virus reactivation (Option D). She is immunocompromised She has an elevated D dimer measurement, but D dimer because of her plasma cell dyscrasia. Treatment guidelines levels progressively increase during the course ofpregnancy, for patients with multiple myeloma (MM) recommend that making interpretation difficult. To assist in the diagnosis of those treated with proteasome inhibitors (e.g.. bortezomib) PE in pregnant women, diagnostic algorithms have been should receive antiviral prophylaxis (acyclovir, valacyclo developed. The YEARS criteria have been shown to reduce vir) to avoid herpes zoster virus reactivation. Prophylaxis the risk ofunnecessary CT angiography in pregnant patients should be administered regardless ol previous immuniza suspected of having a PE. The YEARS algorithm assigns I tion against herpes zoster virus. point each for the presence ofthree cardinal criteria: clinical This patient should not receive epoetin. an erythro signs of deep venous thrombosis, hemoptysis, and PE as the poietin stimulating agent (ESA) (Option A). The American most likely diagnosis (point range 0-3). The score is used in Society of Clinical Oncologz and the American Society of conjunction with four potential D-dimer results (<0.5 pg/ml Hematology recommend restricting ESA use to patients lo.s mg/LJ, >0.s pg/ml [o.s mg/L], <1 pg/ml h mg/LJ, and with chemotherapy associated symptomatic anemia when >1 pg/ml [t mg/LJ). This patient met no YEARS clinical cancer treatment is not curative in intent to reduce the criteria and had a D-dimer measurement less than 1 pg/ml need for erythrocyte transfusions. ESAs are not recom (f mg/L). This corresponds to very low risk for PE, so she mended for patients whose cancer treatment is curative should not undergo additional testing or anticoagulation. in intent. given the risk of ESA-related cancer progression. CT pulmonary angiography can be used in pregnancy Although this recommendation is viewed by some as con to diagnose PE, but it exposes the woman to unnecessary troversial, this patient's anemia is asymptomatic and does radiation ifthe probability ofPE is low such as in this patient not require treatment with either an ESA or erythrocyte (Option A). transfusion. A perfusion only scan can be used to rule out PE in a Antibiotic prophylaxis with trimethoprim pregnant patient, but only after chest radiography has been sulfamethoxazole or levofloxacin is often administered performed and the results are interpreted as normal (Option during induction chemotherapy because of the high B). This patient has a normal respiratory examination and a rate of infection with gram-negative and encapsulated low probabiligz of PE, so a perlusion only scan is not needed. bacteria during the first 3 months of therapy. Trimethoprim Similarly, a ventilation perlusion lung scan is unnecessary sulfamethoxazole has been shown to decrease the number of when the probability of PE is Iow (Option D). bacterial infections and serious inf'ections. and levofloxacin MRI with gadolinium can be used to detect pulmonary prophylaxis has been associated with significantly fewer emboli, but it is an expensive test and not necessary for this deaths and febrile episodes during this time period. The patient with low probability for PE (Option C). Gadolin planned myeloma treatment is not associated with increased ium should not be used early in pregnancy because of the risk of fungal infection; therefore. prophylaxis with flu uncertainty of the effects on the fetus. MRI with gadolinium conazole is not indicated in this patient (Option B). Addi- may be a diagnostic option in select patients in whom tionally, metronidazole has no activity against encapsulated neither CT angiography nor ventilation-perfusion scan can bacteria, a common source of infection in patients with MM, be performed. and is not indicated (Option C).

tt No further evaluation is needed (Option E). According to In addition to chemotherapy, this patient should receive pro the pregnancy-adapted YEARS algorithm, this patient has a phylactic therapy with valacyclovir to prevent herpes zoster o UI very low probability of having a pulmonary embolism (PE). virus reactivation (Option D). She is immunocompromised She has an elevated D dimer measurement, but D dimer because of her plasma cell dyscrasia. Treatment guidelines levels progressively increase during the course ofpregnancy, for patients with multiple myeloma (MM) recommend that making interpretation difficult. To assist in the diagnosis of those treated with proteasome inhibitors (e.g.. bortezomib) PE in pregnant women, diagnostic algorithms have been should receive antiviral prophylaxis (acyclovir, valacyclo developed. The YEARS criteria have been shown to reduce vir) to avoid herpes zoster virus reactivation. Prophylaxis the risk ofunnecessary CT angiography in pregnant patients should be administered regardless ol previous immuniza suspected of having a PE. The YEARS algorithm assigns I tion against herpes zoster virus. point each for the presence ofthree cardinal criteria: clinical This patient should not receive epoetin. an erythro signs of deep venous thrombosis, hemoptysis, and PE as the poietin stimulating agent (ESA) (Option A). The American most likely diagnosis (point range 0-3). The score is used in Society of Clinical Oncologz and the American Society of conjunction with four potential D-dimer results (<0.5 pg/ml Hematology recommend restricting ESA use to patients lo.s mg/LJ, >0.s pg/ml [o.s mg/L], <1 pg/ml h mg/LJ, and with chemotherapy associated symptomatic anemia when >1 pg/ml [t mg/LJ). This patient met no YEARS clinical cancer treatment is not curative in intent to reduce the criteria and had a D-dimer measurement less than 1 pg/ml need for erythrocyte transfusions. ESAs are not recom (f mg/L). This corresponds to very low risk for PE, so she mended for patients whose cancer treatment is curative should not undergo additional testing or anticoagulation. in intent. given the risk of ESA-related cancer progression. CT pulmonary angiography can be used in pregnancy Although this recommendation is viewed by some as con to diagnose PE, but it exposes the woman to unnecessary troversial, this patient's anemia is asymptomatic and does radiation ifthe probability ofPE is low such as in this patient not require treatment with either an ESA or erythrocyte (Option A). transfusion. A perfusion only scan can be used to rule out PE in a Antibiotic prophylaxis with trimethoprim pregnant patient, but only after chest radiography has been sulfamethoxazole or levofloxacin is often administered performed and the results are interpreted as normal (Option during induction chemotherapy because of the high B). This patient has a normal respiratory examination and a rate of infection with gram-negative and encapsulated low probabiligz of PE, so a perlusion only scan is not needed. bacteria during the first 3 months of therapy. Trimethoprim Similarly, a ventilation perlusion lung scan is unnecessary sulfamethoxazole has been shown to decrease the number of when the probability of PE is Iow (Option D). bacterial infections and serious inf'ections. and levofloxacin MRI with gadolinium can be used to detect pulmonary prophylaxis has been associated with significantly fewer emboli, but it is an expensive test and not necessary for this deaths and febrile episodes during this time period. The patient with low probability for PE (Option C). Gadolin planned myeloma treatment is not associated with increased ium should not be used early in pregnancy because of the risk of fungal infection; therefore. prophylaxis with flu uncertainty of the effects on the fetus. MRI with gadolinium conazole is not indicated in this patient (Option B). Addi- may be a diagnostic option in select patients in whom tionally, metronidazole has no activity against encapsulated neither CT angiography nor ventilation-perfusion scan can bacteria, a common source of infection in patients with MM, be performed. and is not indicated (Option C). 90

Answers and Critiques t([Y PO I ]tr This patient consumes a normal diet and has no gastro o Treatment guidelines for patients with multiple mye- intestinal symptoms. Supplemental folate has been added to grains in the United States for many years. As such, dietary loma recommend that those treated with proteasome folate deflciency is uncommon except in patients with mal inhibitors (e.g., bortezomib) should receive antiviral nutrition. Folate deflciency has no association with hypothy prophylaxis (acyclovir, valacyclovir) to avoid herpes roidism or vitiligo. Measuring the serum f,olate level would zoster virus reactivation. be unnecessary (Option C).

t([Y PO I ]tr This patient consumes a normal diet and has no gastro o Treatment guidelines for patients with multiple mye- intestinal symptoms. Supplemental folate has been added to grains in the United States for many years. As such, dietary loma recommend that those treated with proteasome folate deflciency is uncommon except in patients with mal inhibitors (e.g., bortezomib) should receive antiviral nutrition. Folate deflciency has no association with hypothy prophylaxis (acyclovir, valacyclovir) to avoid herpes roidism or vitiligo. Measuring the serum f,olate level would zoster virus reactivation. be unnecessary (Option C). Bibliography KEY POIl{TS Guzdar A, Costelkr C. Supportive care in multiple myeloma. Curr Hematol . Pernicious anemia, characterized by autoimmune Malig Rep. 202Or15:56 61. IPMII): 321723611 doi:10.1007/sll899-O2O- 00570 9 gastritis and intrinsic factor deficiency, is a cause of cobalamin deficiency, which can be evaluated by measuring the serum cobalamin level. UI (D Item 5 Answer: D r Pemicious anemia can occur as an isolated flnding or CT Educational Objective: Diagnose vitamin B,, deficiency with other autoimmune conditions such as autoimmune caused by pernicious anemia. thyroid disease and vitiligo. IJ t The most appropriate diagnostic test fbr this patient is mea Bibliography IE rn suring the serum vitamin 8,, level (Option D). Patients with Wolflbnbuttel BI{R, Wouters HJCM, Heiner Fokkema MR, et al. The many q, vitamin B,, deficiency can present with weight loss, glos faces of cobalamin (vitamin Bl2) deficiency. Mayo Clin Proc [nnov Qual B Outcomes. 2019;3:200 214. [PMID: 31193945] doi:10.1016/i.mayocpiqo. t sitis, and "lemon yellow" skin because of pallor and jaun 2019.03.002 dice resulting from ineffective erythropoiesis. Vitamin B,, deflciency can cause neurologic symptoms, including loss of vibratory sense, loss of proprioception, spastic ataxia, and other dorsal column symptoms. Psychiatric symptoms (megaloblastic mania) can manif'est as dementia, hallucina Item 6 Answer: C Educational Objective: Treat acute chest syndrome tr with exchange transfusion. tions, and lrank psychosis. In patients with vitamin B,, defl ciency, the peripheral blood smear shows oval macrocytes Flrythrocyte erchange transfirsion shoulcl be initiated and hypersegmented neutrophils. Pancytopenia resulting (Option C). This patient has acute chest synclrome (ACS). from ineflective hematopoiesis can also be seen. Other labo which develops as a result of vaso occlusion in the puhao ratory flndings are consistent with intramedullary hemolysis nary r.nicrcvasculature. In patients rvith sickle cell disease caused by ineffective erythropoiesis, including decreased (SCt)). ACS should be consiclered and treatnrent begun in haptoglobin and elevated lactate dehydrogenase levels and those presenting with t'ever, hypoxia, chest pain, and new I indirect hyperbilirubinemia. The reticulocyte count is low consolidatirin on radiogrlphic imaging because patients can in patients with vitamin B,, deficiency. This patient most rapidly deteriorate ancl develop rnultiorgan failure. ACS is likely has vitamin B,, deflciency caused by pernicious ane the leading cause ol cleath in patients with sickle cell ane mia in which autoantibodies to intrinsic factor (lF) prevent mia: although patients n,ith all types of SCI) can develop the formation of vitamin B,r-lF complexes, resulting in the ACS. rates are highest in those with hemoglobin SS dis impaired ability to absorb vitamin B,r. Pernicious anemia easc.'l.reatment consists ol supportive rneilsures. inclutiing can occur as an isolated flnding or with other autoimmune analgesil and supplemental oxygen, with nrany patients conditions such as autoimmune thyroid disease and vitiligo recluiring nrechanical ventilation. Because AOS shares many as seen in this patient. clinical t'eatures lr,ith pncunronia and can be triggered by An elevated serum homocysteine level has a sensitMty and in{ection, enrpiric antibiotic therapy fbr pneunronia is con speciflcity ofgreater than 90'1, in diagnosing folate deflciency siclered accepted care. Ilou,cver. erythrocyte transfusion is and is the preferred test when deficiency is suspected despite a the main treatment intervention. Simple transfusion can be normal serum folate level (Option A). Homocysteine Ievels are used fbr milder presentations, but exchange translitskrn is also elevated in patients with vitamin 8,, deflcienry, but vitamin recornrnended fbr more severe tirrms. the posttrar-rsflusion B,, measurement is the preferred initial diagnostic test. target henroglobin S is less than :10',1, and target hemoglobin Serum vitamin B,, is approximately 957, sensitive in lerrel is I 0 g "clL (100 g, t-). the diagnosis of vitamin B,, deficiency in symptomatic Although n-ryocarclial clamage can occur lionr acute patients. Levels greater than 300 pglmL (221pmol/L) effec- vaso occlnsion. acute coronilry syndrome is rare in SCI) tively exclude vitamin B,, deflciency; lower levels may not and woulcl not be expectecl in l 27 year old piltient. Cardiac adequately represent tissue vitamin B,, levels. As such, an cathcterizirtion is, therefbre. not indicated (Option A). elevated concentration of methylmalonic acid is a more sen Pltients with SCD are lt higher risk for venous throm- sitive indicator of vitamin B,, deficiency (Option B). How boembolisr.n. particularly pulmonary embolism. Ilowever, ever, serum vitamin B,, measurement remains the preferred the prescnce of vaso occlusive pain and herrolysis is more initial diagnostic test because of its sensitivity. sullgestive of ACS than ir pulmonary enrbolus. Aclditionally'.

Bibliography KEY POIl{TS Guzdar A, Costelkr C. Supportive care in multiple myeloma. Curr Hematol . Pernicious anemia, characterized by autoimmune Malig Rep. 202Or15:56 61. IPMII): 321723611 doi:10.1007/sll899-O2O- 00570 9 gastritis and intrinsic factor deficiency, is a cause of cobalamin deficiency, which can be evaluated by measuring the serum cobalamin level. UI (D Item 5 Answer: D r Pemicious anemia can occur as an isolated flnding or CT Educational Objective: Diagnose vitamin B,, deficiency with other autoimmune conditions such as autoimmune caused by pernicious anemia. thyroid disease and vitiligo. IJ t The most appropriate diagnostic test fbr this patient is mea Bibliography IE rn suring the serum vitamin 8,, level (Option D). Patients with Wolflbnbuttel BI{R, Wouters HJCM, Heiner Fokkema MR, et al. The many q, vitamin B,, deficiency can present with weight loss, glos faces of cobalamin (vitamin Bl2) deficiency. Mayo Clin Proc [nnov Qual B Outcomes. 2019;3:200 214. [PMID: 31193945] doi:10.1016/i.mayocpiqo. t sitis, and "lemon yellow" skin because of pallor and jaun 2019.03.002 dice resulting from ineffective erythropoiesis. Vitamin B,, deflciency can cause neurologic symptoms, including loss of vibratory sense, loss of proprioception, spastic ataxia, and other dorsal column symptoms. Psychiatric symptoms (megaloblastic mania) can manif'est as dementia, hallucina Item 6 Answer: C Educational Objective: Treat acute chest syndrome tr with exchange transfusion. tions, and lrank psychosis. In patients with vitamin B,, defl ciency, the peripheral blood smear shows oval macrocytes Flrythrocyte erchange transfirsion shoulcl be initiated and hypersegmented neutrophils. Pancytopenia resulting (Option C). This patient has acute chest synclrome (ACS). from ineflective hematopoiesis can also be seen. Other labo which develops as a result of vaso occlusion in the puhao ratory flndings are consistent with intramedullary hemolysis nary r.nicrcvasculature. In patients rvith sickle cell disease caused by ineffective erythropoiesis, including decreased (SCt)). ACS should be consiclered and treatnrent begun in haptoglobin and elevated lactate dehydrogenase levels and those presenting with t'ever, hypoxia, chest pain, and new I indirect hyperbilirubinemia. The reticulocyte count is low consolidatirin on radiogrlphic imaging because patients can in patients with vitamin B,, deficiency. This patient most rapidly deteriorate ancl develop rnultiorgan failure. ACS is likely has vitamin B,, deflciency caused by pernicious ane the leading cause ol cleath in patients with sickle cell ane mia in which autoantibodies to intrinsic factor (lF) prevent mia: although patients n,ith all types of SCI) can develop the formation of vitamin B,r-lF complexes, resulting in the ACS. rates are highest in those with hemoglobin SS dis impaired ability to absorb vitamin B,r. Pernicious anemia easc.'l.reatment consists ol supportive rneilsures. inclutiing can occur as an isolated flnding or with other autoimmune analgesil and supplemental oxygen, with nrany patients conditions such as autoimmune thyroid disease and vitiligo recluiring nrechanical ventilation. Because AOS shares many as seen in this patient. clinical t'eatures lr,ith pncunronia and can be triggered by An elevated serum homocysteine level has a sensitMty and in{ection, enrpiric antibiotic therapy fbr pneunronia is con speciflcity ofgreater than 90'1, in diagnosing folate deflciency siclered accepted care. Ilou,cver. erythrocyte transfusion is and is the preferred test when deficiency is suspected despite a the main treatment intervention. Simple transfusion can be normal serum folate level (Option A). Homocysteine Ievels are used fbr milder presentations, but exchange translitskrn is also elevated in patients with vitamin 8,, deflcienry, but vitamin recornrnended fbr more severe tirrms. the posttrar-rsflusion B,, measurement is the preferred initial diagnostic test. target henroglobin S is less than :10',1, and target hemoglobin Serum vitamin B,, is approximately 957, sensitive in lerrel is I 0 g "clL (100 g, t-). the diagnosis of vitamin B,, deficiency in symptomatic Although n-ryocarclial clamage can occur lionr acute patients. Levels greater than 300 pglmL (221pmol/L) effec- vaso occlnsion. acute coronilry syndrome is rare in SCI) tively exclude vitamin B,, deflciency; lower levels may not and woulcl not be expectecl in l 27 year old piltient. Cardiac adequately represent tissue vitamin B,, levels. As such, an cathcterizirtion is, therefbre. not indicated (Option A). elevated concentration of methylmalonic acid is a more sen Pltients with SCD are lt higher risk for venous throm- sitive indicator of vitamin B,, deficiency (Option B). How boembolisr.n. particularly pulmonary embolism. Ilowever, ever, serum vitamin B,, measurement remains the preferred the prescnce of vaso occlusive pain and herrolysis is more initial diagnostic test because of its sensitivity. sullgestive of ACS than ir pulmonary enrbolus. Aclditionally'. 91

Answers and Critiques [[ nen' pulmonarl cor.rsolidiitions on radiograpl.ric imaging associated with more significant neutrophilia. including E rvoukl not be e\pected n'itl.r a pulrnonan'enrbolism. There clostridial infections. This patient is asymptomatic and has coNr fb.". CT angiography shoulcl not be the rlext step ir.r this a normal peripheral blood smear, so occult inf'ection is an patient's management (Option B). unlikely cause of his neutrophilia. the patient displal,s no evidence ot'r,olurne overload. Some medications can cause an increase in the abso inclucling jugular venous ciistention, an S j. or lort'er ettren-r lute neutrophil count. Glucocorticoids cause an increase ity eder-na, so flrosentide u,ould not be recommended in release of neutrophils from the bone nrarrort Ml,eloid (Option D). growth factors (granulocyte colony stimulating factor) and lithium are other drugs associated w'ith an increased abso XEY POIf,II lute neutrophil count. However. prtrvastatin and other statins . Acute chest syndrome should be considered in patients are not known to cause significant neutrophilia (Option C). with sickle cell anemia presenting with fever, hypoxia, chest pain, and new consolidation on radiographic rtv Pollrr5 UI imaging. . Smoking is a common cause of acquired neutrophilia; E (D . Erythroclte exchange transfusion is recommended in leukocytosis seen with smoking can persist for a pro l,I longed time even after cessation. severe acute chest syndrome. o, . In addition to smoking, several other factors can cause CL an acquired asymptomatic increase in neutrophil rr Bibliography Dolatkhah R. Dastgiri S. Blood transfusions for treating acute chest s)n count, including asplenia, chronic inflammatory con- clnrme in people rvith sickle cell disease. Cochrane I)atabase S)'st Re\: st 2020;l:CD0078.1:1. I PMID: 319,12751lr ckri:1O.1002r 146.51858.CD0078.13. ditions such as inflammatory bowel disease, obesity. .D pub4 and vigorous exercise. aa

[[ nen' pulmonarl cor.rsolidiitions on radiograpl.ric imaging associated with more significant neutrophilia. including E rvoukl not be e\pected n'itl.r a pulrnonan'enrbolism. There clostridial infections. This patient is asymptomatic and has coNr fb.". CT angiography shoulcl not be the rlext step ir.r this a normal peripheral blood smear, so occult inf'ection is an patient's management (Option B). unlikely cause of his neutrophilia. the patient displal,s no evidence ot'r,olurne overload. Some medications can cause an increase in the abso inclucling jugular venous ciistention, an S j. or lort'er ettren-r lute neutrophil count. Glucocorticoids cause an increase ity eder-na, so flrosentide u,ould not be recommended in release of neutrophils from the bone nrarrort Ml,eloid (Option D). growth factors (granulocyte colony stimulating factor) and lithium are other drugs associated w'ith an increased abso XEY POIf,II lute neutrophil count. However. prtrvastatin and other statins . Acute chest syndrome should be considered in patients are not known to cause significant neutrophilia (Option C). with sickle cell anemia presenting with fever, hypoxia, chest pain, and new consolidation on radiographic rtv Pollrr5 UI imaging. . Smoking is a common cause of acquired neutrophilia; E (D . Erythroclte exchange transfusion is recommended in leukocytosis seen with smoking can persist for a pro l,I longed time even after cessation. severe acute chest syndrome. o, . In addition to smoking, several other factors can cause CL an acquired asymptomatic increase in neutrophil rr Bibliography Dolatkhah R. Dastgiri S. Blood transfusions for treating acute chest s)n count, including asplenia, chronic inflammatory con- clnrme in people rvith sickle cell disease. Cochrane I)atabase S)'st Re\: st 2020;l:CD0078.1:1. I PMID: 319,12751lr ckri:1O.1002r 146.51858.CD0078.13. ditions such as inflammatory bowel disease, obesity. .D pub4 and vigorous exercise. aa Bibliography Item 7 Answer: D \hn Tiel h. Peeters PH. Smit I L\. et al. Quittiltg snroking nla) restore hema k)loUical characteristics $'ithin live 1ears. Ann Epidenliol. 2002:12:i178 Educational Objective: Evaluate neutrophilia. 88. IPMID:121605961 doi:10.1016 s1017 2797(01)00282 I

Bibliography Item 7 Answer: D \hn Tiel h. Peeters PH. Smit I L\. et al. Quittiltg snroking nla) restore hema k)loUical characteristics $'ithin live 1ears. Ann Epidenliol. 2002:12:i178 Educational Objective: Evaluate neutrophilia. 88. IPMID:121605961 doi:10.1016 s1017 2797(01)00282 I Chronic smoking is one of the more common causes of acquired neutrophilia (Option D). How smoking causes an increase in absolute neutrophil count is not entirely clear, but it may be related to inducing an inflammatory process. Item 8 Answer: B Educational Objective: Diagnose acute promyelocl'tic tr leukemia. The degree of neutrophilia appears to be proportional to the amount smoked, and this neutrophilia can persist for a pro this patier.rt has :rcute proml'eloc1'tic leukemia (APL). a clis longed time even after cessation (for years in some persons). tinct viiriant of acute n.r1'eloid leukemia (A\1t-) (Option B). Several other factors can cause an asymptomatic increase in She presents ltith sigr.rs of a bleedit.tg diathesis. Her pro neutrophil count, including asplenia, chronic inflammatory longed prothrombin ancl activated partial thromboplas conditions such as inflammatory bowel disease, obesity, and till tinles. eler,'ated lNR. lort' fibrir.rogen level. and elevatecl vigorous exercise. All patients who smoke should be coun fibrin degr:rdation products are consisteltt \r'ith disserni seled to stop smoking and should be offered pharmacologic nated intravascular coagulation (DIC). Although irnemia atld assistance. thrombricytopenia fionr marro\\ infiltration can be asso Chronic myeloid leukemia (CML) may also cause ciate(l $,ith any ircute leukentia. presentatittlr n'ith DIC is asymptomatic neutrophilia, although patients. not unconl unique to APL. ln APL. normirl leukocl'te difl'erentiation is monly, have systemic symptoms or symptoms related to blocked at the prornvelocl'te stage. u'hich can be detectecl on hepatosplenomegaly, which are absent in this patient the peripheral blood sntear. Auer rods can <tccasionallv be (Option A). Patients with CML often have increased num seen in anl AI\4t- but are classic in the APL variant. bers ol less mature leukocytes, including band tbrms and Acute lyn-rphoblastic leukemia (ALL) is llore corl myelocytes in the peripheral blood. The modest neutrophilia mon in children and aclolescerlts than in adults (Option A). with a normal diflerential, normal peripheral blood smear, Patients present rt'ith rniilaise. thrombocrlopenic bleediltg. and absence of symptoms make smoking or other benign infections. bone pain, or a combination ol these s) lnptonls. cause a much more likely cause in this patient. u,ith ir small subset havir-tg s1'mptonl:rtic central nenous Inf'ections are a common cause of leukocytosis. and s1,'stem involrement at diagnosis. ln adults. 75",, oIALL is ol bacterial infections can cause neutrophilia with a left shitt B cell lineage: nlature B cell At.l- can present as e\trirmedul or presence of'bands, metamyelocytes, or other immature lary disease, including gastrointestinal or testicular invohe granulocytes in the circulation (Option B). Other findings rnent. Although Al-L can occur in l,ounger aclult patients. can include toxic granulations or Dohle bodies seen in the irssocirtion of lcute leukenria u'ith DIC most strongl) circulating neutrophils on review of the peripheral blood supports the diagnosis of APL. smear. In certain severe infections, the leukocyte count can In aplastic anemia. cytoperrias are present in all threc be as high as 1O0,O00/pL (1O0 x fOq/L). Some bacteria are cell lineages (Option C). Unless an associated hen-ratologic

Chronic smoking is one of the more common causes of acquired neutrophilia (Option D). How smoking causes an increase in absolute neutrophil count is not entirely clear, but it may be related to inducing an inflammatory process. Item 8 Answer: B Educational Objective: Diagnose acute promyelocl'tic tr leukemia. The degree of neutrophilia appears to be proportional to the amount smoked, and this neutrophilia can persist for a pro this patier.rt has :rcute proml'eloc1'tic leukemia (APL). a clis longed time even after cessation (for years in some persons). tinct viiriant of acute n.r1'eloid leukemia (A\1t-) (Option B). Several other factors can cause an asymptomatic increase in She presents ltith sigr.rs of a bleedit.tg diathesis. Her pro neutrophil count, including asplenia, chronic inflammatory longed prothrombin ancl activated partial thromboplas conditions such as inflammatory bowel disease, obesity, and till tinles. eler,'ated lNR. lort' fibrir.rogen level. and elevatecl vigorous exercise. All patients who smoke should be coun fibrin degr:rdation products are consisteltt \r'ith disserni seled to stop smoking and should be offered pharmacologic nated intravascular coagulation (DIC). Although irnemia atld assistance. thrombricytopenia fionr marro\\ infiltration can be asso Chronic myeloid leukemia (CML) may also cause ciate(l $,ith any ircute leukentia. presentatittlr n'ith DIC is asymptomatic neutrophilia, although patients. not unconl unique to APL. ln APL. normirl leukocl'te difl'erentiation is monly, have systemic symptoms or symptoms related to blocked at the prornvelocl'te stage. u'hich can be detectecl on hepatosplenomegaly, which are absent in this patient the peripheral blood sntear. Auer rods can <tccasionallv be (Option A). Patients with CML often have increased num seen in anl AI\4t- but are classic in the APL variant. bers ol less mature leukocytes, including band tbrms and Acute lyn-rphoblastic leukemia (ALL) is llore corl myelocytes in the peripheral blood. The modest neutrophilia mon in children and aclolescerlts than in adults (Option A). with a normal diflerential, normal peripheral blood smear, Patients present rt'ith rniilaise. thrombocrlopenic bleediltg. and absence of symptoms make smoking or other benign infections. bone pain, or a combination ol these s) lnptonls. cause a much more likely cause in this patient. u,ith ir small subset havir-tg s1'mptonl:rtic central nenous Inf'ections are a common cause of leukocytosis. and s1,'stem involrement at diagnosis. ln adults. 75",, oIALL is ol bacterial infections can cause neutrophilia with a left shitt B cell lineage: nlature B cell At.l- can present as e\trirmedul or presence of'bands, metamyelocytes, or other immature lary disease, including gastrointestinal or testicular invohe granulocytes in the circulation (Option B). Other findings rnent. Although Al-L can occur in l,ounger aclult patients. can include toxic granulations or Dohle bodies seen in the irssocirtion of lcute leukenria u'ith DIC most strongl) circulating neutrophils on review of the peripheral blood supports the diagnosis of APL. smear. In certain severe infections, the leukocyte count can In aplastic anemia. cytoperrias are present in all threc be as high as 1O0,O00/pL (1O0 x fOq/L). Some bacteria are cell lineages (Option C). Unless an associated hen-ratologic 92

t I L I Answers and Critiques L t : I i tr disorder is identified, aplastic anemia is not associited with at-vpical or abnormal cells in the peripl'reral blood (myelo thrombotic events il1 patients with high risk APLAS. Aspirin is often adcled to anticoagulatit)n in patients with arterial thrombosis and in patients lvitlt a pre existing indication \ CONT, blasts. at)"picirl lymphoid cells), as noted it.t this patient. \4ost importantlyl DIC is nol part of the presentation of aplastic ftlr aspirir-r therapy such as cardiovascular or cerebrovascular I anemia. disease. This paticnt should be trc'ated with rvariarin, not i . Prir.nary rnyelofibrosis (PMIr) is a clonal myeloid ciabigatran, and has no indication fbr the additit>n of aspirin ster.n cell disorcler with characteristic marrort'fibrosis and thc'rirpy' (Option A). L extramedullary henratopoiesis (Option D). Hematopoietic W:rrfarin is the preferred anticoagulirnt in llatients r,l'ith i progenitors iire ir.rcr-eased in the circulation. providing it high risk APLAS bccause clinical trials have clemonstrated I I eukoery t hrobl irstic l.licture ( teardnrp sl.raped erythroc-y-tes, an increasecl risk of thrornboembolic events with ri'r'aror i

. Prir.nary rnyelofibrosis (PMIr) is a clonal myeloid ciabigatran, and has no indication fbr the additit>n of aspirin ster.n cell disorcler with characteristic marrort'fibrosis and thc'rirpy' (Option A). L extramedullary henratopoiesis (Option D). Hematopoietic W:rrfarin is the preferred anticoagulirnt in llatients r,l'ith i progenitors iire ir.rcr-eased in the circulation. providing it high risk APLAS bccause clinical trials have clemonstrated I I eukoery t hrobl irstic l.licture ( teardnrp sl.raped erythroc-y-tes, an increasecl risk of thrornboembolic events with ri'r'aror i t nucleatecl erythrocytcs, imnratnre leukocytes). Most patients aban compar-ed with warflrir-r (Option B). u'ith PMli have [atigue. r,r'eight loss. fer,er. and chills. Massive Guidelines do not recomntettd dual therapy r,rith ar.r L splenorlegaly is common fionr extranredul Iary l-rernatopoie' inferior venil cava filter and anticoagtrlation fbr patients l,l o sis and portal h1'pertensior.r. 'l his patient does not har'-e sple rvith deep venous throtnbclsis (D\zT). even fbr patients rvith I proxirnal DVT ancl signi{icant preexisting cardiclpuhnonary ET I nomegallr ancl patients with l'}N,lF do not present with DIC. I diseasc', as well as fbr patients with pulmonary embolism L' XEY POIXIT ( ar.rd hemodynanric comprornise (Option D). T' o Acute promyelocytic leukemia is a distinct variant of a5 ; ac ute myeloid leukemia. TEY POIXTS l,I I . High risk antiphospholipid antibody syndrome is (I, I o Although anemia and thrombocytopenia from mar- I row infiltration can be associated with any acute leu- defined by the presence oftriple positivity for the vt = E I kemia, presentation with disseminated intravascular lupus anticoagulant, anticardiolipin antibodies, and coagulation is characteristic of acute promyelocytic anti p, glycoprotein antibodies, measured on two ;

t nucleatecl erythrocytcs, imnratnre leukocytes). Most patients aban compar-ed with warflrir-r (Option B). u'ith PMli have [atigue. r,r'eight loss. fer,er. and chills. Massive Guidelines do not recomntettd dual therapy r,rith ar.r L splenorlegaly is common fionr extranredul Iary l-rernatopoie' inferior venil cava filter and anticoagtrlation fbr patients l,l o sis and portal h1'pertensior.r. 'l his patient does not har'-e sple rvith deep venous throtnbclsis (D\zT). even fbr patients rvith I proxirnal DVT ancl signi{icant preexisting cardiclpuhnonary ET I nomegallr ancl patients with l'}N,lF do not present with DIC. I diseasc', as well as fbr patients with pulmonary embolism L' XEY POIXIT ( ar.rd hemodynanric comprornise (Option D). T' o Acute promyelocytic leukemia is a distinct variant of a5 ; ac ute myeloid leukemia. TEY POIXTS l,I I . High risk antiphospholipid antibody syndrome is (I, I o Although anemia and thrombocytopenia from mar- I row infiltration can be associated with any acute leu- defined by the presence oftriple positivity for the vt = E I kemia, presentation with disseminated intravascular lupus anticoagulant, anticardiolipin antibodies, and coagulation is characteristic of acute promyelocytic anti p, glycoprotein antibodies, measured on two ; leukemia. occasions 12 weeks apart. o Warfarin is the preferred oral anticoagulant in Bibliography patients with high risk antiphospholipid antibody l)athner ll. Iistey [. (irimw|de D. et al. Diagnosis and ntanagen]ent oI AML ,

leukemia. occasions 12 weeks apart. o Warfarin is the preferred oral anticoagulant in Bibliography patients with high risk antiphospholipid antibody l)athner ll. Iistey [. (irimw|de D. et al. Diagnosis and ntanagen]ent oI AML , syndrome. : in aclults:2017 I1LN recommendations lionr an international expert t panel. I3lood. 2Ol7 ;129 :424,147. LPMID: 2789505U 1 doi: 10. I I 82/bkxrcl 2016 08 733196 Bibliography L Garcia D, Erkrn D. Diagnosis ancl nranagement of the antiphospholipid syn drome. N EnglJ Med. 2018rll7tl:2010 2021. [PMll): 297918'28] doi:10.1056/

syndrome. : in aclults:2017 I1LN recommendations lionr an international expert t panel. I3lood. 2Ol7 ;129 :424,147. LPMID: 2789505U 1 doi: 10. I I 82/bkxrcl 2016 08 733196 Bibliography L Garcia D, Erkrn D. Diagnosis ancl nranagement of the antiphospholipid syn drome. N EnglJ Med. 2018rll7tl:2010 2021. [PMll): 297918'28] doi:10.1056/ tr N IiJ l\4rai70545.1 Item 9 Answer: C t Educational Objective: Treat a patient with high-risk antiphospholipid antibody syndrome. Item 10 Answer: A L 'lhe mosl appropriate long term treatment for this patient Educationa I Objective : Evaluate macrocytic anemia occurring subsequent to radiation and chemotherapy. is anticoagulation u'ith w:rrfarin (Option C). She rneets the criteria fbr antiphospholipicl ilntibody syndronre (API-AS) The most appropriate diagnostic test to perform next is basecl on her vascular thronrbosis (ircute puhnonary enrb<; bone marrow biopsy (Option A). This patient has symptom b lisnr). history of pregnancy rnorbidity. ancl laboraktry crite atic macrocytic anemia. She has a history of breast cancer riir. Pregrrancy rnorbidity that meets the criteria tbr APLAS treated with chemotherapy and radiation, both of which are itrcludes at lelst one pregnancy loss after 10 wc'eks' gesta independently associated with myelodysplastic syndrome tion: at least orre prenrature birth befbre 34 lveeks'gestation (MDS), so evaluation by bone marrow biopsy will provide bccause of eclampsia, prc'eclampsia, or placental insufli- key information to confirm the suspicion for therapy- ciency: or three or nlore unexplained consecutive sponta related MDS. Patients who develop MDS often present with ncous aborti<-rns belbre the l0th rveek of gestation. API-AS macrocytic (and often symptomatic) anemia. Bone marrow evirluation includes the anticarcliolipin antibodies, anti. biopsy aids in establishing the diagnosis and provides prog B, gl1'coprotein antibodies. lnd lu1'lus anticoagulant: tbr nostic information, including assessment of the percentage A['LAS ctiagnosis, laboratory findings rnust inclucle mediurn of marrow blasts and cytogenetics. If therapy related MDS or high titer urltiphospholipid antibodies on tu() or nrore is conflrmed, the patient may be evaluated for allogeneic occasions at leust 12 weeks lpart. 'll.ris patient hls high risk hematopoietic stem cell transplantation. Although some API-AS based ou triple positivity fbr the lupus anticoagulant, experts believe that therapy related MDS is a high-risk con xrlticardiolipiu antibodies, iind anti B, glycoprotein anti dition independent of cytogenetic abnormalities, obtaining bodies on tvvo occasions measurecl 12 weeks apart. cytogenetic and genetic information may identify a target Erncrging data liorr systematic rel,ielvs inclicate thlt for novel therapies. the use of tlirect oral anticoagulants, such as clabigatran. irre Colonoscopy is indicated in the evaluation ofiron defl rrot as eflecti'ue as rt,arfirrin in the prevention ol recurrent ciency anemia in most men and in postmenopausal women

tr N IiJ l\4rai70545.1 Item 9 Answer: C t Educational Objective: Treat a patient with high-risk antiphospholipid antibody syndrome. Item 10 Answer: A L 'lhe mosl appropriate long term treatment for this patient Educationa I Objective : Evaluate macrocytic anemia occurring subsequent to radiation and chemotherapy. is anticoagulation u'ith w:rrfarin (Option C). She rneets the criteria fbr antiphospholipicl ilntibody syndronre (API-AS) The most appropriate diagnostic test to perform next is basecl on her vascular thronrbosis (ircute puhnonary enrb<; bone marrow biopsy (Option A). This patient has symptom b lisnr). history of pregnancy rnorbidity. ancl laboraktry crite atic macrocytic anemia. She has a history of breast cancer riir. Pregrrancy rnorbidity that meets the criteria tbr APLAS treated with chemotherapy and radiation, both of which are itrcludes at lelst one pregnancy loss after 10 wc'eks' gesta independently associated with myelodysplastic syndrome tion: at least orre prenrature birth befbre 34 lveeks'gestation (MDS), so evaluation by bone marrow biopsy will provide bccause of eclampsia, prc'eclampsia, or placental insufli- key information to confirm the suspicion for therapy- ciency: or three or nlore unexplained consecutive sponta related MDS. Patients who develop MDS often present with ncous aborti<-rns belbre the l0th rveek of gestation. API-AS macrocytic (and often symptomatic) anemia. Bone marrow evirluation includes the anticarcliolipin antibodies, anti. biopsy aids in establishing the diagnosis and provides prog B, gl1'coprotein antibodies. lnd lu1'lus anticoagulant: tbr nostic information, including assessment of the percentage A['LAS ctiagnosis, laboratory findings rnust inclucle mediurn of marrow blasts and cytogenetics. If therapy related MDS or high titer urltiphospholipid antibodies on tu() or nrore is conflrmed, the patient may be evaluated for allogeneic occasions at leust 12 weeks lpart. 'll.ris patient hls high risk hematopoietic stem cell transplantation. Although some API-AS based ou triple positivity fbr the lupus anticoagulant, experts believe that therapy related MDS is a high-risk con xrlticardiolipiu antibodies, iind anti B, glycoprotein anti dition independent of cytogenetic abnormalities, obtaining bodies on tvvo occasions measurecl 12 weeks apart. cytogenetic and genetic information may identify a target Erncrging data liorr systematic rel,ielvs inclicate thlt for novel therapies. the use of tlirect oral anticoagulants, such as clabigatran. irre Colonoscopy is indicated in the evaluation ofiron defl rrot as eflecti'ue as rt,arfirrin in the prevention ol recurrent ciency anemia in most men and in postmenopausal women 93

Answers and Critiques (Option B). Macrocytic anemia and concomitant leukopenia Cytoreductive therapy is added for patients with high and thrombocytopenia would be inconsistent'*,ith iron defl risk PV. u,hich includes those older than 60 years or r.r'ith a ciency, so colonoscopy would be of little help in evaluating history of thrombosis. Cytoreductive options in PV include this patient. hydroxyurea and interferon-a (Options A, C). Ruxolitinib Immune-mediated hemolysis is characterized by has also been shown to be an effective treatment in those antibody binding to erythrocytes causing complement- who are intolerant of flrst line agents or with resistant PV mediated and phagocy.te mediated destruction. The lab- (Option D). Cytoreductive therapy can sometimes be consid oratory hallmark of immune-mediated hemolysis is a ered in patients at otherwise lower risk who have significant positive direct antiglobulin test that detects either IgG or symptom burden or who require frequent phlebotomy; this complement (C3) on the erythrocyte surface (Option C). patient does not have signiflcant symptoms. and her phle- Patients with immune-mediated hemolysis may have ane- botomy requirements have yet to be determined. mia, fatigue, dyspnea, jaundice, splenomegaly, and reticu- lmatinib is a tyrosine kinase inhibitor that is used in D loc1.tosis. Pancytopenia would not be an expected flnding. chronic myelogenous leukemia (CML) (Option B). Although tt This patient has pancytopenia and a low reticulocyte count, imatinib is effective in the treatment of BCR-ABL-positile E which are not consistent with immune-mediated hemolysis. CML. it is not used for lAK2 positive PV. .D t/t A low mean corpuscular volume, elevated red cell dis- q, XEY POIlITS tribution width, and peripheral blood smear showing micro- EL cltosis and anisopoikilocytosis are virtually diagnostic of iron . Patients with primary polycy'themia vera should be n deficiency, especially in premenopausal women. This patient treated with low-dose aspirin and phlebotomy to a has a macrocytic anemia, and the leukopenia and thrombocy target hematocrit of less than 45% to reduce the risk It tr topenia cannot be explained by iron deflcienry. A bone marrow of adverse cardiovascular events. .D a^ examination rather than iron studies is indicated (Option D). . Patients with polycythemia vera and additional risk factors, including age older than 60 years or a history i r(Er P0rilrt I of thromboembolic event should receive c1'toreductive . Patients who develop myelodysplastic syndrome fol- therapy with hydroxyurea or interferon o in addition lowing cancer therapy usually present with sympto- to phlebotomy. matic macrocytic anemia. . Bone marrow biopsy should be performed to confirm Bibliography the diagnosis of myelodysplastic syndrome, to evalu- Mesa RA. Jan]ieson C, Bhatia R. et al. NCCN guidelines insights: myelopro ate the percentage of marrow blasts, and to provide liferative neoplasms, version 2.2018. J Natl Compr Canc Netw: 2017115: 119:1 t2O7. IPM I D: 28982745] doi: 10.600.f inccn.2017.0157 cytogenetic information.

(Option B). Macrocytic anemia and concomitant leukopenia Cytoreductive therapy is added for patients with high and thrombocytopenia would be inconsistent'*,ith iron defl risk PV. u,hich includes those older than 60 years or r.r'ith a ciency, so colonoscopy would be of little help in evaluating history of thrombosis. Cytoreductive options in PV include this patient. hydroxyurea and interferon-a (Options A, C). Ruxolitinib Immune-mediated hemolysis is characterized by has also been shown to be an effective treatment in those antibody binding to erythrocytes causing complement- who are intolerant of flrst line agents or with resistant PV mediated and phagocy.te mediated destruction. The lab- (Option D). Cytoreductive therapy can sometimes be consid oratory hallmark of immune-mediated hemolysis is a ered in patients at otherwise lower risk who have significant positive direct antiglobulin test that detects either IgG or symptom burden or who require frequent phlebotomy; this complement (C3) on the erythrocyte surface (Option C). patient does not have signiflcant symptoms. and her phle- Patients with immune-mediated hemolysis may have ane- botomy requirements have yet to be determined. mia, fatigue, dyspnea, jaundice, splenomegaly, and reticu- lmatinib is a tyrosine kinase inhibitor that is used in D loc1.tosis. Pancytopenia would not be an expected flnding. chronic myelogenous leukemia (CML) (Option B). Although tt This patient has pancytopenia and a low reticulocyte count, imatinib is effective in the treatment of BCR-ABL-positile E which are not consistent with immune-mediated hemolysis. CML. it is not used for lAK2 positive PV. .D t/t A low mean corpuscular volume, elevated red cell dis- q, XEY POIlITS tribution width, and peripheral blood smear showing micro- EL cltosis and anisopoikilocytosis are virtually diagnostic of iron . Patients with primary polycy'themia vera should be n deficiency, especially in premenopausal women. This patient treated with low-dose aspirin and phlebotomy to a has a macrocytic anemia, and the leukopenia and thrombocy target hematocrit of less than 45% to reduce the risk It tr topenia cannot be explained by iron deflcienry. A bone marrow of adverse cardiovascular events. .D a^ examination rather than iron studies is indicated (Option D). . Patients with polycythemia vera and additional risk factors, including age older than 60 years or a history i r(Er P0rilrt I of thromboembolic event should receive c1'toreductive . Patients who develop myelodysplastic syndrome fol- therapy with hydroxyurea or interferon o in addition lowing cancer therapy usually present with sympto- to phlebotomy. matic macrocytic anemia. . Bone marrow biopsy should be performed to confirm Bibliography the diagnosis of myelodysplastic syndrome, to evalu- Mesa RA. Jan]ieson C, Bhatia R. et al. NCCN guidelines insights: myelopro ate the percentage of marrow blasts, and to provide liferative neoplasms, version 2.2018. J Natl Compr Canc Netw: 2017115: 119:1 t2O7. IPM I D: 28982745] doi: 10.600.f inccn.2017.0157 cytogenetic information. Bibliography Item 12 Answer: C CazzolaM. Myelodysplastic syndromes. N Engl J Med. 20201383:1358 1374 EducationaI Objective: Diagnose warm autoimmune [PM I D: 32997910] doi: I 0.1056/NElMral9}4794 hemolytic anemia.

Bibliography Item 12 Answer: C CazzolaM. Myelodysplastic syndromes. N Engl J Med. 20201383:1358 1374 EducationaI Objective: Diagnose warm autoimmune [PM I D: 32997910] doi: I 0.1056/NElMral9}4794 hemolytic anemia. Item 11 Answer: E A direct antiglobulin test (DAT) is the most appropriate choice for this patient (Option C). Her presentation is con- Educational Objective: Treat low-risk polycythemia sistent with an acquired autoimmune hemolytic anemia vera. (AIHA), most likely warm AIHA (WAIHA). In WAIHA, a No further management is needed for this patient (Option E). polyclonal autoantibody interacts with multiple erythroc,'te She has a hemoglobin level greater than 16 g/dl (160 g/L), a antigens, causing extravascular hemolysis. The autoantibody low erythropoietin level, and presence of the /AK2 V617F is typically IgG. although it can rarely be IgM or lgA. Splenic mutation that meet diagnostic criteria for polycythemia vera macrophages phagocytize the IgG on the erythrocyte. as (PV). Some patients may be asymptomatic, with the diagno- well as a portion of the membrane, resulting in spherocy'te sis suspected by flndings on routine complete blood counts; formation. Patients have evidence of hemolysis, including however, many patients have symptoms of fatigue, head- anemia, increased lactate dehydrogenase level, low hapto ache, or itching, particularly after a warm shower (aqua globin level, and an indirect bilirubinemia. Reticulocytosis genic pruritus). Accompanying splenomegaly may present is also seen if no concomitant processes are present that with abdominal fullness, reflux, or early satiety. Unless con- could blunt the compensatory bone marrow response (e.g., traindicated, all patients with PV should undergo phlebot- iron deflciency). Approximately half of patients with WAIHA omy to maintain a hematocrit level less than 45'l" and be will have another underlying disease process. including viral treated with low-dose aspirin to reduce the risk of adverse infections, lymphoproliferative diseases. and other autoim cardiovascular events. Additional management depends on mune conditions such as systemic lupus erythematosus. risk stratification ofthe patient. This patient's age (<60 years) The DAT evaluates fbr the presence of IgG and complement and lack of thrombosis history categorize her as low risk. (C3) on the patient's erythrocl.tes and is positive in 95o1, ol Patients at low risk need no additional therapy. patients with WAIHA.

Item 11 Answer: E A direct antiglobulin test (DAT) is the most appropriate choice for this patient (Option C). Her presentation is con- Educational Objective: Treat low-risk polycythemia sistent with an acquired autoimmune hemolytic anemia vera. (AIHA), most likely warm AIHA (WAIHA). In WAIHA, a No further management is needed for this patient (Option E). polyclonal autoantibody interacts with multiple erythroc,'te She has a hemoglobin level greater than 16 g/dl (160 g/L), a antigens, causing extravascular hemolysis. The autoantibody low erythropoietin level, and presence of the /AK2 V617F is typically IgG. although it can rarely be IgM or lgA. Splenic mutation that meet diagnostic criteria for polycythemia vera macrophages phagocytize the IgG on the erythrocyte. as (PV). Some patients may be asymptomatic, with the diagno- well as a portion of the membrane, resulting in spherocy'te sis suspected by flndings on routine complete blood counts; formation. Patients have evidence of hemolysis, including however, many patients have symptoms of fatigue, head- anemia, increased lactate dehydrogenase level, low hapto ache, or itching, particularly after a warm shower (aqua globin level, and an indirect bilirubinemia. Reticulocytosis genic pruritus). Accompanying splenomegaly may present is also seen if no concomitant processes are present that with abdominal fullness, reflux, or early satiety. Unless con- could blunt the compensatory bone marrow response (e.g., traindicated, all patients with PV should undergo phlebot- iron deflciency). Approximately half of patients with WAIHA omy to maintain a hematocrit level less than 45'l" and be will have another underlying disease process. including viral treated with low-dose aspirin to reduce the risk of adverse infections, lymphoproliferative diseases. and other autoim cardiovascular events. Additional management depends on mune conditions such as systemic lupus erythematosus. risk stratification ofthe patient. This patient's age (<60 years) The DAT evaluates fbr the presence of IgG and complement and lack of thrombosis history categorize her as low risk. (C3) on the patient's erythrocl.tes and is positive in 95o1, ol Patients at low risk need no additional therapy. patients with WAIHA. 94

t t I i t Answers and Critiques I i I Although this patient has a mild degree ol thrombo f'ebrile neutropenia, or fbr patients undergoing induction I cytopenia, no schistocytes are reported on the peripheral chemotherapy for acute leukemia. L blood smear, making a microangiopathic hemolytic ane Reducing this patient's chemotherapy dose for subse mia unlikely. Therefore, evaluating the ADAM1'S13 activity quent cycles would not be an appropriate strates/ (Option A). L would not be helpful (Option A). ADAMTS13 activity would Prophylaxis with G CSF is better management for this patient be expected to be low in the presence of an inhibitor, as in than chemotherapy dose reduction, which might compro thrombotic thrombocytopen ic pu rpura. mise the potential therapeutic outcome of his treatment. A bone marrow biopsy would not be helpful at this time Given the cost, lack of benefit in patients with recovered because the patient's increased reticulocyte count and evi neutrophil counts, and potential adverse effects, weekly dence ofhemolysis indicates a peripheral destructive process administration of G CSF is not warranted (Option B). G CSF causing anemia rather than a defect in the bone marrow has many potential toxicities, including transient leukope- (Option B). nia following administration; systemic reactions that may Osmotic fragility testing is often used to evaluate for include flulike symptoms, hypertension, and increased risk r,l ll, hereditary spherocytosis (Option D). 'lhe test uses hypotonic fbr thrombosis; possible stimulation of malignancy; and ar saline incubation to evaluate for increased sensitivity o1' production ol neutralizing antibodies. spherocytic erythrocytes to hemolysis. The osmotic ttagil Fluoroquinolone prophylaxis is typically used tbr U ity test has a relatively low sensitivity ancl specilicity, with patients at high risk for prolonged neutropenia (Option D). -, positive results being seen in numerous other conditions, Those at high risk include patients undergoing allogeneic r! yt including AIHA.'lhe absence of a family history and onset of stem cell transplantation or receiving induction chemo symptomatic hemolysis at the age of 32 years argue against therapy lbr acute leukemia, neither of which applies to this {, t hereditary spherocy.tosis. patient. = XEY POII{T5 XEY POIilTS o The laboratory hallmark of immune-mediated hemol- r Granulocyte colony stimulating factor can be given ysis is a positive direct antiglobulin test that detects prophylactically to patients receiving chemotherapy IgG, complement (C3), or both on the ery.throcyte that carries a high risk of neutropenia and as second- surface. ary prophylaxis in patients with a previous episode ol o Hemolytic anemia is characterized by the presence ol febrile neutropenia. anemia, reticulocytosis, increased lactate dehydroge- . Granulocyte colony-stimulating factor is not indi- nase level, low haptoglobin level, and an indirect bili cated for most patients with neutropenia who are rubinemia. af'ebrile, as a routine adjunct to empiric antibiotics for patients presenting with febrile neutropenia, or Bibliography for patients undergoing induction chemotherapy for tsrodsky RA. Warm autoimntune hemolytic irnemix. N Engl J Mecl. 2019r acute leukemia. 3t31:647 65,1. IPMII): 31412178] doi:10.1056/NEJMcpl90O5s.1

Although this patient has a mild degree ol thrombo f'ebrile neutropenia, or fbr patients undergoing induction I cytopenia, no schistocytes are reported on the peripheral chemotherapy for acute leukemia. L blood smear, making a microangiopathic hemolytic ane Reducing this patient's chemotherapy dose for subse mia unlikely. Therefore, evaluating the ADAM1'S13 activity quent cycles would not be an appropriate strates/ (Option A). L would not be helpful (Option A). ADAMTS13 activity would Prophylaxis with G CSF is better management for this patient be expected to be low in the presence of an inhibitor, as in than chemotherapy dose reduction, which might compro thrombotic thrombocytopen ic pu rpura. mise the potential therapeutic outcome of his treatment. A bone marrow biopsy would not be helpful at this time Given the cost, lack of benefit in patients with recovered because the patient's increased reticulocyte count and evi neutrophil counts, and potential adverse effects, weekly dence ofhemolysis indicates a peripheral destructive process administration of G CSF is not warranted (Option B). G CSF causing anemia rather than a defect in the bone marrow has many potential toxicities, including transient leukope- (Option B). nia following administration; systemic reactions that may Osmotic fragility testing is often used to evaluate for include flulike symptoms, hypertension, and increased risk r,l ll, hereditary spherocytosis (Option D). 'lhe test uses hypotonic fbr thrombosis; possible stimulation of malignancy; and ar saline incubation to evaluate for increased sensitivity o1' production ol neutralizing antibodies. spherocytic erythrocytes to hemolysis. The osmotic ttagil Fluoroquinolone prophylaxis is typically used tbr U ity test has a relatively low sensitivity ancl specilicity, with patients at high risk for prolonged neutropenia (Option D). -, positive results being seen in numerous other conditions, Those at high risk include patients undergoing allogeneic r! yt including AIHA.'lhe absence of a family history and onset of stem cell transplantation or receiving induction chemo symptomatic hemolysis at the age of 32 years argue against therapy lbr acute leukemia, neither of which applies to this {, t hereditary spherocy.tosis. patient. = XEY POII{T5 XEY POIilTS o The laboratory hallmark of immune-mediated hemol- r Granulocyte colony stimulating factor can be given ysis is a positive direct antiglobulin test that detects prophylactically to patients receiving chemotherapy IgG, complement (C3), or both on the ery.throcyte that carries a high risk of neutropenia and as second- surface. ary prophylaxis in patients with a previous episode ol o Hemolytic anemia is characterized by the presence ol febrile neutropenia. anemia, reticulocytosis, increased lactate dehydroge- . Granulocyte colony-stimulating factor is not indi- nase level, low haptoglobin level, and an indirect bili cated for most patients with neutropenia who are rubinemia. af'ebrile, as a routine adjunct to empiric antibiotics for patients presenting with febrile neutropenia, or Bibliography for patients undergoing induction chemotherapy for tsrodsky RA. Warm autoimntune hemolytic irnemix. N Engl J Mecl. 2019r acute leukemia. 3t31:647 65,1. IPMII): 31412178] doi:10.1056/NEJMcpl90O5s.1 Bibliography Ilecker I)S. Grifliths EA, Alu,an LM. et ,1. NCCN guidelines insights: hemat Item 13 Answer: C opoietic growth factors, version l.2O2O. I Natl (bmpr Canc Netw 2020r I 8:12 - 22. IPMl l), 3l 91038,1] doi: I 0.6004 /jnccn.2020.OO02 Educational Objective: Prevent chemotherapy-induced neutropenia.

Bibliography Ilecker I)S. Grifliths EA, Alu,an LM. et ,1. NCCN guidelines insights: hemat Item 13 Answer: C opoietic growth factors, version l.2O2O. I Natl (bmpr Canc Netw 2020r I 8:12 - 22. IPMl l), 3l 91038,1] doi: I 0.6004 /jnccn.2020.OO02 Educational Objective: Prevent chemotherapy-induced neutropenia. The patient should start granulocy.te colony stimulating fac Item 14 Answer: D tor (G CSF) with his next cycle of chemotherapy (Option C). Educational Objective: Screen for dyslipidemia and Febrile neutropenia is defined as a single fever of 38.3 'C diabetes mellitus in survivors of pediatric leukemia. (101 'F) or sustained fever of 38 'C (100.4'F) in a patient with a current or anticipated absolute neutrophil count less than Screening for diabetes and dyslipidemia should be per 500/pL (0.5 x 10e/L). Chemotherapy,induced neutropenia fbrmed (Option D). Survivors of pediatric leukemia (typi typically occurs within 5 to 15 days lollowing chemother cally acute lymphoblastic leukemia, ALL) are at increased apy. G CSF and granulocyte macrophage colony stimulating risk of developing metabolic syndrome as a result of expo factor can be given prophylactically to patients receiving sure to cancer chemotherapy. 'the primary care physician chemotherapy that carries a high risk of neutropenia and as should also request a treatment summary to fully ascertain secondary prophylaxis in patients with a previous episode the risk of cardiovascular disease, metabolic sl,ndrome, of febrile neutropenia. G CSF administered on day 2 ol the and secondary malignancies for this patient. Studies have next chemotherapy cycle should reduce the risk ofanother shown that adult survivors of childhood ALL are more neutropenic f'ever episode. G CSF is not indicated for most likely to have features of metabolic syndrome, including patients with neutropenia who are afebrile, as a routine high BMI. truncal obesity, dyslipidemia, insulin resistance, adjunct to empiric antibiotics lor patients presenting with and hypertension compared with age matched controls.

The patient should start granulocy.te colony stimulating fac Item 14 Answer: D tor (G CSF) with his next cycle of chemotherapy (Option C). Educational Objective: Screen for dyslipidemia and Febrile neutropenia is defined as a single fever of 38.3 'C diabetes mellitus in survivors of pediatric leukemia. (101 'F) or sustained fever of 38 'C (100.4'F) in a patient with a current or anticipated absolute neutrophil count less than Screening for diabetes and dyslipidemia should be per 500/pL (0.5 x 10e/L). Chemotherapy,induced neutropenia fbrmed (Option D). Survivors of pediatric leukemia (typi typically occurs within 5 to 15 days lollowing chemother cally acute lymphoblastic leukemia, ALL) are at increased apy. G CSF and granulocyte macrophage colony stimulating risk of developing metabolic syndrome as a result of expo factor can be given prophylactically to patients receiving sure to cancer chemotherapy. 'the primary care physician chemotherapy that carries a high risk of neutropenia and as should also request a treatment summary to fully ascertain secondary prophylaxis in patients with a previous episode the risk of cardiovascular disease, metabolic sl,ndrome, of febrile neutropenia. G CSF administered on day 2 ol the and secondary malignancies for this patient. Studies have next chemotherapy cycle should reduce the risk ofanother shown that adult survivors of childhood ALL are more neutropenic f'ever episode. G CSF is not indicated for most likely to have features of metabolic syndrome, including patients with neutropenia who are afebrile, as a routine high BMI. truncal obesity, dyslipidemia, insulin resistance, adjunct to empiric antibiotics lor patients presenting with and hypertension compared with age matched controls. 95

Answers and Critiques Therefore, regular screening for dyslipidemia, diabetes, Factor XI is part ol the intrinsic coagulation pathrtal,l and and hypertension is recommended.'lhose in remission for patients u'ith f:rctor XI deflciency can have isolated activated 20 years or more are not at risk of ALL recurrence. High partial thromboplastin tirne (aPTT) prolongation. Although dose glucocorticoids, typical of ALL regimens. pose a risk patients u'ith severe factor XI deficiency (<20'lr') are rnore fbr osteopenia. A normal bone mineral density measure likel1' to have a history ol'bleeding. this can r'ary and does ment at the time of entry into long term care does not not tightl]' correlate with the measured factor Xl acti\.it): need to be repeated until age 65 years unless other risk fac Patients R.pically do not experience spontaneous bruising. tors for osteoporosis develop. Patients should be counseled muscle hematom:rs, or hemarthrcses but tend to hare post about lifestyle risk factors, age-based screening, and early surgical bleeding. particularll'from sites \\'ith high endog reporting of persistent symptoms. enous fibrinc)lytic activitl, (dentat. nasal. oropharyngeal. Although adult ALL survivors are at risk oltherapy genitourinary). or menorrhagia and postpartum hentor' related acute myeloid leukemia (AML) or myelodysplas rhage. ll.rerefbre. cvell patieuts u'ith sc'r'ere factor Xl defi tic syndrome (MDS), this risk does not usually extend ciencl. do not typically require treatment; they ntal' require U! beyond 15 years. This patient has a normal complete hernostatic prophl'laxis or treatrnent to control bleeding € .D blood count. so bone marrow examination and whole fior.n surgery. Deficiencics in lactors Vlll. IX. and Xll ma1 UI genome sequencing tbr AML or MDS are not indicated also result in isolatc'd aP'fT prolongatiou. Hon'erer. factor Xll o, (Options A, E). deficienc'-v is not associated with a bleeding tenclencl'. and EL Leukemia therapy in childhood does not usually com congenital dcficiencies in f'actors VIII and IX are X linked a.l promise ovarian function. '[his patient has regular menses, disorders primarily altecting men. uhereas \\'omen are which further conflrms normal ovarian function. Check asymptomatic carriers. Thus. the most likely diagnosis in .tt ing estrogen and progesterone levels would not be helplul this patient is a factor XI deficiencl: The mirirrg stud) con (D aa (Option B). firms the presence of a tactor deficier.rcl' bl demonstrating Exposure to anthracycline during therapy for childhood complete correction of the aP'fT lbllort'ittg:t one to onc nrix ALL can lead to heart failure in adulthood. However, exercise u'ith normal plasrna: evaluating lactor XI activity u'ttuld stress testing is not the appropriate test to evaluate cardiac confirnr the presence ol factor XI deficiencli function (Option C). Echocardiography to screen for left The dilute Russell viper venont time is att assal' used ventricular dysfunction should be performed at intervals of to conlirm the presence ot a lupus anticoagulant (LAC). 3 to 5 years, particularly if anthracycline exposure was high rthich nright be a diagnostic consideration ilthe prolonged or if chest irradiation was used. In addition, f'emale survi aP'fT firils to correct fbllon'ing a one to one miring studl' vors have a higher risk ol rnyocardial dysfunction during (Option A). Most patients I'\,ith LAC are as1'mptomatic. pregnancy. Arterial and venous tl.rrombotic events occur in lbout 30'lr, ol patier-rts. Excessive bleeding is not a characteristic ot' r( EY PO I ilTt LAC. . Survivors of pediatric leukemia (typically acute Postoperative bleeding may occur in patients u'ith a lymphoblastic leukemia) are at increased risk of platelet function disorder: however, platelet dysfunctiorl developing metabolic syndrome, so screening for rl'ould be less likely considering the nornral platelet count dyslipidemia, diabetes mellitus, and hypertension is and nonnal platelet lut.tctirtn test resuits. Additionallli a recommended. platelet tunction disorder rvould not explain the increased o In cancer survivors who received either high-dose aPTT. scl an:rggregation study is unhelpful (Option C).

Therefore, regular screening for dyslipidemia, diabetes, Factor XI is part ol the intrinsic coagulation pathrtal,l and and hypertension is recommended.'lhose in remission for patients u'ith f:rctor XI deflciency can have isolated activated 20 years or more are not at risk of ALL recurrence. High partial thromboplastin tirne (aPTT) prolongation. Although dose glucocorticoids, typical of ALL regimens. pose a risk patients u'ith severe factor XI deficiency (<20'lr') are rnore fbr osteopenia. A normal bone mineral density measure likel1' to have a history ol'bleeding. this can r'ary and does ment at the time of entry into long term care does not not tightl]' correlate with the measured factor Xl acti\.it): need to be repeated until age 65 years unless other risk fac Patients R.pically do not experience spontaneous bruising. tors for osteoporosis develop. Patients should be counseled muscle hematom:rs, or hemarthrcses but tend to hare post about lifestyle risk factors, age-based screening, and early surgical bleeding. particularll'from sites \\'ith high endog reporting of persistent symptoms. enous fibrinc)lytic activitl, (dentat. nasal. oropharyngeal. Although adult ALL survivors are at risk oltherapy genitourinary). or menorrhagia and postpartum hentor' related acute myeloid leukemia (AML) or myelodysplas rhage. ll.rerefbre. cvell patieuts u'ith sc'r'ere factor Xl defi tic syndrome (MDS), this risk does not usually extend ciencl. do not typically require treatment; they ntal' require U! beyond 15 years. This patient has a normal complete hernostatic prophl'laxis or treatrnent to control bleeding € .D blood count. so bone marrow examination and whole fior.n surgery. Deficiencics in lactors Vlll. IX. and Xll ma1 UI genome sequencing tbr AML or MDS are not indicated also result in isolatc'd aP'fT prolongatiou. Hon'erer. factor Xll o, (Options A, E). deficienc'-v is not associated with a bleeding tenclencl'. and EL Leukemia therapy in childhood does not usually com congenital dcficiencies in f'actors VIII and IX are X linked a.l promise ovarian function. '[his patient has regular menses, disorders primarily altecting men. uhereas \\'omen are which further conflrms normal ovarian function. Check asymptomatic carriers. Thus. the most likely diagnosis in .tt ing estrogen and progesterone levels would not be helplul this patient is a factor XI deficiencl: The mirirrg stud) con (D aa (Option B). firms the presence of a tactor deficier.rcl' bl demonstrating Exposure to anthracycline during therapy for childhood complete correction of the aP'fT lbllort'ittg:t one to onc nrix ALL can lead to heart failure in adulthood. However, exercise u'ith normal plasrna: evaluating lactor XI activity u'ttuld stress testing is not the appropriate test to evaluate cardiac confirnr the presence ol factor XI deficiencli function (Option C). Echocardiography to screen for left The dilute Russell viper venont time is att assal' used ventricular dysfunction should be performed at intervals of to conlirm the presence ot a lupus anticoagulant (LAC). 3 to 5 years, particularly if anthracycline exposure was high rthich nright be a diagnostic consideration ilthe prolonged or if chest irradiation was used. In addition, f'emale survi aP'fT firils to correct fbllon'ing a one to one miring studl' vors have a higher risk ol rnyocardial dysfunction during (Option A). Most patients I'\,ith LAC are as1'mptomatic. pregnancy. Arterial and venous tl.rrombotic events occur in lbout 30'lr, ol patier-rts. Excessive bleeding is not a characteristic ot' r( EY PO I ilTt LAC. . Survivors of pediatric leukemia (typically acute Postoperative bleeding may occur in patients u'ith a lymphoblastic leukemia) are at increased risk of platelet function disorder: however, platelet dysfunctiorl developing metabolic syndrome, so screening for rl'ould be less likely considering the nornral platelet count dyslipidemia, diabetes mellitus, and hypertension is and nonnal platelet lut.tctirtn test resuits. Additionallli a recommended. platelet tunction disorder rvould not explain the increased o In cancer survivors who received either high-dose aPTT. scl an:rggregation study is unhelpful (Option C). anthracycline or chest irradiation, echocardiography \bn Willebrand disease (r'WD) is caused by either defl ciency or inelfectirer,ess ol von Willebrarrd factor (vWF). to screen for left ventricular dysfunction should be vWF promotes platelet adhesion and functions as a pro performed at intervals of 3 to 5 years. tecti\€ carrier protein lbr lactor VIll. so a mild secondary decrease in factor VIII level occurs in vWD. Although the Bibliography aP1-I may be prolonged or normal. a normal platelet Iunc Friedman DN. Tonorezos I1S. Cohen P Diabetes and metabolic syndrome in survivors ol childhood cancer. Llornl Res Paediatr. 2019:91:ll8 127. tion test rnakes this diagnosis less likel1,. so a vWD antigen IPM Il ): 306504141 doi:1o.1159,' 000495698 assay is unnecessary (Option D).

anthracycline or chest irradiation, echocardiography \bn Willebrand disease (r'WD) is caused by either defl ciency or inelfectirer,ess ol von Willebrarrd factor (vWF). to screen for left ventricular dysfunction should be vWF promotes platelet adhesion and functions as a pro performed at intervals of 3 to 5 years. tecti\€ carrier protein lbr lactor VIll. so a mild secondary decrease in factor VIII level occurs in vWD. Although the Bibliography aP1-I may be prolonged or normal. a normal platelet Iunc Friedman DN. Tonorezos I1S. Cohen P Diabetes and metabolic syndrome in survivors ol childhood cancer. Llornl Res Paediatr. 2019:91:ll8 127. tion test rnakes this diagnosis less likel1,. so a vWD antigen IPM Il ): 306504141 doi:1o.1159,' 000495698 assay is unnecessary (Option D). TEY POIlIIS

anthracycline or chest irradiation, echocardiography \bn Willebrand disease (r'WD) is caused by either defl ciency or inelfectirer,ess ol von Willebrarrd factor (vWF). to screen for left ventricular dysfunction should be vWF promotes platelet adhesion and functions as a pro performed at intervals of 3 to 5 years. tecti\€ carrier protein lbr lactor VIll. so a mild secondary decrease in factor VIII level occurs in vWD. Although the Bibliography aP1-I may be prolonged or normal. a normal platelet Iunc Friedman DN. Tonorezos I1S. Cohen P Diabetes and metabolic syndrome in survivors ol childhood cancer. Llornl Res Paediatr. 2019:91:ll8 127. tion test rnakes this diagnosis less likel1,. so a vWD antigen IPM Il ): 306504141 doi:1o.1159,' 000495698 assay is unnecessary (Option D). TEY POIlIIS tr Item 15 Answer: B Educational Objective: Evaluate a patient for factor XI . The initial diagnostic test for patients with unex- plained prolongation of a clotting test is a mixing deficiency. study. The most appropriate diagnostic test is to measure factor o Patients with factor XI deficiency typically do not levels (Option B). The most likely cause of this patient's experience spontaneous bruising, muscle hemato posttonsillectomy bleeding and history ol menorrhagia is mas, or hemarthroses burt tend to have postsurgical factor XI deficiency (hemophilia C). which is rare overall but bleeding. nlore common among persons ol Ashkenazi Jewish ancestry.

tr Item 15 Answer: B Educational Objective: Evaluate a patient for factor XI . The initial diagnostic test for patients with unex- plained prolongation of a clotting test is a mixing deficiency. study. The most appropriate diagnostic test is to measure factor o Patients with factor XI deficiency typically do not levels (Option B). The most likely cause of this patient's experience spontaneous bruising, muscle hemato posttonsillectomy bleeding and history ol menorrhagia is mas, or hemarthroses burt tend to have postsurgical factor XI deficiency (hemophilia C). which is rare overall but bleeding. nlore common among persons ol Ashkenazi Jewish ancestry. 95

t L t Answers and Critiques I L Item 17 Answer: B I t Bibliography Choi SH, Rambally S. Shen YM. Mixinla stud)' li)r eulurtion ol tllnontttl I Educational Objective: Diagnose o-thalassemia trait. t coagulation testing. JAMA. 2016;316:21-16 2 I 17. LPMI I ): 278931 I I I doi: 10. IOO1 ijanlr.2O16. I5749 'lhe most likely diagnosis is a thalassemia trait (Option B). t 'lhis patient lras a chronic hypochromic and microcytic i t I anemia, with the presence of target cells on the peripheral

Item 17 Answer: B I t Bibliography Choi SH, Rambally S. Shen YM. Mixinla stud)' li)r eulurtion ol tllnontttl I Educational Objective: Diagnose o-thalassemia trait. t coagulation testing. JAMA. 2016;316:21-16 2 I 17. LPMI I ): 278931 I I I doi: 10. IOO1 ijanlr.2O16. I5749 'lhe most likely diagnosis is a thalassemia trait (Option B). t 'lhis patient lras a chronic hypochromic and microcytic i t I anemia, with the presence of target cells on the peripheral L tr Item 16 Answer: C Educational Objective: Treat life-threatening bleeding blood smear characteristic of thalassemia. Patients with cr thalassemia trait have deletions of two or more of the ! in a patient taking unfractionated heparin. t I lbur a globin genes and present with a mild, microcytic t '[hc most appropriate treatmclrt for this palient is prota and hypochromic anemia (hemoglobin level approximately L nrine sulfate (Option C). tlc has developed a potentially l0 g/dl [tOo glt-l) and a normal or elevated iron level. Tha] I lite threatening intracerebral hemorrhage rcquiring cessa ilssemia is conrmon in African and Mediterranean coun L tion ancl rcversal ofthe unfractionated heparin. Unliaction tries, the Middle East, and Southeast Asia. Patients of Asian vt I (u t I atcd l.reparin binds to antithronrbin .lncl inactivates throm descent with a thalassemia trait are more likely to have ET i bin and factor Xa. Dosing is based on the acti\.atecl partirl oflspring with severe manif'estations such as hetnoglobin t thromboplastin time. Ilioavailability varies lr.rd reaching a H (B chain tetramers) or hydrops f'etalis with hemoglobin f., I therapeutic level can take timc. so unlractionated heparin Barts (intrauterine fetal demise resulting tiom deletion of T' I is r.rot the best option firr most hospitalized patients u,ith all four o(-chain genes). Patients with cr thalassemia trait .E \ i an acute thrombosis: hor,vever. because of its short half iile . will have nrild anemia, but hemoglobin electrophoresis t I it remains the icleal trcatment lrlr those patients with an will be otherwise normal. o t cr 'lhalassemia carrier (silent carrier) is defined as dele- Ut lcute thrombosis in u,hom lolt' ntolecularur,eigl-rt heparin = L (lrall-life .1.5 7 hours) is contrlindicrltcd, such as those at tion of a single cr globin gene ( o/cxa) (Option A). Silent car i increasecl risk of bleeding or patients u,ith planned surgical riers do r-rot have anemia, and the mean corpuscular volume t inten'ention. Major bleecling occurs in :t'il, ol patients taking may be normal or only mildly decreased. hcparin. In a patient with lite threatening bleeclirrg, the Patients with p-thalassemia have mutations of one copy t I

L tr Item 16 Answer: C Educational Objective: Treat life-threatening bleeding blood smear characteristic of thalassemia. Patients with cr thalassemia trait have deletions of two or more of the ! in a patient taking unfractionated heparin. t I lbur a globin genes and present with a mild, microcytic t '[hc most appropriate treatmclrt for this palient is prota and hypochromic anemia (hemoglobin level approximately L nrine sulfate (Option C). tlc has developed a potentially l0 g/dl [tOo glt-l) and a normal or elevated iron level. Tha] I lite threatening intracerebral hemorrhage rcquiring cessa ilssemia is conrmon in African and Mediterranean coun L tion ancl rcversal ofthe unfractionated heparin. Unliaction tries, the Middle East, and Southeast Asia. Patients of Asian vt I (u t I atcd l.reparin binds to antithronrbin .lncl inactivates throm descent with a thalassemia trait are more likely to have ET i bin and factor Xa. Dosing is based on the acti\.atecl partirl oflspring with severe manif'estations such as hetnoglobin t thromboplastin time. Ilioavailability varies lr.rd reaching a H (B chain tetramers) or hydrops f'etalis with hemoglobin f., I therapeutic level can take timc. so unlractionated heparin Barts (intrauterine fetal demise resulting tiom deletion of T' I is r.rot the best option firr most hospitalized patients u,ith all four o(-chain genes). Patients with cr thalassemia trait .E \ i an acute thrombosis: hor,vever. because of its short half iile . will have nrild anemia, but hemoglobin electrophoresis t I it remains the icleal trcatment lrlr those patients with an will be otherwise normal. o t cr 'lhalassemia carrier (silent carrier) is defined as dele- Ut lcute thrombosis in u,hom lolt' ntolecularur,eigl-rt heparin = L (lrall-life .1.5 7 hours) is contrlindicrltcd, such as those at tion of a single cr globin gene ( o/cxa) (Option A). Silent car i increasecl risk of bleeding or patients u,ith planned surgical riers do r-rot have anemia, and the mean corpuscular volume t inten'ention. Major bleecling occurs in :t'il, ol patients taking may be normal or only mildly decreased. hcparin. In a patient with lite threatening bleeclirrg, the Patients with p-thalassemia have mutations of one copy t I heparin inlusion should be stopped intmedi:rtel1,. lirllon,ecl or both copies of the p globin gene leading to a reduction (B*) \ I by protamine sultate administration at a d<lse of I mg per or complete absence (0') of p globin production (Option C). I 100 units of heplrin adrninistcrcd in the previous 2 hours. A reduced hemoglobin A level and elevated levels of minor $ Cryoprecipitate is not indicated in the management of' hemoglobin conlponents, hemoglobin F (a2ly2), and hemo : I blcccling related kr unfractionaled hqtarin (Option A). It is globin A, (o.,2162) are seen on hemoglobin electrophoresis. ruscd to replace fibrinogen in thc treatmenl of'ltatients rr'ith This patient's normal hemoglobin electrophoresis is consis t tlisseminated int ravascular coirgulation. tent with cr-thalassemia rather than B thalassemia. i ldarucizumab is an FI)r\ approvcd monocktnal anti Hemoglobin E is commonly found in Southeast Asia I bocly fragrnent that binds lrec and thrombin bound clabig and results from a mutation in the p globin gene (Option D). atran and neutralizes its activity (Option B). lt ruould not be This mutation is associated with reduced expression of the appropri:lte for rcvcrsirl of unfiactionlted heparin. p globin gene and results ir.r a B* thalassemi;r minor phe Vitamin K is usecl to revcrse warfirrin. a vilamin K notype (microcytosis. hypochromia, little or no anemia). A anlagonist. u,hich inhibits vitdmin K cpoxide rcductase and patient with hemoglobin E trait (heterozygous) would have thcrelore inhibits factors [I. VII, lX, and X. as wellas proteins microcytic and hypochromic erythrocytes, as in this patier.rt, C and S (Option D). Blceding risk n'ith rvartarin increases but the hemoglobin electrophoresis r,vould show the pres n,ith age and with INR elevation. Vitantin K should be gir,en ence of hemoglobin E (fypically constituting less than 50'2, k) patients taking n'arfarin with an I\R greater than l0 u.ith of the total hemoglobin). out bleeding. Vitamin K is also giren in addition t, .l factor rEY POIl{TS prothrombin complex concentrate il a patient takifig rlarfa o Patients with o thalassemia have chronic microcytic rin derelops lile threatcning bleccling. \'itamin K is not used to reverse unfractionated hepari n. anemia, target cells on the peripheral blood smear, and a normal hemoglobin electrophoresis. XEY POIilI o Patients with P-thalassemia have chronic microcytic . In patients experiencing lif'e threatening bleeding anemia, target cells on the peripheral blood smear, a while taking unfractionated heparin, the heparin reduced hemoglobin A level, and elevated levels of infusion should be stopped immediately, fbllowed by hemoglobin F and hemoglobin A, on hemoglobin protamine sulfate administration. electrophoresis.

heparin inlusion should be stopped intmedi:rtel1,. lirllon,ecl or both copies of the p globin gene leading to a reduction (B*) \ I by protamine sultate administration at a d<lse of I mg per or complete absence (0') of p globin production (Option C). I 100 units of heplrin adrninistcrcd in the previous 2 hours. A reduced hemoglobin A level and elevated levels of minor $ Cryoprecipitate is not indicated in the management of' hemoglobin conlponents, hemoglobin F (a2ly2), and hemo : I blcccling related kr unfractionaled hqtarin (Option A). It is globin A, (o.,2162) are seen on hemoglobin electrophoresis. ruscd to replace fibrinogen in thc treatmenl of'ltatients rr'ith This patient's normal hemoglobin electrophoresis is consis t tlisseminated int ravascular coirgulation. tent with cr-thalassemia rather than B thalassemia. i ldarucizumab is an FI)r\ approvcd monocktnal anti Hemoglobin E is commonly found in Southeast Asia I bocly fragrnent that binds lrec and thrombin bound clabig and results from a mutation in the p globin gene (Option D). atran and neutralizes its activity (Option B). lt ruould not be This mutation is associated with reduced expression of the appropri:lte for rcvcrsirl of unfiactionlted heparin. p globin gene and results ir.r a B* thalassemi;r minor phe Vitamin K is usecl to revcrse warfirrin. a vilamin K notype (microcytosis. hypochromia, little or no anemia). A anlagonist. u,hich inhibits vitdmin K cpoxide rcductase and patient with hemoglobin E trait (heterozygous) would have thcrelore inhibits factors [I. VII, lX, and X. as wellas proteins microcytic and hypochromic erythrocytes, as in this patier.rt, C and S (Option D). Blceding risk n'ith rvartarin increases but the hemoglobin electrophoresis r,vould show the pres n,ith age and with INR elevation. Vitantin K should be gir,en ence of hemoglobin E (fypically constituting less than 50'2, k) patients taking n'arfarin with an I\R greater than l0 u.ith of the total hemoglobin). out bleeding. Vitamin K is also giren in addition t, .l factor rEY POIl{TS prothrombin complex concentrate il a patient takifig rlarfa o Patients with o thalassemia have chronic microcytic rin derelops lile threatcning bleccling. \'itamin K is not used to reverse unfractionated hepari n. anemia, target cells on the peripheral blood smear, and a normal hemoglobin electrophoresis. XEY POIilI o Patients with P-thalassemia have chronic microcytic . In patients experiencing lif'e threatening bleeding anemia, target cells on the peripheral blood smear, a while taking unfractionated heparin, the heparin reduced hemoglobin A level, and elevated levels of infusion should be stopped immediately, fbllowed by hemoglobin F and hemoglobin A, on hemoglobin protamine sulfate administration. electrophoresis. Bibliography Bibliography Witt Dl\,I, Nieu$,laat R, Clark NP, et al. American Society r)f l lemJtolo$/ 2Olti Vichinsky E. Non transtitsion dependent thirlassemiil and thalassentiit guidelines for management of venous thromboembolism: Optimal man interme(lia: Epitlemiologl, complications, lnd manrgement. Curr Med agemenl of anticoagulation therapy Blood Adv 2O78i2:3257 3291. IPMID: Res Opi n. 2016;:12: 191 204. [P]VI D, 261791')5) doi:10. I 185 103007995.201 304827651 doi: I o. I I 82 'bloodadvances.201802.1893 5. I l 10r28

Bibliography Bibliography Witt Dl\,I, Nieu$,laat R, Clark NP, et al. American Society r)f l lemJtolo$/ 2Olti Vichinsky E. Non transtitsion dependent thirlassemiil and thalassentiit guidelines for management of venous thromboembolism: Optimal man interme(lia: Epitlemiologl, complications, lnd manrgement. Curr Med agemenl of anticoagulation therapy Blood Adv 2O78i2:3257 3291. IPMID: Res Opi n. 2016;:12: 191 204. [P]VI D, 261791')5) doi:10. I 185 103007995.201 304827651 doi: I o. I I 82 'bloodadvances.201802.1893 5. I l 10r28 97

Answers and Critiques Item 18 Answer: A Bibliography Rothman JA. Sterens JL, Gray FL, Kalta TA. Ho$ l approach hereditary Ed u cationa I Objective : Treat hereditary spheroc5rtosis. hemollric anemia and splenectomy Pediatr Blood Cancer. 2020:67: e28337. IP\,llD: 32391969] doi:10.1002, pbc.283:17 The most appropriate treatment is folic acid supplemen- tation (Option A). Most lorms of hereditary spherocytosis (HS) are autosomal dominant, resulting in deficiencies of Item 19 Answer: C the erythrocyte membrane proteins that anchor the q.to Educational Objective: Diagnose the cause of thrombo- skeleton to the plasma membrane. Membrane ioss causes cltopenia in a pregnant patient. a decreased surface to volume ratio and loss ol the bicon The most likely diagnosis is immune thrombocytopenic cave shape, resulting in a more spherical erythrocyte shape purpura (lTP) (Option C). ITP is a diagnosis of exclusion. (spherocytes). The structural erythrocyte changes lead to less although it is oFten difficult to distinguish from gestational defbrmability in the microcirculation and increase phago thrombocytopenia when the thrombocytopenia is mild or cytosis by macrophages, mainly in the spleen, resulting in noted later in pregnancy. However, features suggesting ITP Ut hemolysis. Splenomegaly is common. Laboratory flndings include earlier presentation (flrst trimester). lower platelet € .D include anemia, reticulocytosis, signs of hemolysis. and an count nadir (<zo,ooo/pL [zo x to"rL]), and history ofthrom IA increased mean corpuscular hemoglobin concentration. bocytopenia befbre pregnancy (even if it was only mild). o, The clinical severity of I-lS varies considerably. Mild forms If the platelet count remains greater than 30.000 pL (30 x CL are common, with normal or near normal hemoglobin lev 10"/L). the pregnancy is not at risk. Patients should receive a'! els, and patients can compensate for the hemolysis. Those intravenous immune globulin or glucocorticoids at any with severe forms har,e more brisk hemolysis and a greater time during pregnancy if the platelet count decreases to lt t.D degree of anemia, which often worsens at times of oxida less than 30,000/gl- (30 x 10e/L). Because she does not have UI tive stress, such as viral infections; pigmented gallstones significant bleeding and her platelet count is greater than and aplastic crises from parvovirus infections can also be 30,000/pL (30 x 10'q/L), she requires no intervention at this seen. Treatment depends on disease severity. Mild forms can time. She will need close follow-up. be monitored. Patients with HS, as with other hemolytic Gestational thrombocytopenia affects approximately states, have increased folate requirements and should receive 5'7, of pregnant women (Option A). 'lhe cause is uncertain. supplemental folate. A typical dose for moderate to severe Most patients are asymptomatic, with platelet counts greater hemolysis is 1to 2 mgiday. than 100,000/pL (100 x 10e/L) typical, although platelet In warm autoimmune hemolytic anemia. pathogenic counts mav occasionally reach a nadir of 70,000/[L (70 x lgG antibodies are directed against Rh type antigens on 10elL). The platelet count does not decrease until late in ges- the erythrocyte surface. IgG-coated erythrocytes can be tation. The fetus is unaffected, intervention is unnecessary. completely phagocytized by splenic macrophages via the and platelet counts spontaneously return to normal after Fc receptor and are cleared from the circulation. The basic delivery. The patient's earlier presentation and lower platelet principle of therapy is alleviating immune destruction of count argue against gestational thrombocytopenia. erythrocytes by halting antibody production using gluco HELLP (Hemolysis, Elevated Liver enzymes, and Low corticoids or rituximab (Options B, C). Intravenous immune Platelets) syndrome is a thrombotic microangiopathy of preg globulin may be used as adjunctive therapy by blocking mac nancy manifbsting as a severe complication of preeclampsia rophage Fc receptors and preventing erythrocyte destruction (Option B). HELLP syndrome typically presents with nonspe in the spleen. Because HS is the result of deficiencies of ciflc symptoms such as abdominal pain, nausea with vomit the erythrocyte membrane proteins and not autoantibodies, ing, pruritus, and jaundice, with schistocytes on the periph prednisone or rituximab is not helpfut. eral blood smear. HELLP syndrome would be unlikely to Splenectomy is considered in patients with HS and cause thrombocytopenia at 16 weeks' gestation, usually pre more signiflcant anemia because the spleen is the pri senting in the latter part of the third trimester. The patient's mary location for erythrocy.te destruction (Option D). Most clinical presentation is not compatible with HELLP syndrome. patients who undergo splenectomy experience an improved The patient has no evidence for a microangiopathic hemoglobin level and reduced degree of hemolysis. Typical hemolysis (no schistocytes on peripheral blood smear) or indications for splenectomy include transfusion dependence other symptoms frequently associated with thrombotic or severe symptoms related to anemia. C)ther considerations thrombocytopenic purpura such as fever. fluctuating mental may include abdominal symptoms related to splenomegaly. status, or abnormal kidney function (Option D).

Item 18 Answer: A Bibliography Rothman JA. Sterens JL, Gray FL, Kalta TA. Ho$ l approach hereditary Ed u cationa I Objective : Treat hereditary spheroc5rtosis. hemollric anemia and splenectomy Pediatr Blood Cancer. 2020:67: e28337. IP\,llD: 32391969] doi:10.1002, pbc.283:17 The most appropriate treatment is folic acid supplemen- tation (Option A). Most lorms of hereditary spherocytosis (HS) are autosomal dominant, resulting in deficiencies of Item 19 Answer: C the erythrocyte membrane proteins that anchor the q.to Educational Objective: Diagnose the cause of thrombo- skeleton to the plasma membrane. Membrane ioss causes cltopenia in a pregnant patient. a decreased surface to volume ratio and loss ol the bicon The most likely diagnosis is immune thrombocytopenic cave shape, resulting in a more spherical erythrocyte shape purpura (lTP) (Option C). ITP is a diagnosis of exclusion. (spherocytes). The structural erythrocyte changes lead to less although it is oFten difficult to distinguish from gestational defbrmability in the microcirculation and increase phago thrombocytopenia when the thrombocytopenia is mild or cytosis by macrophages, mainly in the spleen, resulting in noted later in pregnancy. However, features suggesting ITP Ut hemolysis. Splenomegaly is common. Laboratory flndings include earlier presentation (flrst trimester). lower platelet € .D include anemia, reticulocytosis, signs of hemolysis. and an count nadir (<zo,ooo/pL [zo x to"rL]), and history ofthrom IA increased mean corpuscular hemoglobin concentration. bocytopenia befbre pregnancy (even if it was only mild). o, The clinical severity of I-lS varies considerably. Mild forms If the platelet count remains greater than 30.000 pL (30 x CL are common, with normal or near normal hemoglobin lev 10"/L). the pregnancy is not at risk. Patients should receive a'! els, and patients can compensate for the hemolysis. Those intravenous immune globulin or glucocorticoids at any with severe forms har,e more brisk hemolysis and a greater time during pregnancy if the platelet count decreases to lt t.D degree of anemia, which often worsens at times of oxida less than 30,000/gl- (30 x 10e/L). Because she does not have UI tive stress, such as viral infections; pigmented gallstones significant bleeding and her platelet count is greater than and aplastic crises from parvovirus infections can also be 30,000/pL (30 x 10'q/L), she requires no intervention at this seen. Treatment depends on disease severity. Mild forms can time. She will need close follow-up. be monitored. Patients with HS, as with other hemolytic Gestational thrombocytopenia affects approximately states, have increased folate requirements and should receive 5'7, of pregnant women (Option A). 'lhe cause is uncertain. supplemental folate. A typical dose for moderate to severe Most patients are asymptomatic, with platelet counts greater hemolysis is 1to 2 mgiday. than 100,000/pL (100 x 10e/L) typical, although platelet In warm autoimmune hemolytic anemia. pathogenic counts mav occasionally reach a nadir of 70,000/[L (70 x lgG antibodies are directed against Rh type antigens on 10elL). The platelet count does not decrease until late in ges- the erythrocyte surface. IgG-coated erythrocytes can be tation. The fetus is unaffected, intervention is unnecessary. completely phagocytized by splenic macrophages via the and platelet counts spontaneously return to normal after Fc receptor and are cleared from the circulation. The basic delivery. The patient's earlier presentation and lower platelet principle of therapy is alleviating immune destruction of count argue against gestational thrombocytopenia. erythrocytes by halting antibody production using gluco HELLP (Hemolysis, Elevated Liver enzymes, and Low corticoids or rituximab (Options B, C). Intravenous immune Platelets) syndrome is a thrombotic microangiopathy of preg globulin may be used as adjunctive therapy by blocking mac nancy manifbsting as a severe complication of preeclampsia rophage Fc receptors and preventing erythrocyte destruction (Option B). HELLP syndrome typically presents with nonspe in the spleen. Because HS is the result of deficiencies of ciflc symptoms such as abdominal pain, nausea with vomit the erythrocyte membrane proteins and not autoantibodies, ing, pruritus, and jaundice, with schistocytes on the periph prednisone or rituximab is not helpfut. eral blood smear. HELLP syndrome would be unlikely to Splenectomy is considered in patients with HS and cause thrombocytopenia at 16 weeks' gestation, usually pre more signiflcant anemia because the spleen is the pri senting in the latter part of the third trimester. The patient's mary location for erythrocy.te destruction (Option D). Most clinical presentation is not compatible with HELLP syndrome. patients who undergo splenectomy experience an improved The patient has no evidence for a microangiopathic hemoglobin level and reduced degree of hemolysis. Typical hemolysis (no schistocytes on peripheral blood smear) or indications for splenectomy include transfusion dependence other symptoms frequently associated with thrombotic or severe symptoms related to anemia. C)ther considerations thrombocytopenic purpura such as fever. fluctuating mental may include abdominal symptoms related to splenomegaly. status, or abnormal kidney function (Option D). I( EY PO I TTS XEY POIilTS r Patients with mild forms of hereditary spherocytosis can o Features suggesting immune thrombocytopenic pur- be monitored and should receive supplemental folate. pura in pregnancy include earlier presentation (first . Splenectomy is an effective treatment for severe trimester), lower platelet count nadir (<ZO.OOOIpL hereditary spherocytosis (transfusion dependence, [70 x l0'q/Li), and history of thrombocytopenia before symptomatic anemia, massive splenomegaly). pregnancy. (Continued)

I( EY PO I TTS XEY POIilTS r Patients with mild forms of hereditary spherocytosis can o Features suggesting immune thrombocytopenic pur- be monitored and should receive supplemental folate. pura in pregnancy include earlier presentation (first . Splenectomy is an effective treatment for severe trimester), lower platelet count nadir (<ZO.OOOIpL hereditary spherocytosis (transfusion dependence, [70 x l0'q/Li), and history of thrombocytopenia before symptomatic anemia, massive splenomegaly). pregnancy. (Continued) 98

Answers and Critiques XEY P0ll{TS (anttnued) t(EY P0rlrrs o Gestational thrombocytopenia presents late in ges . The hallmark of chronic myeloid leukemia is the tation, with platelet counts typically greater than Philadelphia chromosome, a reciprocal translocation 100,000/pL (100 x 10e/L), although platelet counts of the ABL gene on chromosome 9 to the BCR gene on may reach a nadir of 70,000/pL (70 x 10e/L); plate chromosome 22, designated as t(9 ;22). let counts spontaneously return to normal after . A tyrosine kinase inhibitor such as imatinib is consid- delivery. ered first-line treatment for patients with chronic myeloid leukemia diagnosed in the chronic phase Bibliography (<10'2, blasts in the bone marrow). Care A. Pavord S, Knight M, et al. Severe primary autoimmune thrombocy topenia in pregnancy: a national cohort study. BjOG. 2018;125:604 612. IPMID: 284327361 doi: 10.1111 /1471 0528. 1,1697 Bibliography Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 r recommendations for treating chronic myeloid leukemia. Leukemia. o 2O2O ;31 :966 984. IPM ID: 32127 639) doi :10.1038/s41375 020 o77 6 2 ET Item 20 Answer: B Educational Objective: Treat chronic myeloid (J Item 21 Answer: A leukemia.

XEY P0ll{TS (anttnued) t(EY P0rlrrs o Gestational thrombocytopenia presents late in ges . The hallmark of chronic myeloid leukemia is the tation, with platelet counts typically greater than Philadelphia chromosome, a reciprocal translocation 100,000/pL (100 x 10e/L), although platelet counts of the ABL gene on chromosome 9 to the BCR gene on may reach a nadir of 70,000/pL (70 x 10e/L); plate chromosome 22, designated as t(9 ;22). let counts spontaneously return to normal after . A tyrosine kinase inhibitor such as imatinib is consid- delivery. ered first-line treatment for patients with chronic myeloid leukemia diagnosed in the chronic phase Bibliography (<10'2, blasts in the bone marrow). Care A. Pavord S, Knight M, et al. Severe primary autoimmune thrombocy topenia in pregnancy: a national cohort study. BjOG. 2018;125:604 612. IPMID: 284327361 doi: 10.1111 /1471 0528. 1,1697 Bibliography Hochhaus A, Baccarani M, Silver RT, et al. European LeukemiaNet 2020 r recommendations for treating chronic myeloid leukemia. Leukemia. o 2O2O ;31 :966 984. IPM ID: 32127 639) doi :10.1038/s41375 020 o77 6 2 ET Item 20 Answer: B Educational Objective: Treat chronic myeloid (J Item 21 Answer: A leukemia. lmatinib is the most appropriate treatment fbr this patient Educational Objective: Diagnose an acute hemolytic tr =t E .! UI transfusion reaction. (l, with chronic myeloid leukemia (CML) in the chronic phase (Option B). Patients may present in the accelerated (10% 'lhis patient is having an acute hernolytic transfusiun reac ra = 19'l. blasts) or blast phase (>20'1, blasts) of the disease, with tion (Option A). His symptoms, including fever. dyspnea, blast phase resembling features seen with acute leukemia, hypotension, ancl fl:rnk pain, appeared rt,ithin 1.5 rninr-rtes of but most patients present in the chronic phase (<10'U, blasts trirnsf'usion initiation and are typical for itn acllte hemolytic in the bone marrow). The hallmark of CML is the Philadel rcaction. 'lhe pink color of the urine suggests the release of' phia chromosome, a reciprocal translocation of the ABL fice hemogbbin resulting liont intravascular hernolysis. An gene on chromosome 9 to the BCR gene on chromosome acute hemolytic transfusion reactioll is most often caused by 22. Patients often present with constitutional symptoms an ABO incompatibilitl,, either because the pilot tube used tcr that include night sweats, weight loss, and fatigue, and type and crossmatch the patient was mislabeled or bectruse splenomegaly is common; laboratory studies frequently the unit of blood was administered to the wrong patient. show marked leukocytosis with a left shift, and basophilia llemolysis may also bc caused by an alloantibocly that was and thrombocytosis can be seen. First line treatment with too lorv to be cletected in his pretransfusi<tn evaluation. but a tyrosine kinase inhibitor (TKI) such as imatinib is con- this is more likely to cause a ntore gradual delayed hen.rolytic sidered accepted care for patients with CML in the chronic reirction rather than an acute and lil'e-tl.rreatening event. The phase. TKIs bind to the BCR ABL oncoprotein and prevent trutnsfusion mnst be stoppecl because the degree of l.ren.roly downstream signaling. Other TKIs include nilotinib and sis and prognosis is proportional to the volume transtirsed. dasatinib. Availability of TKIs has dramatically changed Vtrlun-re cxpansion ancl suppor-tive care fbr associated com- outcomes in CML, with the S-year overall survival in CML plications are also necessary. An investigation into the ciruse exceeding 90'1,. of the reaction is ir.ritiated in each ctrse. inclucling a repeat Hydroxyurea is a nonspeciflc myelosuppressive agent that type and screen and a direct antiglobulin test. Adclitional is eflective at reducing granulocyte, erythroc),te, and platelet Iaboratory evaluatior.r r,r,ill support tl.re diagnosis of hcmoly production in myeloproliferative neoplasms (Option A). It sis and assess fbr the preser.rce of disseminlted intravascular can be used as a temporizing measure to reduce peripheral coagulation. blood counts while awaiting a flnal diagnosis. However, in Mild allergic reactions with pruritus and urticaria occur those with a conflrmed diagnosis of CML, TKIs are more in l',1, b 5')1, of recipicr.rts during or:rfter the transfirsion of disease specific and preferred over hydroxyurea. plasma rich components (Option B). lhe patient displays Induction chemotherapy is only considered in some no svnrptoms ol urticaria that would suggest an allergic patients with CML in the blast phase (Option C). It would reaction. Pink urine is not seen in an iillergic transfusiorr not be appropriate first-line therapy for those with CML in re:rction. the chronic phase. Transfusion-associatecl circulatory overload (IACO) Stem cell transplantation is a potentially curative may be the nrost common serious conrplication of blood option for CML but has signiflcant associated morbidity trirnsfusion (Option C). Signs and symptoms ir.rclude respi and mortality (Option D). With the eflicacy and safety of ratory distress within 6 hours ol transtusion, positive fluid TKIs, the need for transplantation has been substantially balance. elevated central venolls pressrlre. ar-rd radiographic reduced. It is typically only considered in patients in the findings of pulmonary edcma. 'l'ransiirsion reluted acute blast phase or in younger patients who do not respond lung ir.rjurv ('lRALl) is noncardiogenic pLllmonary edema to TKIs. that occurs within 6 hours oltransfusion (Option D). Most

lmatinib is the most appropriate treatment fbr this patient Educational Objective: Diagnose an acute hemolytic tr =t E .! UI transfusion reaction. (l, with chronic myeloid leukemia (CML) in the chronic phase (Option B). Patients may present in the accelerated (10% 'lhis patient is having an acute hernolytic transfusiun reac ra = 19'l. blasts) or blast phase (>20'1, blasts) of the disease, with tion (Option A). His symptoms, including fever. dyspnea, blast phase resembling features seen with acute leukemia, hypotension, ancl fl:rnk pain, appeared rt,ithin 1.5 rninr-rtes of but most patients present in the chronic phase (<10'U, blasts trirnsf'usion initiation and are typical for itn acllte hemolytic in the bone marrow). The hallmark of CML is the Philadel rcaction. 'lhe pink color of the urine suggests the release of' phia chromosome, a reciprocal translocation of the ABL fice hemogbbin resulting liont intravascular hernolysis. An gene on chromosome 9 to the BCR gene on chromosome acute hemolytic transfusion reactioll is most often caused by 22. Patients often present with constitutional symptoms an ABO incompatibilitl,, either because the pilot tube used tcr that include night sweats, weight loss, and fatigue, and type and crossmatch the patient was mislabeled or bectruse splenomegaly is common; laboratory studies frequently the unit of blood was administered to the wrong patient. show marked leukocytosis with a left shift, and basophilia llemolysis may also bc caused by an alloantibocly that was and thrombocytosis can be seen. First line treatment with too lorv to be cletected in his pretransfusi<tn evaluation. but a tyrosine kinase inhibitor (TKI) such as imatinib is con- this is more likely to cause a ntore gradual delayed hen.rolytic sidered accepted care for patients with CML in the chronic reirction rather than an acute and lil'e-tl.rreatening event. The phase. TKIs bind to the BCR ABL oncoprotein and prevent trutnsfusion mnst be stoppecl because the degree of l.ren.roly downstream signaling. Other TKIs include nilotinib and sis and prognosis is proportional to the volume transtirsed. dasatinib. Availability of TKIs has dramatically changed Vtrlun-re cxpansion ancl suppor-tive care fbr associated com- outcomes in CML, with the S-year overall survival in CML plications are also necessary. An investigation into the ciruse exceeding 90'1,. of the reaction is ir.ritiated in each ctrse. inclucling a repeat Hydroxyurea is a nonspeciflc myelosuppressive agent that type and screen and a direct antiglobulin test. Adclitional is eflective at reducing granulocyte, erythroc),te, and platelet Iaboratory evaluatior.r r,r,ill support tl.re diagnosis of hcmoly production in myeloproliferative neoplasms (Option A). It sis and assess fbr the preser.rce of disseminlted intravascular can be used as a temporizing measure to reduce peripheral coagulation. blood counts while awaiting a flnal diagnosis. However, in Mild allergic reactions with pruritus and urticaria occur those with a conflrmed diagnosis of CML, TKIs are more in l',1, b 5')1, of recipicr.rts during or:rfter the transfirsion of disease specific and preferred over hydroxyurea. plasma rich components (Option B). lhe patient displays Induction chemotherapy is only considered in some no svnrptoms ol urticaria that would suggest an allergic patients with CML in the blast phase (Option C). It would reaction. Pink urine is not seen in an iillergic transfusiorr not be appropriate first-line therapy for those with CML in re:rction. the chronic phase. Transfusion-associatecl circulatory overload (IACO) Stem cell transplantation is a potentially curative may be the nrost common serious conrplication of blood option for CML but has signiflcant associated morbidity trirnsfusion (Option C). Signs and symptoms ir.rclude respi and mortality (Option D). With the eflicacy and safety of ratory distress within 6 hours ol transtusion, positive fluid TKIs, the need for transplantation has been substantially balance. elevated central venolls pressrlre. ar-rd radiographic reduced. It is typically only considered in patients in the findings of pulmonary edcma. 'l'ransiirsion reluted acute blast phase or in younger patients who do not respond lung ir.rjurv ('lRALl) is noncardiogenic pLllmonary edema to TKIs. that occurs within 6 hours oltransfusion (Option D). Most 99

Answers and Critiques fi cascs of TRALI occnr because ol lILA or nc.utrophil-specific Factor XI deficiency can result in a bleeding diathesis lU antihodies in ntultiparous donors that bincl to and acti because factor XI is activated by thrombin. A ntixing stud,-in C0Nl valc recipient leul<ocytes in the pulmonary vasculature.'lhis a patient $,ith factor XI deflciency would result in complete patient's normal cirrdiopulmonarv exantination. norntirl correction ofthe prolonged aPTT that is sustained after incu oxvgen saturation. and pink urine suggesling intravasculirr baticin. Factor Xll activity is reflected in the aPTT but is not hemoll,sis make TACO :rnd l'R.\t_I unlikell,dilgnoses. of clinical importance in hemostasis. Factor XII deficiencf is a rare autosomal recessive condition in u,hich homozlgous t(EY P0iltT5 patients have a markedly prolonged aPTT but no histon,ot o An acute hemoll.tic transfusion reaction is suggested ercessir,,e bleeding or hemorrhage. In a patient \\'ith factor by fever, dyspnea, hypotension, flank pain, and pink XII deficiencl: the miring study r,r,ould completel)' correct colored urine appearing during or shortly after a the aPTT. These results lvould prompt measurenlent of spe transfusion. ciflc factor levels (Options B, C). o Acute hemolytic transfusion reaction is treated with XEY POITT ut immediate discontinuation of the transfusion. volume E . Evaluation of a prolonged activated partial thrombo o expansion, and supportive care. ut plastin time (aPTT) begins with a mixing study: the o, aPTT will normalize if the cause of the prolongation is Bibliography CL a factor deficiency but will remain prolonged if the rt Panch SR. Montemlyor Garcia C. Klein HG. Hentolllic lranstusion rctc tions. N Engl J Metl. 20191381:150 162. [P\,llD: 3l29lSl7] doi:10.1056 reason is an inhibitor. NEJMra18023il8 lt tr (D Bibliography ta Benzon IlT. Park M. McCarthl'RI. et al. Vixing studies in patients \\'ith Item 22 Answer: D pnrlonged acti\atecl partial thromboplilstin time or pn)tllrombin tinte. Educational Objective: Evaluate a patient with a Anesth Analg. 2019: 128: lO89 1096. IP]\l II): 3109 17731 rkri: 10.121.1 A\ I:. 0000000000003,157 prolonged activated partial thromboplastin time.

fi cascs of TRALI occnr because ol lILA or nc.utrophil-specific Factor XI deficiency can result in a bleeding diathesis lU antihodies in ntultiparous donors that bincl to and acti because factor XI is activated by thrombin. A ntixing stud,-in C0Nl valc recipient leul<ocytes in the pulmonary vasculature.'lhis a patient $,ith factor XI deflciency would result in complete patient's normal cirrdiopulmonarv exantination. norntirl correction ofthe prolonged aPTT that is sustained after incu oxvgen saturation. and pink urine suggesling intravasculirr baticin. Factor Xll activity is reflected in the aPTT but is not hemoll,sis make TACO :rnd l'R.\t_I unlikell,dilgnoses. of clinical importance in hemostasis. Factor XII deficiencf is a rare autosomal recessive condition in u,hich homozlgous t(EY P0iltT5 patients have a markedly prolonged aPTT but no histon,ot o An acute hemoll.tic transfusion reaction is suggested ercessir,,e bleeding or hemorrhage. In a patient \\'ith factor by fever, dyspnea, hypotension, flank pain, and pink XII deficiencl: the miring study r,r,ould completel)' correct colored urine appearing during or shortly after a the aPTT. These results lvould prompt measurenlent of spe transfusion. ciflc factor levels (Options B, C). o Acute hemolytic transfusion reaction is treated with XEY POITT ut immediate discontinuation of the transfusion. volume E . Evaluation of a prolonged activated partial thrombo o expansion, and supportive care. ut plastin time (aPTT) begins with a mixing study: the o, aPTT will normalize if the cause of the prolongation is Bibliography CL a factor deficiency but will remain prolonged if the rt Panch SR. Montemlyor Garcia C. Klein HG. Hentolllic lranstusion rctc tions. N Engl J Metl. 20191381:150 162. [P\,llD: 3l29lSl7] doi:10.1056 reason is an inhibitor. NEJMra18023il8 lt tr (D Bibliography ta Benzon IlT. Park M. McCarthl'RI. et al. Vixing studies in patients \\'ith Item 22 Answer: D pnrlonged acti\atecl partial thromboplilstin time or pn)tllrombin tinte. Educational Objective: Evaluate a patient with a Anesth Analg. 2019: 128: lO89 1096. IP]\l II): 3109 17731 rkri: 10.121.1 A\ I:. 0000000000003,157 prolonged activated partial thromboplastin time. Evaluation of a prolonged activated partial thromboplastin time (aPTT) begins with a mixing study in r,r,hich equal parts Item 23 Answer: A of a patient's plasma and control plasma are combinedr the Educational Objective: Treat high-risk acute myeloid aPTT assay is performed immediately following the mix and leukemia. again tbllowing an incubation period (Option D). The imme diate mixing study will not correct in the presence of most The most appropriate management is allogeneic hemato factor inhibitors. Some ir.rl.ribitors, specifically factor VIII poietic stem cell transplantation (HSCT) (Option A). This inhibitor, will correct immediately but u,ill not correct alter patient developed secondar), or therapl'related acute incubation. Therefbre, mixing study results should always myeloid leukemia (AML) follor,r,ing breast cancer treatment. be reported immediately and after incubation. The result A primary AML diagnosis is often sufncient to recommend of the mixing study for this patient will help to determine allogeneic HSCT. but therapy related AML is even more the general cause of the prolonged aPTT (factor deficiency likely to relapse and is an indication for HSCT. The patient's versus inhibitor) and to guide the subsequent, more specific age. lack of comorbidities, and apparent remission after evaluation. Because this patient has an autoimmune disor recent induction chemotherapy further support the indica der, a lupus anticoagulant might explain the prolonged aPTT tion for allogeneic HSCT. Patients undergo Hl-A typing. ancl without evident bleedingr it is characterized by a prolonged siblings are considered for stem celldonation: Hl-A matched aPTT that fails to correct when mixed with control plasma. unrelated donors may also be a reasonable option. Patients Patients with a lupus anticoagulant may be asymptomatic; in first remission can have similar outcomes using alterna however, approximately 30'7, of patients with a lupus anti tive donors, represented by haploidentical transplantations coagulant may develop arterial andror venous thrombosis. (half matched relatives, such as parent donating to child or Factor VIII inhibitors can arise in the setting of hemo vice versa or siblings $,ho share a haploq'pe) or umbilical philia A, following exposure to factor VIII replacement cord blood transplantations. therapy, or can develop spontaneously in the setting of' Patients with AML who initially achieve complete remis autoimmune disease, malignancy. pregnancy. and certain sion will relapse unless additional postremission therapf is medications. Weak, low titer inhibitors may not cause spon provided. Postremission therapl, is intended to eliminate taneous bleeding. The presence of a factor VIII inhibitor is undetectable disease to achieve cure. or at least long ternt suspected when a mixing study demonstrates immediate control of the disease. Postremission therapy is divided into correction of the prolonged aPTT after mixing but subse consolidation and maintenance treatment phases. Consoli quent prolongation of the aPTT tbllowing incubation. Eval dation treatment consists of intensive treatment soon after uation of factor VIII levels and inhibitor titers would be the attainment of complete remission (Option B). Consolida prompted only if this sequence of events is demonstrated on tion with conventionaI chemotherapy would be indicated in the mixing study (Option A). managing patients at low risk with AI\4L. Low risk includes

Evaluation of a prolonged activated partial thromboplastin time (aPTT) begins with a mixing study in r,r,hich equal parts Item 23 Answer: A of a patient's plasma and control plasma are combinedr the Educational Objective: Treat high-risk acute myeloid aPTT assay is performed immediately following the mix and leukemia. again tbllowing an incubation period (Option D). The imme diate mixing study will not correct in the presence of most The most appropriate management is allogeneic hemato factor inhibitors. Some ir.rl.ribitors, specifically factor VIII poietic stem cell transplantation (HSCT) (Option A). This inhibitor, will correct immediately but u,ill not correct alter patient developed secondar), or therapl'related acute incubation. Therefbre, mixing study results should always myeloid leukemia (AML) follor,r,ing breast cancer treatment. be reported immediately and after incubation. The result A primary AML diagnosis is often sufncient to recommend of the mixing study for this patient will help to determine allogeneic HSCT. but therapy related AML is even more the general cause of the prolonged aPTT (factor deficiency likely to relapse and is an indication for HSCT. The patient's versus inhibitor) and to guide the subsequent, more specific age. lack of comorbidities, and apparent remission after evaluation. Because this patient has an autoimmune disor recent induction chemotherapy further support the indica der, a lupus anticoagulant might explain the prolonged aPTT tion for allogeneic HSCT. Patients undergo Hl-A typing. ancl without evident bleedingr it is characterized by a prolonged siblings are considered for stem celldonation: Hl-A matched aPTT that fails to correct when mixed with control plasma. unrelated donors may also be a reasonable option. Patients Patients with a lupus anticoagulant may be asymptomatic; in first remission can have similar outcomes using alterna however, approximately 30'7, of patients with a lupus anti tive donors, represented by haploidentical transplantations coagulant may develop arterial andror venous thrombosis. (half matched relatives, such as parent donating to child or Factor VIII inhibitors can arise in the setting of hemo vice versa or siblings $,ho share a haploq'pe) or umbilical philia A, following exposure to factor VIII replacement cord blood transplantations. therapy, or can develop spontaneously in the setting of' Patients with AML who initially achieve complete remis autoimmune disease, malignancy. pregnancy. and certain sion will relapse unless additional postremission therapf is medications. Weak, low titer inhibitors may not cause spon provided. Postremission therapl, is intended to eliminate taneous bleeding. The presence of a factor VIII inhibitor is undetectable disease to achieve cure. or at least long ternt suspected when a mixing study demonstrates immediate control of the disease. Postremission therapy is divided into correction of the prolonged aPTT after mixing but subse consolidation and maintenance treatment phases. Consoli quent prolongation of the aPTT tbllowing incubation. Eval dation treatment consists of intensive treatment soon after uation of factor VIII levels and inhibitor titers would be the attainment of complete remission (Option B). Consolida prompted only if this sequence of events is demonstrated on tion with conventionaI chemotherapy would be indicated in the mixing study (Option A). managing patients at low risk with AI\4L. Low risk includes 100

l. Answers and Critiques patients with no previous chemotherapy exposure cncl those marrow cause. This patient has no indications for a bone without genetic mutations or with select mutations (e.g., marrow examination in the absence of pancytopenia and NPMI mutated AML) that are associated with improved normal leukocyte differential. prognosis. Elevation of inflammatory cytokines results in reduced Treatment ol the central nervous system (CNS) with production of' endogenous erythropoietin and signiflcant intrirthecal chemotherapy and whole brain irradiation is blunting of erythropoiesis stimulation despite erythropoi routinely employed and improves outcomes in patients etin being present. The ralue of erythropoiesis stimulating with acute lymphoblastic leukemia because the CNS, even agents is generally limited in treating anemia of inflam in asymptomatic patients, harbors malignant cells that are mation because ot the blunted erythropoiesis response resistant to systemic chemotherapy (Option C). The same (Option C). benefit in improving remission rates and survival is not seen Men and postmenopausal women with iron deflciency in patients with AML. irnemia shoulcl undergo bidirectional endoscopy to discover Maintenance chemotherapy is not the best option in a potential source of occult gastrointestinal bleeding. The vl ,9 patients with higher risk AML, good response to initial ther patient has a reduced serum iron level and total iron-binding ET apy, ancl good overall health (Option D). It may be consid capacily with an elevated serum ferritin level. These findings ered in older patients in whom allogeneic HSCT would be are most consistent with anemia of inflammation rather than r., potentially too toxic (e.g., older than 75 80 years). iron deflciency (in which the total iron binding capacity is Providing no additional therapy would result in AML normal or elevated and the serum f'erritin level is <100 ng/ml =t t! relapse and is not the best option for this patient (Option E). [too pglll). It is unnecessary to investigate iron deficiency vl (u anemia using colonoscopy in this patient (Option B). Addi- KEY POIT{T tionally, oral iron replacement therapy is not indicated in the = U! . Allogeneic hematopoietic stem cell transplantation is absence of confirmed iron deficiency (Option E). 4 used for consolidation therapy in patients with high risk acute myeloid leukemia who respond to induc- XEY POITTS tion therapy. o Patients with anemia of inflammation have a hemo globin level of 8 to 10 g/dl (80-100 g/L), slightly low Bibliography or low-normal mean corpuscular volume, low reticu Dholaritr Il. Savani BN. IIlr-l,liltor.r tsK, et al. Ilentatopoietic cell trlnsplanta locyte count, increased serum ferritin level, and low tion in thc treatmcnt ol newly diagnosctl aclult acute myeloid lcukentia: au eviclence based review fiom the Americirn Society of Trttnsplantation serum iron level and total iron-binding capacity. ancl (lellular Therlp1,. Trilnsplant Cell Ihcr. 2021:27:6 2O. Il,MID: o Anemia of inflammation usually occurs in response to 32966881 I ckri:10. l0l6 j.bbmr.2020.09.O20 an underlying condition, and treatment is primarily directed toward identification and treatment of the llem 24 Answer: D underlying condition. Educational Objective: Manage anemia of inflammation. Bibliography (ianz'[. Anemia of inl'hnlniation. N [ngl J l\,led.2019;381:ll l8 1157. [PMID: This patient should begin low-dose prednisone (Option D). :tts:rgotl doi: 10.t056 NEJNlral80t23l She most likely has anemia of inflammation resulting from polymyalgia rheumatica (suggested by history of pain, phys Item 25 Answer: A ical exanrination findings of tenderness and limited range of Ed ucationa I Objective: Manage minimally symptomatic motion in the shoulders and hips, irr.rd elevated markers of immune thromboc5rtopenic purpura with significant inflanrmation). Patients with anemia of inflammation have thrombocytopenia. a hemoglobin level of B ro 10 g/dl. (80 100 g/L). slighrly low or low normal mean corpuscular volume, Iow reticulocyte 'lhis patient should be treated with glucocorticoids count, increased serum ferritin level. and low serunr iron (Option A). Clinical features and laboratory studies support level ancl total iron binding capacity. Treatment of anemia the diagnosis of immune thrombocytopenic purpura (lTP). of inflanrmation is primarily directed toward identification Petechiae and ecchymoses without lymphadenopathy or and treirtment of the Llnderlying inflammatory condition. In splenomegaly are supportive findings. Laborltory findings this patient, treatment of her polymyalgia rheumirtic with are limited to a low platelet count. On the peripheral blood low dose prednisone will reduce inf lammation ancl improve smear, platelets appear as small purplish cells without :r the anemia. nucleus. As a rule of thumb, approximately seven platelets ln lddition to the cornplete blood count and review of lre normally seen per 100 power fleld. Giant platelets are the peripheral blood smear, a bone nrarrow aspirate and typically associated with increased platelet production sec biopsy can be helpful to anemia when assessing stenl cell ondary to the stress of increased peripheral platelet destruc disorders such as aplastic anemia. dysmyelopoietic syn tion. ln adults with newly diagnosed ITP and a platelet count drome, and acute leukemia (Option A). Anemia combined less than 30,0001UL (30 x 10"/l-) who are asymptomatic 'n{,ith other cytopenias increases the likelihood of a prinrary or have minor nrucocutaneous bleeding, treatment with

patients with no previous chemotherapy exposure cncl those marrow cause. This patient has no indications for a bone without genetic mutations or with select mutations (e.g., marrow examination in the absence of pancytopenia and NPMI mutated AML) that are associated with improved normal leukocyte differential. prognosis. Elevation of inflammatory cytokines results in reduced Treatment ol the central nervous system (CNS) with production of' endogenous erythropoietin and signiflcant intrirthecal chemotherapy and whole brain irradiation is blunting of erythropoiesis stimulation despite erythropoi routinely employed and improves outcomes in patients etin being present. The ralue of erythropoiesis stimulating with acute lymphoblastic leukemia because the CNS, even agents is generally limited in treating anemia of inflam in asymptomatic patients, harbors malignant cells that are mation because ot the blunted erythropoiesis response resistant to systemic chemotherapy (Option C). The same (Option C). benefit in improving remission rates and survival is not seen Men and postmenopausal women with iron deflciency in patients with AML. irnemia shoulcl undergo bidirectional endoscopy to discover Maintenance chemotherapy is not the best option in a potential source of occult gastrointestinal bleeding. The vl ,9 patients with higher risk AML, good response to initial ther patient has a reduced serum iron level and total iron-binding ET apy, ancl good overall health (Option D). It may be consid capacily with an elevated serum ferritin level. These findings ered in older patients in whom allogeneic HSCT would be are most consistent with anemia of inflammation rather than r., potentially too toxic (e.g., older than 75 80 years). iron deflciency (in which the total iron binding capacity is Providing no additional therapy would result in AML normal or elevated and the serum f'erritin level is <100 ng/ml =t t! relapse and is not the best option for this patient (Option E). [too pglll). It is unnecessary to investigate iron deficiency vl (u anemia using colonoscopy in this patient (Option B). Addi- KEY POIT{T tionally, oral iron replacement therapy is not indicated in the = U! . Allogeneic hematopoietic stem cell transplantation is absence of confirmed iron deficiency (Option E). 4 used for consolidation therapy in patients with high risk acute myeloid leukemia who respond to induc- XEY POITTS tion therapy. o Patients with anemia of inflammation have a hemo globin level of 8 to 10 g/dl (80-100 g/L), slightly low Bibliography or low-normal mean corpuscular volume, low reticu Dholaritr Il. Savani BN. IIlr-l,liltor.r tsK, et al. Ilentatopoietic cell trlnsplanta locyte count, increased serum ferritin level, and low tion in thc treatmcnt ol newly diagnosctl aclult acute myeloid lcukentia: au eviclence based review fiom the Americirn Society of Trttnsplantation serum iron level and total iron-binding capacity. ancl (lellular Therlp1,. Trilnsplant Cell Ihcr. 2021:27:6 2O. Il,MID: o Anemia of inflammation usually occurs in response to 32966881 I ckri:10. l0l6 j.bbmr.2020.09.O20 an underlying condition, and treatment is primarily directed toward identification and treatment of the llem 24 Answer: D underlying condition. Educational Objective: Manage anemia of inflammation. Bibliography (ianz'[. Anemia of inl'hnlniation. N [ngl J l\,led.2019;381:ll l8 1157. [PMID: This patient should begin low-dose prednisone (Option D). :tts:rgotl doi: 10.t056 NEJNlral80t23l She most likely has anemia of inflammation resulting from polymyalgia rheumatica (suggested by history of pain, phys Item 25 Answer: A ical exanrination findings of tenderness and limited range of Ed ucationa I Objective: Manage minimally symptomatic motion in the shoulders and hips, irr.rd elevated markers of immune thromboc5rtopenic purpura with significant inflanrmation). Patients with anemia of inflammation have thrombocytopenia. a hemoglobin level of B ro 10 g/dl. (80 100 g/L). slighrly low or low normal mean corpuscular volume, Iow reticulocyte 'lhis patient should be treated with glucocorticoids count, increased serum ferritin level. and low serunr iron (Option A). Clinical features and laboratory studies support level ancl total iron binding capacity. Treatment of anemia the diagnosis of immune thrombocytopenic purpura (lTP). of inflanrmation is primarily directed toward identification Petechiae and ecchymoses without lymphadenopathy or and treirtment of the Llnderlying inflammatory condition. In splenomegaly are supportive findings. Laborltory findings this patient, treatment of her polymyalgia rheumirtic with are limited to a low platelet count. On the peripheral blood low dose prednisone will reduce inf lammation ancl improve smear, platelets appear as small purplish cells without :r the anemia. nucleus. As a rule of thumb, approximately seven platelets ln lddition to the cornplete blood count and review of lre normally seen per 100 power fleld. Giant platelets are the peripheral blood smear, a bone nrarrow aspirate and typically associated with increased platelet production sec biopsy can be helpful to anemia when assessing stenl cell ondary to the stress of increased peripheral platelet destruc disorders such as aplastic anemia. dysmyelopoietic syn tion. ln adults with newly diagnosed ITP and a platelet count drome, and acute leukemia (Option A). Anemia combined less than 30,0001UL (30 x 10"/l-) who are asymptomatic 'n{,ith other cytopenias increases the likelihood of a prinrary or have minor nrucocutaneous bleeding, treatment with 101

Answers and Critiques glucocorticoids is recommended. Initial therapy includes a adenocarcinofia: and in pregnancli $'ith complications of short course (<6 weeks) ofprednisone or dexamethasone. placental abruption and eclarnpsia. The initial pathogenesis The response to intravenous immune globulin is faster and involves n'idespread endothelial injury ar.rd circulating pro may be indicated in patients with more severe thrombocy- coagulants that lead to disseminated micror.ascular thrombi. topenia and Iife threatening bleeding. rvith consumption of platelets and clotting factors. and Initial treatment of thrombotic thromboqtopenic pur- erythroc)1e shearing injury leading to hemoll,sis. Fibrinolv pura (TTP) involves therapeutic plasma exchange to remove sis is accelerated. resulting in dissolution of the microrascu the high molecular weight von Willebrand factor multimers lar thrombus, usually before thrombotic complications are and replace the deficient ADAMTS13 (Option B). Glucocor- noted. Classic laboratory flndings include tl.rronrbocytopenia. ticoids are added to decrease autoantibody production. This prolonged activated partial thrornboplastin and prothrombin patient lacks any evidence for microangiopathic hemolysis times (aPTT. PT), elevated INR. hypoflbrinogenemia. and needed to establish the diagnosis ofTTP such as schistocy.tes elevated D dimer level. Managenlent is directed primarill'at on the peripheral blood smear. the inciting cause of DIC and suppofied n'ith platelet transfu (,I Platelet transfusion is not generally indicated in patients sions. cryoprecipitate, and fresh frozen plasma as needed. In (D with thrombocytopenia in the absence of trauma, surgery this previously well, 1,oung patient with DIC associated u'ith = vl or bleeding unless the platelet count decreases to less than panc]{openia. an underlying leukemia should be suspected. q, 10,000 to 20,000/pL (10 20 x loe/L); the lower platelet count A characteristic I'eature of acute promlelocl'tic leukemia is CL is more applicable to patients with chronic thrombocytope- presentation with DIC at the tinre of diagnosis. a.| nia who are otherwise stable. The transfusion threshold for Aplastic anemia can explain the patient's pancytopenia patients with bleeding, trauma, or both is approximately but does not account for other aspects of the coagulopathl' lt E 50,000/pL (50 x 10'/L). This mildly symptomatic patient that are present (Option A). .D ul without overt bleeding does not require a platelet transfu- [-ir,er disease resu]Is in procoagulant ar-rd anticoagulant sion (Option C). {actor reduction and in mild to moderate thrombocl'topenia. ITP may be asymptomatic and discovered in the eval- Redr-rced procoagulant factors can result in prolongation of' uation of thrombocytopenia as an incidental finding on PT and aPTT: hou,ever. these results do not correlate u'itl.t a routine complete blood count. Patients with such inci- bleeding risk becluse thel'cio not reflect the parallel reduc dentally discovered ITP and platelet counts greater than tion in anticoagulant factors. Distinguisl.ring betrt'een liver 30,000/pL (30 x 10e/L) may be observed without the need disease and DIC may be challenging because patients. not for drug therapy or platelet transfusions (Option D). this tuncommonly, have components ol both disorders. Horvever. patient's symptoms indicate more severe thrombocyto- this previously well patient rvith normal lirer function tests penia requiring treatment with glucocorticoids; platelet and serere pancytopenia is ncit likell'to hiive coagulopathl' transfusions are not indicated for patients with ITP who are of liver disease (Option B). 'lhrombocl,'topenia and nricroangiopathic hemoll-sis are not actively bleeding. tl.re hallmarks of thrombotic thrombocl-'topenic purpura XEY POITTT (TTP) (Option D). However. TTP is not associated $'ith coag o Platelet transfusion is not generally indicated in patients ulation abnornralities or severe h1 pofibrinogenemia as seen with thromboqtopenia in the absence of trauma, sur- in this patient. gery or bleeding unless the platelet count decreases to rEY POIXT less than 10,000 to 20,000/pL (10-20 x 10e/L). o Glucocorticoid treatment is indicated in patients with . Typical findings of disseminated intravascular coagu lation include thrombocytopenia, prolonged coagula- I immune thrombocytopenic purpura and a platelet tion measures, hypofibrinogenemia, and elevated count less than 30,000/pL (30 x l0e/L). D-dimer level. Bibliography Estcourt IJ, Birchall J, Allard S. et al; British Committee for Standards in Bibliography Haematolos/. Guidelines for the use of platelet transfusions. Br J Levi M, Sivapalaratnam S. Disseminated intravascular coagulation: An Haematol. 2Ol7 :176:365 -394. IPMID: 28OO9056] doi:10.11Ulbih.l4423 update on pathogenesis and diagnosis. Expen Re! Hematol. 2018:ll:663 672. [PMID: 29999440] doi:10.1080 r17174086.2018.1500173

glucocorticoids is recommended. Initial therapy includes a adenocarcinofia: and in pregnancli $'ith complications of short course (<6 weeks) ofprednisone or dexamethasone. placental abruption and eclarnpsia. The initial pathogenesis The response to intravenous immune globulin is faster and involves n'idespread endothelial injury ar.rd circulating pro may be indicated in patients with more severe thrombocy- coagulants that lead to disseminated micror.ascular thrombi. topenia and Iife threatening bleeding. rvith consumption of platelets and clotting factors. and Initial treatment of thrombotic thromboqtopenic pur- erythroc)1e shearing injury leading to hemoll,sis. Fibrinolv pura (TTP) involves therapeutic plasma exchange to remove sis is accelerated. resulting in dissolution of the microrascu the high molecular weight von Willebrand factor multimers lar thrombus, usually before thrombotic complications are and replace the deficient ADAMTS13 (Option B). Glucocor- noted. Classic laboratory flndings include tl.rronrbocytopenia. ticoids are added to decrease autoantibody production. This prolonged activated partial thrornboplastin and prothrombin patient lacks any evidence for microangiopathic hemolysis times (aPTT. PT), elevated INR. hypoflbrinogenemia. and needed to establish the diagnosis ofTTP such as schistocy.tes elevated D dimer level. Managenlent is directed primarill'at on the peripheral blood smear. the inciting cause of DIC and suppofied n'ith platelet transfu (,I Platelet transfusion is not generally indicated in patients sions. cryoprecipitate, and fresh frozen plasma as needed. In (D with thrombocytopenia in the absence of trauma, surgery this previously well, 1,oung patient with DIC associated u'ith = vl or bleeding unless the platelet count decreases to less than panc]{openia. an underlying leukemia should be suspected. q, 10,000 to 20,000/pL (10 20 x loe/L); the lower platelet count A characteristic I'eature of acute promlelocl'tic leukemia is CL is more applicable to patients with chronic thrombocytope- presentation with DIC at the tinre of diagnosis. a.| nia who are otherwise stable. The transfusion threshold for Aplastic anemia can explain the patient's pancytopenia patients with bleeding, trauma, or both is approximately but does not account for other aspects of the coagulopathl' lt E 50,000/pL (50 x 10'/L). This mildly symptomatic patient that are present (Option A). .D ul without overt bleeding does not require a platelet transfu- [-ir,er disease resu]Is in procoagulant ar-rd anticoagulant sion (Option C). {actor reduction and in mild to moderate thrombocl'topenia. ITP may be asymptomatic and discovered in the eval- Redr-rced procoagulant factors can result in prolongation of' uation of thrombocytopenia as an incidental finding on PT and aPTT: hou,ever. these results do not correlate u'itl.t a routine complete blood count. Patients with such inci- bleeding risk becluse thel'cio not reflect the parallel reduc dentally discovered ITP and platelet counts greater than tion in anticoagulant factors. Distinguisl.ring betrt'een liver 30,000/pL (30 x 10e/L) may be observed without the need disease and DIC may be challenging because patients. not for drug therapy or platelet transfusions (Option D). this tuncommonly, have components ol both disorders. Horvever. patient's symptoms indicate more severe thrombocyto- this previously well patient rvith normal lirer function tests penia requiring treatment with glucocorticoids; platelet and serere pancytopenia is ncit likell'to hiive coagulopathl' transfusions are not indicated for patients with ITP who are of liver disease (Option B). 'lhrombocl,'topenia and nricroangiopathic hemoll-sis are not actively bleeding. tl.re hallmarks of thrombotic thrombocl-'topenic purpura XEY POITTT (TTP) (Option D). However. TTP is not associated $'ith coag o Platelet transfusion is not generally indicated in patients ulation abnornralities or severe h1 pofibrinogenemia as seen with thromboqtopenia in the absence of trauma, sur- in this patient. gery or bleeding unless the platelet count decreases to rEY POIXT less than 10,000 to 20,000/pL (10-20 x 10e/L). o Glucocorticoid treatment is indicated in patients with . Typical findings of disseminated intravascular coagu lation include thrombocytopenia, prolonged coagula- I immune thrombocytopenic purpura and a platelet tion measures, hypofibrinogenemia, and elevated count less than 30,000/pL (30 x l0e/L). D-dimer level. Bibliography Estcourt IJ, Birchall J, Allard S. et al; British Committee for Standards in Bibliography Haematolos/. Guidelines for the use of platelet transfusions. Br J Levi M, Sivapalaratnam S. Disseminated intravascular coagulation: An Haematol. 2Ol7 :176:365 -394. IPMID: 28OO9056] doi:10.11Ulbih.l4423 update on pathogenesis and diagnosis. Expen Re! Hematol. 2018:ll:663 672. [PMID: 29999440] doi:10.1080 r17174086.2018.1500173 tr Item 26 Answer: C Educationa I Objective: Diagnose disseminated intra- Item 27 Answer: B vascular coagulation. Educational Obiective: Identi$ a patient with pulmo- nary embolism at low risk for complications with outpa- The most likely diagnosis is disseminated intravascular coag tient treatment. ulation (DIC) (Option C). DIC results lrom the simultaneous activation of coagulation and fibrinolysis. It is associated with The most appropriate recommendation is to discharge the severc scpsis. usually with septic shock; r,tith disseminated patient home on a direct oral anticoagulant (DOAC) such as malignancy, most classically u,ith mucin secreting pirncreatic rivaroxaban (Option B). For patients with pulmonary embolism

tr Item 26 Answer: C Educationa I Objective: Diagnose disseminated intra- Item 27 Answer: B vascular coagulation. Educational Obiective: Identi$ a patient with pulmo- nary embolism at low risk for complications with outpa- The most likely diagnosis is disseminated intravascular coag tient treatment. ulation (DIC) (Option C). DIC results lrom the simultaneous activation of coagulation and fibrinolysis. It is associated with The most appropriate recommendation is to discharge the severc scpsis. usually with septic shock; r,tith disseminated patient home on a direct oral anticoagulant (DOAC) such as malignancy, most classically u,ith mucin secreting pirncreatic rivaroxaban (Option B). For patients with pulmonary embolism 102

Answers and Critiques (PE) with a low risk fbr complications, the American Society of meningitis should undergo lumbar puncture lbllou,ed by Hematologl guideline suggests oflering home treatment over immediate antibiotic therapy guided by the ceretrrospi hospital treatment. Clinical prediction scores have a moderate na1 fluid (CSF) results. If perfbrnting a lumbar punctllre ability to predict patient outcomes and do not replace clinical must be delayed, en.rpiric antibiotics atrd dexantetl.titsone judgment. Howevet they may help to select patients at low risk should be adn.rir-risterecl after obtaining blooti cultures. ll.ris for complications. The Pulmonary Embolism Severity Index patient likely has n-rer-ringitis ancl requires lutnbar pLlncturc (PESI) and simplified PESI have been most widely validated. urgentl1,. but his platelet count is less than the tltresl.told This recommendation does not apply to patients who have other (50,000rUL [so x toq.'i.]) cor.rsidered safe firr this procedure. conditions that would require hospitalization, have limited or Transfusing a single ur.rit of platelets shoulcl raise tlte pllte no support at home, and cannot aflord medications or have a let count by around 20.000 to30.000.'pl. (20 30 x l0"it.), history of poor adherence. The simplified PESI assigns 1 point after rthich lumbar puncture can be pursued. The cattse o1 for each of the following: age older than 80 years, history of this patient's thrombocytopenia is not iurmediately clear cardiopulmonary disease, history of cancer, pulse rate 110/min but may be a drug ir.rduced imnrune thromltocytopenia tt (l, or greater, systolic blood pressure less than 100 mm Hg, and caused by carbamazepine ancl will require firrther ir.rvesti ET oxygen saturation less than 9O"/,,. lf none of these criteria are gation and management. met, the patient is considered low risk, with a 30 day mortality In patients r,vitl.r platelet counts less than 50,000/pL t, of 1.1'l"; these patients can be considered fbr home anticoag (50 x 10"1L). platelet transfusior.r is neeclecl befbre undergo !t ulation treatment with either rivaroxaban or apixaban. This ing invasive procedures or general surgery. Thereltrre. tl.ris (, patient meets none of the risk criteria, and treatment at home patient should not undergo lumbar puncture without first Ut e, is reasonable. receiving a platelet transfusior-r to reduce tlre risk ol spinal Rivaroxaban and apixaban are both approved for mono- epidural hematoma (Option A). vt = therapy of venous thromboembolism (VTE; deep venous Plasma exchange is inclicated in the rnanagemcnt of thrombosis and PE). Dabigatran has not been approved for thrombotic thrombocytopenic purpurrr (T'lP) (Option B). monotherapy of VTE; treatment must be preceded by hep- Acquired 'fTP presents with microangiopathic hemolytic arin, preferably low molecular-weight heparin (Option A). anemia (elevated lactate dehydroflenase level, clepressecl Thrombolytic therapy is recommended for patients with haptoglobin level. negative direct antiglobulin test, and massive PE and shock related to low cardiac output. This schistocytes on peripheral bloocl smear).'lhis patient has no patient does not require thrombolytic therapy (Option C). evidence of microar.rgiopathic hemolytic anemil. Intravenous anticoagulation with unfractionated heparin No further intervention or treatnlellt is incorrect (UFH) would require hospital admission, and intravenous UFH (Option D). Patients with suspected n.rcningitis should have would not be the ideal anticoagulant because of the potential a lumbar puncture with subsequent CSF analysis, which is delay in reaching therapeutic levels and the variations in bio critical fbr establishing the diagnosis of bacterial nren ingitis. availability. Finally, guidelines suggest DOACs for treatment of identifying the causative organism, ancl pertbrming suscep VTE over vitamin K antagonists like warfarin (Option D). tibility testing that'"vill guide therapl,: rEV POIilTS rEV POIilIS . For patients with pulmonary embolism and low risk o Platelet transfusions are needed in patients with for complications, the American Society of Hematologr platelet counts less than 50,000/pL (50 x 10e/L) before guideline suggests offering home treatment over hospi- undergoing invasive procedures or general surgery tal treatment. with a sigrrificant risk of bleeding. . Clinical prediction scores, such as the Pulmonary . One unit of platelets should raise the platelet count by Embolism Severity Index, have a moderate ability to around 20,000 to 30,000/pL (20 30 x 10e/L). predict patient outcomes but do not replace clinical judgment. Bibliography Kaufman RM, Djulbegovic B. Gernsheimer T, et al; AABB. Platelet transfu sionr A clinical practice guideline from the AABB. Ann lntern Med. 2015; Bibliography 162:205 13. IPMID: 253836711 doi:10.7326lMl4 1589 Ortel TL, Neumann I, Ageno W et al. American Society of HematoloEs/ 2020 guidelines for management of venous thromboembolism: Treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020;4:4693- 4738. IPMID: 33007077] doi: 10.1182/bloodadvances.202o00i830 Item 29 Answer: C Educational Objective: Diagnose drug-induced neutropenia. Item 28 tr Answer: C Educational Objective: Treat thrombocytopenia in a The most likely diagnosis is drug induced neutropenia (Option C). Neutropenia is deflned as a circulating absolute neutrophil patient requiring an invasive procedure. count (ANC) less than 1500/pL (t.S x tOe/L); severe neutrope The most appropriatc managentent fbr this patient is plate nia is an ANC less than SOO/pL (0.5 x 10e/L). The diflerential let transfirsion (Option C). All patients r,t,ith suspected diagnosis for neutropenia is broad. Degree of neutropenia,

(PE) with a low risk fbr complications, the American Society of meningitis should undergo lumbar puncture lbllou,ed by Hematologl guideline suggests oflering home treatment over immediate antibiotic therapy guided by the ceretrrospi hospital treatment. Clinical prediction scores have a moderate na1 fluid (CSF) results. If perfbrnting a lumbar punctllre ability to predict patient outcomes and do not replace clinical must be delayed, en.rpiric antibiotics atrd dexantetl.titsone judgment. Howevet they may help to select patients at low risk should be adn.rir-risterecl after obtaining blooti cultures. ll.ris for complications. The Pulmonary Embolism Severity Index patient likely has n-rer-ringitis ancl requires lutnbar pLlncturc (PESI) and simplified PESI have been most widely validated. urgentl1,. but his platelet count is less than the tltresl.told This recommendation does not apply to patients who have other (50,000rUL [so x toq.'i.]) cor.rsidered safe firr this procedure. conditions that would require hospitalization, have limited or Transfusing a single ur.rit of platelets shoulcl raise tlte pllte no support at home, and cannot aflord medications or have a let count by around 20.000 to30.000.'pl. (20 30 x l0"it.), history of poor adherence. The simplified PESI assigns 1 point after rthich lumbar puncture can be pursued. The cattse o1 for each of the following: age older than 80 years, history of this patient's thrombocytopenia is not iurmediately clear cardiopulmonary disease, history of cancer, pulse rate 110/min but may be a drug ir.rduced imnrune thromltocytopenia tt (l, or greater, systolic blood pressure less than 100 mm Hg, and caused by carbamazepine ancl will require firrther ir.rvesti ET oxygen saturation less than 9O"/,,. lf none of these criteria are gation and management. met, the patient is considered low risk, with a 30 day mortality In patients r,vitl.r platelet counts less than 50,000/pL t, of 1.1'l"; these patients can be considered fbr home anticoag (50 x 10"1L). platelet transfusior.r is neeclecl befbre undergo !t ulation treatment with either rivaroxaban or apixaban. This ing invasive procedures or general surgery. Thereltrre. tl.ris (, patient meets none of the risk criteria, and treatment at home patient should not undergo lumbar puncture without first Ut e, is reasonable. receiving a platelet transfusior-r to reduce tlre risk ol spinal Rivaroxaban and apixaban are both approved for mono- epidural hematoma (Option A). vt = therapy of venous thromboembolism (VTE; deep venous Plasma exchange is inclicated in the rnanagemcnt of thrombosis and PE). Dabigatran has not been approved for thrombotic thrombocytopenic purpurrr (T'lP) (Option B). monotherapy of VTE; treatment must be preceded by hep- Acquired 'fTP presents with microangiopathic hemolytic arin, preferably low molecular-weight heparin (Option A). anemia (elevated lactate dehydroflenase level, clepressecl Thrombolytic therapy is recommended for patients with haptoglobin level. negative direct antiglobulin test, and massive PE and shock related to low cardiac output. This schistocytes on peripheral bloocl smear).'lhis patient has no patient does not require thrombolytic therapy (Option C). evidence of microar.rgiopathic hemolytic anemil. Intravenous anticoagulation with unfractionated heparin No further intervention or treatnlellt is incorrect (UFH) would require hospital admission, and intravenous UFH (Option D). Patients with suspected n.rcningitis should have would not be the ideal anticoagulant because of the potential a lumbar puncture with subsequent CSF analysis, which is delay in reaching therapeutic levels and the variations in bio critical fbr establishing the diagnosis of bacterial nren ingitis. availability. Finally, guidelines suggest DOACs for treatment of identifying the causative organism, ancl pertbrming suscep VTE over vitamin K antagonists like warfarin (Option D). tibility testing that'"vill guide therapl,: rEV POIilTS rEV POIilIS . For patients with pulmonary embolism and low risk o Platelet transfusions are needed in patients with for complications, the American Society of Hematologr platelet counts less than 50,000/pL (50 x 10e/L) before guideline suggests offering home treatment over hospi- undergoing invasive procedures or general surgery tal treatment. with a sigrrificant risk of bleeding. . Clinical prediction scores, such as the Pulmonary . One unit of platelets should raise the platelet count by Embolism Severity Index, have a moderate ability to around 20,000 to 30,000/pL (20 30 x 10e/L). predict patient outcomes but do not replace clinical judgment. Bibliography Kaufman RM, Djulbegovic B. Gernsheimer T, et al; AABB. Platelet transfu sionr A clinical practice guideline from the AABB. Ann lntern Med. 2015; Bibliography 162:205 13. IPMID: 253836711 doi:10.7326lMl4 1589 Ortel TL, Neumann I, Ageno W et al. American Society of HematoloEs/ 2020 guidelines for management of venous thromboembolism: Treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020;4:4693- 4738. IPMID: 33007077] doi: 10.1182/bloodadvances.202o00i830 Item 29 Answer: C Educational Objective: Diagnose drug-induced neutropenia. Item 28 tr Answer: C Educational Objective: Treat thrombocytopenia in a The most likely diagnosis is drug induced neutropenia (Option C). Neutropenia is deflned as a circulating absolute neutrophil patient requiring an invasive procedure. count (ANC) less than 1500/pL (t.S x tOe/L); severe neutrope The most appropriatc managentent fbr this patient is plate nia is an ANC less than SOO/pL (0.5 x 10e/L). The diflerential let transfirsion (Option C). All patients r,t,ith suspected diagnosis for neutropenia is broad. Degree of neutropenia, 103

Answers and Critiques -lhese acuity of onset, and presence of other abnormalities in the thromboses can occur in the venous or arterial s!-s complete blood count, such as anemia or thrombocytopenia, tem. Although venous thromboembolism (\-TE) usuallv are helpful in differentiirting the potential cause. Review of inclucles pulmonary embolisnr and deep \enous throm medications is important in the evaluation of neutropenia bosis. portal vein thrombosis or Budd Chiari s1'ndrome because medications are a common cause. Drug induced neu (hepatic venous outflor,r, obstruction) can also occur. tropenia results from impairment ol normal granulopoiesis Causes of Budd Chiari syndrome ma] include h1'perccr in the bone marow or through a drug dependent. antibody agulable states such as a myeloproliferative neoplasm. mediated immune destruction of circulating neutrophils. The pregnanc\. oral contraceptir.e use. inflammatory borvel thionamides propylthiouracil and methimazole are among the disease. or inherited thrombophilias. Underlf ing malig drugs known to cause agranulocytosisl although the overall nanc!. cspecialty hepatocellular carcinoma. must be prevalence is low (around 0.5'2,), the risk is higher compared considered. T1'pical symptoms of Budd Chiari s1'ndrome with other drug classes. Agranulocytosis is more likely to occur include hepatomegaly, ascites. and right upper quadrant D within the first 3 months of drug initiation, is more common abdominal pain. Br"rdd Chiari sy'ndrome is t1'picalll' diag U, in women, and appears to be dose related with methimazole. nosed by ultrasound with Doppler. CT. or I{Rl in the t lD The ANC should recover within 1 to 3 weeks after discontinu appropriate clinical setting. Approximatel]' half of patients t, ing the medication. ruith Budd Ohiari synclrome are diagnosed rvith an \,1P\: o, Benign ethnic neutropenia (BEN) is more common in therefbre, patients rvith splanchnic vein thrombosis (por €L patients of African descent (Option A). Estimates are that tal vein. splenic vein. hepatic vein. or mesenteric \-ein r) approximately 4'2, of Blacks in the United States have BEN. thrombosis) should be evaluated for \{P\s. including test. Patients with BEN are asymptomatic, and its presence does not ing fbr the,/A(2 tyrosine kinase mutation. Complete blood lt increase risk for infections. It is associated with a persistent, counts are not alu,ays abnormal \f ith an underlf ing \{P\. tD ,rt mild to moderate degree of neutropenia, rarely with an ANC so this patient's normal blood profile n'ould not erclude less than 1000/pl. (1 x 100/L). This patient's degree ofneutrope the presence of a /.,1K2 t1'rosine kinase mutation. nia is much greater than would be expected with BEN. Antithrombin III (ATIll) is a natural anticoagulant Cyclic neutropenia is a rare genetic cause of symptom that inhibits thrombin and activated factors IX and X. atic neutropenia that recurs every 3 weeks (Option B). The lnherited ATIII deficiencies are rare. but acquired ATIII neutropenia can be severe (<200/pL [o.z x toerL])l lasts for 2 deficiencies are more common. Acquired deficiencies to 3 days; and is associated with recurrent fever, oral ulcer can occur during an acute thrombosis. so this patient's ations, and infections. ln this patient, the recent initiation of antithrombin level should not be evaluated at this time methimazole is a more likely cause of neutropenia. (Option A). Vitamin B,, is necessary for DNA synthesis and can Protcin C and S deficiencies are thrombophilias that be associated with pancytopenia. Vitamin B,, deflciency is can be inherited rtr acquired. Patients h'ith protein C more likely to occur in those who are vegetarians because or S deficienc), most commonly present at a loung age vitamin B,, is not found in plant based foods. However, her (<50 vears) with VTE. rather than arterial thrombosis. normal hemoglobin level and mean corpuscular volume do and olten hlve a strong family history ol thrombosis. The not support a diagnosis of vitamin B,, deflciency (Option D). absence of a stror.rg tamilrv history of thrombosis and the patient's age significantll, reduce the probability of protein XEY POIl{Ig (. or S deficiencyi Additior.rally protein C and S measurement o Neutropenia is defined as a circulating absolute neu during an ircute thrombotic erent can retum falsell'reduced trophil count (ANC) less than 1500/pL (1.5 x 10e/L); levels (Options C, D). For these reasons. testing should not severe neutropenia is an ANC less than 500/pL be performcd in this patient. (0.5 x 1oq/L). XEY POITTS . Medications are a common cause of neutropenia. o In patients with splanchnic vein thrombosis (portal vein, splenic vein, hepatic vein, or mesenteric vein Bibliography Curtis BR. Non chemotherapy drug induced neutropenia: key points to thrombosis), evaluation lor evidence of a myeloprolif- manage the challenges. HematoloE0/ Am Soc Hematol Educ Program. erative neoplasm should be considered, including 2Ol7 2017 :187 193. Il'N{ll): 292222551 doi:10.1182 asheducation 2017. 1.187 evaluation lor the /AK2 tyrosine kinase mutation. o Evidence of a myeloproliferative neoplasm is discov- ered in approximately 507, of patients with Budd-

-lhese acuity of onset, and presence of other abnormalities in the thromboses can occur in the venous or arterial s!-s complete blood count, such as anemia or thrombocytopenia, tem. Although venous thromboembolism (\-TE) usuallv are helpful in differentiirting the potential cause. Review of inclucles pulmonary embolisnr and deep \enous throm medications is important in the evaluation of neutropenia bosis. portal vein thrombosis or Budd Chiari s1'ndrome because medications are a common cause. Drug induced neu (hepatic venous outflor,r, obstruction) can also occur. tropenia results from impairment ol normal granulopoiesis Causes of Budd Chiari syndrome ma] include h1'perccr in the bone marow or through a drug dependent. antibody agulable states such as a myeloproliferative neoplasm. mediated immune destruction of circulating neutrophils. The pregnanc\. oral contraceptir.e use. inflammatory borvel thionamides propylthiouracil and methimazole are among the disease. or inherited thrombophilias. Underlf ing malig drugs known to cause agranulocytosisl although the overall nanc!. cspecialty hepatocellular carcinoma. must be prevalence is low (around 0.5'2,), the risk is higher compared considered. T1'pical symptoms of Budd Chiari s1'ndrome with other drug classes. Agranulocytosis is more likely to occur include hepatomegaly, ascites. and right upper quadrant D within the first 3 months of drug initiation, is more common abdominal pain. Br"rdd Chiari sy'ndrome is t1'picalll' diag U, in women, and appears to be dose related with methimazole. nosed by ultrasound with Doppler. CT. or I{Rl in the t lD The ANC should recover within 1 to 3 weeks after discontinu appropriate clinical setting. Approximatel]' half of patients t, ing the medication. ruith Budd Ohiari synclrome are diagnosed rvith an \,1P\: o, Benign ethnic neutropenia (BEN) is more common in therefbre, patients rvith splanchnic vein thrombosis (por €L patients of African descent (Option A). Estimates are that tal vein. splenic vein. hepatic vein. or mesenteric \-ein r) approximately 4'2, of Blacks in the United States have BEN. thrombosis) should be evaluated for \{P\s. including test. Patients with BEN are asymptomatic, and its presence does not ing fbr the,/A(2 tyrosine kinase mutation. Complete blood lt increase risk for infections. It is associated with a persistent, counts are not alu,ays abnormal \f ith an underlf ing \{P\. tD ,rt mild to moderate degree of neutropenia, rarely with an ANC so this patient's normal blood profile n'ould not erclude less than 1000/pl. (1 x 100/L). This patient's degree ofneutrope the presence of a /.,1K2 t1'rosine kinase mutation. nia is much greater than would be expected with BEN. Antithrombin III (ATIll) is a natural anticoagulant Cyclic neutropenia is a rare genetic cause of symptom that inhibits thrombin and activated factors IX and X. atic neutropenia that recurs every 3 weeks (Option B). The lnherited ATIII deficiencies are rare. but acquired ATIII neutropenia can be severe (<200/pL [o.z x toerL])l lasts for 2 deficiencies are more common. Acquired deficiencies to 3 days; and is associated with recurrent fever, oral ulcer can occur during an acute thrombosis. so this patient's ations, and infections. ln this patient, the recent initiation of antithrombin level should not be evaluated at this time methimazole is a more likely cause of neutropenia. (Option A). Vitamin B,, is necessary for DNA synthesis and can Protcin C and S deficiencies are thrombophilias that be associated with pancytopenia. Vitamin B,, deflciency is can be inherited rtr acquired. Patients h'ith protein C more likely to occur in those who are vegetarians because or S deficienc), most commonly present at a loung age vitamin B,, is not found in plant based foods. However, her (<50 vears) with VTE. rather than arterial thrombosis. normal hemoglobin level and mean corpuscular volume do and olten hlve a strong family history ol thrombosis. The not support a diagnosis of vitamin B,, deflciency (Option D). absence of a stror.rg tamilrv history of thrombosis and the patient's age significantll, reduce the probability of protein XEY POIl{Ig (. or S deficiencyi Additior.rally protein C and S measurement o Neutropenia is defined as a circulating absolute neu during an ircute thrombotic erent can retum falsell'reduced trophil count (ANC) less than 1500/pL (1.5 x 10e/L); levels (Options C, D). For these reasons. testing should not severe neutropenia is an ANC less than 500/pL be performcd in this patient. (0.5 x 1oq/L). XEY POITTS . Medications are a common cause of neutropenia. o In patients with splanchnic vein thrombosis (portal vein, splenic vein, hepatic vein, or mesenteric vein Bibliography Curtis BR. Non chemotherapy drug induced neutropenia: key points to thrombosis), evaluation lor evidence of a myeloprolif- manage the challenges. HematoloE0/ Am Soc Hematol Educ Program. erative neoplasm should be considered, including 2Ol7 2017 :187 193. Il'N{ll): 292222551 doi:10.1182 asheducation 2017. 1.187 evaluation lor the /AK2 tyrosine kinase mutation. o Evidence of a myeloproliferative neoplasm is discov- ered in approximately 507, of patients with Budd- tr Item 30 Answer: B Educational Objective: Evaluate a patient with splanch- Chiari syndrome, even when the complete blood count is normal. nic vein thrombosis for lAK2tyrosine kinase mutation. Bibliography This patient should be tested for the JAK2 tyrosine kinase Dentali I.-. Squizzat0 A, Ilrivio I-, et al. JAK2\'617F mutation for the earll diagnosis ot [)h ntyeloproliferative neoplasms in patients with venous mutation (Option B). Patients with myeloproliferative thromboembolism: A mete analysis. Blood. 2009;113:5617 23. [PMID: neoplasms (MPNs) have an increased risk of thrombosis. 192738371 cioi:1O.il82/blood 2OO8 t2 196014

tr Item 30 Answer: B Educational Objective: Evaluate a patient with splanch- Chiari syndrome, even when the complete blood count is normal. nic vein thrombosis for lAK2tyrosine kinase mutation. Bibliography This patient should be tested for the JAK2 tyrosine kinase Dentali I.-. Squizzat0 A, Ilrivio I-, et al. JAK2\'617F mutation for the earll diagnosis ot [)h ntyeloproliferative neoplasms in patients with venous mutation (Option B). Patients with myeloproliferative thromboembolism: A mete analysis. Blood. 2009;113:5617 23. [PMID: neoplasms (MPNs) have an increased risk of thrombosis. 192738371 cioi:1O.il82/blood 2OO8 t2 196014 104

Answers and Critiques Item 31 Answer: C (AL) amyloidosis. These light chains can deposit in the kid Ed ucationa I Objective: Manage heparin-induced ney, heart, skin, liver, and other organs. Soft tissue mani thrombocy.topenia. f'estations are present in 30'7, to 40'l, of patients and include generalized waxy appearance; easy bruising with minor I)iscontinuing heparin. testing fbr heparin induced thntmbo pressure (pinch purpura) ; periorbital ecchymoses ("raccoon cyt<4>enia (tllT). and starting rivaroxaban is the most appnrpri eyes," shown);yellow waxy papules and plaques, especially atc management fbr this patient (Option C). tlis platelet count in a periorbital location; dystrophic nails; and macroglossia. clecreased by more than 501, from admission, and hc rtas He also has an IgG l" monoclonal gammopathy detectable in exposed to heparin lbllowing bypass grafl surgery 3 wccks ago. the serum, which further confirms a plasma cell dyscrasia. 'll.tis gives him a .1T score of 5 (platelet c'ount dccrcasc >50'X, = Diagnosis requires tissue biopsy that demonstrates charac 2 points: onset >1 day with previous exposurc rtithin 130 days = teristic apple green birelringence with Congo red staining. I point: no other likell' cause of thron.rboc-vtopenia = 2 points). Fat pad biopsy is pref'erred even in multiorgan involvement A .l'l' score of 5 suggests an intermediate. or l0',1,. risk <tf ttlT. because it is less invasive than biopsying other organs (sen vl (u Bccausc he does not have kidnel,disease. rivaroxaban or apix sitivity, 60"/,,-80"/.,).lf unrevealing, kidney, bone marrow or aban is acceplable treatment for this patient rrith HIT rcquiring ET other organ biopsy can be performed (Option C). Protein thcn4xutic anticoagulation for pulmonary embolisrnr arga typing using mass spectrometry is important to identiff the (J tnrban and fbndaparinu-r are acceptable parentcral options. In speciflc protein causing amyloidosis. Proper identification of E' this patient. discontinuing heparin in fhr.,or of'rivaroxaban plus the amyloid type is key fbr deciding optimal management. ag aspirin is reasonable to decrease the risk o1'nrajor blccding. tt Monotherapy rt ith aspirin or dual antiplatelet therapy rt ith o aspirin and clopidogrel is used in patients ltrlkrwing coronary UI = artery bylrass gmft surgery 'lhey are unlikely to callsc thrcrmbo- cytopenia. and disc'ontinuation of all antiplatclet therapy rt,cruld raise the risk of an ischemic cardiac event (Option A). In palicr.rts rt ith Hl I. the American Socicty ol'Hcmatol oS, 2018 guideline reconxrrends against rcutine inserlion of an inlbrior vena cava (lVC) filter (Option B). No comparative studics have er,.aluated l\C filter insertion compared r,r.ith n<t inserti<.rn in patients rtith acute HII but signilicant harm is likely associated,,r,ith IVC fl lters. \Varfarin rt'ill lolrer protein C and protein S lel,els. result ing in short tenn hypercoagulabiiity (Option D). Warfarin can be used as an alternati\e to heparin. but it is not immediately' ef Iective ancl should not be started until sufllcient anticoagula All patients with amyloidosis are evaluated for extent of tion is acl.rieved with an aiternative non heparin ar.rticoagulant. organ involvement. Cardiac involvement is common with AL KEY POII{TS amyloidosis, and evaluation with echocardiography, electro- . In patients with suspected heparin induced thrombo cardiography, N terminal pro B type natriuretic peptide, and cytopenia, use of the 4T score is recommended to serum troponin T is commonly perfbrmed. Cardiac MRI is guide clinical decisions and management. more sensitive than echocardiography and has a distinctive pattern. Iffat pad or other organ biopsies are not feasible, an . Heparin should be discontinued in patients with sus endomyocardial biopsy can be perfbrmed to establish the diag pected heparin-induced thrombocytopenia (HIT) and an nosis but should not be the initial diagnostic test (Option B). intermediate or high 4T score, and HIT laboratory test This patient's orthostatic hypotension is a manifestation ing should be obtained; in most cases, a non heparin of amyloid-related autonomic dysf unction. Tilt-table testing anticoagulant should be initiated. may be helpful in persons with reflex syncope triggered by standing or with a single unexplained episode of syncope Bibliography but will not assist in the diagnosis of amyloidosis (Option D). (lukcr A. Arepally GM, Chong BII, et al. American Society of llenlrtolos/ 20 l tt guidelines fbr management of venous thr0mboemb0lism: I Ieparin t(tY Polla15 induced thrombocytopenia. Blood Adv 2018;2::l:160 3392. IPMID: 304U27(rtt I doi : 10. I 182/bloodadvances.20l 8024489 . Patients with light chain amyloidosis may present with kidney, heart, skin, and liver dysfunction, easy bruising, waxy papules and plaques, and macroglossia. Item 32 Answer: A . Diagnosing amyloidosis requires biopsy of the affected Ed ucational Objective: Diagnose amyloidosis. tissue that shows the characteristic pathologic findings; to avoid a more invasive biopsy, abdominal fat pad or The most appropriate test to perform next is abdominal fat bone marrow biopsy may be preferred initially. pad biopsy (Option A). This patient likely has light chain

Item 31 Answer: C (AL) amyloidosis. These light chains can deposit in the kid Ed ucationa I Objective: Manage heparin-induced ney, heart, skin, liver, and other organs. Soft tissue mani thrombocy.topenia. f'estations are present in 30'7, to 40'l, of patients and include generalized waxy appearance; easy bruising with minor I)iscontinuing heparin. testing fbr heparin induced thntmbo pressure (pinch purpura) ; periorbital ecchymoses ("raccoon cyt<4>enia (tllT). and starting rivaroxaban is the most appnrpri eyes," shown);yellow waxy papules and plaques, especially atc management fbr this patient (Option C). tlis platelet count in a periorbital location; dystrophic nails; and macroglossia. clecreased by more than 501, from admission, and hc rtas He also has an IgG l" monoclonal gammopathy detectable in exposed to heparin lbllowing bypass grafl surgery 3 wccks ago. the serum, which further confirms a plasma cell dyscrasia. 'll.tis gives him a .1T score of 5 (platelet c'ount dccrcasc >50'X, = Diagnosis requires tissue biopsy that demonstrates charac 2 points: onset >1 day with previous exposurc rtithin 130 days = teristic apple green birelringence with Congo red staining. I point: no other likell' cause of thron.rboc-vtopenia = 2 points). Fat pad biopsy is pref'erred even in multiorgan involvement A .l'l' score of 5 suggests an intermediate. or l0',1,. risk <tf ttlT. because it is less invasive than biopsying other organs (sen vl (u Bccausc he does not have kidnel,disease. rivaroxaban or apix sitivity, 60"/,,-80"/.,).lf unrevealing, kidney, bone marrow or aban is acceplable treatment for this patient rrith HIT rcquiring ET other organ biopsy can be performed (Option C). Protein thcn4xutic anticoagulation for pulmonary embolisrnr arga typing using mass spectrometry is important to identiff the (J tnrban and fbndaparinu-r are acceptable parentcral options. In speciflc protein causing amyloidosis. Proper identification of E' this patient. discontinuing heparin in fhr.,or of'rivaroxaban plus the amyloid type is key fbr deciding optimal management. ag aspirin is reasonable to decrease the risk o1'nrajor blccding. tt Monotherapy rt ith aspirin or dual antiplatelet therapy rt ith o aspirin and clopidogrel is used in patients ltrlkrwing coronary UI = artery bylrass gmft surgery 'lhey are unlikely to callsc thrcrmbo- cytopenia. and disc'ontinuation of all antiplatclet therapy rt,cruld raise the risk of an ischemic cardiac event (Option A). In palicr.rts rt ith Hl I. the American Socicty ol'Hcmatol oS, 2018 guideline reconxrrends against rcutine inserlion of an inlbrior vena cava (lVC) filter (Option B). No comparative studics have er,.aluated l\C filter insertion compared r,r.ith n<t inserti<.rn in patients rtith acute HII but signilicant harm is likely associated,,r,ith IVC fl lters. \Varfarin rt'ill lolrer protein C and protein S lel,els. result ing in short tenn hypercoagulabiiity (Option D). Warfarin can be used as an alternati\e to heparin. but it is not immediately' ef Iective ancl should not be started until sufllcient anticoagula All patients with amyloidosis are evaluated for extent of tion is acl.rieved with an aiternative non heparin ar.rticoagulant. organ involvement. Cardiac involvement is common with AL KEY POII{TS amyloidosis, and evaluation with echocardiography, electro- . In patients with suspected heparin induced thrombo cardiography, N terminal pro B type natriuretic peptide, and cytopenia, use of the 4T score is recommended to serum troponin T is commonly perfbrmed. Cardiac MRI is guide clinical decisions and management. more sensitive than echocardiography and has a distinctive pattern. Iffat pad or other organ biopsies are not feasible, an . Heparin should be discontinued in patients with sus endomyocardial biopsy can be perfbrmed to establish the diag pected heparin-induced thrombocytopenia (HIT) and an nosis but should not be the initial diagnostic test (Option B). intermediate or high 4T score, and HIT laboratory test This patient's orthostatic hypotension is a manifestation ing should be obtained; in most cases, a non heparin of amyloid-related autonomic dysf unction. Tilt-table testing anticoagulant should be initiated. may be helpful in persons with reflex syncope triggered by standing or with a single unexplained episode of syncope Bibliography but will not assist in the diagnosis of amyloidosis (Option D). (lukcr A. Arepally GM, Chong BII, et al. American Society of llenlrtolos/ 20 l tt guidelines fbr management of venous thr0mboemb0lism: I Ieparin t(tY Polla15 induced thrombocytopenia. Blood Adv 2018;2::l:160 3392. IPMID: 304U27(rtt I doi : 10. I 182/bloodadvances.20l 8024489 . Patients with light chain amyloidosis may present with kidney, heart, skin, and liver dysfunction, easy bruising, waxy papules and plaques, and macroglossia. Item 32 Answer: A . Diagnosing amyloidosis requires biopsy of the affected Ed ucational Objective: Diagnose amyloidosis. tissue that shows the characteristic pathologic findings; to avoid a more invasive biopsy, abdominal fat pad or The most appropriate test to perform next is abdominal fat bone marrow biopsy may be preferred initially. pad biopsy (Option A). This patient likely has light chain 105

lry1:t'-:l9 cti!'-u:'- Bibliography Bibliography Gertz MA, Dispenzieri A. Systemic amyloidosis recognition. prognosis, and Young NS. Aplastic anemia. N Engl j Med. 2018r379:16'13-1656. IPMID: therapy: A systematic review. IAMA. 2020;321:79 89. IPMll): 32633805] 303519581 doi:10. 1056 NEJMral413485 doi:10.1001 /jama.2o2o.5493 Item 34 Answer: E Item 33 Answer: A Educational Obiective: Manage an elevated INR in an Educational Objective: Treat aplastic anemia. asymptomatic patient taking warfarin.

Bibliography Bibliography Gertz MA, Dispenzieri A. Systemic amyloidosis recognition. prognosis, and Young NS. Aplastic anemia. N Engl j Med. 2018r379:16'13-1656. IPMID: therapy: A systematic review. IAMA. 2020;321:79 89. IPMll): 32633805] 303519581 doi:10. 1056 NEJMral413485 doi:10.1001 /jama.2o2o.5493 Item 34 Answer: E Item 33 Answer: A Educational Obiective: Manage an elevated INR in an Educational Objective: Treat aplastic anemia. asymptomatic patient taking warfarin. The most effective treatment is allogeneic hematopoietic The most appropriate management of this patient in addi stem cell transplantation (HSCT) with an HLA matched sib tion to withholding warfarin is observation (Option E). He Iing (Option A). The blood and bone marrow findings are has an elevated INR on routine laboratory testing but no consistent with aplastic anemia, an acquired hematopoi- signs or symptoms of bleeding. Bleeding risk increases as etic stem cell disorder characterized by severely decreased the INR increases. Additionally, patients older than 75 years, bone marrow cellularity and pancytopenia. Although it is those with previous cerebrovascular accidents, and those r,t classifled as an anemia, patients usually have a combina with previous gastrointestinal bleeding are at increased risk = .D tion of anemia, neutropenia, and thrombocytopenia. The of bleeding independent of the INR. Bleeding risk is elevated ut o, bone marrow typically shows marked hypocellularity with a to a higher degree in patients taking concomitant aspirin. EL commensurate increase in fat tissue. Typically, no dysplastic clopidogrel, or other antiplatelet agents. If a patient's INR is n features of cell maturation are seen, as would be seen in the between 4.5 and 10, warfarin must be withheld until the INR hypocellular variant of myelodysplastic syndrome, or an retums to the therapeutic range; without bleeding, no other tt treatment is required, and observation is recommended. lf the increase in cellularity and immature leukocytes, as would (D UI be seen in "aleukemic" acute leukemia. Younger patients INR is greater than 10 without any bleeding, then vitamin K is recommended in addition to withholding warfarin (Option with a suitable HLA matched donor are usually treated with allogeneic HSCT. With advances in immunosuppression and D). ln any patient taking warfarin with an elevated INR who supportive care, the overall survival of young patients fol- presents with life threatening bleeding, then warfarin is lowing HSCT with a good risk proflle is greater than 80%. withheld, and vitamin K and a prothrombin complex con- Most aplastic anemia is felt to be related to stem cell centrate (PCC) should be administered (Option A). The PCC autoimmunity. In patients older than 50 years and in younger may be 3 factor (containing factors ll, IX, and X) or 4 factor (containing factors Il, VII, IX, and X), although 4 factor PCC is patients without a suitable stem cell donor, autoimmune preferred because of more predictable warfarin reversal. aplastic anemia is treated by immunosuppression with anti thymoqte globulin, cyclosporine, and prednisone (Option B). Factor VIIa is used to treat bleeding in patients with Allogenic HSCT is preferred in this younger patient. hemophilia (Option B). It plays no role in warfarin reversal. Azacytidine or other hypomethylating agents may be Fresh frozen plasma (FFP) is not the preferred agent useful in managing symptomatic patients with myelodys when treatment of life threatening bleeding is necessary for plastic syndrome, decreasing transfusion requirements and a patient with a supratherapeutic INR (Option C). 4-Factor delaying conversion to acute leukemia. Azacytidine is not PCC has been found to be noninferior to FFP in the treat used in managing aplastic anemia (Option C). ment of life threatening bleeding. Additionally, 4 factor PCC Intravenous immune globulin (IVIG) is useful in treat- has a faster infusion time, more rapid reversal of INR, and ing pure red cell aplasia, which is characterized by normo lower risk of volume overload. For these reasons, 4 factor c).tic or macrocl.tic anemia with decreased reticulocltes and PCC is the preferred agent for warfarin reversal when a absent or decreased erythrocyte precursors in the bone mar- reversal agent is necessary. row. Parvovirus B19 is cytotoxic to the erythrocyte precur XEY POIilTS sors in the bone marrow. Immunocompromised patients can o In patients taking warfarin with a supratherapeutic INR have sustained viremia leading to prolonged anemia requir less than 10 and no signs ofbleeding, warfarin should be ing IVIG treatment to hasten viral clearance and recover erythrocyte production. IVIG has no role in managing aplas withheld until the INR returns to the therapeutic range. tic anemia (Option D). o For INR elevation greater than 10 without bleeding, vitamin K is recommended in addition to withholding XEY POIl{TS warfarin; if the INR is elevated and life-threatening r Allogeneic hematopoietic stem cell transplantation is bleeding is present, then warfarin is withheld, and the preferred treatment for aplastic anemia in younger vitamin K and a prothrombin complex concentrate patients who have an HlA-matched stem cell donor. should be administered. o In patients older than 50 years and in younger patients without a suitable stem cell donor, aplastic anemia is Bibliography Witt DM, Nieuwlaat R, Clark NP et al. American Society of Hematolos/ 2018 treated by immunosuppression with antithymoclte guidelines for management of venous thromboembolism: Optimal man globulin, cyclosporine, and prednisone. xgement of anticoagulation therapy. Blood Adv 2Ol 8;2:3257-3291. I PM I D: 304827651 doi: 10. I 182/bloodadvances.2018024893

The most effective treatment is allogeneic hematopoietic The most appropriate management of this patient in addi stem cell transplantation (HSCT) with an HLA matched sib tion to withholding warfarin is observation (Option E). He Iing (Option A). The blood and bone marrow findings are has an elevated INR on routine laboratory testing but no consistent with aplastic anemia, an acquired hematopoi- signs or symptoms of bleeding. Bleeding risk increases as etic stem cell disorder characterized by severely decreased the INR increases. Additionally, patients older than 75 years, bone marrow cellularity and pancytopenia. Although it is those with previous cerebrovascular accidents, and those r,t classifled as an anemia, patients usually have a combina with previous gastrointestinal bleeding are at increased risk = .D tion of anemia, neutropenia, and thrombocytopenia. The of bleeding independent of the INR. Bleeding risk is elevated ut o, bone marrow typically shows marked hypocellularity with a to a higher degree in patients taking concomitant aspirin. EL commensurate increase in fat tissue. Typically, no dysplastic clopidogrel, or other antiplatelet agents. If a patient's INR is n features of cell maturation are seen, as would be seen in the between 4.5 and 10, warfarin must be withheld until the INR hypocellular variant of myelodysplastic syndrome, or an retums to the therapeutic range; without bleeding, no other tt treatment is required, and observation is recommended. lf the increase in cellularity and immature leukocytes, as would (D UI be seen in "aleukemic" acute leukemia. Younger patients INR is greater than 10 without any bleeding, then vitamin K is recommended in addition to withholding warfarin (Option with a suitable HLA matched donor are usually treated with allogeneic HSCT. With advances in immunosuppression and D). ln any patient taking warfarin with an elevated INR who supportive care, the overall survival of young patients fol- presents with life threatening bleeding, then warfarin is lowing HSCT with a good risk proflle is greater than 80%. withheld, and vitamin K and a prothrombin complex con- Most aplastic anemia is felt to be related to stem cell centrate (PCC) should be administered (Option A). The PCC autoimmunity. In patients older than 50 years and in younger may be 3 factor (containing factors ll, IX, and X) or 4 factor (containing factors Il, VII, IX, and X), although 4 factor PCC is patients without a suitable stem cell donor, autoimmune preferred because of more predictable warfarin reversal. aplastic anemia is treated by immunosuppression with anti thymoqte globulin, cyclosporine, and prednisone (Option B). Factor VIIa is used to treat bleeding in patients with Allogenic HSCT is preferred in this younger patient. hemophilia (Option B). It plays no role in warfarin reversal. Azacytidine or other hypomethylating agents may be Fresh frozen plasma (FFP) is not the preferred agent useful in managing symptomatic patients with myelodys when treatment of life threatening bleeding is necessary for plastic syndrome, decreasing transfusion requirements and a patient with a supratherapeutic INR (Option C). 4-Factor delaying conversion to acute leukemia. Azacytidine is not PCC has been found to be noninferior to FFP in the treat used in managing aplastic anemia (Option C). ment of life threatening bleeding. Additionally, 4 factor PCC Intravenous immune globulin (IVIG) is useful in treat- has a faster infusion time, more rapid reversal of INR, and ing pure red cell aplasia, which is characterized by normo lower risk of volume overload. For these reasons, 4 factor c).tic or macrocl.tic anemia with decreased reticulocltes and PCC is the preferred agent for warfarin reversal when a absent or decreased erythrocyte precursors in the bone mar- reversal agent is necessary. row. Parvovirus B19 is cytotoxic to the erythrocyte precur XEY POIilTS sors in the bone marrow. Immunocompromised patients can o In patients taking warfarin with a supratherapeutic INR have sustained viremia leading to prolonged anemia requir less than 10 and no signs ofbleeding, warfarin should be ing IVIG treatment to hasten viral clearance and recover erythrocyte production. IVIG has no role in managing aplas withheld until the INR returns to the therapeutic range. tic anemia (Option D). o For INR elevation greater than 10 without bleeding, vitamin K is recommended in addition to withholding XEY POIl{TS warfarin; if the INR is elevated and life-threatening r Allogeneic hematopoietic stem cell transplantation is bleeding is present, then warfarin is withheld, and the preferred treatment for aplastic anemia in younger vitamin K and a prothrombin complex concentrate patients who have an HlA-matched stem cell donor. should be administered. o In patients older than 50 years and in younger patients without a suitable stem cell donor, aplastic anemia is Bibliography Witt DM, Nieuwlaat R, Clark NP et al. American Society of Hematolos/ 2018 treated by immunosuppression with antithymoclte guidelines for management of venous thromboembolism: Optimal man globulin, cyclosporine, and prednisone. xgement of anticoagulation therapy. Blood Adv 2Ol 8;2:3257-3291. I PM I D: 304827651 doi: 10. I 182/bloodadvances.2018024893 106

Answers and Critiques Item 35 Answer: B Item 36 Answer: B Educational Objective: Diagnose anemia of kidney Ed ucation a I O bjective : Treat essential thrombocythemia disease. with the JAK2 V617F mutation.

Item 35 Answer: B Item 36 Answer: B Educational Objective: Diagnose anemia of kidney Ed ucation a I O bjective : Treat essential thrombocythemia disease. with the JAK2 V617F mutation. Anemia of kidney disease is the most likely diagrosis (Option B). Hydroxyurea plus aspirin is the most appropriate treat The increased serum creatinine level and the small echo ment for this patient (Option B). Her diagnosis of essential genic kidneys seen on the ultrasound support this diagno- thrombocythemia (ET) is based on the presence of the sis. The anemia, resulting fiom ery.thropoietin deflciency, is IAK2 V6l7F mutation and elevated platelet count with normochromic and hypoprolilbrative (a normal or low retic normal leukocyte count and hemoglobin level. ET is a ulocyte count despite moderate anemia), and erythrocytes chronic myeloproliferative neoplasm, with the lAK2muia typically have normal morpholory on peripheral blood tion being the most common, occurring in approximately smear. Some patients with uremia may demonstrate echi 50% to 60% of patients; the CAL-R mutation is seen in 25u1, nocytes on the peripheral blood spear characterized by to 35'/" of patients, and 5'2, have the MPI mutation. Patients aa o, small, uniform spikes on the erythrocyte surface. A low or with ET and an underlying -IAK2 mutation are at higher ET low-normal serum erythropoietin level is typical, and initi- risk for developing thrombotic complications than those ating erythropoietin-stimulating agents results in a robust with the CAL R or MPL mutations, and aspirin is recom- t, improvement of anemia in the absence of concomitant iron mended in this population. Aspirin is also recommended !tE deficiency. The anemia of kidney disease is more prevalent for those older than 60 years regardless of mutation sta- .E and more severe among patients with more severe kidney tus. Cytoreductive therapy, which is aimed at decreasing UI

Anemia of kidney disease is the most likely diagrosis (Option B). Hydroxyurea plus aspirin is the most appropriate treat The increased serum creatinine level and the small echo ment for this patient (Option B). Her diagnosis of essential genic kidneys seen on the ultrasound support this diagno- thrombocythemia (ET) is based on the presence of the sis. The anemia, resulting fiom ery.thropoietin deflciency, is IAK2 V6l7F mutation and elevated platelet count with normochromic and hypoprolilbrative (a normal or low retic normal leukocyte count and hemoglobin level. ET is a ulocyte count despite moderate anemia), and erythrocytes chronic myeloproliferative neoplasm, with the lAK2muia typically have normal morpholory on peripheral blood tion being the most common, occurring in approximately smear. Some patients with uremia may demonstrate echi 50% to 60% of patients; the CAL-R mutation is seen in 25u1, nocytes on the peripheral blood spear characterized by to 35'/" of patients, and 5'2, have the MPI mutation. Patients aa o, small, uniform spikes on the erythrocyte surface. A low or with ET and an underlying -IAK2 mutation are at higher ET low-normal serum erythropoietin level is typical, and initi- risk for developing thrombotic complications than those ating erythropoietin-stimulating agents results in a robust with the CAL R or MPL mutations, and aspirin is recom- t, improvement of anemia in the absence of concomitant iron mended in this population. Aspirin is also recommended !tE deficiency. The anemia of kidney disease is more prevalent for those older than 60 years regardless of mutation sta- .E and more severe among patients with more severe kidney tus. Cytoreductive therapy, which is aimed at decreasing UI disease, especially ifit is advanced enough to warrant dialysis. the platelet count, is accepted care in those older than o The anemia of inflammation can occur with chronic 60 years, as well as those with a history of thrombo- vt = inf'ections, cancer, or autclimmune inflammatory conditions sis regardless of age. Cytoreductive medications include and results from elevated interleukin 6 and other inflam hydroxyurea, interferon, and anagrelide. Hydroxyurea is matory cytokines that up regulate hepcidin (Option A). often used initially because of its tolerability and efflcacy. tlepcidin elevation limits iron absorption from enterocytes Because the myelosuppressive effects are not speciflc to and reduces iron binding capacity and is characterized by platelets, it is necessary to monitor fbr leukopenia and low serum iron and total iron-binding capacity levels with a anemia. normal or elevated serum ferritin level. This patient's history Because this patient is older than 60 years, hydroxyurea and iron studies do not support anemia of inflammation. should be included in the treatment plan. Aspirin alone Microangiopathic hemolytic anemia (MAHA) is asso- would be insufficient (Option A). ciated with elevated reticulocyte count, elevated lactate Ruxolitinib is an oral lAKl/lAK2 inhibitor approved dehydrogenase and aspartate aminotransferase levels, and for use in polycythemia vera and myeloflbrosis (Option C). schistocy.tes on the peripheral blood smear (Option C). MAHA It has been shown to be e{Iective at reducing spleen vol may be associated with lilb threatening conditions such as ume and symptom burden in these diseases, but it is not thrombotic thrombocy.topenic purpura, disseminated intravas- approved for use in ET. cular coagulation, malignant hypertension, or malfunctioning Stem cell transplantation is the only curative option cardiac valves or left ventricular assist devices. This patient in BCR-ABt-negative myeloproliferative neoplasms has no underlying condition associated with MAHA, and the (Option D). However, stem cell transplantation has an peripheral blood smear does not support this diagnosis. associated mortality risk and signiflcant potential mor Myelodysplastic syndrome (MDS) is a common cause of bidity. Therefore, it is not considered in patients with ET or anemia in older adultsr however, it is often associated with polycythemia vera because prognosis in these diseases is additional cytopenias or an abnormal leukocyte differential generally excellent with other therapies. Stem cell trans- in addition to anemia (Option D). Anemia can be an isolated plantation is typically reserved for those with higher risk finding in low risk MDS but is typically associated with myeloflbrosis whose prognosis is otherwise estimated to macrocytosis. The absence of these findings makes MDS an be poor. unlikely cause of this patient's anemia. t(EY P0lilrs KEY POIilT5 . In patients with essential thrombocythemia who have . The anemia of kidney disease is normochromic and the lAK2Y6l7F mutation, hydroxyurea plus aspirin hypoproliferative and typically has normal erythrocyte should be the initial treatment choice. morphologi on peripheral blood smear. . Patients with essential thromborythemia who are . The anemia of kidney disease is associated with a low older than 60 years should be treated with aspirin and or inappropriately low-normal erythropoietin level. hydroxyurea regardless of mutation status.

disease, especially ifit is advanced enough to warrant dialysis. the platelet count, is accepted care in those older than o The anemia of inflammation can occur with chronic 60 years, as well as those with a history of thrombo- vt = inf'ections, cancer, or autclimmune inflammatory conditions sis regardless of age. Cytoreductive medications include and results from elevated interleukin 6 and other inflam hydroxyurea, interferon, and anagrelide. Hydroxyurea is matory cytokines that up regulate hepcidin (Option A). often used initially because of its tolerability and efflcacy. tlepcidin elevation limits iron absorption from enterocytes Because the myelosuppressive effects are not speciflc to and reduces iron binding capacity and is characterized by platelets, it is necessary to monitor fbr leukopenia and low serum iron and total iron-binding capacity levels with a anemia. normal or elevated serum ferritin level. This patient's history Because this patient is older than 60 years, hydroxyurea and iron studies do not support anemia of inflammation. should be included in the treatment plan. Aspirin alone Microangiopathic hemolytic anemia (MAHA) is asso- would be insufficient (Option A). ciated with elevated reticulocyte count, elevated lactate Ruxolitinib is an oral lAKl/lAK2 inhibitor approved dehydrogenase and aspartate aminotransferase levels, and for use in polycythemia vera and myeloflbrosis (Option C). schistocy.tes on the peripheral blood smear (Option C). MAHA It has been shown to be e{Iective at reducing spleen vol may be associated with lilb threatening conditions such as ume and symptom burden in these diseases, but it is not thrombotic thrombocy.topenic purpura, disseminated intravas- approved for use in ET. cular coagulation, malignant hypertension, or malfunctioning Stem cell transplantation is the only curative option cardiac valves or left ventricular assist devices. This patient in BCR-ABt-negative myeloproliferative neoplasms has no underlying condition associated with MAHA, and the (Option D). However, stem cell transplantation has an peripheral blood smear does not support this diagnosis. associated mortality risk and signiflcant potential mor Myelodysplastic syndrome (MDS) is a common cause of bidity. Therefore, it is not considered in patients with ET or anemia in older adultsr however, it is often associated with polycythemia vera because prognosis in these diseases is additional cytopenias or an abnormal leukocyte differential generally excellent with other therapies. Stem cell trans- in addition to anemia (Option D). Anemia can be an isolated plantation is typically reserved for those with higher risk finding in low risk MDS but is typically associated with myeloflbrosis whose prognosis is otherwise estimated to macrocytosis. The absence of these findings makes MDS an be poor. unlikely cause of this patient's anemia. t(EY P0lilrs KEY POIilT5 . In patients with essential thrombocythemia who have . The anemia of kidney disease is normochromic and the lAK2Y6l7F mutation, hydroxyurea plus aspirin hypoproliferative and typically has normal erythrocyte should be the initial treatment choice. morphologi on peripheral blood smear. . Patients with essential thromborythemia who are . The anemia of kidney disease is associated with a low older than 60 years should be treated with aspirin and or inappropriately low-normal erythropoietin level. hydroxyurea regardless of mutation status. Bibliography Bonomini M. Del Vecchio I.. Sinrlli V et al. New treatment approaches for the Bibliography irnemia of CKD. Am J Kidney Dis. 2016;67:133 ,12. [PMID: 26372086] Tefferi A, Pardanani A. Essential thrombocythemia. N tingl J Med. doi.10.10s3li.aikd.201s.06.030 2o19;381:2135 2144. IPMID: 317749581 doi:10. 1056/NEJMcpl8l6082

Bibliography Bonomini M. Del Vecchio I.. Sinrlli V et al. New treatment approaches for the Bibliography irnemia of CKD. Am J Kidney Dis. 2016;67:133 ,12. [PMID: 26372086] Tefferi A, Pardanani A. Essential thrombocythemia. N tingl J Med. doi.10.10s3li.aikd.201s.06.030 2o19;381:2135 2144. IPMID: 317749581 doi:10. 1056/NEJMcpl8l6082 107

Answers and Critiques Item 37 Answer: A Bibliography Educational Objective: Assess risk for venous thrombo- Ke1'NS. Khorana.\A. Kuderer NM. et al. !'enous thromboentbolism prophv laxis and treatnrent in patients with cancer' AS(-O clinicirl practice embolism before starting chemotherapy. guideline updrlte. J Clin Oncol. 2020:38:.196 .520. [[,\1ll), 3138U6-1] doi:10.1200 JC(). 19.01461 Calculation of the Khorana score should be done as the initial step in managing venous thromboembolism (VTE) risk in this patient (Option A). According to the 2020 American Society of Item 38 Answer: B Clinical Oncologr guideline on WE prevention and treatment Educational Objective: Diagnose iron overload in a in patients with cancer, routine pharmacologic thrombopro patient with thalassemia. phylaxis should not be oflbred to all outpatients w.ith cancer. Iron studies are the most appropriate additional manage Increased thrombotic risk in patients with cancer is measured ment (Option B). In patients with thalassemia. iron or'er using the Khorana score. The guideline recommends that high load related heart lailure and/or arrhythmias are the major risk outpatients with cancer (l(horana score of 2 or higher cause of death. Baseline iron studies should be obtained. t before starting a new systemic chemotherapy regimen) may be and serial measurements of serum ferritin can monitor iron € (D of Ibred thromboprophyLuis with aplraban, rivaroxaban, or low stores, particularly if transfusion requirements increase. In U, molecular weight heparin (LMWH) provided no significant risk addition to standard cardiac assessment u'ith electrocar o, factors for bleeding and no drug interactions are identified. Con diography and echocardiography. MRI is used to monitor EL sideration of such therapy should be accompanied by a discus cardiac and hepatic iron stores. This patient has mant'of n sion with the patient about the relative beneflts and harms. drug the manifestations of p thalassemia. including lnernia. cost, and duration of prophylrrxis in this setting. The Khorana extramedullary hematopoiesis, hepatosplenomegalr. and lt score places highest risk of VTE on gastric and pancreatic cancers (D bone marrow space expansion u,ith characteristic skele Vt (2 points), with llnnphoma and lung, gmecologic, bladder, and tal changes. Patients olten remain translusion independent testicular cancers also being high risk (1 point). An additional during childhood and young adulthood but require trans point is given for BMI greater than 35, platelet count greater fusions beginning in the third and fourth decacles of life. than 350,000/[L (350 x 10e/L). hemoglobin level less than Heightened gastrointestinal absorption of iron that accom 10 g/dl (100 g/L), and leukocy'te count greater than 11,000iUL panies ineflective erythropoiesis adds to the transfusion (11 x 10e/L). During this patient's visit, data should be collected related iron overload. Excess iron deposition in the organs to calculate the score. and the results should be used to initiate a can lead to arrhythmia and heart failure. cirrhosis and discussion regarding VTE prophylaxis benelits and harms. portal hypertension. and endocrinopathies (diabetes. hypo Apixaban, rivaroxaban, and LMWH are recommended pituitarism. hypogonadism). Patients should avoid iron fbr VTE prophylaxis in patients with cancer at high risk for supplementation. and transfusions should be performed VTE who are about to start a new chemotherapeutic regi judiciously. Patients with secondary iron overload require men (Options B, C). However, befbre starting either of'these chelation therapy with parenteral desferrioxamine or oral agents, the patient's risk fbr VTE should be estimated by iron chelators (deferasirox or deferiprone) befbre the onset calculating the Khorana score. ofend organ damage. Even in patients'nvith cancer at high risk for VTE. war Like patients with chronic hemolytic anemias. farin would not be the appropriate treatment choice (Option patients with thalirssemia are at increased risk for D). Data do not support the use of warfarin in the primary pigment gallstones. For patients rt,ithout symptoms prophylaxis of VTE in patients with cancer. In those with attributable to gallstones. neither routine screening u,ith cancer and active VTE disease, LMWH compared with war abdominal ultrasonography nor prophylactic cholecystec f'arin was associated with a reduction in the rate of recurrent tomy is recommended (Option A). For patients undergo VTE at 6 months (9"/,, vs 17"1,) and was not associated with an ing splenectomy, cholecystectomy is an option that can be increased rate of major bleeding (0"1, vs q']l\ or olerall mor discussed with the surgical team. tality (39'1, vs 41'1,). In patients with cancer, warfarin is not Patients with thalassemia are at increased risk for generally recommended fbr either primary VTE prophylaxis venous thromboembolism, and the risk increases fbllort'ing or treatment, although its use may be considered in patients splenectomy. Hortever. no evidence-based recommenda with multiple myeloma at high risk who are treated with tions support prophylactic anticoagulation or antiplate thalidomide, lenalidomide. or pomalidomide combined let therapy in asymptomatic patients lvith thalassemia with other agents such as glucocorticoids, doxorubicin, or (Option C). Physicians and patients should be arvare of erythropoietin. In these patients, LMWH may be preferred. the increased risk and have a low threshold to investigate t(tY PoltT suspicious symptoms. . In the absence of contraindications, outpatients with In select :rdult patients with thalassemia. splenec- tomy may be indicated (Option D). Generally agreed upon cancer at high risk of WE (Khorana score of 2 or higher indications include severe anemia resulting Irom thal before starting a new systemic chemotherapy regimen) assemia. sudden and dramatic increase in transfusion may be offered thromboprophylaxis with apixaban, requirements, hypersplenism-related cytopenias, and rivaroxaban, or low molecular-weight heparin. symptomatic splenomegaly (abdominal fullness, pain,

Item 37 Answer: A Bibliography Educational Objective: Assess risk for venous thrombo- Ke1'NS. Khorana.\A. Kuderer NM. et al. !'enous thromboentbolism prophv laxis and treatnrent in patients with cancer' AS(-O clinicirl practice embolism before starting chemotherapy. guideline updrlte. J Clin Oncol. 2020:38:.196 .520. [[,\1ll), 3138U6-1] doi:10.1200 JC(). 19.01461 Calculation of the Khorana score should be done as the initial step in managing venous thromboembolism (VTE) risk in this patient (Option A). According to the 2020 American Society of Item 38 Answer: B Clinical Oncologr guideline on WE prevention and treatment Educational Objective: Diagnose iron overload in a in patients with cancer, routine pharmacologic thrombopro patient with thalassemia. phylaxis should not be oflbred to all outpatients w.ith cancer. Iron studies are the most appropriate additional manage Increased thrombotic risk in patients with cancer is measured ment (Option B). In patients with thalassemia. iron or'er using the Khorana score. The guideline recommends that high load related heart lailure and/or arrhythmias are the major risk outpatients with cancer (l(horana score of 2 or higher cause of death. Baseline iron studies should be obtained. t before starting a new systemic chemotherapy regimen) may be and serial measurements of serum ferritin can monitor iron € (D of Ibred thromboprophyLuis with aplraban, rivaroxaban, or low stores, particularly if transfusion requirements increase. In U, molecular weight heparin (LMWH) provided no significant risk addition to standard cardiac assessment u'ith electrocar o, factors for bleeding and no drug interactions are identified. Con diography and echocardiography. MRI is used to monitor EL sideration of such therapy should be accompanied by a discus cardiac and hepatic iron stores. This patient has mant'of n sion with the patient about the relative beneflts and harms. drug the manifestations of p thalassemia. including lnernia. cost, and duration of prophylrrxis in this setting. The Khorana extramedullary hematopoiesis, hepatosplenomegalr. and lt score places highest risk of VTE on gastric and pancreatic cancers (D bone marrow space expansion u,ith characteristic skele Vt (2 points), with llnnphoma and lung, gmecologic, bladder, and tal changes. Patients olten remain translusion independent testicular cancers also being high risk (1 point). An additional during childhood and young adulthood but require trans point is given for BMI greater than 35, platelet count greater fusions beginning in the third and fourth decacles of life. than 350,000/[L (350 x 10e/L). hemoglobin level less than Heightened gastrointestinal absorption of iron that accom 10 g/dl (100 g/L), and leukocy'te count greater than 11,000iUL panies ineflective erythropoiesis adds to the transfusion (11 x 10e/L). During this patient's visit, data should be collected related iron overload. Excess iron deposition in the organs to calculate the score. and the results should be used to initiate a can lead to arrhythmia and heart failure. cirrhosis and discussion regarding VTE prophylaxis benelits and harms. portal hypertension. and endocrinopathies (diabetes. hypo Apixaban, rivaroxaban, and LMWH are recommended pituitarism. hypogonadism). Patients should avoid iron fbr VTE prophylaxis in patients with cancer at high risk for supplementation. and transfusions should be performed VTE who are about to start a new chemotherapeutic regi judiciously. Patients with secondary iron overload require men (Options B, C). However, befbre starting either of'these chelation therapy with parenteral desferrioxamine or oral agents, the patient's risk fbr VTE should be estimated by iron chelators (deferasirox or deferiprone) befbre the onset calculating the Khorana score. ofend organ damage. Even in patients'nvith cancer at high risk for VTE. war Like patients with chronic hemolytic anemias. farin would not be the appropriate treatment choice (Option patients with thalirssemia are at increased risk for D). Data do not support the use of warfarin in the primary pigment gallstones. For patients rt,ithout symptoms prophylaxis of VTE in patients with cancer. In those with attributable to gallstones. neither routine screening u,ith cancer and active VTE disease, LMWH compared with war abdominal ultrasonography nor prophylactic cholecystec f'arin was associated with a reduction in the rate of recurrent tomy is recommended (Option A). For patients undergo VTE at 6 months (9"/,, vs 17"1,) and was not associated with an ing splenectomy, cholecystectomy is an option that can be increased rate of major bleeding (0"1, vs q']l\ or olerall mor discussed with the surgical team. tality (39'1, vs 41'1,). In patients with cancer, warfarin is not Patients with thalassemia are at increased risk for generally recommended fbr either primary VTE prophylaxis venous thromboembolism, and the risk increases fbllort'ing or treatment, although its use may be considered in patients splenectomy. Hortever. no evidence-based recommenda with multiple myeloma at high risk who are treated with tions support prophylactic anticoagulation or antiplate thalidomide, lenalidomide. or pomalidomide combined let therapy in asymptomatic patients lvith thalassemia with other agents such as glucocorticoids, doxorubicin, or (Option C). Physicians and patients should be arvare of erythropoietin. In these patients, LMWH may be preferred. the increased risk and have a low threshold to investigate t(tY PoltT suspicious symptoms. . In the absence of contraindications, outpatients with In select :rdult patients with thalassemia. splenec- tomy may be indicated (Option D). Generally agreed upon cancer at high risk of WE (Khorana score of 2 or higher indications include severe anemia resulting Irom thal before starting a new systemic chemotherapy regimen) assemia. sudden and dramatic increase in transfusion may be offered thromboprophylaxis with apixaban, requirements, hypersplenism-related cytopenias, and rivaroxaban, or low molecular-weight heparin. symptomatic splenomegaly (abdominal fullness, pain, 108

Answers and Critiques early satiety). This patient has no indication for splenec- t(EY POIilTS tomv at this time. r The initial evaluation for patients with immune t(EY POtt{rs thrombocltopenic purpura should include testing for o Iron overload related heart failure and arrhythmias FIIV and hepatitis C virus because thrombocytopenia are the major causes ot'death in patients with thalas may be the initial presenting sign in these infections. semia. . In addition to testing for HIV and hepatitis C virus, . In patients with thalassemia, iron stores can be moni other tests in patients with immune thrombocyto- tored with serial serum ferritin measurements, and penic purpura may be reasonable depending on the MRI can monitor cardiac and hepatic iron stores. clinical setting and associated symptoms. Bibliography Bibliography C(x)per N. Ghanima W Immune thnrnrbocytopenia. N Engl J Med. 2019; vt Vichinsky E. Non transfusion depenclcnt thalassemia and thalassenria (l, :l8l :945 955. IPMID: 31483965] doi: 10. l056rNEJMcp1810479 intermedia: Epidemiology, con]plicat iol.ls. antl management. Curr Med Res Opin. 2016;32:191 204. IPMI l):')64791 )5] doi: 10.1185/03007995.201 EF 5.1 I l0 128

Bibliography Bibliography C(x)per N. Ghanima W Immune thnrnrbocytopenia. N Engl J Med. 2019; vt Vichinsky E. Non transfusion depenclcnt thalassemia and thalassenria (l, :l8l :945 955. IPMID: 31483965] doi: 10. l056rNEJMcp1810479 intermedia: Epidemiology, con]plicat iol.ls. antl management. Curr Med Res Opin. 2016;32:191 204. IPMI l):')64791 )5] doi: 10.1185/03007995.201 EF 5.1 I l0 128 Item 4O Answer: C IJ .E, Educational Objective: Diagnose vitamin 8,2 deficiency. IE Item 39 Answer: C UI The most likely cause of this patient's anemia is an impaired (u Educational Objective: Evaluate a patient with acute ability to absorb vitan-rin B,, resulting in ineffective eryth immune thrombocytopenic purpura. vt = ropoiesis and megaloblastic anemia (Option C). Anemia '[he most appropriate diagnostic tests are HIV and hepatitis associated with elevated lactate dehydrogenase (LDH), indi C virus (Option C). This patient has acute immune throm rect bilirubin, and aspartate aminotransferase (AST) levels bocytopenic purpura (lTP). The initial evaluation for patients without an elevated reticulocyte count suggests ineffective with t'fP should include testing fbr tllV and hepatitis C virus erythropoiesis, which, in the presence of Srpical morpho- because thrombocy.topenia may be the initial presenting sign logic findings (macrocytosis, macro ovalocytes, and hyper in these infections. Patients with HIV infection may have ITP segmented neutrophils as shown in the peripheral blood independent of HIV viral load or CD4 cell count and may be smear), suggests vitamin B,, or fblate deflciency. Vitamin otherwise asymptomatic. Although many patients with hep B,, absorption depends on various factors (gastric acidity, atitis C have symptoms, they are nonspecific and may not be presence ofR binders, intrinsic tactor production by gastric clirectly related to the viral inf'ection but rather to associated parietal cells, presence of pancreatic proteases, and intrin comorbid conditions. Testing for Ilelicobacter pylori may sic factor vitamin 8,, complex absorption in the ileum). also be reasonable if the patient is from an endemic region. This patient has reduced absorptive surface because of the Testing for systemic lupus erythematosus would urinary diversion procedure with resection of a signilicant be appropriate if the patient reported symptoms such as segment ofthe ileum and decreased gastric acidiff because arthralgia, pleuritic chest pain, photosensitiviff, or rash or olproton pump inhibitor use. had other cytopenias or evidence of kidney disease. Because Hypothyroidism may be associated with a mild macro none of these is present, antinuclear antibody and comple cytic anemia, but the mechanism is not known (Option A). r.nent level testing is not necessary (Option A). Hypothyroidism is not associated with hypersegmented Although the pathogenesis of'll'P is presumably related neutrophils in the peripheral blood smear or with features to autoantibody-mediated platelet destruction, the current ol i neffect ive ery.1 hropoiesis. methodologr for antiplatelet antibody testing is not sensitive Immune mediated hemolytic anemia can be associated or speciflc enough to assist in the diagnosis. The patient also with similarly elevated LDH, indirect bilirubin, and AST has no signs of concurrent hemolysis (normal hemoglobin Ievels but would also be associated with an increased retic level, reticulocyte count), so a direct antiglobulin test is not ulocyte count and microspherocytes in the peripheral blood needed (Option B). smear (Option B). Hypersegmented neutrophils are not seen Vitamin B,, and folic acid are needed for normal in immune mediated hemolytic anemia. hematopoiesis (Option D). However, isolated thrombcr The anemia of liver disease of'ten develops from multiple cytopenia would be an unusual manifestation of these causes, including gastrointestinal blood loss, folate deficiency, vitamin deflciencies. Although sonre patients with vita hypersplenism, and the anemia of inflammation (Option D). min B,, deficiency are not anemic, they are apt to have Patients with advanced liver disease may have abnormal- macrocytosis, which is absent in this patient, as shown appearing erythrocytes such as acanthocltes, echinocytes, by the normal mean corpuscular volume. The patient has and target cells on the peripheral blood smear. Echinoc)'tes ir normal leukocyte count, and no hypersegmented poly and acanthocl.tes are two types of spiculated erythrocl'tes. nrorphonuclear cells are noted on his peripheral blood Although liver disease can result in macroc5,'tic erj,throc],tes, it smear, so a vitamin deficiency is unlikely to be the cause would typically only cause a mildly elevated mean corpuscular of his thrombocytopenia. volume and does not cause hypersegmented neutrophils.

Item 4O Answer: C IJ .E, Educational Objective: Diagnose vitamin 8,2 deficiency. IE Item 39 Answer: C UI The most likely cause of this patient's anemia is an impaired (u Educational Objective: Evaluate a patient with acute ability to absorb vitan-rin B,, resulting in ineffective eryth immune thrombocytopenic purpura. vt = ropoiesis and megaloblastic anemia (Option C). Anemia '[he most appropriate diagnostic tests are HIV and hepatitis associated with elevated lactate dehydrogenase (LDH), indi C virus (Option C). This patient has acute immune throm rect bilirubin, and aspartate aminotransferase (AST) levels bocytopenic purpura (lTP). The initial evaluation for patients without an elevated reticulocyte count suggests ineffective with t'fP should include testing fbr tllV and hepatitis C virus erythropoiesis, which, in the presence of Srpical morpho- because thrombocy.topenia may be the initial presenting sign logic findings (macrocytosis, macro ovalocytes, and hyper in these infections. Patients with HIV infection may have ITP segmented neutrophils as shown in the peripheral blood independent of HIV viral load or CD4 cell count and may be smear), suggests vitamin B,, or fblate deflciency. Vitamin otherwise asymptomatic. Although many patients with hep B,, absorption depends on various factors (gastric acidity, atitis C have symptoms, they are nonspecific and may not be presence ofR binders, intrinsic tactor production by gastric clirectly related to the viral inf'ection but rather to associated parietal cells, presence of pancreatic proteases, and intrin comorbid conditions. Testing for Ilelicobacter pylori may sic factor vitamin 8,, complex absorption in the ileum). also be reasonable if the patient is from an endemic region. This patient has reduced absorptive surface because of the Testing for systemic lupus erythematosus would urinary diversion procedure with resection of a signilicant be appropriate if the patient reported symptoms such as segment ofthe ileum and decreased gastric acidiff because arthralgia, pleuritic chest pain, photosensitiviff, or rash or olproton pump inhibitor use. had other cytopenias or evidence of kidney disease. Because Hypothyroidism may be associated with a mild macro none of these is present, antinuclear antibody and comple cytic anemia, but the mechanism is not known (Option A). r.nent level testing is not necessary (Option A). Hypothyroidism is not associated with hypersegmented Although the pathogenesis of'll'P is presumably related neutrophils in the peripheral blood smear or with features to autoantibody-mediated platelet destruction, the current ol i neffect ive ery.1 hropoiesis. methodologr for antiplatelet antibody testing is not sensitive Immune mediated hemolytic anemia can be associated or speciflc enough to assist in the diagnosis. The patient also with similarly elevated LDH, indirect bilirubin, and AST has no signs of concurrent hemolysis (normal hemoglobin Ievels but would also be associated with an increased retic level, reticulocyte count), so a direct antiglobulin test is not ulocyte count and microspherocytes in the peripheral blood needed (Option B). smear (Option B). Hypersegmented neutrophils are not seen Vitamin B,, and folic acid are needed for normal in immune mediated hemolytic anemia. hematopoiesis (Option D). However, isolated thrombcr The anemia of liver disease of'ten develops from multiple cytopenia would be an unusual manifestation of these causes, including gastrointestinal blood loss, folate deficiency, vitamin deflciencies. Although sonre patients with vita hypersplenism, and the anemia of inflammation (Option D). min B,, deficiency are not anemic, they are apt to have Patients with advanced liver disease may have abnormal- macrocytosis, which is absent in this patient, as shown appearing erythrocytes such as acanthocltes, echinocytes, by the normal mean corpuscular volume. The patient has and target cells on the peripheral blood smear. Echinoc)'tes ir normal leukocyte count, and no hypersegmented poly and acanthocl.tes are two types of spiculated erythrocl'tes. nrorphonuclear cells are noted on his peripheral blood Although liver disease can result in macroc5,'tic erj,throc],tes, it smear, so a vitamin deficiency is unlikely to be the cause would typically only cause a mildly elevated mean corpuscular of his thrombocytopenia. volume and does not cause hypersegmented neutrophils. 109

Answers and Critiques X EY PO I IITS Plasma cloes not conrpletely're\€rse the effects oldabig . Anemia associated with elevated lactate dehydrogenase, iltran. a clirect thrombin inhibitor (Option D). Additionallll idarucizunrirb is a specific and much more effective inter indirect bilirubin, and aspartate aminotransferase levels ventiolt fbr patients with lif'e threatening bleeding secor]d without an elevated reticuloryte count suggests ineffec- ary to dabigatran. tive erythropoiesis. . The morphologic findings of macrocytosis, macro XEY POIXIS ovalocytes, and hypersegmented neutrophils suggest o Idarucizumab is safe and effective in reversing the vitamin B,, or folate deficiency. anticoagulant effects of dabigatran in patients with life-threatening bleeding or who require an urgent Bibliography invasive procedure. Shipton MJ, Thachil J. Vitamin B12 deficiency a 21st century perspective. o Four-factor prothrombin complex concentrate or Clin Med (Lond). 2015;15:145 50. IPMID: 25824066] doi:10.7861/clin medicine.lS-2-145 andexanet alfa can be used to reverse bleeding result- gr ing from oral direct Xa inhibitors (apixaban, rivaroxa- € .D ban, edoxaban). t^ o, CL tr Item 41 Answer: C Educational Objective: Treat a patient taking dabigatran Bibliography r't who has life-threatening bleeding. Cuker A, Burnett A, Triller D, et al. Reversal ofdirect oral anticoagulants: Guidance fiom the Anticoagulation Forum. Am J Hematol. 2ol9:91:697 'lhe rnost appropriate treatment is to adn.rinister idaruci 709. IPMID: 30916798] doi:10.1002'ajh.25.175 Itg (D zumab (Option C). this patient has a retroperit<-rneal hem UI orrhage, which is a lif'e threatening condition. The standard Item 42 Answer: D approach to patients experiencing bleeding lionr anticcl Educational Objective: Prevent infection in a patient agulants involves hemodynamic monitoring and resusci with newly diagnosed multiple myeloma. tation with fluid and blood pr<tducts. Activated charcoal can be considered if the direct oral anticoagulant (DOAC) Pneumococcal vaccination is indicated today (Option D). was ingested recently (<6 hours). She is taking dabigatran Patients with multiple myeloma (MM) are at increased risk fbr atrial flbrillation. and the anticoagulant eftects must for bacterial infection owing to impaired lymphocy'te and be immediately reversed. Idarucizurnab is a humanized plasma cell function and hypogammaglobulinemia. The monoclonal antibody fiagment that binds to dabigatran and most commonly encountered organisms are Streptococcus rapidly reverses its anticoagulant eflects (rn,ithin t hour). pneumoniae, Haemophilus influenzae, and Escherichio coli ldarucizumab is indicated to treat patients taking clabigatran presenting as sinusitis, pneumonia, and urinary tract infec- who experience life threatening bleeding or u,ho require an tions. Because of the altered immune state associated with urgent invasive procedure. If idarucizumab is not available. MM, pneumococcal vaccination with the 13-valent pneumo hemociialysis is another option. Up to 68'l;, of dabigatran coccal conjugate vaccine followed at least B weeks later by can be removed in ,1 hours using hen-rodialysis; however. a the 23-valent pneumococcal polysaccharide vaccine should rebound increase may fbllow because of redistribution of be provided in accordance with Advisory Committee on the drug. Immunization Practices guidelines. Ideally, immunization Andexanet alfa is a recombinant modified factor Xa with inactivated vaccines should be provided at least 2 weeks that conrpetes fbr binding to lactor X lvith tl.re tactor Xa before initiation of chemotherapy. In addition, annual influ inhibitors (apixaban, rivaroxaban. and edoxaban) (Option A). enza vaccination with standard-dose killed vaccine should Fbr patients with life tl.rreatening bleeding who are tak be administered to all patients with MM and to household ing an oral direct Xa inhibitor. the American Society of members. Response to vaccinations may be suboptimal, I{enratology suglEests stopping the oral direct Xa inhibitor but vaccination still provides beneflt and is recommended and considering treatment w'ith either 4-factor prothrom for all patients with MM. bin complex concentrate (4f PCC) or andexanet alfa (ofl: Many medications, such as proteasome inhibitors (e.g., label use fbr edoxaban). Because of.the lack ol comparative bortezomib) and monoclonal antibodies, are associated with data on 4f-PCC ancl andexanet alfa, a prelerred strategl' an increased risk ofherpes zoster virus reactivation. Patients cannot be identified. Anderanet alfa $,ould not be useful treated with bortezomib should receive antiviral prophylaxis for reversing the clirect thrombin inhibition caused by with acyclovir or valacyclovir (Option A). This patient is not dabigatran. yet being treated with bortezomib, so prophylactic antiviral 4F PCC is used to treat warfarin associatccl lil'e threat therapy is not indicated today. ening bleeding (Option B). 4F PCC may also be used tcr Select patientswith recurrent infections and hypogam manage life-threatening hemorrhage in patients taking an maglobulinemia benefit from intravenous immune globu oral direct Xa inhibitor. ,lF PCC may be less bencficial in lin (IVIG) infusions (Option B). IVIG provides protection reversing dabigatran anticoagulation than idarucizumab but from infection by providing passive immunity. However, nright be helpful if idarucizun.rab is not available. patients with acquired hypogammaglobulinemia without

X EY PO I IITS Plasma cloes not conrpletely're\€rse the effects oldabig . Anemia associated with elevated lactate dehydrogenase, iltran. a clirect thrombin inhibitor (Option D). Additionallll idarucizunrirb is a specific and much more effective inter indirect bilirubin, and aspartate aminotransferase levels ventiolt fbr patients with lif'e threatening bleeding secor]d without an elevated reticuloryte count suggests ineffec- ary to dabigatran. tive erythropoiesis. . The morphologic findings of macrocytosis, macro XEY POIXIS ovalocytes, and hypersegmented neutrophils suggest o Idarucizumab is safe and effective in reversing the vitamin B,, or folate deficiency. anticoagulant effects of dabigatran in patients with life-threatening bleeding or who require an urgent Bibliography invasive procedure. Shipton MJ, Thachil J. Vitamin B12 deficiency a 21st century perspective. o Four-factor prothrombin complex concentrate or Clin Med (Lond). 2015;15:145 50. IPMID: 25824066] doi:10.7861/clin medicine.lS-2-145 andexanet alfa can be used to reverse bleeding result- gr ing from oral direct Xa inhibitors (apixaban, rivaroxa- € .D ban, edoxaban). t^ o, CL tr Item 41 Answer: C Educational Objective: Treat a patient taking dabigatran Bibliography r't who has life-threatening bleeding. Cuker A, Burnett A, Triller D, et al. Reversal ofdirect oral anticoagulants: Guidance fiom the Anticoagulation Forum. Am J Hematol. 2ol9:91:697 'lhe rnost appropriate treatment is to adn.rinister idaruci 709. IPMID: 30916798] doi:10.1002'ajh.25.175 Itg (D zumab (Option C). this patient has a retroperit<-rneal hem UI orrhage, which is a lif'e threatening condition. The standard Item 42 Answer: D approach to patients experiencing bleeding lionr anticcl Educational Objective: Prevent infection in a patient agulants involves hemodynamic monitoring and resusci with newly diagnosed multiple myeloma. tation with fluid and blood pr<tducts. Activated charcoal can be considered if the direct oral anticoagulant (DOAC) Pneumococcal vaccination is indicated today (Option D). was ingested recently (<6 hours). She is taking dabigatran Patients with multiple myeloma (MM) are at increased risk fbr atrial flbrillation. and the anticoagulant eftects must for bacterial infection owing to impaired lymphocy'te and be immediately reversed. Idarucizurnab is a humanized plasma cell function and hypogammaglobulinemia. The monoclonal antibody fiagment that binds to dabigatran and most commonly encountered organisms are Streptococcus rapidly reverses its anticoagulant eflects (rn,ithin t hour). pneumoniae, Haemophilus influenzae, and Escherichio coli ldarucizumab is indicated to treat patients taking clabigatran presenting as sinusitis, pneumonia, and urinary tract infec- who experience life threatening bleeding or u,ho require an tions. Because of the altered immune state associated with urgent invasive procedure. If idarucizumab is not available. MM, pneumococcal vaccination with the 13-valent pneumo hemociialysis is another option. Up to 68'l;, of dabigatran coccal conjugate vaccine followed at least B weeks later by can be removed in ,1 hours using hen-rodialysis; however. a the 23-valent pneumococcal polysaccharide vaccine should rebound increase may fbllow because of redistribution of be provided in accordance with Advisory Committee on the drug. Immunization Practices guidelines. Ideally, immunization Andexanet alfa is a recombinant modified factor Xa with inactivated vaccines should be provided at least 2 weeks that conrpetes fbr binding to lactor X lvith tl.re tactor Xa before initiation of chemotherapy. In addition, annual influ inhibitors (apixaban, rivaroxaban. and edoxaban) (Option A). enza vaccination with standard-dose killed vaccine should Fbr patients with life tl.rreatening bleeding who are tak be administered to all patients with MM and to household ing an oral direct Xa inhibitor. the American Society of members. Response to vaccinations may be suboptimal, I{enratology suglEests stopping the oral direct Xa inhibitor but vaccination still provides beneflt and is recommended and considering treatment w'ith either 4-factor prothrom for all patients with MM. bin complex concentrate (4f PCC) or andexanet alfa (ofl: Many medications, such as proteasome inhibitors (e.g., label use fbr edoxaban). Because of.the lack ol comparative bortezomib) and monoclonal antibodies, are associated with data on 4f-PCC ancl andexanet alfa, a prelerred strategl' an increased risk ofherpes zoster virus reactivation. Patients cannot be identified. Anderanet alfa $,ould not be useful treated with bortezomib should receive antiviral prophylaxis for reversing the clirect thrombin inhibition caused by with acyclovir or valacyclovir (Option A). This patient is not dabigatran. yet being treated with bortezomib, so prophylactic antiviral 4F PCC is used to treat warfarin associatccl lil'e threat therapy is not indicated today. ening bleeding (Option B). 4F PCC may also be used tcr Select patientswith recurrent infections and hypogam manage life-threatening hemorrhage in patients taking an maglobulinemia benefit from intravenous immune globu oral direct Xa inhibitor. ,lF PCC may be less bencficial in lin (IVIG) infusions (Option B). IVIG provides protection reversing dabigatran anticoagulation than idarucizumab but from infection by providing passive immunity. However, nright be helpful if idarucizun.rab is not available. patients with acquired hypogammaglobulinemia without 110

Answers and Critiques recurrent infections should not be oll'ered IVIG. Replace- considered for a patient with an absolute contraindication to ment IVIG has numerous adverse effects, including ana anticoagulation but is not appropriate in this patient. phylaxis, serum sickness, kidney failure, hypertension, and According to the 2020 ASH guideline, thrombolysis is a headache, and its use should be restricted to patients with reasonable consideration in patients with limb threatening recurrent infections. DVT and for selected younger patients at low risk fbr bleed Because patients undergoing treatment for MM are at ing with symptomatic DVT involving the iliac and common significantly increased risk for bacterial inf'ection, prophy femoral veins. Extensive thrombosis olthese proximal veins lactic antibiotics are often started at the beginning oftherapy is associated with higher risk for more severe postthrom and continued for the first 3 months (Option C). However, botic syndrome. This patient does not have an indication fbr initiation of prophylactic antibiotics is not indicated today thrombolytic therapy (Option D). because the patient has not started chemotherapy and has I(EY POIII no indication of infection. . In patients with an unprovoked proximal deep venous vt t(EY POt ltrS thrombosis, extended anticoagulation should be pre- o r Patients with multiple myeloma are at increased risk for scribed, with periodic reevaluation of the benefits and ET bacterial infection owing to impaired lymphocyte and harms of long-term therapy. lr, plasma cell function and hypogammaglobulinemia. .C, . All patients with multiple myeloma should receive Bibliography .E Ortel Tt-, Neumann [, Ageno W. et al. American Society of Hematolo$,, 2020 .A pneumococcal vaccination with the 13-valent pneu, guidelines fbr management of venous thromboembolism: Treatment of o mococcal conjugate vaccine and the 23-valent deep vein thrombosis and pulmonary embolism. Bbod Adv. 202O;4:4693 UI pneumococcal polysaccharide vaccine and annual 4738. I PMID: 33OO7O77] &ri:10.1182/bloodadvances.2020001830 = influenza vaccination. Item 44 Answer: E Bibliography Educational Objective: Manage secondary causes of Cuzdar A, Q)stello C. Supportive care in multiple myeloma. Curr Hematol erythrocltosis. Malig Rep. 202O;15:56-61. IPMID: 321723611 doi:10.1007/s11899 020 oo570 I Besides smoking cessation and adherence to continuous positive airway pressure (CPAP) ventilation, no further Item 43 Answer: C management is needed at this time (Option E). This patient Educational Objective: Treat an unprovoked deep has erythrocytosis, likely resulting from smoking and obstructive sleep apnea. His erythropoietin level is high venous thrombosis. normal, and he is negative for the lAK2Y677F mutation, The most appropriate management fbr this patient is which strongly indicates a secondary cause of erythrocyto extended anticoagulation (Option C). She is a young, oth sis. Primary polycythemia vera (PV) is often characterized erwise healthy woman with no history of thrombosis and by an elevated erythrocyte mass and a low erythropoietin no known risk factors fbr thrombosis (injury recent surgery level, and approximately 95% of patients have the JAK2 periods of immobility, airplane travel, smoking, history of mutation, resulting in overproduction of erythrocytes, cancer, contraceptive use). Without known provoking or granulocytes, and platelets. Secondary erythrocytosis is reversible risk factors, anticoagulation should be prescribed more common, with hypoxia-induced reactive increases for an extended period, with plans for yearly evaluation to in erythrocyte production often being the underlying discuss the risks and beneflts ofcontinued anticoagulation. cause. This is seen with conditions such as COPD and sleep Additionally, if the patient is being treated with a direct oral disordered breathing such as obstructive sleep apnea. Car anticoagulant such as rivaroxaban or apixaban, the dose can bon monoxide exposure and chronic hypoxia associated potentially be reduced atter 6 months of therapy with cigarette smoking are also secondary causes of eryth- In the setting ol a provoked proximal deep venous rocytosis. This patient should stop smoking, overcome thrombosis (D\rT), the recommended treatment would be obstacles for use of CPAP ventilation. and continue to be anticoagulation for 3 to 6 months (Option A). Anticoagula monitored. tion could be stopped after this limited period of treatment Bone marrow biopsy is rarely indicated in evaluating with removable or reversible risk factors. This patient has an erythrocytosis (Option A). The bone marrow in patients unprovoked DVI and consideration fbr extended anticoag with PV will typically show hypercellularity with an ulation is recommended. increase in megakaryocytes and erythroid and myeloid In patients with signiflcant preexisting cardiopulmo precursors; the marrow may also reveal increased flbrosis. nary disease, the 2020 American Society of Hematolos/ Even if PV is suspected, diagnosis is usually confirmed (ASH) guideline suggests anticoagulation alone rather than without the need of bone marrow evaluation. In secondary anticoagulation plus insertion of an inferior vena cava (lVC) erythrocytosis, the marrow will show a reactive increase in fllter fbr primary treatment of patients with DVT and/or erythroid precursors but will not be helpful in establishing pulmonary embolism (Option B). An IVC filter might be the cause.

recurrent infections should not be oll'ered IVIG. Replace- considered for a patient with an absolute contraindication to ment IVIG has numerous adverse effects, including ana anticoagulation but is not appropriate in this patient. phylaxis, serum sickness, kidney failure, hypertension, and According to the 2020 ASH guideline, thrombolysis is a headache, and its use should be restricted to patients with reasonable consideration in patients with limb threatening recurrent infections. DVT and for selected younger patients at low risk fbr bleed Because patients undergoing treatment for MM are at ing with symptomatic DVT involving the iliac and common significantly increased risk for bacterial inf'ection, prophy femoral veins. Extensive thrombosis olthese proximal veins lactic antibiotics are often started at the beginning oftherapy is associated with higher risk for more severe postthrom and continued for the first 3 months (Option C). However, botic syndrome. This patient does not have an indication fbr initiation of prophylactic antibiotics is not indicated today thrombolytic therapy (Option D). because the patient has not started chemotherapy and has I(EY POIII no indication of infection. . In patients with an unprovoked proximal deep venous vt t(EY POt ltrS thrombosis, extended anticoagulation should be pre- o r Patients with multiple myeloma are at increased risk for scribed, with periodic reevaluation of the benefits and ET bacterial infection owing to impaired lymphocyte and harms of long-term therapy. lr, plasma cell function and hypogammaglobulinemia. .C, . All patients with multiple myeloma should receive Bibliography .E Ortel Tt-, Neumann [, Ageno W. et al. American Society of Hematolo$,, 2020 .A pneumococcal vaccination with the 13-valent pneu, guidelines fbr management of venous thromboembolism: Treatment of o mococcal conjugate vaccine and the 23-valent deep vein thrombosis and pulmonary embolism. Bbod Adv. 202O;4:4693 UI pneumococcal polysaccharide vaccine and annual 4738. I PMID: 33OO7O77] &ri:10.1182/bloodadvances.2020001830 = influenza vaccination. Item 44 Answer: E Bibliography Educational Objective: Manage secondary causes of Cuzdar A, Q)stello C. Supportive care in multiple myeloma. Curr Hematol erythrocltosis. Malig Rep. 202O;15:56-61. IPMID: 321723611 doi:10.1007/s11899 020 oo570 I Besides smoking cessation and adherence to continuous positive airway pressure (CPAP) ventilation, no further Item 43 Answer: C management is needed at this time (Option E). This patient Educational Objective: Treat an unprovoked deep has erythrocytosis, likely resulting from smoking and obstructive sleep apnea. His erythropoietin level is high venous thrombosis. normal, and he is negative for the lAK2Y677F mutation, The most appropriate management fbr this patient is which strongly indicates a secondary cause of erythrocyto extended anticoagulation (Option C). She is a young, oth sis. Primary polycythemia vera (PV) is often characterized erwise healthy woman with no history of thrombosis and by an elevated erythrocyte mass and a low erythropoietin no known risk factors fbr thrombosis (injury recent surgery level, and approximately 95% of patients have the JAK2 periods of immobility, airplane travel, smoking, history of mutation, resulting in overproduction of erythrocytes, cancer, contraceptive use). Without known provoking or granulocytes, and platelets. Secondary erythrocytosis is reversible risk factors, anticoagulation should be prescribed more common, with hypoxia-induced reactive increases for an extended period, with plans for yearly evaluation to in erythrocyte production often being the underlying discuss the risks and beneflts ofcontinued anticoagulation. cause. This is seen with conditions such as COPD and sleep Additionally, if the patient is being treated with a direct oral disordered breathing such as obstructive sleep apnea. Car anticoagulant such as rivaroxaban or apixaban, the dose can bon monoxide exposure and chronic hypoxia associated potentially be reduced atter 6 months of therapy with cigarette smoking are also secondary causes of eryth- In the setting ol a provoked proximal deep venous rocytosis. This patient should stop smoking, overcome thrombosis (D\rT), the recommended treatment would be obstacles for use of CPAP ventilation. and continue to be anticoagulation for 3 to 6 months (Option A). Anticoagula monitored. tion could be stopped after this limited period of treatment Bone marrow biopsy is rarely indicated in evaluating with removable or reversible risk factors. This patient has an erythrocytosis (Option A). The bone marrow in patients unprovoked DVI and consideration fbr extended anticoag with PV will typically show hypercellularity with an ulation is recommended. increase in megakaryocytes and erythroid and myeloid In patients with signiflcant preexisting cardiopulmo precursors; the marrow may also reveal increased flbrosis. nary disease, the 2020 American Society of Hematolos/ Even if PV is suspected, diagnosis is usually confirmed (ASH) guideline suggests anticoagulation alone rather than without the need of bone marrow evaluation. In secondary anticoagulation plus insertion of an inferior vena cava (lVC) erythrocytosis, the marrow will show a reactive increase in fllter fbr primary treatment of patients with DVT and/or erythroid precursors but will not be helpful in establishing pulmonary embolism (Option B). An IVC filter might be the cause. 111

Answers and Critiques Hydroxyurea and ruxolitinib are treatment options fbr Factor V Leiden (FVL) is the most common inherited primary PV but are not indicated for secondary erythrocy thrombophilia (Option B). Approximatell' 5'11, of White tosis (Options B, D). patients are heterozygous lor FVL. Less than l'X, of Whites The lAK2 mutation seen in primary PV is associated are homozygous fbr the mutation. This mutation is rare in with an increased risk fbr thrombotic events. and studies Asians. Africans. Black Americans. and American Indians. have shown that maintaining a hematocrit less than 45'7, F\'L can be detected by genetic testing (DNA testing) or a reduces the risk for adverse cardiovascular and thrombotic functional coagulation test for acti\ated protein C resistance. events. Because the increase in erythrocyte mass in sec Although genetic testing nolr,nould not affect immediate ondary erythrocy.tosis is a compensatory response to tis- treatment options for this patient, testing can be perfbrmed sue hypoxia. reducing the number of erythrocJ.tes through independent of the presence of an acute thrombosis. Ther- phlebotomy may worsen outcomes (Option C). Phlebotomy ap1' rrith a direct thrombin inhibitor (argatroban, dabig- in reactive situations is considered on a case-by-case basis atran) or an oral factor Xa inhibitor (apixaban. edoxaban. F and is often limited to patients with extreme hematocrit rivaroxaban) can result in falsely normal activated protein C vt elevations (>S+%) and who have symptoms attributable to functional test results. € lt hyperviscosity. Proteins C and S are vitamin K dependent proteins atl that degrade activated factors V and \tlll (Option C). lnher q, ltY P0tf,r ited deficiencies arc generally associated r,r'ith thromboses CL . Secondary causes of erythrocytosis arise through before the age o1'50 years and are associated u'ith a strong n chronic or intermittent hypoxia, and correcting these family history ol thrombosis. These proteins are also reduced underlying causes (e.g., cigarette smoking, obstructive in the setting of acute \'TE. and measurement nou' u'ould ll (D sleep apnea) is the first step in management. not provide usetul infbrmation or influence immediate l^ treatment. Bibliography f,EY POIilIt Rumi E, Cazzola M. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood. 2017:129:680 692. IPMID: o The acute management of patients with venous 280280261 doi:10.1l821blood 2Ol6 l0 695957 thromboembolism does not differ based on the pres- ence or absence of an inherited thrombophilia; there- fore, testing is not necessary. tr Item 45 Ed u cational Objective: Answer: D Avoid inappropriate thrombo- o Treatment duration for venous thromboembolism disease is typically determined by whether the event philia testing in patients with acute venous thromboem- trolism. was provoked by a reversible or self-limited insult and not by the presence or absence ofthrombophilia. No hereditary thrombophilia testing perlormed now will inform immediate treatment decisions (Option D). Bibliography Although identiflcation ol the inherited thrombophilias Connors JM. Thrombophilia testing and \€nous thrombosis. N Engl J Med. has advanced the understanding ol venous thromboem 2017 :377 :1177 1187. I PM I D: 28930509] doi:10.1056 NEJMTa 1700365

Hydroxyurea and ruxolitinib are treatment options fbr Factor V Leiden (FVL) is the most common inherited primary PV but are not indicated for secondary erythrocy thrombophilia (Option B). Approximatell' 5'11, of White tosis (Options B, D). patients are heterozygous lor FVL. Less than l'X, of Whites The lAK2 mutation seen in primary PV is associated are homozygous fbr the mutation. This mutation is rare in with an increased risk fbr thrombotic events. and studies Asians. Africans. Black Americans. and American Indians. have shown that maintaining a hematocrit less than 45'7, F\'L can be detected by genetic testing (DNA testing) or a reduces the risk for adverse cardiovascular and thrombotic functional coagulation test for acti\ated protein C resistance. events. Because the increase in erythrocyte mass in sec Although genetic testing nolr,nould not affect immediate ondary erythrocy.tosis is a compensatory response to tis- treatment options for this patient, testing can be perfbrmed sue hypoxia. reducing the number of erythrocJ.tes through independent of the presence of an acute thrombosis. Ther- phlebotomy may worsen outcomes (Option C). Phlebotomy ap1' rrith a direct thrombin inhibitor (argatroban, dabig- in reactive situations is considered on a case-by-case basis atran) or an oral factor Xa inhibitor (apixaban. edoxaban. F and is often limited to patients with extreme hematocrit rivaroxaban) can result in falsely normal activated protein C vt elevations (>S+%) and who have symptoms attributable to functional test results. € lt hyperviscosity. Proteins C and S are vitamin K dependent proteins atl that degrade activated factors V and \tlll (Option C). lnher q, ltY P0tf,r ited deficiencies arc generally associated r,r'ith thromboses CL . Secondary causes of erythrocytosis arise through before the age o1'50 years and are associated u'ith a strong n chronic or intermittent hypoxia, and correcting these family history ol thrombosis. These proteins are also reduced underlying causes (e.g., cigarette smoking, obstructive in the setting of acute \'TE. and measurement nou' u'ould ll (D sleep apnea) is the first step in management. not provide usetul infbrmation or influence immediate l^ treatment. Bibliography f,EY POIilIt Rumi E, Cazzola M. Diagnosis, risk stratification, and response evaluation in classical myeloproliferative neoplasms. Blood. 2017:129:680 692. IPMID: o The acute management of patients with venous 280280261 doi:10.1l821blood 2Ol6 l0 695957 thromboembolism does not differ based on the pres- ence or absence of an inherited thrombophilia; there- fore, testing is not necessary. tr Item 45 Ed u cational Objective: Answer: D Avoid inappropriate thrombo- o Treatment duration for venous thromboembolism disease is typically determined by whether the event philia testing in patients with acute venous thromboem- trolism. was provoked by a reversible or self-limited insult and not by the presence or absence ofthrombophilia. No hereditary thrombophilia testing perlormed now will inform immediate treatment decisions (Option D). Bibliography Although identiflcation ol the inherited thrombophilias Connors JM. Thrombophilia testing and \€nous thrombosis. N Engl J Med. has advanced the understanding ol venous thromboem 2017 :377 :1177 1187. I PM I D: 28930509] doi:10.1056 NEJMTa 1700365 bolism (WE) pathophysiolog,l it has little influence on clinical management. which does not differ acutcly based on the presence of an inherited thrombophilia. Manage Item 46 Answer: D ment duration is typically determined by r,r,hether the V'l'E Educational Objective: Diagnose von Willebrand disease. event was provoked by a reversible or self limited insult. In this patient with an unprovoked deep renous thrombosis, The most likely cause of this patient's bruising and menor- guidelines suggest that extcnded anticoagulant therapy rhagia is von Willebrand disease (vWD) (Option D). vWD, should be considered regardless of the presence or absence the most common hereditary bleeding disorder. is caused of an inherited thrombophilia. Ihe choice of extended by deflciency or ineffectiveness of von Willebrand factor thromboprophylaxis should be informed b1, blecding risk (vWF). vWF promotes platelet adhesion and functions as and reevalualed each year. The choice of anticoagulant a protective carrier protein for factor Vlll, so a mild sec- may be influenced by the presence of antiphospholipid ondary decrease in factor VIII level occurs in patients with antibody syndrome. but this patient's antiphospholipid vWD. vWF deficiency leads to mucocutaneous bleeding that evaluation was unremarkable. mimics thrombocytopenia. Menorrhagia and bleeding after Antithrombin III (ATIIl) is a natural anticoagulant that minor procedures such as dental extraction or tonsillectomy can lead to thrombophilia in the setting ol an inherited or are common maniflestations. As in typical cases of vWD, acquired deficiency. the prevalence of inherited AI'lll defi this patient was young at the onset of bleeding symptoms ciency is approximately 1 in 3000 to 5000 persons and leads and has a family history of bleeding. vWD is an autosomal to a strong predisposition fbr VTE. ATIII is reduced during an dominant disease and can affect men and women, so acute VTE, and measurement at this time nould not provide her family history is also consistent with this diagnosis. useful information (Option A). Although the activated partial thromboplastin time may be

bolism (WE) pathophysiolog,l it has little influence on clinical management. which does not differ acutcly based on the presence of an inherited thrombophilia. Manage Item 46 Answer: D ment duration is typically determined by r,r,hether the V'l'E Educational Objective: Diagnose von Willebrand disease. event was provoked by a reversible or self limited insult. In this patient with an unprovoked deep renous thrombosis, The most likely cause of this patient's bruising and menor- guidelines suggest that extcnded anticoagulant therapy rhagia is von Willebrand disease (vWD) (Option D). vWD, should be considered regardless of the presence or absence the most common hereditary bleeding disorder. is caused of an inherited thrombophilia. Ihe choice of extended by deflciency or ineffectiveness of von Willebrand factor thromboprophylaxis should be informed b1, blecding risk (vWF). vWF promotes platelet adhesion and functions as and reevalualed each year. The choice of anticoagulant a protective carrier protein for factor Vlll, so a mild sec- may be influenced by the presence of antiphospholipid ondary decrease in factor VIII level occurs in patients with antibody syndrome. but this patient's antiphospholipid vWD. vWF deficiency leads to mucocutaneous bleeding that evaluation was unremarkable. mimics thrombocytopenia. Menorrhagia and bleeding after Antithrombin III (ATIIl) is a natural anticoagulant that minor procedures such as dental extraction or tonsillectomy can lead to thrombophilia in the setting ol an inherited or are common maniflestations. As in typical cases of vWD, acquired deficiency. the prevalence of inherited AI'lll defi this patient was young at the onset of bleeding symptoms ciency is approximately 1 in 3000 to 5000 persons and leads and has a family history of bleeding. vWD is an autosomal to a strong predisposition fbr VTE. ATIII is reduced during an dominant disease and can affect men and women, so acute VTE, and measurement at this time nould not provide her family history is also consistent with this diagnosis. useful information (Option A). Although the activated partial thromboplastin time may be 112

Answers and Critiques prolonged or normal, an abnorrrill platelet f'unction testing each criterion that is present. If an alternative explanation result would suggest vWD, nraking this a uselul initial eval for leg symptoms is present, then two points are removed. uation tool. The diagnosis is confirnred by finding a reduc For patients with a score of 0 or l, a D dimer me.lsurement tior.r in von Willebrar.rd ar.rtigen (quar.rtitative analysis) and should be obtained; no additional testing is indicated fbr a reduced vWF ristocetin cotactor activity (a measurement ot negative D dimer result. For a Wells criteria score greater the functional affcct). than 1, pretest probability of a DVT is high and duplex ultra Ehlers Danlos syndrome (liDS) describes a group of sonography should be performed without initial D dinter rare genetic disorders aflecting connective tissue and char- evaluation. This patient's leg swetling with pitting edema acterized by one of several f'eatures, including skin hyper and recent cancer therapy earn a Wells criteria score of 3, so elasticity. skin fragility, and joint hypermobility. all of which duplex ultrasonography should be performed. are absent in this patient. Bruising can be a common symp The Pulmonary Embolism Rule Out Criteria (PERC) tom of EDS; however, EDS would not explain the mucocu score can identify patients at very low risk for pulmonary taneous bleeding pattern or the laboratory abnormalities in embolism (PE) and is the recommended initial test fbr tt {, this patient (Option A). patients at low risk for PE (Option A). If the PERC score is EF Although a factor VIll level of 40',X, can be seen in car zero, no D dimer testing is needed, and no CT angiography riers of hemophilia A, the patient's family history is incon should be performed. However, this test is not applicable to TJ sistent with this diagnosis (Option B). Ilemophilia A has an a patient with suspected DVT, such as this patient. .E, X linked recessive pattern of inheritance, with men being CT angiography is unnecessary because the patient has aflected and women remaining asymptomatic carriers. symptoms of a lower extremity DVT, not PE (Option B). If' tl'E (u Platelet function testing would be normal in patients with duplex ultrasonography of the lower extremity is diagnostic 3 *7 hemophilia A. for DVT, then CT angiography does not need to be per Immune thrombocytopenic purpura is associated with formed, because the treatment for DVT and PFI are the same a low platelet count but not a qualitative platelet abnormal, and the risk associated with C'l'contrast can be avoided. ity (Option C). The platelet count is normal. ln patients with a high probability fbr DVT, the D dimer I measurement should not be obtained (Option C). Imaging is l(Ev P0tt{T5 recommended in these patients regardless of the D din.rer . Von Willebrand disease, the most common hereditary result. t bleeding disorder, is caused by either deficiency or ineffectiveness of von Willebrand factor. I(EY POII{I

prolonged or normal, an abnorrrill platelet f'unction testing each criterion that is present. If an alternative explanation result would suggest vWD, nraking this a uselul initial eval for leg symptoms is present, then two points are removed. uation tool. The diagnosis is confirnred by finding a reduc For patients with a score of 0 or l, a D dimer me.lsurement tior.r in von Willebrar.rd ar.rtigen (quar.rtitative analysis) and should be obtained; no additional testing is indicated fbr a reduced vWF ristocetin cotactor activity (a measurement ot negative D dimer result. For a Wells criteria score greater the functional affcct). than 1, pretest probability of a DVT is high and duplex ultra Ehlers Danlos syndrome (liDS) describes a group of sonography should be performed without initial D dinter rare genetic disorders aflecting connective tissue and char- evaluation. This patient's leg swetling with pitting edema acterized by one of several f'eatures, including skin hyper and recent cancer therapy earn a Wells criteria score of 3, so elasticity. skin fragility, and joint hypermobility. all of which duplex ultrasonography should be performed. are absent in this patient. Bruising can be a common symp The Pulmonary Embolism Rule Out Criteria (PERC) tom of EDS; however, EDS would not explain the mucocu score can identify patients at very low risk for pulmonary taneous bleeding pattern or the laboratory abnormalities in embolism (PE) and is the recommended initial test fbr tt {, this patient (Option A). patients at low risk for PE (Option A). If the PERC score is EF Although a factor VIll level of 40',X, can be seen in car zero, no D dimer testing is needed, and no CT angiography riers of hemophilia A, the patient's family history is incon should be performed. However, this test is not applicable to TJ sistent with this diagnosis (Option B). Ilemophilia A has an a patient with suspected DVT, such as this patient. .E, X linked recessive pattern of inheritance, with men being CT angiography is unnecessary because the patient has aflected and women remaining asymptomatic carriers. symptoms of a lower extremity DVT, not PE (Option B). If' tl'E (u Platelet function testing would be normal in patients with duplex ultrasonography of the lower extremity is diagnostic 3 *7 hemophilia A. for DVT, then CT angiography does not need to be per Immune thrombocytopenic purpura is associated with formed, because the treatment for DVT and PFI are the same a low platelet count but not a qualitative platelet abnormal, and the risk associated with C'l'contrast can be avoided. ity (Option C). The platelet count is normal. ln patients with a high probability fbr DVT, the D dimer I measurement should not be obtained (Option C). Imaging is l(Ev P0tt{T5 recommended in these patients regardless of the D din.rer . Von Willebrand disease, the most common hereditary result. t bleeding disorder, is caused by either deficiency or ineffectiveness of von Willebrand factor. I(EY POII{I . Young age of onset of bleeding symptoms and family o For patients with a high pretest probability of deep history of bleeding in both sexes are indications of venous thrombosis measured by the Wells criteria, von Willebrand disease (vWD); the bleeding pattern duplex ultrasonography is recommended without ini in vWD is typically mucocutaneous, and menorrhagia tial D-dimer measurement. and bleeding after minor procedures are common manifestations. Bibliography Lim W Le Gdl G. Bates SM, et al. Ar.nericln Society ol'llematolotry 2018 guidelir.res Ibr management of venous throntboerrbolisrr: I)iagnosis ot Bibliography venous thromboembolism. Bkrocl Adr: 2018r2::1226 t]256. Il,MII): 304827 61]| doi: 10. I I 82 bkxrclach,ances.20l 802182u Leebeek FW Flikenbrxrm lC. Vrn Willebrancl's clisease. N Engl I Mecl. 20l6rll75:2067 2080. I PM I l): 279597 ltl tloi: 10. t056 NEJMral60156l

. Young age of onset of bleeding symptoms and family o For patients with a high pretest probability of deep history of bleeding in both sexes are indications of venous thrombosis measured by the Wells criteria, von Willebrand disease (vWD); the bleeding pattern duplex ultrasonography is recommended without ini in vWD is typically mucocutaneous, and menorrhagia tial D-dimer measurement. and bleeding after minor procedures are common manifestations. Bibliography Lim W Le Gdl G. Bates SM, et al. Ar.nericln Society ol'llematolotry 2018 guidelir.res Ibr management of venous throntboerrbolisrr: I)iagnosis ot Bibliography venous thromboembolism. Bkrocl Adr: 2018r2::1226 t]256. Il,MII): 304827 61]| doi: 10. I I 82 bkxrclach,ances.20l 802182u Leebeek FW Flikenbrxrm lC. Vrn Willebrancl's clisease. N Engl I Mecl. 20l6rll75:2067 2080. I PM I l): 279597 ltl tloi: 10. t056 NEJMral60156l Item 48 Answer: A Item 47 Answer: D Educational Objective: Diagnose hydroxyurea-induced I Educational Objective: Evaluate a patient with a high macrocytic anemia. probability of deep venous thrombosis. The most likely cause of this patient's macrocytic anemia According to Wells criteria for deep venous thrombosis is hydroxyurea therapy (Option A). Reviewing the com (DVT), this patient has a high probability of DVT and should plete blood count, mean corpuscular volume (MCV), and undergo duplex ultrasonography (Option D). The Wells cri reticulocyte count along with the peripheral blood smear teria include leg sympk)ms and examination findings as can provide valuable diagnostic infbrmation when assess well as patient history. Flxamination findings and symptoms ing patients with anemia. The reticulocyte count provides include calf swelling of ll cm or more, swollen unilateral information on the marrow response to anemia. A normal superficial veins, ur.rilateral pitting edema, swelling of the marrow will produce reticulocytes in response to anemia or entire leg, and localized tenderness along the deep venous hypoxia. ln contrast, patients with vitamin B,,,,, fblate, or iron system. Patient history criteria include previously docu deflciency or those with marrow cliseases such as myelo mented DVT; active cancer or treatment of cancer in the past dysplasia or aplastic anemia have a low reticulocyte count 6 months; paralysis, paresis, immobilization, or bedridden for their degree of anemia. Most macrocytic anemias with status for 3 days or more: and surgery. One point is given fbr MCV values greater than 110 to ll5 fl. are caused by vitamin

Item 48 Answer: A Item 47 Answer: D Educational Objective: Diagnose hydroxyurea-induced I Educational Objective: Evaluate a patient with a high macrocytic anemia. probability of deep venous thrombosis. The most likely cause of this patient's macrocytic anemia According to Wells criteria for deep venous thrombosis is hydroxyurea therapy (Option A). Reviewing the com (DVT), this patient has a high probability of DVT and should plete blood count, mean corpuscular volume (MCV), and undergo duplex ultrasonography (Option D). The Wells cri reticulocyte count along with the peripheral blood smear teria include leg sympk)ms and examination findings as can provide valuable diagnostic infbrmation when assess well as patient history. Flxamination findings and symptoms ing patients with anemia. The reticulocyte count provides include calf swelling of ll cm or more, swollen unilateral information on the marrow response to anemia. A normal superficial veins, ur.rilateral pitting edema, swelling of the marrow will produce reticulocytes in response to anemia or entire leg, and localized tenderness along the deep venous hypoxia. ln contrast, patients with vitamin B,,,,, fblate, or iron system. Patient history criteria include previously docu deflciency or those with marrow cliseases such as myelo mented DVT; active cancer or treatment of cancer in the past dysplasia or aplastic anemia have a low reticulocyte count 6 months; paralysis, paresis, immobilization, or bedridden for their degree of anemia. Most macrocytic anemias with status for 3 days or more: and surgery. One point is given fbr MCV values greater than 110 to ll5 fl. are caused by vitamin 113

Answers and Critiques B,, or folate deflciency, treatment of HIV infection with is a s!'stemic process with widespreacl and inapp()priate antiretroviral therapy, or the antimetabolite hydroxyurea. activation ol coagulation and concomitirnt fibrinoll'sis. ln Hydroxyurea prevents the conversion of ribonucleotides acute DIC. coagulation f'actors and platelets are rapidll con to deoxyribonucleotides, halting the cell cycle at the Gl/S sumed. leadirrg to bleeding. organ d1'sfunction. and micro phase. This inhibition of ribonucleotide synthesis results in angiopathic hemoll,tic anemia manilbsting as schistocl,tes a myelosuppressive eflect and macrocytosis. Unlike vitamin on the peripheral bloocl snrear (see figure in Stem). Nor B, deflciency, no intramedullary hemolysis occurs, so the mal compensatory nrechanisnrs are unablc to kecp up rvith lactate dehydrogenase (LDH), haptoglobin, and total bili the consnmption of nrany' blood curlponents, resulting in rubin levels are normal. This patient's macrocltic anemia, depletion of'platclets arrd coagulatir)n protcirls. Patients nr:U, mild leukopenia, and thrombocytopenia are common and have bleeding resr-rltirrg from lack of available procoagulrnt expected consequences of hydroxyurea therapy. fhctors in addition to large rmounts of fibrin degraclation An elevated LDH level and reticulocyte count with products releasecl fiom accompanying fibrinoll'sis. rthich spherocytes or microspherocytes on the peripheral blood interleres n'ith nornlal phtelet function ancl tibrirr firrnra (^ smear would be expected in immune-mediated hemo- tion. Bleeding can olten be seen at nrucosal sites ancl areas G lytic anemia (Option B). this patient does not have these of proceclures (e.g., r,enous cathetcrs). Orgun dlsfunction. = eh findings. including kidney and liver inlpdinxent, is also conrnron. gt Paroxysmal nocturnal hemoglobinuria (PNH) is a rare l-aboratory findings in acute t)lC include prolongation of the CL acquired, intrinsic erythrocyte defect arising from somatic prothnrrnbin and activatecl partial thrornboplastin tinres. al mutations in the PIGA gene (Option C). Patients may pres thronrbocytopenia, lou' fibrinogen level. and markers of 4l ent with intravascular hemolysis or venous and arterial fibrinoll,sis such as an elevatecl I) dirner. Sepsis is the nrost thrombosis. PNH is not a cause of macrocytosis to the common cause ol acttte I)lC. 'l'rcatrnent fircuscs on :tdclrcss G IA degree seen in this patient. He also lacks a history of throm- ing the ur.rderlying condition. [)latelet transf'usions. cn()l)re bosis or laboratory conflrmation of hemolysis. Macrocy- cipitate, and fiesh lrozen plastna are providerl its neetletl ltrr tosis of 115 fL is more likely to be caused by hydroxyurea bleedi ng nran ilbstations. than PNH. Flculizunrab is a nronoclonal antibocll' directecl irgirinst A low vitamin B,, level is associated with intramed- complenrent conrponent C5 and inhibits conrlllemcnt acti ullary hemolysis because of ineffective erythropoiesis and vation (Option A). It has been shorvtt to be cftec'tive firr resultant elevated LDH, haptoglobin, and bilirubin (indirect) use in parorl,smirl nocturnirl henrogkrbinuria antl at1'lticitl levels, which are normal in this patient (Option D). Addi- l.rernolr,tic urentic sl,nclrome (aI IUS).,\lthough thrrtmbocy tionally, vitamin B,, stores are abundant and can remain suf- topenia. thrombr,rtic micnrangiopathll lnd kiclnel cliscitsc ficient for a long time even in complete cessation of dietary are seen uith aflUS. it is not associlted \\'ith coagtllation intake. The development of macrocy.tosis over 1 year's time abnormalities. is more consistent with medication effect than vitamin B, Glucocorticoids. suclr as ltredttisr.rnc, rrrlultl bc cott deflciency. siderecl in patients '"r'ith autoitnmune hcntolltic ilnttlliil or immune thrombocltopenic purpura ltut not lt'ith l)l(. rtY Potilts (Option B). These entities Jre n()t itssociatcd uith crugulit . Defining anemia as microc).tic, macrocltic, or nor tion abnormalities or schistocl'tes on thc pcriltheral blood mocytic as well as by reticulocy,te response can nar- smear. row the differential diagnosis. Therapeutic plasnra exchrnge is it tnlinstitl' of tlrcr o Most macrocytic anemias with mean corpuscular vol ap}' in pat ierlts r.r'it h th ronrbt)t ic t ltrornboc)'topen ic l)u rpu rd (TTP) (Option C). Thrombocvlopenia rttrd nticroangiopathic ume values greater than 110 to 115 fL are caused by vitamin B,, or folate deficiency, treatment of HIV hemoll'tic anenria are hallmarks ol 'l'1'l), ltut coagulation infection with antiretroviral therapy, or the antime- abnormalities are not. 'lheralrer.rtic plitsma cxchangc is not used for trcirtnrent oI l)l(]. tabolite hydroxyurea. TEY POIXIS Bibliography . Disseminated intravascular coagulation is character Nagao I Hirokaraa M. Diagnosis and treatment of macrocytic anemias in ized by thrombocytopenia, coagulation abnormalities, adults. J Gen Fam Med. 2017:18:2OO 204. [PMID: 29264027ldoi:lO.lOO2i jgf2.31 hypofi brinogenemia, and microangiopathic hemolyic anemia.

B,, or folate deflciency, treatment of HIV infection with is a s!'stemic process with widespreacl and inapp()priate antiretroviral therapy, or the antimetabolite hydroxyurea. activation ol coagulation and concomitirnt fibrinoll'sis. ln Hydroxyurea prevents the conversion of ribonucleotides acute DIC. coagulation f'actors and platelets are rapidll con to deoxyribonucleotides, halting the cell cycle at the Gl/S sumed. leadirrg to bleeding. organ d1'sfunction. and micro phase. This inhibition of ribonucleotide synthesis results in angiopathic hemoll,tic anemia manilbsting as schistocl,tes a myelosuppressive eflect and macrocytosis. Unlike vitamin on the peripheral bloocl snrear (see figure in Stem). Nor B, deflciency, no intramedullary hemolysis occurs, so the mal compensatory nrechanisnrs are unablc to kecp up rvith lactate dehydrogenase (LDH), haptoglobin, and total bili the consnmption of nrany' blood curlponents, resulting in rubin levels are normal. This patient's macrocltic anemia, depletion of'platclets arrd coagulatir)n protcirls. Patients nr:U, mild leukopenia, and thrombocytopenia are common and have bleeding resr-rltirrg from lack of available procoagulrnt expected consequences of hydroxyurea therapy. fhctors in addition to large rmounts of fibrin degraclation An elevated LDH level and reticulocyte count with products releasecl fiom accompanying fibrinoll'sis. rthich spherocytes or microspherocytes on the peripheral blood interleres n'ith nornlal phtelet function ancl tibrirr firrnra (^ smear would be expected in immune-mediated hemo- tion. Bleeding can olten be seen at nrucosal sites ancl areas G lytic anemia (Option B). this patient does not have these of proceclures (e.g., r,enous cathetcrs). Orgun dlsfunction. = eh findings. including kidney and liver inlpdinxent, is also conrnron. gt Paroxysmal nocturnal hemoglobinuria (PNH) is a rare l-aboratory findings in acute t)lC include prolongation of the CL acquired, intrinsic erythrocyte defect arising from somatic prothnrrnbin and activatecl partial thrornboplastin tinres. al mutations in the PIGA gene (Option C). Patients may pres thronrbocytopenia, lou' fibrinogen level. and markers of 4l ent with intravascular hemolysis or venous and arterial fibrinoll,sis such as an elevatecl I) dirner. Sepsis is the nrost thrombosis. PNH is not a cause of macrocytosis to the common cause ol acttte I)lC. 'l'rcatrnent fircuscs on :tdclrcss G IA degree seen in this patient. He also lacks a history of throm- ing the ur.rderlying condition. [)latelet transf'usions. cn()l)re bosis or laboratory conflrmation of hemolysis. Macrocy- cipitate, and fiesh lrozen plastna are providerl its neetletl ltrr tosis of 115 fL is more likely to be caused by hydroxyurea bleedi ng nran ilbstations. than PNH. Flculizunrab is a nronoclonal antibocll' directecl irgirinst A low vitamin B,, level is associated with intramed- complenrent conrponent C5 and inhibits conrlllemcnt acti ullary hemolysis because of ineffective erythropoiesis and vation (Option A). It has been shorvtt to be cftec'tive firr resultant elevated LDH, haptoglobin, and bilirubin (indirect) use in parorl,smirl nocturnirl henrogkrbinuria antl at1'lticitl levels, which are normal in this patient (Option D). Addi- l.rernolr,tic urentic sl,nclrome (aI IUS).,\lthough thrrtmbocy tionally, vitamin B,, stores are abundant and can remain suf- topenia. thrombr,rtic micnrangiopathll lnd kiclnel cliscitsc ficient for a long time even in complete cessation of dietary are seen uith aflUS. it is not associlted \\'ith coagtllation intake. The development of macrocy.tosis over 1 year's time abnormalities. is more consistent with medication effect than vitamin B, Glucocorticoids. suclr as ltredttisr.rnc, rrrlultl bc cott deflciency. siderecl in patients '"r'ith autoitnmune hcntolltic ilnttlliil or immune thrombocltopenic purpura ltut not lt'ith l)l(. rtY Potilts (Option B). These entities Jre n()t itssociatcd uith crugulit . Defining anemia as microc).tic, macrocltic, or nor tion abnormalities or schistocl'tes on thc pcriltheral blood mocytic as well as by reticulocy,te response can nar- smear. row the differential diagnosis. Therapeutic plasnra exchrnge is it tnlinstitl' of tlrcr o Most macrocytic anemias with mean corpuscular vol ap}' in pat ierlts r.r'it h th ronrbt)t ic t ltrornboc)'topen ic l)u rpu rd (TTP) (Option C). Thrombocvlopenia rttrd nticroangiopathic ume values greater than 110 to 115 fL are caused by vitamin B,, or folate deficiency, treatment of HIV hemoll'tic anenria are hallmarks ol 'l'1'l), ltut coagulation infection with antiretroviral therapy, or the antime- abnormalities are not. 'lheralrer.rtic plitsma cxchangc is not used for trcirtnrent oI l)l(]. tabolite hydroxyurea. TEY POIXIS Bibliography . Disseminated intravascular coagulation is character Nagao I Hirokaraa M. Diagnosis and treatment of macrocytic anemias in ized by thrombocytopenia, coagulation abnormalities, adults. J Gen Fam Med. 2017:18:2OO 204. [PMID: 29264027ldoi:lO.lOO2i jgf2.31 hypofi brinogenemia, and microangiopathic hemolyic anemia. Item 49 . Treatment of disseminated intravascular coagulation tr Answer: D Educational Objective: Treat disseminated intravascular focuses on the underlying disorder.

B,, or folate deflciency, treatment of HIV infection with is a s!'stemic process with widespreacl and inapp()priate antiretroviral therapy, or the antimetabolite hydroxyurea. activation ol coagulation and concomitirnt fibrinoll'sis. ln Hydroxyurea prevents the conversion of ribonucleotides acute DIC. coagulation f'actors and platelets are rapidll con to deoxyribonucleotides, halting the cell cycle at the Gl/S sumed. leadirrg to bleeding. organ d1'sfunction. and micro phase. This inhibition of ribonucleotide synthesis results in angiopathic hemoll,tic anemia manilbsting as schistocl,tes a myelosuppressive eflect and macrocytosis. Unlike vitamin on the peripheral bloocl snrear (see figure in Stem). Nor B, deflciency, no intramedullary hemolysis occurs, so the mal compensatory nrechanisnrs are unablc to kecp up rvith lactate dehydrogenase (LDH), haptoglobin, and total bili the consnmption of nrany' blood curlponents, resulting in rubin levels are normal. This patient's macrocltic anemia, depletion of'platclets arrd coagulatir)n protcirls. Patients nr:U, mild leukopenia, and thrombocytopenia are common and have bleeding resr-rltirrg from lack of available procoagulrnt expected consequences of hydroxyurea therapy. fhctors in addition to large rmounts of fibrin degraclation An elevated LDH level and reticulocyte count with products releasecl fiom accompanying fibrinoll'sis. rthich spherocytes or microspherocytes on the peripheral blood interleres n'ith nornlal phtelet function ancl tibrirr firrnra (^ smear would be expected in immune-mediated hemo- tion. Bleeding can olten be seen at nrucosal sites ancl areas G lytic anemia (Option B). this patient does not have these of proceclures (e.g., r,enous cathetcrs). Orgun dlsfunction. = eh findings. including kidney and liver inlpdinxent, is also conrnron. gt Paroxysmal nocturnal hemoglobinuria (PNH) is a rare l-aboratory findings in acute t)lC include prolongation of the CL acquired, intrinsic erythrocyte defect arising from somatic prothnrrnbin and activatecl partial thrornboplastin tinres. al mutations in the PIGA gene (Option C). Patients may pres thronrbocytopenia, lou' fibrinogen level. and markers of 4l ent with intravascular hemolysis or venous and arterial fibrinoll,sis such as an elevatecl I) dirner. Sepsis is the nrost thrombosis. PNH is not a cause of macrocytosis to the common cause ol acttte I)lC. 'l'rcatrnent fircuscs on :tdclrcss G IA degree seen in this patient. He also lacks a history of throm- ing the ur.rderlying condition. [)latelet transf'usions. cn()l)re bosis or laboratory conflrmation of hemolysis. Macrocy- cipitate, and fiesh lrozen plastna are providerl its neetletl ltrr tosis of 115 fL is more likely to be caused by hydroxyurea bleedi ng nran ilbstations. than PNH. Flculizunrab is a nronoclonal antibocll' directecl irgirinst A low vitamin B,, level is associated with intramed- complenrent conrponent C5 and inhibits conrlllemcnt acti ullary hemolysis because of ineffective erythropoiesis and vation (Option A). It has been shorvtt to be cftec'tive firr resultant elevated LDH, haptoglobin, and bilirubin (indirect) use in parorl,smirl nocturnirl henrogkrbinuria antl at1'lticitl levels, which are normal in this patient (Option D). Addi- l.rernolr,tic urentic sl,nclrome (aI IUS).,\lthough thrrtmbocy tionally, vitamin B,, stores are abundant and can remain suf- topenia. thrombr,rtic micnrangiopathll lnd kiclnel cliscitsc ficient for a long time even in complete cessation of dietary are seen uith aflUS. it is not associlted \\'ith coagtllation intake. The development of macrocy.tosis over 1 year's time abnormalities. is more consistent with medication effect than vitamin B, Glucocorticoids. suclr as ltredttisr.rnc, rrrlultl bc cott deflciency. siderecl in patients '"r'ith autoitnmune hcntolltic ilnttlliil or immune thrombocltopenic purpura ltut not lt'ith l)l(. rtY Potilts (Option B). These entities Jre n()t itssociatcd uith crugulit . Defining anemia as microc).tic, macrocltic, or nor tion abnormalities or schistocl'tes on thc pcriltheral blood mocytic as well as by reticulocy,te response can nar- smear. row the differential diagnosis. Therapeutic plasnra exchrnge is it tnlinstitl' of tlrcr o Most macrocytic anemias with mean corpuscular vol ap}' in pat ierlts r.r'it h th ronrbt)t ic t ltrornboc)'topen ic l)u rpu rd (TTP) (Option C). Thrombocvlopenia rttrd nticroangiopathic ume values greater than 110 to 115 fL are caused by vitamin B,, or folate deficiency, treatment of HIV hemoll'tic anenria are hallmarks ol 'l'1'l), ltut coagulation infection with antiretroviral therapy, or the antime- abnormalities are not. 'lheralrer.rtic plitsma cxchangc is not used for trcirtnrent oI l)l(]. tabolite hydroxyurea. TEY POIXIS Bibliography . Disseminated intravascular coagulation is character Nagao I Hirokaraa M. Diagnosis and treatment of macrocytic anemias in ized by thrombocytopenia, coagulation abnormalities, adults. J Gen Fam Med. 2017:18:2OO 204. [PMID: 29264027ldoi:lO.lOO2i jgf2.31 hypofi brinogenemia, and microangiopathic hemolyic anemia. Item 49 . Treatment of disseminated intravascular coagulation tr Answer: D Educational Objective: Treat disseminated intravascular focuses on the underlying disorder. coagulation. Bibliography No additional treatment is required fbr this patient's coag Squizzato A, Hunt BJ. Kinase$,itz GT, et al. Supporti\e management strategies for disseminated intravascular coagulation. An intemational consensus. ulopathy (Option D). He has disseminated intravascular Thromb I laemost. 2o16;115:896 9O4. IPMID: 26676927] doi:10.1160/THl5- coagulation (DIC). which has been triggered by sepsis. DIC 09 0740

coagulation. Bibliography No additional treatment is required fbr this patient's coag Squizzato A, Hunt BJ. Kinase$,itz GT, et al. Supporti\e management strategies for disseminated intravascular coagulation. An intemational consensus. ulopathy (Option D). He has disseminated intravascular Thromb I laemost. 2o16;115:896 9O4. IPMID: 26676927] doi:10.1160/THl5- coagulation (DIC). which has been triggered by sepsis. DIC 09 0740 114

Answers and Critiques I Answer: D tr Item 5O Answer: A Educational Obiective: Diagnose cytokine release syn- Item 51 Educational Objective: Evaluate a patient with low-risk drome in a patient undergoing chimeric antigen receptor monoclonal gammopathy of undetermined significance. T*cell therapy. This patient has been found to have a low risk monoclonal The most likely diagnosis in this patiellt is cytokiue release gammopathy of underdetermined signiflcance (MGUS), and syndrome (CRS) (Option A). He lTas relapsed/refractory clinical observation alone is recommended (Option D). No fur acute lymphoblastic leukernia (Al-L) and rccently receivecl ther testing is necessary at this time. MGUS is characterDed by treatment rt,ith chimeric antigen receptor (CAR) T cells tar an M protein level less than 3 g/dl (or less than 500 mgl24hof geting the CD19 antigen on the leukemic cells. CAR'l' cells urinary monoclonal free light chains [FLCs]), clonal plasma cells can expand in the body, driven by the presence of cancer comprising less than 10'X, of the bone marrow cellularity, and cel1s. The treatment is quite effective. and patients with higll the absence of related sigrs and symptoms of end-organ dam- tumor burden. in whom the genetically engineered 1' cells age. The patient's serum hemoglobin, calcium, and creatinine tt (l, effectively expand, may experience a severe inflammatory levels are normal. and she has no skeletal lesions. The chance reaction triggered by the release of inflanrmatory cytokines, ET of progression to multiple myeloma or a lymphoproliferative such as interleukin 6, ar-rd by numerous activated lynrpho cytes and other immune cells. 'lhe clinical presentation of' disorder depends on risk factors. Because her monoclonal pro (, tein spike is less than 1.5 g/dl, and the serum FLCs are normal, CRS can range fron-r mild, with fbver, ntalaise, and myalgia, her risk ofprogression is low (S'2, over 20 years). Patients with =, .E to a severe inflammatory syndrome. Severe CRS requiring MGUS commonly undergo follow up for signs and slmptoms of t q, ICU admissi<tr.r is often characterized by vascular leak, hypo progression, initially at 6 months and then yearly if stable. tensioll, pulmonary edema. cardiac dysfunction, kidney A small subgroup of patients with MGUS may also have t = dysfur.rction, I iver f ailure. coagulopathyl multiorgan systetn kidney disease (monoclonal gammopathy of renal signifi failure. and even death. Treatment protocols ir-rclude early cance). However, this patient's kidney function is normal, supportive care u,ith antipyretics fbr lor,rrer grades o1 CRS and she has no concerning features of a plasma cell dyscra and higl-r doses of glucocorticoids nrith cytokine blocking sia, so kidney biopsy is not indicated (Option A). monoclonal antibodies (e.g.. tocilizumab) lbr higher grades MRI of the spine is not necessary in patients with low of CRS. The patient should also be evaluated ftir infection risk MGUS (Option B). MRI imaging can detect bony lesions related sepsis. earlier than skeletal survey. MRI and CT can be used to risk Progressive leukemia is untikely (Option B).'lhc strati$z patients with smoldering myeloma and may also be decrease in the leukocyte courlt and circulirting lympho important in assessing spinal cord compression in multiple blasts in the peripheral blood suggests an initial response myeloma requiring therapy. to the (CAR) T cell therapy rather than relapsing leukenria. Measurement of serum p, microglobulin is part of risk This patient could derelop tumor lysis svnclrome. but stratiflcation after a diagnosis of multiple myeloma is estab l-ris elevated serum creatinine level is more likely causecl lry lished (Option C). It is not necessary in patients with MGUS. CRS and hypotension considering his norrnal elcctrolyte and XEY POIIITt serum urate levels (Option C). 'lhis patient's high fever. declining lcukocyte count o Monoclonal gammopathy of underdetermined signifi- follor,r'ing CAR T therapy .,1 dalrs agcl, and eler,ated scrur.n cance is characterized by an M protein level less than creatinine level argue more strongly lbr a cliagnosis of CRS 3 g/dl (or less than 500 mg/24 h of urinary monoclonal than venous thron.rboembolism (Option D). free light chains), clonal plasma cells comprising less than 10% of the bone marrow cellularity, and the absence xEv PotxTs of related signs and symptoms of end-organ damage. o Chimeric antigen receptor T cell therapies are highly o Patients with low risk monoclonal gammopathy of effective; however, patients with a high disease burden undetermined significance can be clinically observed may develop dangerous cytokine release syndrome. and do not require follow-up testing. o The clinical presentation of cytokine release syn drome can range from mild, with fever, malaise, and Bibliography myalgia, to a severe inflammatory syndrome charac- Kyle RA, l.arson DR, Therneau TM, et al. l.ong-term fbllow-up of monoclo- terized by vascular leak, hypotension, pulmonary nal gammopathy of undetermined significance. N Engl J Med. 2018; 378:241 249. IPMID: 29342381] doi:10.1056/NEJMoa17}9974 edema, cardiac dysfunction, kidney dysfunction, Iiver failure, coagulopathy, multiorgan system failure, and Item 52 Answer: B even death.

Answer: D tr Item 5O Answer: A Educational Obiective: Diagnose cytokine release syn- Item 51 Educational Objective: Evaluate a patient with low-risk drome in a patient undergoing chimeric antigen receptor monoclonal gammopathy of undetermined significance. T*cell therapy. This patient has been found to have a low risk monoclonal The most likely diagnosis in this patiellt is cytokiue release gammopathy of underdetermined signiflcance (MGUS), and syndrome (CRS) (Option A). He lTas relapsed/refractory clinical observation alone is recommended (Option D). No fur acute lymphoblastic leukernia (Al-L) and rccently receivecl ther testing is necessary at this time. MGUS is characterDed by treatment rt,ith chimeric antigen receptor (CAR) T cells tar an M protein level less than 3 g/dl (or less than 500 mgl24hof geting the CD19 antigen on the leukemic cells. CAR'l' cells urinary monoclonal free light chains [FLCs]), clonal plasma cells can expand in the body, driven by the presence of cancer comprising less than 10'X, of the bone marrow cellularity, and cel1s. The treatment is quite effective. and patients with higll the absence of related sigrs and symptoms of end-organ dam- tumor burden. in whom the genetically engineered 1' cells age. The patient's serum hemoglobin, calcium, and creatinine tt (l, effectively expand, may experience a severe inflammatory levels are normal. and she has no skeletal lesions. The chance reaction triggered by the release of inflanrmatory cytokines, ET of progression to multiple myeloma or a lymphoproliferative such as interleukin 6, ar-rd by numerous activated lynrpho cytes and other immune cells. 'lhe clinical presentation of' disorder depends on risk factors. Because her monoclonal pro (, tein spike is less than 1.5 g/dl, and the serum FLCs are normal, CRS can range fron-r mild, with fbver, ntalaise, and myalgia, her risk ofprogression is low (S'2, over 20 years). Patients with =, .E to a severe inflammatory syndrome. Severe CRS requiring MGUS commonly undergo follow up for signs and slmptoms of t q, ICU admissi<tr.r is often characterized by vascular leak, hypo progression, initially at 6 months and then yearly if stable. tensioll, pulmonary edema. cardiac dysfunction, kidney A small subgroup of patients with MGUS may also have t = dysfur.rction, I iver f ailure. coagulopathyl multiorgan systetn kidney disease (monoclonal gammopathy of renal signifi failure. and even death. Treatment protocols ir-rclude early cance). However, this patient's kidney function is normal, supportive care u,ith antipyretics fbr lor,rrer grades o1 CRS and she has no concerning features of a plasma cell dyscra and higl-r doses of glucocorticoids nrith cytokine blocking sia, so kidney biopsy is not indicated (Option A). monoclonal antibodies (e.g.. tocilizumab) lbr higher grades MRI of the spine is not necessary in patients with low of CRS. The patient should also be evaluated ftir infection risk MGUS (Option B). MRI imaging can detect bony lesions related sepsis. earlier than skeletal survey. MRI and CT can be used to risk Progressive leukemia is untikely (Option B).'lhc strati$z patients with smoldering myeloma and may also be decrease in the leukocyte courlt and circulirting lympho important in assessing spinal cord compression in multiple blasts in the peripheral blood suggests an initial response myeloma requiring therapy. to the (CAR) T cell therapy rather than relapsing leukenria. Measurement of serum p, microglobulin is part of risk This patient could derelop tumor lysis svnclrome. but stratiflcation after a diagnosis of multiple myeloma is estab l-ris elevated serum creatinine level is more likely causecl lry lished (Option C). It is not necessary in patients with MGUS. CRS and hypotension considering his norrnal elcctrolyte and XEY POIIITt serum urate levels (Option C). 'lhis patient's high fever. declining lcukocyte count o Monoclonal gammopathy of underdetermined signifi- follor,r'ing CAR T therapy .,1 dalrs agcl, and eler,ated scrur.n cance is characterized by an M protein level less than creatinine level argue more strongly lbr a cliagnosis of CRS 3 g/dl (or less than 500 mg/24 h of urinary monoclonal than venous thron.rboembolism (Option D). free light chains), clonal plasma cells comprising less than 10% of the bone marrow cellularity, and the absence xEv PotxTs of related signs and symptoms of end-organ damage. o Chimeric antigen receptor T cell therapies are highly o Patients with low risk monoclonal gammopathy of effective; however, patients with a high disease burden undetermined significance can be clinically observed may develop dangerous cytokine release syndrome. and do not require follow-up testing. o The clinical presentation of cytokine release syn drome can range from mild, with fever, malaise, and Bibliography myalgia, to a severe inflammatory syndrome charac- Kyle RA, l.arson DR, Therneau TM, et al. l.ong-term fbllow-up of monoclo- terized by vascular leak, hypotension, pulmonary nal gammopathy of undetermined significance. N Engl J Med. 2018; 378:241 249. IPMID: 29342381] doi:10.1056/NEJMoa17}9974 edema, cardiac dysfunction, kidney dysfunction, Iiver failure, coagulopathy, multiorgan system failure, and Item 52 Answer: B even death. Educational Objective: Treat warm autoimmune tr Bibliography hemolytic anemia with transfusion. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood .2O16;127:3321 30. IPMIDT 272077991 l:irythrocyte trirnsfirsion is thc most appropriate inrnrecli doi:10.1182/blood 2016 04 -703751 ate miulagcment of this patient (Option B). He has warn.r

Educational Objective: Treat warm autoimmune tr Bibliography hemolytic anemia with transfusion. Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood .2O16;127:3321 30. IPMIDT 272077991 l:irythrocyte trirnsfirsion is thc most appropriate inrnrecli doi:10.1182/blood 2016 04 -703751 ate miulagcment of this patient (Option B). He has warn.r 115

Answers and Critiques tr CONI autoimmune hemolytic anemia (WAIHA). Mcnagement of WAItIA includes stabilizing the patient. :rddressing any potential precipitating cause, reducing erythrocyte and the clinicopathologic manif'estation of ll-mphoptas macvtic ll.mphoma. The disease ma1' be indolent and as!'mptomatic. or it mav be associated rvith svstemic destruction. and eradicating the antibodl,. The most press s)'mptoms. such as fever. sr,r'eats. and lteight loss. The ing initial intervention should address patient stabiliza Ig\'t monoclonal protein is quite large and usualll. does tion, which may require transfusion in those u,ith severe not cause severe damagc to thc kidne1.. but kidnel'disease anenria (hemoglobin <7 gldL [70 g,'l-]). hemodvnamic is fbund in approximately :3')1, of patients. Tissue infiltra instability, or significant comorbidities such as cardio tion leads to hepatosplenomegalr,, ll,mphadenopathl'. and pulmonary disease; this patient has all of'these complica gastrointestinal dysfunction. Increased serum viscosit]' tions. The autoantibodies are typically IgG. and some sub from the circulating lgM can lead to h1'pen'iscosilr's1'n types nlay {ix complement. These autoantibodics arc olten drome, four.rd in approximatelv 3O'il, of patients u'ith \\'\4. directed against a core erythrocyte antigen component that Although r-iscositl' measurement can establish the diag is present, as r.r,ell. on almost all donor erythrocytes. mak nosis of hvperviscosit-r, syndrome. treatment should be UI ing them all crossmatch incompatible. Therefbre. if cross initiated based on the patient's svmptoms and findings. match compatible units cannot be identified. type specific H1'pen'iscosity syndrome has various manifestations such = 'D ut blood should be slorvly transfused and the patient closell' as headache. altered mental status. change in r,ision and a, monitored. Although the autoantibody witl shorten the hearing. nystagmus. and ataxia. Funduscopic evaluation CL survival of the transfused cells, the hemoglobin level n,ill ma1' reveal dilated retinal veins. papilledema. and flame a often remain improved for several days, providing signifi hemorrhages. Mucosal bleeding and petechiae are related cant clinical benefit. to platelet dysfunction and d1'sfibrinogenemia. Symptom ll Glucocorticoids and rituximab are eft'ective fbr elimi atic patients i\,ith hyperviscositv svndrome require urgent {D ( nating antibody production in WAIHA. Howcver. use sin treatment with plasmapheresis, lvh ich effi ciently removes gly or in combination does not address the immediate need the IgM paraprotein and reduces serum viscosity rt'ith to improve oxygen delivery in this patient with severe anemia symptom improvement. 'lhe underlf ing disease process and hemodynamic instability (Options A, D). Response rates requires chemotherapl' dirccted against the malignant u,hen glucocorticoids are used as a single agent are more cells. than 80'7,. Ilowever. more than hatf of patients require Hydroxyurea along n'ith leukapheresis rvould be indi additional therapy because of glucocorticoid dependence cated in managing the h1'perleukoc\,tosis s-vndrome that rur relapse. Rituximab can be used in relapsecl or refrac mal.occur in acute leukemia (Option A). It u'ill not affect the tory disease but has been shou,n to improve response rates slonly replicating cells in WN/t and is ineffectire in managing r.t'hen used initially in combination rvith glucocorticoids in h1'pen iscosih svndrome. ne'*,ly diagnosed disease (Option E). Intravenous immune globulin ma1' be indicated in Splenectomy is an effectir,e treatment fbr WAII IA, u,ith patients $'ith plasma cell d1'scrasias rvho have repeated response rates around 75'X, (Option C). lt is typically resened infections related to hypogammaglobulinemia (Option fbr patients who do not respond to glucocorticoids and rit B). It has no role in the treatment of hl'pen,iscositl,'s1'n uximab or who have multiple reiapses. drome. Ultrafiltration is a dialysis technique used in the man IEY POITIS agement of acute kidney injury to remo\e excess fluid . The autoantibody in warm autoimmune hemolytic (Option D). Although the h1'pen'iscositl' syndrome may anemia obscures detection of alloantibodies, compli- result in the expansion of plasma volume and ma1' precipi cating identification of compatible donors. tate or aggravate herrt tailure. plasmapheresis. not ultrafil r Transfusion of type specific blood that is otherwise tration. is the preferred treatment. incompatible may be required in patients with warm f,EY POIXTS autoimmune hemolytic anemia with severe anemia, o In Waldenstr0m macroglobulinemia, the increased symptoms, or significant comorbidities. IgM level may lead to hyperviscosity syndrome, which can manifest as headache, altered mental status, change Bibliography in vision and hearing, nystagmus, and ataxia. Brodsky RA. Warm autoimmune hemolytic anemir. N Fingl J Med. 2019: 381 :647 654. IPMID: 31412178] doi:10.1056/NIlJMcpt9OO554 . Symptomatic patients with hyperviscosity syndrome require urgent treatment with plasmapheresis, which efficiently removes the IgM paraprotein and reduces

tr CONI autoimmune hemolytic anemia (WAIHA). Mcnagement of WAItIA includes stabilizing the patient. :rddressing any potential precipitating cause, reducing erythrocyte and the clinicopathologic manif'estation of ll-mphoptas macvtic ll.mphoma. The disease ma1' be indolent and as!'mptomatic. or it mav be associated rvith svstemic destruction. and eradicating the antibodl,. The most press s)'mptoms. such as fever. sr,r'eats. and lteight loss. The ing initial intervention should address patient stabiliza Ig\'t monoclonal protein is quite large and usualll. does tion, which may require transfusion in those u,ith severe not cause severe damagc to thc kidne1.. but kidnel'disease anenria (hemoglobin <7 gldL [70 g,'l-]). hemodvnamic is fbund in approximately :3')1, of patients. Tissue infiltra instability, or significant comorbidities such as cardio tion leads to hepatosplenomegalr,, ll,mphadenopathl'. and pulmonary disease; this patient has all of'these complica gastrointestinal dysfunction. Increased serum viscosit]' tions. The autoantibodies are typically IgG. and some sub from the circulating lgM can lead to h1'pen'iscosilr's1'n types nlay {ix complement. These autoantibodics arc olten drome, four.rd in approximatelv 3O'il, of patients u'ith \\'\4. directed against a core erythrocyte antigen component that Although r-iscositl' measurement can establish the diag is present, as r.r,ell. on almost all donor erythrocytes. mak nosis of hvperviscosit-r, syndrome. treatment should be UI ing them all crossmatch incompatible. Therefbre. if cross initiated based on the patient's svmptoms and findings. match compatible units cannot be identified. type specific H1'pen'iscosity syndrome has various manifestations such = 'D ut blood should be slorvly transfused and the patient closell' as headache. altered mental status. change in r,ision and a, monitored. Although the autoantibody witl shorten the hearing. nystagmus. and ataxia. Funduscopic evaluation CL survival of the transfused cells, the hemoglobin level n,ill ma1' reveal dilated retinal veins. papilledema. and flame a often remain improved for several days, providing signifi hemorrhages. Mucosal bleeding and petechiae are related cant clinical benefit. to platelet dysfunction and d1'sfibrinogenemia. Symptom ll Glucocorticoids and rituximab are eft'ective fbr elimi atic patients i\,ith hyperviscositv svndrome require urgent {D ( nating antibody production in WAIHA. Howcver. use sin treatment with plasmapheresis, lvh ich effi ciently removes gly or in combination does not address the immediate need the IgM paraprotein and reduces serum viscosity rt'ith to improve oxygen delivery in this patient with severe anemia symptom improvement. 'lhe underlf ing disease process and hemodynamic instability (Options A, D). Response rates requires chemotherapl' dirccted against the malignant u,hen glucocorticoids are used as a single agent are more cells. than 80'7,. Ilowever. more than hatf of patients require Hydroxyurea along n'ith leukapheresis rvould be indi additional therapy because of glucocorticoid dependence cated in managing the h1'perleukoc\,tosis s-vndrome that rur relapse. Rituximab can be used in relapsecl or refrac mal.occur in acute leukemia (Option A). It u'ill not affect the tory disease but has been shou,n to improve response rates slonly replicating cells in WN/t and is ineffectire in managing r.t'hen used initially in combination rvith glucocorticoids in h1'pen iscosih svndrome. ne'*,ly diagnosed disease (Option E). Intravenous immune globulin ma1' be indicated in Splenectomy is an effectir,e treatment fbr WAII IA, u,ith patients $'ith plasma cell d1'scrasias rvho have repeated response rates around 75'X, (Option C). lt is typically resened infections related to hypogammaglobulinemia (Option fbr patients who do not respond to glucocorticoids and rit B). It has no role in the treatment of hl'pen,iscositl,'s1'n uximab or who have multiple reiapses. drome. Ultrafiltration is a dialysis technique used in the man IEY POITIS agement of acute kidney injury to remo\e excess fluid . The autoantibody in warm autoimmune hemolytic (Option D). Although the h1'pen'iscositl' syndrome may anemia obscures detection of alloantibodies, compli- result in the expansion of plasma volume and ma1' precipi cating identification of compatible donors. tate or aggravate herrt tailure. plasmapheresis. not ultrafil r Transfusion of type specific blood that is otherwise tration. is the preferred treatment. incompatible may be required in patients with warm f,EY POIXTS autoimmune hemolytic anemia with severe anemia, o In Waldenstr0m macroglobulinemia, the increased symptoms, or significant comorbidities. IgM level may lead to hyperviscosity syndrome, which can manifest as headache, altered mental status, change Bibliography in vision and hearing, nystagmus, and ataxia. Brodsky RA. Warm autoimmune hemolytic anemir. N Fingl J Med. 2019: 381 :647 654. IPMID: 31412178] doi:10.1056/NIlJMcpt9OO554 . Symptomatic patients with hyperviscosity syndrome require urgent treatment with plasmapheresis, which efficiently removes the IgM paraprotein and reduces tr Item 53 Answer: C Ed ucatio n a I O bjective: Treat hyperviscosity syndrome. serum viscosity.

tr CONI autoimmune hemolytic anemia (WAIHA). Mcnagement of WAItIA includes stabilizing the patient. :rddressing any potential precipitating cause, reducing erythrocyte and the clinicopathologic manif'estation of ll-mphoptas macvtic ll.mphoma. The disease ma1' be indolent and as!'mptomatic. or it mav be associated rvith svstemic destruction. and eradicating the antibodl,. The most press s)'mptoms. such as fever. sr,r'eats. and lteight loss. The ing initial intervention should address patient stabiliza Ig\'t monoclonal protein is quite large and usualll. does tion, which may require transfusion in those u,ith severe not cause severe damagc to thc kidne1.. but kidnel'disease anenria (hemoglobin <7 gldL [70 g,'l-]). hemodvnamic is fbund in approximately :3')1, of patients. Tissue infiltra instability, or significant comorbidities such as cardio tion leads to hepatosplenomegalr,, ll,mphadenopathl'. and pulmonary disease; this patient has all of'these complica gastrointestinal dysfunction. Increased serum viscosit]' tions. The autoantibodies are typically IgG. and some sub from the circulating lgM can lead to h1'pen'iscosilr's1'n types nlay {ix complement. These autoantibodics arc olten drome, four.rd in approximatelv 3O'il, of patients u'ith \\'\4. directed against a core erythrocyte antigen component that Although r-iscositl' measurement can establish the diag is present, as r.r,ell. on almost all donor erythrocytes. mak nosis of hvperviscosit-r, syndrome. treatment should be UI ing them all crossmatch incompatible. Therefbre. if cross initiated based on the patient's svmptoms and findings. match compatible units cannot be identified. type specific H1'pen'iscosity syndrome has various manifestations such = 'D ut blood should be slorvly transfused and the patient closell' as headache. altered mental status. change in r,ision and a, monitored. Although the autoantibody witl shorten the hearing. nystagmus. and ataxia. Funduscopic evaluation CL survival of the transfused cells, the hemoglobin level n,ill ma1' reveal dilated retinal veins. papilledema. and flame a often remain improved for several days, providing signifi hemorrhages. Mucosal bleeding and petechiae are related cant clinical benefit. to platelet dysfunction and d1'sfibrinogenemia. Symptom ll Glucocorticoids and rituximab are eft'ective fbr elimi atic patients i\,ith hyperviscositv svndrome require urgent {D ( nating antibody production in WAIHA. Howcver. use sin treatment with plasmapheresis, lvh ich effi ciently removes gly or in combination does not address the immediate need the IgM paraprotein and reduces serum viscosity rt'ith to improve oxygen delivery in this patient with severe anemia symptom improvement. 'lhe underlf ing disease process and hemodynamic instability (Options A, D). Response rates requires chemotherapl' dirccted against the malignant u,hen glucocorticoids are used as a single agent are more cells. than 80'7,. Ilowever. more than hatf of patients require Hydroxyurea along n'ith leukapheresis rvould be indi additional therapy because of glucocorticoid dependence cated in managing the h1'perleukoc\,tosis s-vndrome that rur relapse. Rituximab can be used in relapsecl or refrac mal.occur in acute leukemia (Option A). It u'ill not affect the tory disease but has been shou,n to improve response rates slonly replicating cells in WN/t and is ineffectire in managing r.t'hen used initially in combination rvith glucocorticoids in h1'pen iscosih svndrome. ne'*,ly diagnosed disease (Option E). Intravenous immune globulin ma1' be indicated in Splenectomy is an effectir,e treatment fbr WAII IA, u,ith patients $'ith plasma cell d1'scrasias rvho have repeated response rates around 75'X, (Option C). lt is typically resened infections related to hypogammaglobulinemia (Option fbr patients who do not respond to glucocorticoids and rit B). It has no role in the treatment of hl'pen,iscositl,'s1'n uximab or who have multiple reiapses. drome. Ultrafiltration is a dialysis technique used in the man IEY POITIS agement of acute kidney injury to remo\e excess fluid . The autoantibody in warm autoimmune hemolytic (Option D). Although the h1'pen'iscositl' syndrome may anemia obscures detection of alloantibodies, compli- result in the expansion of plasma volume and ma1' precipi cating identification of compatible donors. tate or aggravate herrt tailure. plasmapheresis. not ultrafil r Transfusion of type specific blood that is otherwise tration. is the preferred treatment. incompatible may be required in patients with warm f,EY POIXTS autoimmune hemolytic anemia with severe anemia, o In Waldenstr0m macroglobulinemia, the increased symptoms, or significant comorbidities. IgM level may lead to hyperviscosity syndrome, which can manifest as headache, altered mental status, change Bibliography in vision and hearing, nystagmus, and ataxia. Brodsky RA. Warm autoimmune hemolytic anemir. N Fingl J Med. 2019: 381 :647 654. IPMID: 31412178] doi:10.1056/NIlJMcpt9OO554 . Symptomatic patients with hyperviscosity syndrome require urgent treatment with plasmapheresis, which efficiently removes the IgM paraprotein and reduces tr Item 53 Answer: C Ed ucatio n a I O bjective: Treat hyperviscosity syndrome. serum viscosity. thc most appropriate immediate therapy is plasmapher Bibliography Castillo JJ. Treon SP Management of Waldenstrom macroglobulinemia in esis (Option C). This patient has WaldenstrOm nlacro 2020. Hematolos/ Am Soc Ilemak)l liduc Program. 2O2O;202O:372 379. globulinemia (WM). an IgM monoclonal gammopathy IPMID: 33275726] doi: 10.1 182/hemak)loS/.2020000121

thc most appropriate immediate therapy is plasmapher Bibliography Castillo JJ. Treon SP Management of Waldenstrom macroglobulinemia in esis (Option C). This patient has WaldenstrOm nlacro 2020. Hematolos/ Am Soc Ilemak)l liduc Program. 2O2O;202O:372 379. globulinemia (WM). an IgM monoclonal gammopathy IPMID: 33275726] doi: 10.1 182/hemak)loS/.2020000121 116 I

h, Answers and Critiques tr Item 54 Answer: A Educational Objective: Treat acute pulmonary embolism I(EY POIilTS . For patients with venous thromboembolism, the in a patient requiring hospitalization. American Society of Hematologz suggests using direct oral anticoagulants, such as apixaban, rivaroxaban, Thc nrost appropriate treatnrent lbr this patient is apix dabigatran, and edoxaban, over vitamin K antagonists, ahan (Option A). Furthernrore, she has a score of I (putse such as warfarin. ratc >110,nrin) on thc simplifiecl Pulmonary Embolism Sevcrity lnclex (PFISI), which placcs her at high risk Ibr o Dabigatran and edoxaban, like warfarin, require a adverse outcomes irnd necessitates treatment in the transition period with parenteral therapy before con- hospital. Apixaban is a direct factor Xa inhibitor that is tinuing oral treatment. approved to treat acute venous thromboembolism (V'l'tj) rvithout concomitant parentcral thcrapy on initiation; Bibliography it cln be uscd in patients with kidney injury ancl does Ortel TI-. Neumann I, Ageno W et al. American Society of Hematolos/ 2020 UI (l, guidelines for nranagement of venous thromboemholism: Treatment of nol require dose adjustmenl lor VTI,. treatmcnt, cven in deep vein thrombosis and pulmonary embolism. t3lrxrd Adv 2020;4:469:l ET patients undergoing dialysis. Rivaroraban, another clirect ,17i18. PMID: i3OO7O77l doi: l0.11821bloodadvances.202000l830 J

tr Item 54 Answer: A Educational Objective: Treat acute pulmonary embolism I(EY POIilTS . For patients with venous thromboembolism, the in a patient requiring hospitalization. American Society of Hematologz suggests using direct oral anticoagulants, such as apixaban, rivaroxaban, Thc nrost appropriate treatnrent lbr this patient is apix dabigatran, and edoxaban, over vitamin K antagonists, ahan (Option A). Furthernrore, she has a score of I (putse such as warfarin. ratc >110,nrin) on thc simplifiecl Pulmonary Embolism Sevcrity lnclex (PFISI), which placcs her at high risk Ibr o Dabigatran and edoxaban, like warfarin, require a adverse outcomes irnd necessitates treatment in the transition period with parenteral therapy before con- hospital. Apixaban is a direct factor Xa inhibitor that is tinuing oral treatment. approved to treat acute venous thromboembolism (V'l'tj) rvithout concomitant parentcral thcrapy on initiation; Bibliography it cln be uscd in patients with kidney injury ancl does Ortel TI-. Neumann I, Ageno W et al. American Society of Hematolos/ 2020 UI (l, guidelines for nranagement of venous thromboemholism: Treatment of nol require dose adjustmenl lor VTI,. treatmcnt, cven in deep vein thrombosis and pulmonary embolism. t3lrxrd Adv 2020;4:469:l ET patients undergoing dialysis. Rivaroraban, another clirect ,17i18. PMID: i3OO7O77l doi: l0.11821bloodadvances.202000l830 J factor Xa inhibitor. woulcl alsri bc a treatrnent option rJ fbr this patient. For patients with VTE, the Americln E E Society'of llematolog'(ASll) suggcsts using direct oral Item 55 Answer: A ag vt anticoagulants (DOACs), such as apixaban, rivarox:tban, dahigatran, and edoxaban, over vitamin K antagonists, Educational Objective: Manage cold agglutinin disease. o vt = such as u,arlarin. Dabigatran and ecloxlban. like u'arf lrin, The most appropriate management is to obtain cold agglu g require a transition period with parenteral therapy befitre tinin titers (Option A). This patient's laboratory flndings continuing lhe oral lreatment. are consistent with cold agllutinin hemolytic anemia. Cold l'irr patients u,ith \zTE ancl significant preexisting car- agglutinins are IgM antibodies that can cause erythrocyte diopulmonrry cliseasc, as well as for patients with pulmo agglutination and hemolytic anemia, with extravascular nary embolisrn (PE) and hernodynamic cclmpromise, the hemolysis driven by complement flxation. In cold agglutinin ASll guidelinc suggcsts anticoagulation alone rather than disease, the direct antiglobulin test result is positive for anti anticoagulation plus insertion olan intbrior vena cava (lVC) complement (C:) and negative for anti IgG. Cold agpllutinin filter: the guideline also suglgcsts that an IVC filter may be hemolytic anemia can arise as a primary process or second consiclcred in patients u,ith an absolute, contraindication ary to an underlying condition such as infection, lympho to anticoagulation. '[his patient has no contraindication to proliferative disorders, or autoimmune disease. Mgcoplasma anticoagulati<)n, so iln I\C filter r.toultl not be inclicated pneumoniae is a common infectious issue associated with (Option B). Studies have shown that. in patients',vith severe development of cold agglutinins. This may arise because the PIl. the use of an IVC filter with anticoagulation cloes not lead organism causes alterations in antigens on the erythrocyte to a reduction in sympk)matic recurrent PE compared w,ith membrane to which IgM autoantibodies are directed. The anticoagulation alone. so it should not be recommencled in hemolysis associated with M. pneumoniae is often mild this patient. and self limited. Based on her symptoms of cough and fever l)irected thrombolytic therap!' is generally recom and their resolution with a macrolide. this patient may have mended in the setting of massive [)[,. resulting in shock, had preceding M. pneumonioe infection. The presence of hypotension. or severe carcliac compromise (profbund a cold agglutinin can be conflrmed by checking a titer, braclycardia or pulselessness) (Option C). I.irr paticnts whereby the ability ofl the patient's serum to agglutinate with PE and echocardiogrrrphic evidence or biomark erythrocytes is evaluated through serial dilutions. ers compalible nrith right ventricular dysfunction with Some interest exists in developing anticomplement out hemodynamic compromise (submassive PF.). the therapies for cold agglutinin disease, with promising agents AStl guideline suggests anticoagulation alonc insteacl of directed at Cl and C3. Eculizumab is an anticomplement throntbolytic therapy and anticoagulation.'l'his patient drug that targets C5, so it would not be as useful in cold does not have massir,'e PE, so thronrbolytic therapy would agglutinin disease because the hemolysis occurs from earlier not be appropriate. components in the complement pathway (Option B). Eculi Parenteral therapl- with unlractionated heparin zumab is approved for use in paroxysmal nocturnal hemo (L, FII) is not pref'errcd, because variations in bioavailabil globinuria (PNH) and atypical hemolytic uremic syndronte ity and potcntial dclay in arriving irt a therapeutic close but not in cold agglutinin disease. are nlore likely than with lou, molecular lveight heparin Detection of CD55 and CD59 by flow cytometry would ([-MWII) or a DOAC (Option D). UI.H shoulcl therefbre be appropriate ifPNH were a concern, but that is not the case be reserved fbr patients lbr whom I.MWH is contraincli with this patient whose direct antiglobulin test results are cated or in those nho requirc anticoagulatior-r that can be consistent with a cold agglutinin process (Option C). stopped quickll', genc'rally in anticipation of an invlsive lf treatment for primary cold aggtutinin hemolytic procedure or surgery. anemia is needed, a rituximab based regimen is preferred.

factor Xa inhibitor. woulcl alsri bc a treatrnent option rJ fbr this patient. For patients with VTE, the Americln E E Society'of llematolog'(ASll) suggcsts using direct oral Item 55 Answer: A ag vt anticoagulants (DOACs), such as apixaban, rivarox:tban, dahigatran, and edoxaban, over vitamin K antagonists, Educational Objective: Manage cold agglutinin disease. o vt = such as u,arlarin. Dabigatran and ecloxlban. like u'arf lrin, The most appropriate management is to obtain cold agglu g require a transition period with parenteral therapy befitre tinin titers (Option A). This patient's laboratory flndings continuing lhe oral lreatment. are consistent with cold agllutinin hemolytic anemia. Cold l'irr patients u,ith \zTE ancl significant preexisting car- agglutinins are IgM antibodies that can cause erythrocyte diopulmonrry cliseasc, as well as for patients with pulmo agglutination and hemolytic anemia, with extravascular nary embolisrn (PE) and hernodynamic cclmpromise, the hemolysis driven by complement flxation. In cold agglutinin ASll guidelinc suggcsts anticoagulation alone rather than disease, the direct antiglobulin test result is positive for anti anticoagulation plus insertion olan intbrior vena cava (lVC) complement (C:) and negative for anti IgG. Cold agpllutinin filter: the guideline also suglgcsts that an IVC filter may be hemolytic anemia can arise as a primary process or second consiclcred in patients u,ith an absolute, contraindication ary to an underlying condition such as infection, lympho to anticoagulation. '[his patient has no contraindication to proliferative disorders, or autoimmune disease. Mgcoplasma anticoagulati<)n, so iln I\C filter r.toultl not be inclicated pneumoniae is a common infectious issue associated with (Option B). Studies have shown that. in patients',vith severe development of cold agglutinins. This may arise because the PIl. the use of an IVC filter with anticoagulation cloes not lead organism causes alterations in antigens on the erythrocyte to a reduction in sympk)matic recurrent PE compared w,ith membrane to which IgM autoantibodies are directed. The anticoagulation alone. so it should not be recommencled in hemolysis associated with M. pneumoniae is often mild this patient. and self limited. Based on her symptoms of cough and fever l)irected thrombolytic therap!' is generally recom and their resolution with a macrolide. this patient may have mended in the setting of massive [)[,. resulting in shock, had preceding M. pneumonioe infection. The presence of hypotension. or severe carcliac compromise (profbund a cold agglutinin can be conflrmed by checking a titer, braclycardia or pulselessness) (Option C). I.irr paticnts whereby the ability ofl the patient's serum to agglutinate with PE and echocardiogrrrphic evidence or biomark erythrocytes is evaluated through serial dilutions. ers compalible nrith right ventricular dysfunction with Some interest exists in developing anticomplement out hemodynamic compromise (submassive PF.). the therapies for cold agglutinin disease, with promising agents AStl guideline suggests anticoagulation alonc insteacl of directed at Cl and C3. Eculizumab is an anticomplement throntbolytic therapy and anticoagulation.'l'his patient drug that targets C5, so it would not be as useful in cold does not have massir,'e PE, so thronrbolytic therapy would agglutinin disease because the hemolysis occurs from earlier not be appropriate. components in the complement pathway (Option B). Eculi Parenteral therapl- with unlractionated heparin zumab is approved for use in paroxysmal nocturnal hemo (L, FII) is not pref'errcd, because variations in bioavailabil globinuria (PNH) and atypical hemolytic uremic syndronte ity and potcntial dclay in arriving irt a therapeutic close but not in cold agglutinin disease. are nlore likely than with lou, molecular lveight heparin Detection of CD55 and CD59 by flow cytometry would ([-MWII) or a DOAC (Option D). UI.H shoulcl therefbre be appropriate ifPNH were a concern, but that is not the case be reserved fbr patients lbr whom I.MWH is contraincli with this patient whose direct antiglobulin test results are cated or in those nho requirc anticoagulatior-r that can be consistent with a cold agglutinin process (Option C). stopped quickll', genc'rally in anticipation of an invlsive lf treatment for primary cold aggtutinin hemolytic procedure or surgery. anemia is needed, a rituximab based regimen is preferred. 117

Answers and Critiques a 1 Treatment with glucocorticoids, intravenous immune glob if the D dimer is elevated or the patient has a moderate to ulin, or splenectomy is seldom effective in cold agglutinin high pretest probability based on Wells criteria. hemolyic anemia (Option D). Although PE is not the likely cause of his symptoms, :

1 Treatment with glucocorticoids, intravenous immune glob if the D dimer is elevated or the patient has a moderate to ulin, or splenectomy is seldom effective in cold agglutinin high pretest probability based on Wells criteria. hemolyic anemia (Option D). Although PE is not the likely cause of his symptoms, : this patient will require further testing to evaluate the cause f,EY POITIS i of his dyspnea (Option D). For patients who present with o In patients with hemolytic anemia and a positive symptoms suspicious for an acute PE, validated prediction direct antiglobulin test to anticomplement (C3) but rules have been developed to help effectively evaluate this not IgG, the diagnosis ofcold agglutinin disease can condition. The Wells criteria for PE and the Geneva Score by confirmed by a cold agglutinin titer. for PE are well studied tools in this setting. A subset of . Cold agglutinin hemolytic anemia can arise as a pri- patients at very low risk can be identified using the PERC mary process or secondary to an underlying condition score. These prediction rules should be used to effectively such as infection, lymphoproliferative disorders, or and cost-efficiently evaluate suspected PE. autoimmune disease. TEY POIXTT Ut o For patients who present with symptoms suspicious .D = Bibliography ur for an acute pulmonary embolism, validated predic- Berentsen S. How I manage patients with cold agglutinin disease. Br J o, tion rules should be used to help effectively and cost Haematol. 2018;181:320 330. IPMID: 29363757] doi:10.111i /bjh.l5109 TL efficiently evaluate this condition. n o Patients with a Pulmonary Embolism Rule-Out Criteria lt Item 56 Answer: C score ofzero have a very low pretest probability ofpul- (D Ed ucati o na I O bjective : Evaluate low-risk pulmonary monary embolism (PE) and require no further testing (,I embolism with Pulmonary Embolism Rule-Out Criteria for PE. score.

this patient will require further testing to evaluate the cause f,EY POITIS i of his dyspnea (Option D). For patients who present with o In patients with hemolytic anemia and a positive symptoms suspicious for an acute PE, validated prediction direct antiglobulin test to anticomplement (C3) but rules have been developed to help effectively evaluate this not IgG, the diagnosis ofcold agglutinin disease can condition. The Wells criteria for PE and the Geneva Score by confirmed by a cold agglutinin titer. for PE are well studied tools in this setting. A subset of . Cold agglutinin hemolytic anemia can arise as a pri- patients at very low risk can be identified using the PERC mary process or secondary to an underlying condition score. These prediction rules should be used to effectively such as infection, lymphoproliferative disorders, or and cost-efficiently evaluate suspected PE. autoimmune disease. TEY POIXTT Ut o For patients who present with symptoms suspicious .D = Bibliography ur for an acute pulmonary embolism, validated predic- Berentsen S. How I manage patients with cold agglutinin disease. Br J o, tion rules should be used to help effectively and cost Haematol. 2018;181:320 330. IPMID: 29363757] doi:10.111i /bjh.l5109 TL efficiently evaluate this condition. n o Patients with a Pulmonary Embolism Rule-Out Criteria lt Item 56 Answer: C score ofzero have a very low pretest probability ofpul- (D Ed ucati o na I O bjective : Evaluate low-risk pulmonary monary embolism (PE) and require no further testing (,I embolism with Pulmonary Embolism Rule-Out Criteria for PE. score. The most appropriate management is to calculate the Pulmo Bibliography Lim W Le Gal G, Bates SM, et al. American Society of Hematolos/ 2018 guide nary Embolism Rule-Out Criteria (PERC) score (Option C). lines for management of venous thromboembolism: Diagnosis of venous Guidelines recommend using the PERC as the initial step thromboembolism. Blood Adv. 2018;2:3226 3256. [PMID, 30482764) in evaluating patients at low risk for pulmonary embolism doi:10.11 82/bloodadvances.20l 8024828

The most appropriate management is to calculate the Pulmo Bibliography Lim W Le Gal G, Bates SM, et al. American Society of Hematolos/ 2018 guide nary Embolism Rule-Out Criteria (PERC) score (Option C). lines for management of venous thromboembolism: Diagnosis of venous Guidelines recommend using the PERC as the initial step thromboembolism. Blood Adv. 2018;2:3226 3256. [PMID, 30482764) in evaluating patients at low risk for pulmonary embolism doi:10.11 82/bloodadvances.20l 8024828 (PE). The PERC includes eight criteria. With a PERC score of zero, D-dimer testing and CT angiography should not Item 57 be performed. A meta-analysis of 12 studies showed that if the PERC is used, only 0.3'X, of PEs would be missed and Answer: D Educational Objective: Manage sickle cell anemia tr 22"/,, of D-dimer testing would have been safely avoided. perioperatively. This patient meets no PERC criteria (score = 0), so he has Preoperative simple transtusion should be performed. tar a low pretest probability of PE and requires no additional geting a l.remoglobin level ol 10 g dt- (100 g L) (Option D). PE-related testing. Sickle cell disease (SCD) carries an increased risk <tf periop erative complications with surgeries othcr than lorv risk Pulmonary Embolism Rule-Out Criteria procedures (e.g.. skin biopsl'). This increased risk is partic Age <50 y ularly true in thosc with hemoglobin SS or hemoglobin Sp' lnitial heart rate <100 beats/min disease. Evidence based care fbr patients u'ith hemoglobirt lnitial oxygen saturation >947o on room air SS diseasc undergoing surgeries other than lou'risk prrt cedures is to provide sinrple erythrocyte transfusion. This No unilateral leg swelling rccommendation is based on results from a clinical trial in No hemoptysis which patients $'ere randomizecl either to no transfusion No surgery or trauma within 4 weeks or to simple transtusion to achieve a hemoglobir.r level of' No history of venous thromboembolism 10 g dl. (100 g L) preoperatively A significant increase irr No estrogen use serious adverse events u'as seen in those u,ho did not receive transfusion. Patients lvho receivecl transfusion rlso had a In patients at low risk according to Wells criteria with lou,er incidence of developing acute chest sl ndrome. \o data a PERC score greater than zero, D-dimer testing should are available on outcomes using postoperati\,e transfusion be performed (Option A). If D-dimer is negative, then no (Option A). additional testing is required. If D-dimer is positive, further llydroryurea reduces vaso occlusive e\ents in SCD. evaluation with imaging is merited. u,ith some data demonstrating improved sunival u'ith In a patient with a PERC score of zero, duplex imaging Iong term use. Its efficacl'appears to be partialll relatecl would not be appropriate to perform next; D dimer level to increasing hemoglobin F production and decreasing should be measured instead (Option B). In patients with a the relative concentration of hemoglobin S. It should bc PERC score greater than 0, duplex imaging may be necessary considercd fbr usc in adtrlts who have signiflcant clinical

(PE). The PERC includes eight criteria. With a PERC score of zero, D-dimer testing and CT angiography should not Item 57 be performed. A meta-analysis of 12 studies showed that if the PERC is used, only 0.3'X, of PEs would be missed and Answer: D Educational Objective: Manage sickle cell anemia tr 22"/,, of D-dimer testing would have been safely avoided. perioperatively. This patient meets no PERC criteria (score = 0), so he has Preoperative simple transtusion should be performed. tar a low pretest probability of PE and requires no additional geting a l.remoglobin level ol 10 g dt- (100 g L) (Option D). PE-related testing. Sickle cell disease (SCD) carries an increased risk <tf periop erative complications with surgeries othcr than lorv risk Pulmonary Embolism Rule-Out Criteria procedures (e.g.. skin biopsl'). This increased risk is partic Age <50 y ularly true in thosc with hemoglobin SS or hemoglobin Sp' lnitial heart rate <100 beats/min disease. Evidence based care fbr patients u'ith hemoglobirt lnitial oxygen saturation >947o on room air SS diseasc undergoing surgeries other than lou'risk prrt cedures is to provide sinrple erythrocyte transfusion. This No unilateral leg swelling rccommendation is based on results from a clinical trial in No hemoptysis which patients $'ere randomizecl either to no transfusion No surgery or trauma within 4 weeks or to simple transtusion to achieve a hemoglobir.r level of' No history of venous thromboembolism 10 g dl. (100 g L) preoperatively A significant increase irr No estrogen use serious adverse events u'as seen in those u,ho did not receive transfusion. Patients lvho receivecl transfusion rlso had a In patients at low risk according to Wells criteria with lou,er incidence of developing acute chest sl ndrome. \o data a PERC score greater than zero, D-dimer testing should are available on outcomes using postoperati\,e transfusion be performed (Option A). If D-dimer is negative, then no (Option A). additional testing is required. If D-dimer is positive, further llydroryurea reduces vaso occlusive e\ents in SCD. evaluation with imaging is merited. u,ith some data demonstrating improved sunival u'ith In a patient with a PERC score of zero, duplex imaging Iong term use. Its efficacl'appears to be partialll relatecl would not be appropriate to perform next; D dimer level to increasing hemoglobin F production and decreasing should be measured instead (Option B). In patients with a the relative concentration of hemoglobin S. It should bc PERC score greater than 0, duplex imaging may be necessary considercd fbr usc in adtrlts who have signiflcant clinical 118 t

Answers and Critiques FII r.nanifc'strltions. includir.rg three or tnore painful vascl Il thc decision were milde to remove the catheter, the Ll r,cclusirc evenls per )'ear. Httrtever. l-tvciroxyurea usc has patient should receive 3 mottths ol anticoagulation. [lor'r' CONT not been stucliecl specifically tbr the perioperirtilr setting ever. catheter removal is not indicatecl, and thc catheter is 'lhercfilre, (Option B). Benefits are tyltically seen with chrot.tic use, required kl deliver extendcd antibiotic therapy. and it is unlikely to havc a positive eftect fbr this piltient rcrroving the catheter ancl providing anticoagulation is not harring r srlrgery in I rt'eck. thc besl option (Option C). A more aggrcssive upproach using exchirnge transfu thrombolytic therapy shtluld not be considered in this sion to reduce the hcnioglobin S to less thirn ll0'll, is no nrore patient, although it n.ray be appropriatc in patients with tho eflectile at reclucing acivcrsc outcolres rt'ith surgerl' than racic outlet syndrome. severe symptonls, or concern fbr Iitn[.1 preoperative sin.rple transf usion, including no di{feretrce in ischemir (Option D). None of these conditiolls are present. rates of lcute chcst syndror.ne (Option C). Additirtnally, f!1a,s1 t(EY P0lilrt 1ranstusion relltccl complicatior-rs lre experiencecl in those rvho receive sirrrplc translusion. o In patients who have upper extremity thrombosis (a associated with a central venous catheter that is o I( EY PO I l{IS ET removed, guidelines recommend 3 months of antico- . Sickle cell disease carries an increased risk ofperiop- agulation. TJ erative complications with surgeries other than low- o In patients who have upper extremity thrombosis that !tE risk procedures. .! is associated with a central venous catheter that is not . Patients with sickle cell disease, particularly hemo- removed, guidelines recommend that anticoagulation UI (u globin SS disease, benefit from preoperative simple be continued as long as the central venous catheter Ut transfusion to achieve a hemoglobin level of 10 g/dl remains in place. = (1oo s/L). Bibliography Bibliography Debourdeau B Farge D, Beckers M, et al. International clinical practice Davis BA, Allard S, Qureshi A, et al; British Society fbr Haematobry. guidelines for the treatment and prophylaxis of thrombosis associated Guidelines on red cell transfusion in sickle cell disease part II: Indications with central venous catheters in patients with cancer. J Thromb Haemost. for transtusion. Ilr J Haematol. 2Ol7:776:192 209. IPMID: 278589941 2013;11 :71 80. [PMI D: 23217208] doi:10.1111 /jth.12071 doi:1 0.1 111 /bjh.14:)8:3

FII r.nanifc'strltions. includir.rg three or tnore painful vascl Il thc decision were milde to remove the catheter, the Ll r,cclusirc evenls per )'ear. Httrtever. l-tvciroxyurea usc has patient should receive 3 mottths ol anticoagulation. [lor'r' CONT not been stucliecl specifically tbr the perioperirtilr setting ever. catheter removal is not indicatecl, and thc catheter is 'lhercfilre, (Option B). Benefits are tyltically seen with chrot.tic use, required kl deliver extendcd antibiotic therapy. and it is unlikely to havc a positive eftect fbr this piltient rcrroving the catheter ancl providing anticoagulation is not harring r srlrgery in I rt'eck. thc besl option (Option C). A more aggrcssive upproach using exchirnge transfu thrombolytic therapy shtluld not be considered in this sion to reduce the hcnioglobin S to less thirn ll0'll, is no nrore patient, although it n.ray be appropriatc in patients with tho eflectile at reclucing acivcrsc outcolres rt'ith surgerl' than racic outlet syndrome. severe symptonls, or concern fbr Iitn[.1 preoperative sin.rple transf usion, including no di{feretrce in ischemir (Option D). None of these conditiolls are present. rates of lcute chcst syndror.ne (Option C). Additirtnally, f!1a,s1 t(EY P0lilrt 1ranstusion relltccl complicatior-rs lre experiencecl in those rvho receive sirrrplc translusion. o In patients who have upper extremity thrombosis (a associated with a central venous catheter that is o I( EY PO I l{IS ET removed, guidelines recommend 3 months of antico- . Sickle cell disease carries an increased risk ofperiop- agulation. TJ erative complications with surgeries other than low- o In patients who have upper extremity thrombosis that !tE risk procedures. .! is associated with a central venous catheter that is not . Patients with sickle cell disease, particularly hemo- removed, guidelines recommend that anticoagulation UI (u globin SS disease, benefit from preoperative simple be continued as long as the central venous catheter Ut transfusion to achieve a hemoglobin level of 10 g/dl remains in place. = (1oo s/L). Bibliography Bibliography Debourdeau B Farge D, Beckers M, et al. International clinical practice Davis BA, Allard S, Qureshi A, et al; British Society fbr Haematobry. guidelines for the treatment and prophylaxis of thrombosis associated Guidelines on red cell transfusion in sickle cell disease part II: Indications with central venous catheters in patients with cancer. J Thromb Haemost. for transtusion. Ilr J Haematol. 2Ol7:776:192 209. IPMID: 278589941 2013;11 :71 80. [PMI D: 23217208] doi:10.1111 /jth.12071 doi:1 0.1 111 /bjh.14:)8:3 Item 59 Answer: B tr Item 58 Answer: A Educational Objective: Treat an upper extremity deep Educational Objective: Treat iron deficiency anemia. Beginning oral iron replacement therapy every other day is venous thrombosis with anticoagulation. the most appropriate management option for this patient 'lhe nrost appropriate llraltagelrcnt is itrlticoirguliition (Option B). A low mean corpuscular volume, elevated (Option A). Eviclcnce regar-dir-rg the proper managentellt red cell distribution width, and peripheral blood smear ol catheter relatrcl throntltosis is sparse ar-rd u,eak. Many showing microcytosis and anisopoikilocytosis are virtually of the re-comr-nendations ltrcr-rs on piltients u,ith cancer. ln diagnostic of iron deflciency, especially in premenopausal general. central vclious crtheters ((lv(ls) thit are associirted women; these flndings may obviate the need for additional rt'ith upper extremity thrornbclsis cuu remlin in placc as laboratory testing provided that a follow up blood count long as the catheter is lur.rctioning. rernains wcll positioned. is performed to assess response to iron therapy. Even in and is not infected. [n patients wl.ro have upper extrcntity developed nations, iron deficiency may be present in 2O'k thrombosis associateci with a CV(l that is rcr.nored, guicle to 30% of otherwise healthy women of childbearing age. lines rccornmer-rcl ll months ol anticoagulation over a krnger Menstrual iron Ioss is the most common cause of anemia duration ol therirpyr ln patients r,vho have uplrer extrernity in this population. Iron deflciency anemia is also a common thrombosis that is associated u,ith a (lV(l thal is not removed. pregnancy complication because of the heightened iron guidelines recornrnend that anticoagulatior.r be continuccl as requirements that occur in the second and third trimestersl long as the CVC remains in place. lhis ilatient urill reqr-rire it can be further exacerbated by inadequate oral iron intake lnticoagulatir>n wl.rile the catheter is in place ftlr thc next because of nausea and vomiting. Iron deflciency is typically .1 rveeks to comple te 6 r,r'ecks of'antibiotic therupll Atter thc treated with oral iron salts. Frequent dosing (two or three catheter is removed, anticoxgLllation shoulcl be providerl fbr times daily) of oral iron can lead to increased hepcidin pro- an aclclitional 2 rnonths kl complete a total of ll months of duction, which actually reduces iron absorption (Option C). anticoagu latior.r. For this reason, a single daily or every-other-day dose of oral 'lhis patient has a fLnctioning. rvell positioned. and iron sulfate may be the best replacement dose. noninfbctcd CVC. She requires an lclditior.ral 4 weeks ol Gastrointestinal iron loss is a common cause of anemia antibiotic therapy Unless circumstances change. this patient in adults. Considering her age and lack of suggestive symp does not require removirl of the cirtheter but doe's recluire toms, this patient is more likely to have iron deficiency from anticoagulation while thc catheter is in place (Option li). menstrual Iosses before pregnancy and from the heightened

Item 59 Answer: B tr Item 58 Answer: A Educational Objective: Treat an upper extremity deep Educational Objective: Treat iron deficiency anemia. Beginning oral iron replacement therapy every other day is venous thrombosis with anticoagulation. the most appropriate management option for this patient 'lhe nrost appropriate llraltagelrcnt is itrlticoirguliition (Option B). A low mean corpuscular volume, elevated (Option A). Eviclcnce regar-dir-rg the proper managentellt red cell distribution width, and peripheral blood smear ol catheter relatrcl throntltosis is sparse ar-rd u,eak. Many showing microcytosis and anisopoikilocytosis are virtually of the re-comr-nendations ltrcr-rs on piltients u,ith cancer. ln diagnostic of iron deflciency, especially in premenopausal general. central vclious crtheters ((lv(ls) thit are associirted women; these flndings may obviate the need for additional rt'ith upper extremity thrornbclsis cuu remlin in placc as laboratory testing provided that a follow up blood count long as the catheter is lur.rctioning. rernains wcll positioned. is performed to assess response to iron therapy. Even in and is not infected. [n patients wl.ro have upper extrcntity developed nations, iron deficiency may be present in 2O'k thrombosis associateci with a CV(l that is rcr.nored, guicle to 30% of otherwise healthy women of childbearing age. lines rccornmer-rcl ll months ol anticoagulation over a krnger Menstrual iron Ioss is the most common cause of anemia duration ol therirpyr ln patients r,vho have uplrer extrernity in this population. Iron deflciency anemia is also a common thrombosis that is associated u,ith a (lV(l thal is not removed. pregnancy complication because of the heightened iron guidelines recornrnend that anticoagulatior.r be continuccl as requirements that occur in the second and third trimestersl long as the CVC remains in place. lhis ilatient urill reqr-rire it can be further exacerbated by inadequate oral iron intake lnticoagulatir>n wl.rile the catheter is in place ftlr thc next because of nausea and vomiting. Iron deflciency is typically .1 rveeks to comple te 6 r,r'ecks of'antibiotic therupll Atter thc treated with oral iron salts. Frequent dosing (two or three catheter is removed, anticoxgLllation shoulcl be providerl fbr times daily) of oral iron can lead to increased hepcidin pro- an aclclitional 2 rnonths kl complete a total of ll months of duction, which actually reduces iron absorption (Option C). anticoagu latior.r. For this reason, a single daily or every-other-day dose of oral 'lhis patient has a fLnctioning. rvell positioned. and iron sulfate may be the best replacement dose. noninfbctcd CVC. She requires an lclditior.ral 4 weeks ol Gastrointestinal iron loss is a common cause of anemia antibiotic therapy Unless circumstances change. this patient in adults. Considering her age and lack of suggestive symp does not require removirl of the cirtheter but doe's recluire toms, this patient is more likely to have iron deficiency from anticoagulation while thc catheter is in place (Option li). menstrual Iosses before pregnancy and from the heightened 119

Answers and Critiques iron requirements during pregnancy rather than from gas vitamin K antagonists like warfarin in patients with early trointestinal iron loss. A 2020 guideline from the Ameri stage chronic kidney disease (estimated glomerular filtra can Gastroenterological Association notes that patients who tion rate <60 ml/min/1.73 nt2) and atrial flbrillation. A key place a high value on avoiding the smalt risk of endoscopy, finding h,as that DOACS were associated r,r,ith relative risk particularly those who are young and might have other plau reductions of 21"1, for stroke or systemic embolism. 52')1, for sible reasons fbr iron deficiency anemia, and a low value on hemorrhagic stroke, and 51'1, fbr intracranial hemorrhage. the very small risk of missing a gastrointestinal malignancy Apixaban has the lowest renal elimination of the direct oral would reasonably select an initial course of iron replace anticoagulants (25'l,) and can be used by patients under ment therapy and no initial investigation with bidirectional going dialysis with close monitoring. Apixaban is the only endoscopy (Option A). DOAC approved for use in patients on dialysis. Warfarin is an Microcytosis with or without anemia is a manit'estatior.r acceptable anticoagulant in patients treated witl.r hemodial of thalassemia. However, thalassemia is not the most likely ysis. It has the advantages ol long clinical experience and the explanation ol this patient's anemia; the prominent anis<t ability to monitor the INR and adjust the dose to maintain = U| poikilocytosis and the decrease in the hemoglobin level safe and therapeutic anticoagulation levels. E (D and mean corpuscular volume that occurred during this Dabigatran has the highest renal excretior.r. 807,. of the UI patient's pregnancy are more suggestive of iron deflciency. DOACs. and edoxaban, another Xa inhibitor. is approri o, Therefbre, hemoglobin electrophoresis (Option D) would mately 50'X, cleared by the kidneys (Options B, C). Neither is EL provide no additional diagnostic information. specifically approved tbr use in patients undergoing dialysis. a.t Rivaroxaban also has significant renal elimination I(EY POIilIt (66'X,), and dose adjustment is needed in patients u'ith 5t . Hypochromic and microcy'tic anemia, low reticulocyte E (D advanced chronic kidney disease (Option D). lt is not UI count, and anisocytosis and poikilocytosis are charac approved for patients undergoing henrodiall'sis. teristic of iron deficiency anemia. t(EY POl]tIS . Frequent dosing (two or three times daily) of oral iron . All ofthe direct oral anticoagulants are at least partially can lead to increased hepcidin production, which eliminated through the kidney; however, apixaban has the reduces iron absorption; a single daily or every-other lowest renal elimination and is approved for use in patients day dose of oral iron sulfate may be the best strateg/. with advanced kidney disease undergoing dialysis. Bibliography r Direct oral anticoagulants may be preferred to warfarin Camaschella C. New insights into iron deliciency:lnd iron deticienc; ane in patients with early stage chronic kidney disease (esti mia. Blood Rer: 2017r31:225 233. IPN'llD, 282162631 doi:10.1016 j.blre. mated glomerular filtration rate <60 ml/minl1.73 m2) 2017.o2.oo1 and at rial fi brillation.

iron requirements during pregnancy rather than from gas vitamin K antagonists like warfarin in patients with early trointestinal iron loss. A 2020 guideline from the Ameri stage chronic kidney disease (estimated glomerular filtra can Gastroenterological Association notes that patients who tion rate <60 ml/min/1.73 nt2) and atrial flbrillation. A key place a high value on avoiding the smalt risk of endoscopy, finding h,as that DOACS were associated r,r,ith relative risk particularly those who are young and might have other plau reductions of 21"1, for stroke or systemic embolism. 52')1, for sible reasons fbr iron deficiency anemia, and a low value on hemorrhagic stroke, and 51'1, fbr intracranial hemorrhage. the very small risk of missing a gastrointestinal malignancy Apixaban has the lowest renal elimination of the direct oral would reasonably select an initial course of iron replace anticoagulants (25'l,) and can be used by patients under ment therapy and no initial investigation with bidirectional going dialysis with close monitoring. Apixaban is the only endoscopy (Option A). DOAC approved for use in patients on dialysis. Warfarin is an Microcytosis with or without anemia is a manit'estatior.r acceptable anticoagulant in patients treated witl.r hemodial of thalassemia. However, thalassemia is not the most likely ysis. It has the advantages ol long clinical experience and the explanation ol this patient's anemia; the prominent anis<t ability to monitor the INR and adjust the dose to maintain = U| poikilocytosis and the decrease in the hemoglobin level safe and therapeutic anticoagulation levels. E (D and mean corpuscular volume that occurred during this Dabigatran has the highest renal excretior.r. 807,. of the UI patient's pregnancy are more suggestive of iron deflciency. DOACs. and edoxaban, another Xa inhibitor. is approri o, Therefbre, hemoglobin electrophoresis (Option D) would mately 50'X, cleared by the kidneys (Options B, C). Neither is EL provide no additional diagnostic information. specifically approved tbr use in patients undergoing dialysis. a.t Rivaroxaban also has significant renal elimination I(EY POIilIt (66'X,), and dose adjustment is needed in patients u'ith 5t . Hypochromic and microcy'tic anemia, low reticulocyte E (D advanced chronic kidney disease (Option D). lt is not UI count, and anisocytosis and poikilocytosis are charac approved for patients undergoing henrodiall'sis. teristic of iron deficiency anemia. t(EY POl]tIS . Frequent dosing (two or three times daily) of oral iron . All ofthe direct oral anticoagulants are at least partially can lead to increased hepcidin production, which eliminated through the kidney; however, apixaban has the reduces iron absorption; a single daily or every-other lowest renal elimination and is approved for use in patients day dose of oral iron sulfate may be the best strateg/. with advanced kidney disease undergoing dialysis. Bibliography r Direct oral anticoagulants may be preferred to warfarin Camaschella C. New insights into iron deliciency:lnd iron deticienc; ane in patients with early stage chronic kidney disease (esti mia. Blood Rer: 2017r31:225 233. IPN'llD, 282162631 doi:10.1016 j.blre. mated glomerular filtration rate <60 ml/minl1.73 m2) 2017.o2.oo1 and at rial fi brillation. Item 60 Answer: A Bibliography Educational Objective: Treat deep venous thrombosis Hanni C, Petrovitch E, Ali M. et al. Outcomes associated s,ith apixal)an vs rvarfarin in patients with renal d1'slunction. Blood Adl: 2020:.1:2:166 in a patient with end-stage kidney disease. 2371. IPIr4 I l): 32.163871 | doi:10. I 182 bloodadrlnces.20l9000972

Item 60 Answer: A Bibliography Educational Objective: Treat deep venous thrombosis Hanni C, Petrovitch E, Ali M. et al. Outcomes associated s,ith apixal)an vs rvarfarin in patients with renal d1'slunction. Blood Adl: 2020:.1:2:166 in a patient with end-stage kidney disease. 2371. IPIr4 I l): 32.163871 | doi:10. I 182 bloodadrlnces.20l9000972 The most appropriate treatment fbr this patient is apixaban (OptionA). The direct oral anticoagulants (DOACs) are a safe, effective treatment for most patients with venous thrombo embolism (VTE). The DOACs available fbr use in the United Item 61 Answer: C Ed ucatio na I Objeaive: Treat thrombotic thrombocyto- tr penic purpura. States are dabigatran, rivaroxaban. apixaban, and edoxaban. In clinical trials olpatients with VTE, patients were initially 'lhc rnost appropriiite treatment for this paticnt is pllsma treated with a parenteral agent, usually heparin, and transi exchange u'itl.r adnrinistratiorr ol prcdnisone and rituxiurirb tioned to dabigatran or edoxaban. Rivaroxaban and apixaban (Option C). She has thronrbotic thromboc\topeniu pur were studied without concomitant parenteral therapy and pura (TTI') based on the pr-esence of thrombocvtopenir and are approved as monotherapy for VTE. Dabigatran functions r.nicroangiopirthic henrolytic anentia (MAHA). u ith support as a direct thrombin inhibitor, whereas the other agents ing featr.rres of f'evcr and heldache. Acquireil 'l"l'P is ntrst are factor Xa inhibitors. Advantages of DOACs include no oftcn caused b1'procluction ol an autoantiboclr that lcacls need fbr routine monitoring, rapid onset of action and short to a deficienc'_v ir.r the metalk)protease r\DAN'l'l'Sl:1. u.hich is half life, flxed dosing, and fewer drug drug interactions. responsible fbr cleavir.rg high molecr-rlar u'eight vclr.r \\'ille These drugs are as effective as warfarin in VTE preventioni br:rnd factor (r-WF) nrr-rltimers. .\n erccss of high moleculzrr although the overall bleeding risk was comparable, less cen rteight vWli multinrers ciiuses platclet clr-rnrping in the tral nervous system bleeding, fatal bleeding, and use ofblood nricror,asculature thJt leacls to platelet consunlption and product support among patients taking DOACs was seen N'lAHA. Plasrna exch:rnge uith tiesh Irozen pllsrna is a cru than with warfarin. Data from a 2019 systematic review ciirlcompone'r-rt of thcrapy tlut will rcmove thc autoantibody and meta analysis suggest that DOACs may be preferred t<t ancl replace the deficient ADr\MTS13. Prednisone is nsed to

The most appropriate treatment fbr this patient is apixaban (OptionA). The direct oral anticoagulants (DOACs) are a safe, effective treatment for most patients with venous thrombo embolism (VTE). The DOACs available fbr use in the United Item 61 Answer: C Ed ucatio na I Objeaive: Treat thrombotic thrombocyto- tr penic purpura. States are dabigatran, rivaroxaban. apixaban, and edoxaban. In clinical trials olpatients with VTE, patients were initially 'lhc rnost appropriiite treatment for this paticnt is pllsma treated with a parenteral agent, usually heparin, and transi exchange u'itl.r adnrinistratiorr ol prcdnisone and rituxiurirb tioned to dabigatran or edoxaban. Rivaroxaban and apixaban (Option C). She has thronrbotic thromboc\topeniu pur were studied without concomitant parenteral therapy and pura (TTI') based on the pr-esence of thrombocvtopenir and are approved as monotherapy for VTE. Dabigatran functions r.nicroangiopirthic henrolytic anentia (MAHA). u ith support as a direct thrombin inhibitor, whereas the other agents ing featr.rres of f'evcr and heldache. Acquireil 'l"l'P is ntrst are factor Xa inhibitors. Advantages of DOACs include no oftcn caused b1'procluction ol an autoantiboclr that lcacls need fbr routine monitoring, rapid onset of action and short to a deficienc'_v ir.r the metalk)protease r\DAN'l'l'Sl:1. u.hich is half life, flxed dosing, and fewer drug drug interactions. responsible fbr cleavir.rg high molecr-rlar u'eight vclr.r \\'ille These drugs are as effective as warfarin in VTE preventioni br:rnd factor (r-WF) nrr-rltimers. .\n erccss of high moleculzrr although the overall bleeding risk was comparable, less cen rteight vWli multinrers ciiuses platclet clr-rnrping in the tral nervous system bleeding, fatal bleeding, and use ofblood nricror,asculature thJt leacls to platelet consunlption and product support among patients taking DOACs was seen N'lAHA. Plasrna exch:rnge uith tiesh Irozen pllsrna is a cru than with warfarin. Data from a 2019 systematic review ciirlcompone'r-rt of thcrapy tlut will rcmove thc autoantibody and meta analysis suggest that DOACs may be preferred t<t ancl replace the deficient ADr\MTS13. Prednisone is nsed to 120

Answers and _Critiq.les decrease continued autoantibody productior.r. Rituximab paticnts with prcviotts stmke or gastrointestinal bleeding. further suppresses autoantibody pr<tdttction and the risk <lt' For an INR between,1.5 and l0 in palients rvithout bleed CONT, recLlrrence. ing. w,arfarin can be r,t'ithheld without other treattnent. ln Caplacizumab is ir nronoclon:il antibocly that bincis to vWIr paticnts rt'ith ar.r tNR greater than l0 without bleeding, oral and blocks the ir.rteraction ol vWF kr platelets (Option A). lt is vitamin K should be given aud rvarfarin withheld until thc approved as an ancilhry trcatment for 'l'TP in sevcre cases INR returns to a therapeutic rauge. Howcver, patients \ /ith but would not be initiated bclore a trial ol plasnta exchange. lif'e threatening bleecling. as in this patient. should lte given glucocorticoids, and rituximab. 4f PCC in additiun to illtravenous vitiimin K. .ltr PCC is the Hypertensive energency can be associated rt'ith MAI lA. pref'erred :rgent lbr r,r,arfaritr reversal. If .1f PC(l is no1 avail Ilypertensive emergency refers to elevated blood pressure :rble, tl.rer.r il factor PC(l or lresh fi<,rzen plasr.nl can be used. significantly above the nomal rirnge causir-tg acute orgirn 4F I')CC is prefbrred over ll factor PCC because it contaitrs damage or dysfunction. The cnd organ damagc is the defin consistent amoLlrlts ol factor VII and warfarin revcrsal is ing characteristic. manifesting as d_vsfunctior.r of the central more reliable. vt o neruous system (ischemic or hem<lrrhagic stroke, enceph' Andexanet alla, a rec<-rnrbinant moclified lactor Xa pnl ET alopathy). the renal systen.r (acute kidney injury). or the teir1. is not indicateci fbr r.tirrlarir.r reversal (Option A). It is cardiovascular system (acute myrcardiirl infarction, aortic approved lbr revcrsal of firckir X:r inhibibrs such rts ri'r'ur (J dissection, acute heart failure). 'lhese ef iects often occur at oxaban and apiraban. Alternatively, 4f PCC can be used lbr !t blood pressures greatcr than 1B0rl20 mrn [-lg. This patierrt fbctor Xa inhibitor revcrsal. |g has no clinical cvidence ol hypertensive e'mergency. ancl ldarucizunrab is a humanizecl monoclonal antibody to vt intruvenous nitroprusside is not indicated (Option B). dabigatran and is used to reverse clabigatran's anticoagulant o Although she has a lor,v platelet count witl.r evidence o1' eflects in the setting ot life threatening bleeding (Option C). lrl = petechiac, platclct trarrsfusion should not be perlbrmed {br a It is not indicated fbr warf'arin associated bleeding. patient with T'l'l']lr,ithout life thrcatening bleeding because Protamine sulfatc is used to rcverse heparin: it lvould it increases the risk ol lrterial thrombosis (Option D). r-rot be approprilte for this p.ltient (Option D). Perlorm ing plasmapheresis rvith non plasma replacement, f,EY pOtilIS such as saline and alburnin, will remove. the autoantibody but does r-rot ctlrect the ADAM1'SI3 deficiency (Option E). l)lasma o ln patients taking warfarin who are experiencing lif'e exchange and immunosuppressive therapy are crucial [o threatening bleeding, intravenous vitamin K plus remove the auto:rntibody. replace the cleficient ADAM'|Sl3. 4 factor prothrombin complex concentrate should be ancl prevent the fonnation of new autoantibody. used to reverse anticoagulation.

decrease continued autoantibody productior.r. Rituximab paticnts with prcviotts stmke or gastrointestinal bleeding. further suppresses autoantibody pr<tdttction and the risk <lt' For an INR between,1.5 and l0 in palients rvithout bleed CONT, recLlrrence. ing. w,arfarin can be r,t'ithheld without other treattnent. ln Caplacizumab is ir nronoclon:il antibocly that bincis to vWIr paticnts rt'ith ar.r tNR greater than l0 without bleeding, oral and blocks the ir.rteraction ol vWF kr platelets (Option A). lt is vitamin K should be given aud rvarfarin withheld until thc approved as an ancilhry trcatment for 'l'TP in sevcre cases INR returns to a therapeutic rauge. Howcver, patients \ /ith but would not be initiated bclore a trial ol plasnta exchange. lif'e threatening bleecling. as in this patient. should lte given glucocorticoids, and rituximab. 4f PCC in additiun to illtravenous vitiimin K. .ltr PCC is the Hypertensive energency can be associated rt'ith MAI lA. pref'erred :rgent lbr r,r,arfaritr reversal. If .1f PC(l is no1 avail Ilypertensive emergency refers to elevated blood pressure :rble, tl.rer.r il factor PC(l or lresh fi<,rzen plasr.nl can be used. significantly above the nomal rirnge causir-tg acute orgirn 4F I')CC is prefbrred over ll factor PCC because it contaitrs damage or dysfunction. The cnd organ damagc is the defin consistent amoLlrlts ol factor VII and warfarin revcrsal is ing characteristic. manifesting as d_vsfunctior.r of the central more reliable. vt o neruous system (ischemic or hem<lrrhagic stroke, enceph' Andexanet alla, a rec<-rnrbinant moclified lactor Xa pnl ET alopathy). the renal systen.r (acute kidney injury). or the teir1. is not indicateci fbr r.tirrlarir.r reversal (Option A). It is cardiovascular system (acute myrcardiirl infarction, aortic approved lbr revcrsal of firckir X:r inhibibrs such rts ri'r'ur (J dissection, acute heart failure). 'lhese ef iects often occur at oxaban and apiraban. Alternatively, 4f PCC can be used lbr !t blood pressures greatcr than 1B0rl20 mrn [-lg. This patierrt fbctor Xa inhibitor revcrsal. |g has no clinical cvidence ol hypertensive e'mergency. ancl ldarucizunrab is a humanizecl monoclonal antibody to vt intruvenous nitroprusside is not indicated (Option B). dabigatran and is used to reverse clabigatran's anticoagulant o Although she has a lor,v platelet count witl.r evidence o1' eflects in the setting ot life threatening bleeding (Option C). lrl = petechiac, platclct trarrsfusion should not be perlbrmed {br a It is not indicated fbr warf'arin associated bleeding. patient with T'l'l']lr,ithout life thrcatening bleeding because Protamine sulfatc is used to rcverse heparin: it lvould it increases the risk ol lrterial thrombosis (Option D). r-rot be approprilte for this p.ltient (Option D). Perlorm ing plasmapheresis rvith non plasma replacement, f,EY pOtilIS such as saline and alburnin, will remove. the autoantibody but does r-rot ctlrect the ADAM1'SI3 deficiency (Option E). l)lasma o ln patients taking warfarin who are experiencing lif'e exchange and immunosuppressive therapy are crucial [o threatening bleeding, intravenous vitamin K plus remove the auto:rntibody. replace the cleficient ADAM'|Sl3. 4 factor prothrombin complex concentrate should be ancl prevent the fonnation of new autoantibody. used to reverse anticoagulation. TEY POIilIS o ln patients without bleeding, a supratherapeutic INR . The key clinical features of thrombotic thrclmbocy.to between 4.5 and l0 should be managed by withhold ing warfarin until the INR normalizes; an INR greater penic purpura are microangiopathic hemolytic anemia than 10 should be managed by withholding warfarin and thrombocytopenia. and administering oral vitamin K. o The initial treatment of thrombotic thrombocytopenia purpura includes plasma exchange, glucocorticoids, Bibliography and rituximab. Witt l)M. Nieuwlaat R. Clark NII et al. American Society ol I lematolos/ 2018 guidelines lbr manitgentent of venOus thronrboembolisnt: Optintal man agement of anticoagulation theralry Blord Adv. 2018;2::1257 329 l. IPMID: Bibliography 304827651 doi:10. I 182/bloodadvances.2Ol 802,ltt9ll Zwicker Jl. Muia l, l)olatslrilhi L, et al. Adjuvant krw dose rituximab and plasma exchange ttrr acquired"l'l'l? Blood. 2019;l:14:11ttO. IPMID' 31331919] dOi:10.1182/bkxrd.2Ol 9(X)O795 Item 63 Answer: D Ed u cati o na I Obj ective : Manage newly diagnosed

TEY POIilIS o ln patients without bleeding, a supratherapeutic INR . The key clinical features of thrombotic thrclmbocy.to between 4.5 and l0 should be managed by withhold ing warfarin until the INR normalizes; an INR greater penic purpura are microangiopathic hemolytic anemia than 10 should be managed by withholding warfarin and thrombocytopenia. and administering oral vitamin K. o The initial treatment of thrombotic thrombocytopenia purpura includes plasma exchange, glucocorticoids, Bibliography and rituximab. Witt l)M. Nieuwlaat R. Clark NII et al. American Society ol I lematolos/ 2018 guidelines lbr manitgentent of venOus thronrboembolisnt: Optintal man agement of anticoagulation theralry Blord Adv. 2018;2::1257 329 l. IPMID: Bibliography 304827651 doi:10. I 182/bloodadvances.2Ol 802,ltt9ll Zwicker Jl. Muia l, l)olatslrilhi L, et al. Adjuvant krw dose rituximab and plasma exchange ttrr acquired"l'l'l? Blood. 2019;l:14:11ttO. IPMID' 31331919] dOi:10.1182/bkxrd.2Ol 9(X)O795 Item 63 Answer: D Ed u cati o na I Obj ective : Manage newly diagnosed tr Item 62 Answer: B Educational Objective: Treat a patient with warfarin hereditary hemochromatosis.

TEY POIilIS o ln patients without bleeding, a supratherapeutic INR . The key clinical features of thrombotic thrclmbocy.to between 4.5 and l0 should be managed by withhold ing warfarin until the INR normalizes; an INR greater penic purpura are microangiopathic hemolytic anemia than 10 should be managed by withholding warfarin and thrombocytopenia. and administering oral vitamin K. o The initial treatment of thrombotic thrombocytopenia purpura includes plasma exchange, glucocorticoids, Bibliography and rituximab. Witt l)M. Nieuwlaat R. Clark NII et al. American Society ol I lematolos/ 2018 guidelines lbr manitgentent of venOus thronrboembolisnt: Optintal man agement of anticoagulation theralry Blord Adv. 2018;2::1257 329 l. IPMID: Bibliography 304827651 doi:10. I 182/bloodadvances.2Ol 802,ltt9ll Zwicker Jl. Muia l, l)olatslrilhi L, et al. Adjuvant krw dose rituximab and plasma exchange ttrr acquired"l'l'l? Blood. 2019;l:14:11ttO. IPMID' 31331919] dOi:10.1182/bkxrd.2Ol 9(X)O795 Item 63 Answer: D Ed u cati o na I Obj ective : Manage newly diagnosed tr Item 62 Answer: B Educational Objective: Treat a patient with warfarin hereditary hemochromatosis. This patient does not require any intervention currently toxicity with 4-factor prothrombin complex concentrate. (Option D). She has hereditary hemochromatosis, with het '[his paticnt should also be given .1 firctor protl.rrombin erozygous C282Y mutation of the HFEgene. Mutations in the complex concentrate (4f PCC) (Option B). She is taking HFE gene comprise the most prevalent tbrnr o1'hereditary r,r,arfarin, a vitanrin K antagonist that ir-rhibits vitarnin K hemochromatosis, with a prevalence o1'1 in 250 persons of reductase, and has clinically significant bleeding and an northern European descent. 'lhe C2B2Y H63D, and S65C elev:rted lNR. \Variarin levels are monitored by prothrombin mutations are the three most common, and homozygos time and lNR. 'lypically, a therapcutic warfarin level has ity fbr C282Y accounts for 80'1, to 90'X, of patients with an INR ol 2 to 3. Bleeciing risk increases as tlte INR level hemochromatosis who have a genetic mutation. Hetero increases, and risk is also clevatcd ir.r patienls oldcr than zygosity has been reported to be as high as 10%, among 75 years. in paticnts taking an antiplatelet rgent, and in non Hispanic White populations in the United States. Iron

This patient does not require any intervention currently toxicity with 4-factor prothrombin complex concentrate. (Option D). She has hereditary hemochromatosis, with het '[his paticnt should also be given .1 firctor protl.rrombin erozygous C282Y mutation of the HFEgene. Mutations in the complex concentrate (4f PCC) (Option B). She is taking HFE gene comprise the most prevalent tbrnr o1'hereditary r,r,arfarin, a vitanrin K antagonist that ir-rhibits vitarnin K hemochromatosis, with a prevalence o1'1 in 250 persons of reductase, and has clinically significant bleeding and an northern European descent. 'lhe C2B2Y H63D, and S65C elev:rted lNR. \Variarin levels are monitored by prothrombin mutations are the three most common, and homozygos time and lNR. 'lypically, a therapcutic warfarin level has ity fbr C282Y accounts for 80'1, to 90'X, of patients with an INR ol 2 to 3. Bleeciing risk increases as tlte INR level hemochromatosis who have a genetic mutation. Hetero increases, and risk is also clevatcd ir.r patienls oldcr than zygosity has been reported to be as high as 10%, among 75 years. in paticnts taking an antiplatelet rgent, and in non Hispanic White populations in the United States. Iron 121

Answers and Critiques overload is extremely rare in heterozygous individuals, and For patients with venous thromboembolism (VTE), ASH evidence of elevated iron indices (ferritin level >1000 ng/ml suggests using direct oral anticoagulants (DOACs), such as [1000 pg/L], transferrin saturation >45'7,) should raise sus apixaban, rivaroxaban, dabigatran, or edoxaban, over vita- picion for a concomitant rare mutation that may not be min K antagonists (VKAs), such as warfarin. However, this detected with standardized testing. The 2019 guideline from recommendation may not apply to certain subgroups of the American College of Gastroenterologz (ACG) recom patients, such as those with kidney disease (creatinine clear- mends treatment in patients with homozygous C282Y muta- ance less than 30 ml/min, except for apixaban), moderate to tions with serum ferritin greater than 300 ng/ml (300 pg/L) severe liver disease, or antiphospholipid antibody syndrome. in men and greater than 200 ng/ml (200 pg/L) in women, In some of these patients, warfarin will be preferred. Apix along with a transferrin saturation of 45"/,, or more. Other aban is a factor Xa inhibitor. It is approved for treatment of sources recommend observation for serum ferritin levels WE as monotherapy, without the need for initial parenteral less than 500 ng/ml (500 pg/L) regardless of genotype. This anticoagulation. For an acute VTE, initial dosing is 10 mg patient has a heterozygous C282Y mutation without elevated twice daily for l week and then 5 mg twice daily thereafter. vt iron indices; therefore, without symptoms, no intervention Rivaroxaban. another factor Xa inhibitor, can also be initi- € (D or ongoing surveillance is required. ated without initial parenteral therapy. Both apixaban and (r! Chelation with agents such as deferasirox is reserved rivaroxaban allow for discharge directly to home with oral o, for patients with iron overload who cannot undergo phle therapy. In some instances, the cost of DOACs and the lack of CL botomy because of concomitant anemia (Option A). This insurance coverage may iead patients who do not otherwise a-t patient is not experiencing iron overload, so iron chelation require hospitalization to choose low molecular-weight is not necessary. heparin for the acute home-based management of WE. ll c.D Phlebotomy is preferred fbr lowering iron levels in Dabigatran and edoxaban are also approved for VTE ul patients with hereditary hemochromatosis who require treatment (Options B, C). However, initial therapy with treatment (Option B). However, phlebotomy is unnecessary low molecular-weight heparin or unfractionated heparin in those who are asymptomatic, have a lerritin level less than for at least 5 days is required with both of these agents. 500 ng/mL (soo pg/L) (or less than 300 ng/ml [300 ]rglLlin Therefore, because initial parenteral treatment is necessary men and 200 ng/ml [200 [g/L] in women, according to the when using dabigatran or edoxaban, these would not be the ACG), and have no evidence of organ iron deposition even best choices for this patient. with an HFEhomozygous genetic mutation. However, those Warfarin is a VI(A that also inhibits proteins C and S patients should be monitored for symptoms and have peri- (Option D). Warlarin initially lowers protein C levels and odic evaluation of iron levels (Option C). This patient, with a may cause a transient increase in coagulability. 'lhere heterozygous C282Y mutation and normal iron stores, does fore, patients initiating warfarin for a newly diagnosed not require monitoring. VTE require concomitant initial treatment with parenteral heparin for at least 5 days and until the INR is at least 2 for f,EY POITITS 24 hours. o The C282Y, H63D, and S65C mutations are the three TCY POIXT most common in patients with hereditary hemochro matosis, and homozygosity for C282Y accounts for o The direct oral anticoagulants apixaban and rivaroxa B0% to 907, of patients who have a genetic mutation. ban are approved for treatment of acute venous . Iron overload is extremely rare in persons with hered- thromboembolism as monotherapy without initial parenteral therapy with heparin. itary hemochromatosis and a heterozygous HFE mutation, so without symptoms or elevated iron indi ces, no treatment or monitoring is necessary in these Bibliography Ortel TL, Neumann I, Ageno W et al. American Society of Hematolory 2020 patients. guidelines for management of venous thromboembolism: Treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4:4693 4738. IPMID: 3300707] doi:10.1182/bloodadvances.2020001830 Bibliography Kowdley KV. Brou,n KE. Ahn J. Sundaram V ACC clinical guideline: heredi- Item 65 tary hemochromatosis. Am J Gastroenterol. 2Ol9:114:12O2 1218. [PMID: 313353s91 doi: 10.14309 /ajg.0000000000000315 Answer: D Ed u cati o n a I Obj ective : Conflrm thrombocltopenia tr with a peripheral blood smear. Item 64 Answer: A A peripheral bloocl smear (PBS) should be obtained (Option D). Ed ucatio na I O bjective : Treat venous thromboembolism 1l.ris patient has severe thrombocl'topenia in the absence of with a direct oral anticoagulant. petechiae, ecchymoses. or other bleeciing manifestations. -lhe The most appropriate treatment is apixaban (Option A). first step in the eraluation of anl'patient u'ith throm For patients with uncomplicated deep venous thrombosis bocytopenia is to revie$ the PBS and confirm the platelet (DVT), the American Society of Hematologr (ASH) guideline cour-rt. l)seudothronrbocytopenia occurs when a patient suggests offering home treatment over hospital treatment. has antibodies to ethylcnediaminetetra:rcetic acid (IIDTA),

overload is extremely rare in heterozygous individuals, and For patients with venous thromboembolism (VTE), ASH evidence of elevated iron indices (ferritin level >1000 ng/ml suggests using direct oral anticoagulants (DOACs), such as [1000 pg/L], transferrin saturation >45'7,) should raise sus apixaban, rivaroxaban, dabigatran, or edoxaban, over vita- picion for a concomitant rare mutation that may not be min K antagonists (VKAs), such as warfarin. However, this detected with standardized testing. The 2019 guideline from recommendation may not apply to certain subgroups of the American College of Gastroenterologz (ACG) recom patients, such as those with kidney disease (creatinine clear- mends treatment in patients with homozygous C282Y muta- ance less than 30 ml/min, except for apixaban), moderate to tions with serum ferritin greater than 300 ng/ml (300 pg/L) severe liver disease, or antiphospholipid antibody syndrome. in men and greater than 200 ng/ml (200 pg/L) in women, In some of these patients, warfarin will be preferred. Apix along with a transferrin saturation of 45"/,, or more. Other aban is a factor Xa inhibitor. It is approved for treatment of sources recommend observation for serum ferritin levels WE as monotherapy, without the need for initial parenteral less than 500 ng/ml (500 pg/L) regardless of genotype. This anticoagulation. For an acute VTE, initial dosing is 10 mg patient has a heterozygous C282Y mutation without elevated twice daily for l week and then 5 mg twice daily thereafter. vt iron indices; therefore, without symptoms, no intervention Rivaroxaban. another factor Xa inhibitor, can also be initi- € (D or ongoing surveillance is required. ated without initial parenteral therapy. Both apixaban and (r! Chelation with agents such as deferasirox is reserved rivaroxaban allow for discharge directly to home with oral o, for patients with iron overload who cannot undergo phle therapy. In some instances, the cost of DOACs and the lack of CL botomy because of concomitant anemia (Option A). This insurance coverage may iead patients who do not otherwise a-t patient is not experiencing iron overload, so iron chelation require hospitalization to choose low molecular-weight is not necessary. heparin for the acute home-based management of WE. ll c.D Phlebotomy is preferred fbr lowering iron levels in Dabigatran and edoxaban are also approved for VTE ul patients with hereditary hemochromatosis who require treatment (Options B, C). However, initial therapy with treatment (Option B). However, phlebotomy is unnecessary low molecular-weight heparin or unfractionated heparin in those who are asymptomatic, have a lerritin level less than for at least 5 days is required with both of these agents. 500 ng/mL (soo pg/L) (or less than 300 ng/ml [300 ]rglLlin Therefore, because initial parenteral treatment is necessary men and 200 ng/ml [200 [g/L] in women, according to the when using dabigatran or edoxaban, these would not be the ACG), and have no evidence of organ iron deposition even best choices for this patient. with an HFEhomozygous genetic mutation. However, those Warfarin is a VI(A that also inhibits proteins C and S patients should be monitored for symptoms and have peri- (Option D). Warlarin initially lowers protein C levels and odic evaluation of iron levels (Option C). This patient, with a may cause a transient increase in coagulability. 'lhere heterozygous C282Y mutation and normal iron stores, does fore, patients initiating warfarin for a newly diagnosed not require monitoring. VTE require concomitant initial treatment with parenteral heparin for at least 5 days and until the INR is at least 2 for f,EY POITITS 24 hours. o The C282Y, H63D, and S65C mutations are the three TCY POIXT most common in patients with hereditary hemochro matosis, and homozygosity for C282Y accounts for o The direct oral anticoagulants apixaban and rivaroxa B0% to 907, of patients who have a genetic mutation. ban are approved for treatment of acute venous . Iron overload is extremely rare in persons with hered- thromboembolism as monotherapy without initial parenteral therapy with heparin. itary hemochromatosis and a heterozygous HFE mutation, so without symptoms or elevated iron indi ces, no treatment or monitoring is necessary in these Bibliography Ortel TL, Neumann I, Ageno W et al. American Society of Hematolory 2020 patients. guidelines for management of venous thromboembolism: Treatment of deep vein thrombosis and pulmonary embolism. Blood Adv. 2020;4:4693 4738. IPMID: 3300707] doi:10.1182/bloodadvances.2020001830 Bibliography Kowdley KV. Brou,n KE. Ahn J. Sundaram V ACC clinical guideline: heredi- Item 65 tary hemochromatosis. Am J Gastroenterol. 2Ol9:114:12O2 1218. [PMID: 313353s91 doi: 10.14309 /ajg.0000000000000315 Answer: D Ed u cati o n a I Obj ective : Conflrm thrombocltopenia tr with a peripheral blood smear. Item 64 Answer: A A peripheral bloocl smear (PBS) should be obtained (Option D). Ed ucatio na I O bjective : Treat venous thromboembolism 1l.ris patient has severe thrombocl'topenia in the absence of with a direct oral anticoagulant. petechiae, ecchymoses. or other bleeciing manifestations. -lhe The most appropriate treatment is apixaban (Option A). first step in the eraluation of anl'patient u'ith throm For patients with uncomplicated deep venous thrombosis bocytopenia is to revie$ the PBS and confirm the platelet (DVT), the American Society of Hematologr (ASH) guideline cour-rt. l)seudothronrbocytopenia occurs when a patient suggests offering home treatment over hospital treatment. has antibodies to ethylcnediaminetetra:rcetic acid (IIDTA), 122

Answers and Critiques lr[ cirusing plrtelets to c1ltmp togcther in vitro. In pirtients Item 66 Answer: C lfl with platelet clurnping on the t)US. an tccurute count can Educational Objective: Evaluate anemia with a coNl be <lbtainect fron.r bloocl clrar,r't.t in citrate or heparin insteatl reticulocyte count. of l'lDTA. lnaccurate platclet courlts ntay also rtccur it the platelets are exceptionally largc (contplete blood cor-rnt The most appropriate next test is a reticulocyte count and machine may count tlrern as er1'throcytes) or il crythrocyte peripheral blood smear (Option C). In assessing patients fiagments (schistocytes) lre counted by the machitte ls if with anemia, reviewing the complete blood count, mean they,uere platelets (leacling to a higl-rer than actual platelet corpuscular volume, and reticulocyte count along with coun t). the peripheral blood smear can provide valuable diag- Patients rvith thrombotic thromboc!'topcnic purpura nostic information. Deflning the anemia as microcytic, ('f'fP) present n,ith microangiopathic henrolylic anenria macrocytic, or normocytic as well as by bone marrow (MAIJA) and thrombocytopenia. 'fhe lrresencc of MAIIA response (elevated versus normal or suppressed reticu is er,idenced by elevatecl lactate ilehlcln)genilse (l-DI I) tnd locyte production) can narrow the differential diagnosis. ta (I, dccreasecl haptogklbin lcvels, schistocytes on PBS. ancl a The reticulocyte count provides information on the mar CT negatire direct rntiglobulin test result. If the PBS confirms row response to anemia. A normal marrow will produce thrombocytopenia and is positive fbr schistocytes. and i{ reticulocytes in response to anemia or hypoxia. In the (J additional tests confirm the prcsence of crythroc'_vte destruc absence of hypoxemia (and by implication, hypoxia), ane- rE tion. an AI)AMI'S13 level less th:rn 10'll, uould support the mia associated with an elevated reticulocyte count is most IE diagnosis of 1'IP (Option A). lf the PBS clemonstrates clunrp often secondary to bleeding or hemolysis. Hypoprolifer t^ (u ing, repeating the platelet count fiom blood drtwn in citrate ative anemia is associated with a low or inappropriately 3 rur heparin is the next stcp. normal reticulocyte count; in this situation, the bone UI

lr[ cirusing plrtelets to c1ltmp togcther in vitro. In pirtients Item 66 Answer: C lfl with platelet clurnping on the t)US. an tccurute count can Educational Objective: Evaluate anemia with a coNl be <lbtainect fron.r bloocl clrar,r't.t in citrate or heparin insteatl reticulocyte count. of l'lDTA. lnaccurate platclet courlts ntay also rtccur it the platelets are exceptionally largc (contplete blood cor-rnt The most appropriate next test is a reticulocyte count and machine may count tlrern as er1'throcytes) or il crythrocyte peripheral blood smear (Option C). In assessing patients fiagments (schistocytes) lre counted by the machitte ls if with anemia, reviewing the complete blood count, mean they,uere platelets (leacling to a higl-rer than actual platelet corpuscular volume, and reticulocyte count along with coun t). the peripheral blood smear can provide valuable diag- Patients rvith thrombotic thromboc!'topcnic purpura nostic information. Deflning the anemia as microcytic, ('f'fP) present n,ith microangiopathic henrolylic anenria macrocytic, or normocytic as well as by bone marrow (MAIJA) and thrombocytopenia. 'fhe lrresencc of MAIIA response (elevated versus normal or suppressed reticu is er,idenced by elevatecl lactate ilehlcln)genilse (l-DI I) tnd locyte production) can narrow the differential diagnosis. ta (I, dccreasecl haptogklbin lcvels, schistocytes on PBS. ancl a The reticulocyte count provides information on the mar CT negatire direct rntiglobulin test result. If the PBS confirms row response to anemia. A normal marrow will produce thrombocytopenia and is positive fbr schistocytes. and i{ reticulocytes in response to anemia or hypoxia. In the (J additional tests confirm the prcsence of crythroc'_vte destruc absence of hypoxemia (and by implication, hypoxia), ane- rE tion. an AI)AMI'S13 level less th:rn 10'll, uould support the mia associated with an elevated reticulocyte count is most IE diagnosis of 1'IP (Option A). lf the PBS clemonstrates clunrp often secondary to bleeding or hemolysis. Hypoprolifer t^ (u ing, repeating the platelet count fiom blood drtwn in citrate ative anemia is associated with a low or inappropriately 3 rur heparin is the next stcp. normal reticulocyte count; in this situation, the bone UI Imnrune thromboc_Vtopenic purpnra (tTP) is a clinical marrow is abnormal or lacks substrate for erythrocyte cliagnosis made b1'exclusion of other causes fbr throntboo, production. topenia, bllt even in patients u,ith confirmed thrombocyto The laboratory hallmark of immune mediated hemoly- pcnia. antiplatelct antibodies are not helpful cliagnostically sis is a positive direct antiglobulin test that detects either IgG bccause they are neither sensiti\"e nor specific in the diagno, or complement (C3) on the ery.throcyte surface (Option B). sis of I'IP (Option B). this paticnt does not have confirrned This test is useful in the diagnosis olautoimmune hemolytic thrombocytopenia. and lny aclditional testing lo evirluate anemia, in which the reticulocyte count will be elevated ciruses of thrombocytopenia are premirture until the PRS is and the peripheral blood smear will show either sphero examined. cytes (warm autoimmune hemolytic anemia) or erythrocyte In a patient lvith lnemia and thnrmbocytopenia, a agglutination (cold agglutinin disease). However, the need direcf antiglobulin test would bc useful in cvaluating fbr to obtain a direct antiglobulin test should be informed by an possible F.r,ans syndrome (autoimmune hemolytic ane elevated reticulocyte count and/or an abnormal peripheral rnil and l't'P) (Option C). However, bclbre this diagnosis is blood smear. entertained. thnlmbocytopenia ntust first he verified. A I)BS Older age is associated with an increased prevalence rnav also support the diagr.rosis of autoimmune hernolytic of anemia, which can remain unexplained even after a anemia by the ltresence of' spherocytes. If hernolysis is a thorough evaluation. Unexplained anemia in older adults consideration. supporting evidence {br er1,throc1,le dcstruc is typically hypoproliferative, normochromic anemia. tion should be obtained, including a rcticulocyte count to Common identiflable causes of hypoproliferative anemia evrluate fbr reticuloc'vtosis, seruln LI)tl. lree hemoglobin include vitamin B,r, folate, or iron deficiency or mar level. ancl a urinalvsis Iirr hentoglobinuriir. lf crythr<tcyte row diseases such as myelodysplasia or aplastic anemia destructior.r is confirmetl, a clirect antiglobulin lest slrould (Options A, D, E). These hypoproliferative conditions often be obtained. have unique flndings on the peripheral blood smear that will help focus the differential diagnosis and additional rEY POI]IIS testing. However, the decision to obtain any ofthese tests o The first step in the evaluation of thrombocytopenia is should be informed by the reticulocyte count and periph- to review the peripheral blood smear and confirm the eral blood smear results. platelet count. I(EY POIilT . Pseudothromborytopenia occurs when patients have . In assessing patients with anemia, reviewing the antibodies to ethylenediaminetetraacetic acid, causing complete blood count, mean corpuscular volume, and platelets to clump together in vitro; an accurate count reticulocyte count along with the peripheral blood can be obtained from blood drawn in citrate or heparin. smear can provide valuable diagnostic information.

Imnrune thromboc_Vtopenic purpnra (tTP) is a clinical marrow is abnormal or lacks substrate for erythrocyte cliagnosis made b1'exclusion of other causes fbr throntboo, production. topenia, bllt even in patients u,ith confirmed thrombocyto The laboratory hallmark of immune mediated hemoly- pcnia. antiplatelct antibodies are not helpful cliagnostically sis is a positive direct antiglobulin test that detects either IgG bccause they are neither sensiti\"e nor specific in the diagno, or complement (C3) on the ery.throcyte surface (Option B). sis of I'IP (Option B). this paticnt does not have confirrned This test is useful in the diagnosis olautoimmune hemolytic thrombocytopenia. and lny aclditional testing lo evirluate anemia, in which the reticulocyte count will be elevated ciruses of thrombocytopenia are premirture until the PRS is and the peripheral blood smear will show either sphero examined. cytes (warm autoimmune hemolytic anemia) or erythrocyte In a patient lvith lnemia and thnrmbocytopenia, a agglutination (cold agglutinin disease). However, the need direcf antiglobulin test would bc useful in cvaluating fbr to obtain a direct antiglobulin test should be informed by an possible F.r,ans syndrome (autoimmune hemolytic ane elevated reticulocyte count and/or an abnormal peripheral rnil and l't'P) (Option C). However, bclbre this diagnosis is blood smear. entertained. thnlmbocytopenia ntust first he verified. A I)BS Older age is associated with an increased prevalence rnav also support the diagr.rosis of autoimmune hernolytic of anemia, which can remain unexplained even after a anemia by the ltresence of' spherocytes. If hernolysis is a thorough evaluation. Unexplained anemia in older adults consideration. supporting evidence {br er1,throc1,le dcstruc is typically hypoproliferative, normochromic anemia. tion should be obtained, including a rcticulocyte count to Common identiflable causes of hypoproliferative anemia evrluate fbr reticuloc'vtosis, seruln LI)tl. lree hemoglobin include vitamin B,r, folate, or iron deficiency or mar level. ancl a urinalvsis Iirr hentoglobinuriir. lf crythr<tcyte row diseases such as myelodysplasia or aplastic anemia destructior.r is confirmetl, a clirect antiglobulin lest slrould (Options A, D, E). These hypoproliferative conditions often be obtained. have unique flndings on the peripheral blood smear that will help focus the differential diagnosis and additional rEY POI]IIS testing. However, the decision to obtain any ofthese tests o The first step in the evaluation of thrombocytopenia is should be informed by the reticulocyte count and periph- to review the peripheral blood smear and confirm the eral blood smear results. platelet count. I(EY POIilT . Pseudothromborytopenia occurs when patients have . In assessing patients with anemia, reviewing the antibodies to ethylenediaminetetraacetic acid, causing complete blood count, mean corpuscular volume, and platelets to clump together in vitro; an accurate count reticulocyte count along with the peripheral blood can be obtained from blood drawn in citrate or heparin. smear can provide valuable diagnostic information. Bibliography Musson EN, Lomas O, Murphy ME Acute thrombocytopenia: Picking a way Bibliography through a paucity of platelets. Br J }losp Med (Lond). 2019;80:5o7 512. Ershler WB. Unexplained anemia in the elderly. Clin Geriatr Med. 2ol9 IPMID: 314986681 doi:10.12968/hmed.2019.80.9.507 35:295 305. IPMID: 31230731] doi:10.1016/j.cger.2019.03.002

Bibliography Musson EN, Lomas O, Murphy ME Acute thrombocytopenia: Picking a way Bibliography through a paucity of platelets. Br J }losp Med (Lond). 2019;80:5o7 512. Ershler WB. Unexplained anemia in the elderly. Clin Geriatr Med. 2ol9 IPMID: 314986681 doi:10.12968/hmed.2019.80.9.507 35:295 305. IPMID: 31230731] doi:10.1016/j.cger.2019.03.002 123

Ans_y91s and Critiques Item 67 Answer: B nith a more liberal trigger of 9 g dL (eo g I-). Patients u'ith Educational ObjeAive: Treat superficial vein thrombosis. the louer transfusion trigler had in-rprored 30 dal,mortalitl, and a lorrer rate of complications. such as pulmonan edem:r The most appropriate management is anticoagulation for or acute mrocardial iniarction. A subgroup of'patients u'ith 6 weeks to treat a superflcial vein thrombosis (SVT) active ischemic heart disease did better u'ith the rnore lib (Option B). SVT often aflects the lower ertremities and is er:rl transfusi<)n stratest Guidelines support these findings. thought to account for 10'1, of lower extremity thromboses. strongll. recommending a restrictive erl.throc)'te transfusion The lesser saphenous vein is a distal superflcial vein. Treatment threshold in r,vhich transfusion is not indicated until the is indicated for SW when the thrombus is 5 cm or greater hernoglobin level is 7 gldl. (7O g,l.) for hospitalized adult in length or is close to the deep venous system or if other patients rvho are hemodynamicalll' stable. including crit thrombophilic risk factors are present. This patient's thrombus icallf ill patients, rather than when the hemoglobin level length is 7 cm, so anticoagulation for 6 weeks is indicated. is 10 to 12 grcll (tOo tzo g/1.) (Options B, C). These reconr D An anticoagulant therapy duration of 3 to 6 months is mendations do not apply to patients rn'ith acute coronar)' UI appropriate management of an acute proximal deep venous s1'ndrome, severe thrombocytopenia (patients treated fbr E thrombosis (DVT) that is provoked by reversible risk factors hematologic or oncologic reasons rtho are at risk of bleed .D tt (Option A). SVT. provoked or unprovoked. can be treated ing). and chronic transfusion dependent anemia. o, with only 6 weeks of anticoagulation. Erythropoietin is important in the treatment of the a Vein ligation might be considered for patients at higher anenria of chronic kidney disease (CKD) and is often needed rr risk who have an absolute contraindication to anticoagula in patients with end stage kidney disease receiving diall' tion to prevent propagation of the thrombus into the deep sis (Option A). Guiclelines recommend that erythropoietin .Et venous system (Option C). Vein ligation is not pan of routine stimulating agents be withheld in patients nith CKD not .D t/t care. In this patient, anticoagulation is the preferred therapy. requiring dialysis who have a hemoglobin level greater than Observation would be an trppropriate management 10 g dl- (100 g L). Higher hemoglobin targets are associated option for a superficial vein thrombosis without high risk r,vith adverse events, including worsening hypertension and features (Option D). Patients with low risk lower extremity volume orerload. This patient has an acute rt'orsening of SVT can be managed conservatively with warm compresses. mild. asl,mptomatic anemiir, most likely because of sepsis analgesics, and NSAIDs. Compression stockings may hasten (inflammation) ancl dilution owing to fluid resuscitation. the resolution of the thrombus. Follow up should be sched u'hich should improve as he continues to reco\er lrom his uled in I week to ensure symptom resolution. If symptoms current illness. No evidence supports any'benefit to erythro persist or worsen, repeat duplex ultrasonography should poietin therapy in this setting. be performed to evaluate for extension of the thrombus. If XEY POIXIS repeat ultrasound shows thrombus extension, anticoagula tion would then be indicated. . A restrictive transfusion threshold (l gtaL [zO glLJ) should be used to manage critically ill patients who XEY POTTIS are euvolemic. are not actively bleeding, and do not . Six weeks of anticoagulation is indicated for superfi have acute ischemic heart disease. cial vein thrombosis when the thrombus is 5 cm or . The restrictive transfusion threshold (7 g/dl [zO glL]) Aoes greater in length or is close to the deep venous system not apply to patients with acute coronary syndrome. or when other thrombophilic risk factors present. severe thrombocltopenia, and chronic transfusion . For patients with low-risk superficial vein thrombo dependent anemia. sis, observation with follow up in 1 week to ensure symptom resolution is reasonable; if symptoms per Bibliography sist or worsen, repeat duplex ultrasonography should Dochertv AB. Turgeon All \lhlsh-IS. Best practice in critical care: Anaemia be performed. in acr-lte and critical illness. l'ransfus Med. 2018;28:181 189. IPMll)' 2936q1371 rloi:l0.llll /tme.125o5

Item 67 Answer: B nith a more liberal trigger of 9 g dL (eo g I-). Patients u'ith Educational ObjeAive: Treat superficial vein thrombosis. the louer transfusion trigler had in-rprored 30 dal,mortalitl, and a lorrer rate of complications. such as pulmonan edem:r The most appropriate management is anticoagulation for or acute mrocardial iniarction. A subgroup of'patients u'ith 6 weeks to treat a superflcial vein thrombosis (SVT) active ischemic heart disease did better u'ith the rnore lib (Option B). SVT often aflects the lower ertremities and is er:rl transfusi<)n stratest Guidelines support these findings. thought to account for 10'1, of lower extremity thromboses. strongll. recommending a restrictive erl.throc)'te transfusion The lesser saphenous vein is a distal superflcial vein. Treatment threshold in r,vhich transfusion is not indicated until the is indicated for SW when the thrombus is 5 cm or greater hernoglobin level is 7 gldl. (7O g,l.) for hospitalized adult in length or is close to the deep venous system or if other patients rvho are hemodynamicalll' stable. including crit thrombophilic risk factors are present. This patient's thrombus icallf ill patients, rather than when the hemoglobin level length is 7 cm, so anticoagulation for 6 weeks is indicated. is 10 to 12 grcll (tOo tzo g/1.) (Options B, C). These reconr D An anticoagulant therapy duration of 3 to 6 months is mendations do not apply to patients rn'ith acute coronar)' UI appropriate management of an acute proximal deep venous s1'ndrome, severe thrombocytopenia (patients treated fbr E thrombosis (DVT) that is provoked by reversible risk factors hematologic or oncologic reasons rtho are at risk of bleed .D tt (Option A). SVT. provoked or unprovoked. can be treated ing). and chronic transfusion dependent anemia. o, with only 6 weeks of anticoagulation. Erythropoietin is important in the treatment of the a Vein ligation might be considered for patients at higher anenria of chronic kidney disease (CKD) and is often needed rr risk who have an absolute contraindication to anticoagula in patients with end stage kidney disease receiving diall' tion to prevent propagation of the thrombus into the deep sis (Option A). Guiclelines recommend that erythropoietin .Et venous system (Option C). Vein ligation is not pan of routine stimulating agents be withheld in patients nith CKD not .D t/t care. In this patient, anticoagulation is the preferred therapy. requiring dialysis who have a hemoglobin level greater than Observation would be an trppropriate management 10 g dl- (100 g L). Higher hemoglobin targets are associated option for a superficial vein thrombosis without high risk r,vith adverse events, including worsening hypertension and features (Option D). Patients with low risk lower extremity volume orerload. This patient has an acute rt'orsening of SVT can be managed conservatively with warm compresses. mild. asl,mptomatic anemiir, most likely because of sepsis analgesics, and NSAIDs. Compression stockings may hasten (inflammation) ancl dilution owing to fluid resuscitation. the resolution of the thrombus. Follow up should be sched u'hich should improve as he continues to reco\er lrom his uled in I week to ensure symptom resolution. If symptoms current illness. No evidence supports any'benefit to erythro persist or worsen, repeat duplex ultrasonography should poietin therapy in this setting. be performed to evaluate for extension of the thrombus. If XEY POIXIS repeat ultrasound shows thrombus extension, anticoagula tion would then be indicated. . A restrictive transfusion threshold (l gtaL [zO glLJ) should be used to manage critically ill patients who XEY POTTIS are euvolemic. are not actively bleeding, and do not . Six weeks of anticoagulation is indicated for superfi have acute ischemic heart disease. cial vein thrombosis when the thrombus is 5 cm or . The restrictive transfusion threshold (7 g/dl [zO glL]) Aoes greater in length or is close to the deep venous system not apply to patients with acute coronary syndrome. or when other thrombophilic risk factors present. severe thrombocltopenia, and chronic transfusion . For patients with low-risk superficial vein thrombo dependent anemia. sis, observation with follow up in 1 week to ensure symptom resolution is reasonable; if symptoms per Bibliography sist or worsen, repeat duplex ultrasonography should Dochertv AB. Turgeon All \lhlsh-IS. Best practice in critical care: Anaemia be performed. in acr-lte and critical illness. l'ransfus Med. 2018;28:181 189. IPMll)' 2936q1371 rloi:l0.llll /tme.125o5 Bibliography Cosmi B. Management of superticial vein thromhosis. I Thromb Haemost. Item 69 Answer: A 201.5:1:l:l 175 83. IPM ID: 2590368.1] doi:l0.l1ll jth.l2986 Educational Objective: Treat secondary iron overload with iron chelation therapy. Item 68 Answer: D Oral iron chelation is the most appropriate treatment for Educational Objective: Avoid unnecessary transfusions. this patient (Option A). She has secondary iron overload and this patient does not require transfusion support or other requires intervention to decrease the iron burden to reduce slrecific management for his ancmia (Option D). i\ ran the risk for organ damage. particularly liver and cardiac donrized controlled studl' rileuvolemic critically ill patients toxicity. Iron overload is a signiflcant complication for trans confirmed the benefit ol a morc cautious transfusion Irigger. fusion dependent patients with P thalassemia major. Excess with a hemoglobin level less than 7 gtdL(7O g/L), compared iron accumulates from repeat erythrocyte transfusions and

Bibliography Cosmi B. Management of superticial vein thromhosis. I Thromb Haemost. Item 69 Answer: A 201.5:1:l:l 175 83. IPM ID: 2590368.1] doi:l0.l1ll jth.l2986 Educational Objective: Treat secondary iron overload with iron chelation therapy. Item 68 Answer: D Oral iron chelation is the most appropriate treatment for Educational Objective: Avoid unnecessary transfusions. this patient (Option A). She has secondary iron overload and this patient does not require transfusion support or other requires intervention to decrease the iron burden to reduce slrecific management for his ancmia (Option D). i\ ran the risk for organ damage. particularly liver and cardiac donrized controlled studl' rileuvolemic critically ill patients toxicity. Iron overload is a signiflcant complication for trans confirmed the benefit ol a morc cautious transfusion Irigger. fusion dependent patients with P thalassemia major. Excess with a hemoglobin level less than 7 gtdL(7O g/L), compared iron accumulates from repeat erythrocyte transfusions and 124

Answers and Critiques t lrom increased gastrointestinal absorption. Overt iron over- are not considered chrot.tic inflamnrattlry tliseases. lhis I load can be seen after transfusion of 15 to 20 units of blood. anemia is most o[ten norntochrotnic and normocl'tic or slightly microcytic. Inflantn.rati<ln results in releirsc ol :

t lrom increased gastrointestinal absorption. Overt iron over- are not considered chrot.tic inflamnrattlry tliseases. lhis I load can be seen after transfusion of 15 to 20 units of blood. anemia is most o[ten norntochrotnic and normocl'tic or slightly microcytic. Inflantn.rati<ln results in releirsc ol : F Patients requiring chronic transfusions are therefore at risk i ) for developing secondary iron overload. Individuals should interlcukin I and interleukin 6 from nlacrophages, r'r'hich t be monitored for evidence of iron overload with serial fer in tLlrn stintulates hepcidin release ttonr the livcr. Hepcidin t lr ritin level measurements. and MRI should be considered regulates iron balance by reducing the inrn transport chan I to evaluate iron deposition in the liver or heart. Chelation nel (Icrroportin) on enteroc]'-tes ilnd ntircrophages. lcircling I t therapy should begin before end organ injury to the liver or to reduced intestinal absorlttion ar.rd recluced release of iron I heart is evident. Chelation has been demonstrated to reduce from macrophages, erplaining the characteristically lou' t I organ iron levels and prolong survival in patients with thal serurn iron level and total iron binding capacity. The serun.t L assemia. It is often initiated when the serum ferritin level territin level is rypicall),elevatecl. Management is priniarill' I exceeds 1000 ng/ml (1000 pg/L), alter approximately 15 to directcd tow,nrd treatment of the underlying c<tnditirtn; in \ 20 units of blood have been transfused, or with evidence of this patient. the plannecl wouncl care tirr the pressurc ulcer Ut q, i I organ deposition (>3 mg of iron per gram dry weight in the and antibiotics firr the osteomyelitis should bc su{ficient ET ; liver or cardiac T2. <20 milliseconds on MRI). treatment. l. Regularly scheduled phlebotomy is the accepted care in ['.rytl.rrocyte triinsfusion is inclicated for patients u'ith tJ I managing patients with primary hemochromatosis and iron anemia of inllamnration only lbr severe, life threafcning, t =, I overload but is contraindicated in patients who are transfu symptomirlic anenrir that cannot artait the treirtment of the .E i sion dependent because of existing anemia (Option B). underlying condition (Option A). Most oltcn, thc transtusion tt (l, Apheresis and plasmapheresis are not effective means trigger is a hemoglobin lcvel less than 7 g1dl. (70 g/t-). 'this I for reducing iron levels (Option C). Much of the excess iron is paticnt has no indication tbr transtusion at this time. t = E I stored in extravascular sites and is not accessible for removal Illevated inflammatory cykrkir-res result irr reducc'cl pro by pheresis. duction ancl blunted actior.r ol' endogenous erytl.rropoictin. i 5 Evidence based care of patients with p-thalassemia IJryth ropoiesis stir.nulating agen ts gene rally provide I i rniteci major is regular transfusion. with a therapeutic target of value in aner.nia of ir.rflammation (Option B). I 'ilre r-educed serum iron level ancl krtal iron binding 9.5 to 10.5 g/dl (9S 105 g/L). Restricting transfusion would t not be recommended nor would it address the patient's iron capacit!'rt'ith the elevated serum ferritin level are consistent overload (Option D). with anen.ria of infliimmation rather th:rn ircn deficiency (in which thc total iron-bincling capacitl, is typically normal r(EY POtltTS t or elevated and the ferritin level is <100 ng,ml. [100 pg l-]). . In patients requiring chronic blood transfusions, Intravcr-tous iron is inefleclive in treating the anenria of t chelation therapy should be instituted when labora it.tflitnrmation (Option C). Becar-rse bactcria rccluire iron as tory evidence indicates iron overload but before signs a grorvth tactor, the use of intravenous iron during an irctive h of end-organ injury to the liver or heart appear. inl'ection may increase the risk of uncontrollecl infection. . Patients requiring chronic blood transfusions should {EY POIIITS be monitored for evidence of iron overload with serial i . Anemia of inflammation is characterized by normo- ferritin level measurements. and MRI should be con- ; cytic or mildly microcytic anemia, increased serum t sidered to evaluate iron deposition in the liver or ferritin level, low serum iron level, and a reduced total heart. iron binding capacity. Bibliography . The treatment of anemia of inflammation is directed Coates TD. lron overload in transfusion dependent patients. llematologr toward the underlying disorder. Am Soc Hematol Educ Program. 2019;2019:337-344. IPMID: 31808901] doi:1 0. I I 82r hematologr.20l 9000036 Bibliography \ Ganz T. Anemia of inflammation. N Engl J Med. 2019:381:1148 1157. IPMID

F Patients requiring chronic transfusions are therefore at risk i ) for developing secondary iron overload. Individuals should interlcukin I and interleukin 6 from nlacrophages, r'r'hich t be monitored for evidence of iron overload with serial fer in tLlrn stintulates hepcidin release ttonr the livcr. Hepcidin t lr ritin level measurements. and MRI should be considered regulates iron balance by reducing the inrn transport chan I to evaluate iron deposition in the liver or heart. Chelation nel (Icrroportin) on enteroc]'-tes ilnd ntircrophages. lcircling I t therapy should begin before end organ injury to the liver or to reduced intestinal absorlttion ar.rd recluced release of iron I heart is evident. Chelation has been demonstrated to reduce from macrophages, erplaining the characteristically lou' t I organ iron levels and prolong survival in patients with thal serurn iron level and total iron binding capacity. The serun.t L assemia. It is often initiated when the serum ferritin level territin level is rypicall),elevatecl. Management is priniarill' I exceeds 1000 ng/ml (1000 pg/L), alter approximately 15 to directcd tow,nrd treatment of the underlying c<tnditirtn; in \ 20 units of blood have been transfused, or with evidence of this patient. the plannecl wouncl care tirr the pressurc ulcer Ut q, i I organ deposition (>3 mg of iron per gram dry weight in the and antibiotics firr the osteomyelitis should bc su{ficient ET ; liver or cardiac T2. <20 milliseconds on MRI). treatment. l. Regularly scheduled phlebotomy is the accepted care in ['.rytl.rrocyte triinsfusion is inclicated for patients u'ith tJ I managing patients with primary hemochromatosis and iron anemia of inllamnration only lbr severe, life threafcning, t =, I overload but is contraindicated in patients who are transfu symptomirlic anenrir that cannot artait the treirtment of the .E i sion dependent because of existing anemia (Option B). underlying condition (Option A). Most oltcn, thc transtusion tt (l, Apheresis and plasmapheresis are not effective means trigger is a hemoglobin lcvel less than 7 g1dl. (70 g/t-). 'this I for reducing iron levels (Option C). Much of the excess iron is paticnt has no indication tbr transtusion at this time. t = E I stored in extravascular sites and is not accessible for removal Illevated inflammatory cykrkir-res result irr reducc'cl pro by pheresis. duction ancl blunted actior.r ol' endogenous erytl.rropoictin. i 5 Evidence based care of patients with p-thalassemia IJryth ropoiesis stir.nulating agen ts gene rally provide I i rniteci major is regular transfusion. with a therapeutic target of value in aner.nia of ir.rflammation (Option B). I 'ilre r-educed serum iron level ancl krtal iron binding 9.5 to 10.5 g/dl (9S 105 g/L). Restricting transfusion would t not be recommended nor would it address the patient's iron capacit!'rt'ith the elevated serum ferritin level are consistent overload (Option D). with anen.ria of infliimmation rather th:rn ircn deficiency (in which thc total iron-bincling capacitl, is typically normal r(EY POtltTS t or elevated and the ferritin level is <100 ng,ml. [100 pg l-]). . In patients requiring chronic blood transfusions, Intravcr-tous iron is inefleclive in treating the anenria of t chelation therapy should be instituted when labora it.tflitnrmation (Option C). Becar-rse bactcria rccluire iron as tory evidence indicates iron overload but before signs a grorvth tactor, the use of intravenous iron during an irctive h of end-organ injury to the liver or heart appear. inl'ection may increase the risk of uncontrollecl infection. . Patients requiring chronic blood transfusions should {EY POIIITS be monitored for evidence of iron overload with serial i . Anemia of inflammation is characterized by normo- ferritin level measurements. and MRI should be con- ; cytic or mildly microcytic anemia, increased serum t sidered to evaluate iron deposition in the liver or ferritin level, low serum iron level, and a reduced total heart. iron binding capacity. Bibliography . The treatment of anemia of inflammation is directed Coates TD. lron overload in transfusion dependent patients. llematologr toward the underlying disorder. Am Soc Hematol Educ Program. 2019;2019:337-344. IPMID: 31808901] doi:1 0. I I 82r hematologr.20l 9000036 Bibliography \ Ganz T. Anemia of inflammation. N Engl J Med. 2019:381:1148 1157. IPMID tr Item 70 Answer: D Educational Objective: Treat a patient with anemia of 315329611 doi:10.1056,NEJ1\4ra1804281

F Patients requiring chronic transfusions are therefore at risk i ) for developing secondary iron overload. Individuals should interlcukin I and interleukin 6 from nlacrophages, r'r'hich t be monitored for evidence of iron overload with serial fer in tLlrn stintulates hepcidin release ttonr the livcr. Hepcidin t lr ritin level measurements. and MRI should be considered regulates iron balance by reducing the inrn transport chan I to evaluate iron deposition in the liver or heart. Chelation nel (Icrroportin) on enteroc]'-tes ilnd ntircrophages. lcircling I t therapy should begin before end organ injury to the liver or to reduced intestinal absorlttion ar.rd recluced release of iron I heart is evident. Chelation has been demonstrated to reduce from macrophages, erplaining the characteristically lou' t I organ iron levels and prolong survival in patients with thal serurn iron level and total iron binding capacity. The serun.t L assemia. It is often initiated when the serum ferritin level territin level is rypicall),elevatecl. Management is priniarill' I exceeds 1000 ng/ml (1000 pg/L), alter approximately 15 to directcd tow,nrd treatment of the underlying c<tnditirtn; in \ 20 units of blood have been transfused, or with evidence of this patient. the plannecl wouncl care tirr the pressurc ulcer Ut q, i I organ deposition (>3 mg of iron per gram dry weight in the and antibiotics firr the osteomyelitis should bc su{ficient ET ; liver or cardiac T2. <20 milliseconds on MRI). treatment. l. Regularly scheduled phlebotomy is the accepted care in ['.rytl.rrocyte triinsfusion is inclicated for patients u'ith tJ I managing patients with primary hemochromatosis and iron anemia of inllamnration only lbr severe, life threafcning, t =, I overload but is contraindicated in patients who are transfu symptomirlic anenrir that cannot artait the treirtment of the .E i sion dependent because of existing anemia (Option B). underlying condition (Option A). Most oltcn, thc transtusion tt (l, Apheresis and plasmapheresis are not effective means trigger is a hemoglobin lcvel less than 7 g1dl. (70 g/t-). 'this I for reducing iron levels (Option C). Much of the excess iron is paticnt has no indication tbr transtusion at this time. t = E I stored in extravascular sites and is not accessible for removal Illevated inflammatory cykrkir-res result irr reducc'cl pro by pheresis. duction ancl blunted actior.r ol' endogenous erytl.rropoictin. i 5 Evidence based care of patients with p-thalassemia IJryth ropoiesis stir.nulating agen ts gene rally provide I i rniteci major is regular transfusion. with a therapeutic target of value in aner.nia of ir.rflammation (Option B). I 'ilre r-educed serum iron level ancl krtal iron binding 9.5 to 10.5 g/dl (9S 105 g/L). Restricting transfusion would t not be recommended nor would it address the patient's iron capacit!'rt'ith the elevated serum ferritin level are consistent overload (Option D). with anen.ria of infliimmation rather th:rn ircn deficiency (in which thc total iron-bincling capacitl, is typically normal r(EY POtltTS t or elevated and the ferritin level is <100 ng,ml. [100 pg l-]). . In patients requiring chronic blood transfusions, Intravcr-tous iron is inefleclive in treating the anenria of t chelation therapy should be instituted when labora it.tflitnrmation (Option C). Becar-rse bactcria rccluire iron as tory evidence indicates iron overload but before signs a grorvth tactor, the use of intravenous iron during an irctive h of end-organ injury to the liver or heart appear. inl'ection may increase the risk of uncontrollecl infection. . Patients requiring chronic blood transfusions should {EY POIIITS be monitored for evidence of iron overload with serial i . Anemia of inflammation is characterized by normo- ferritin level measurements. and MRI should be con- ; cytic or mildly microcytic anemia, increased serum t sidered to evaluate iron deposition in the liver or ferritin level, low serum iron level, and a reduced total heart. iron binding capacity. Bibliography . The treatment of anemia of inflammation is directed Coates TD. lron overload in transfusion dependent patients. llematologr toward the underlying disorder. Am Soc Hematol Educ Program. 2019;2019:337-344. IPMID: 31808901] doi:1 0. I I 82r hematologr.20l 9000036 Bibliography \ Ganz T. Anemia of inflammation. N Engl J Med. 2019:381:1148 1157. IPMID tr Item 70 Answer: D Educational Objective: Treat a patient with anemia of 315329611 doi:10.1056,NEJ1\4ra1804281 inflammation. Item 71 Answer: A Educational Objective: Diagnose myelodysplastic \o further trextlnent is needed (Option D). 'Ihis patient syndrome. most likely has anemia ol inf lammation resulting fiom the I infectecl sacrll pressure nlcer with undcrlying osteomv The most appropriate diagnostic test to perlorm next is clitis. ,\ncnria of inflirrnmation can ;rccompilny significar-rt bone marrow biopsy (Option A). This patient most likely inf'ections (e.g.. tuberculosis. endocarditis. osteomyelitis). has a myelodysplastic syndrome (MDS), a clonal stem cell in[lamnritlory clisorclers (e.g.. rheunratoirl arthritis or rirs disorder rvith ineffective hematopoiesis leading to dys cLllitis), and n.ralignancies. Occasionally it can be seen in plastic bone marrow and peripheral blood cytopenias. The conditions such :rs heart failure and diabetes rnellitus tl'rlt developing trilineage cytopenia supports the diagnosis of

inflammation. Item 71 Answer: A Educational Objective: Diagnose myelodysplastic \o further trextlnent is needed (Option D). 'Ihis patient syndrome. most likely has anemia ol inf lammation resulting fiom the I infectecl sacrll pressure nlcer with undcrlying osteomv The most appropriate diagnostic test to perlorm next is clitis. ,\ncnria of inflirrnmation can ;rccompilny significar-rt bone marrow biopsy (Option A). This patient most likely inf'ections (e.g.. tuberculosis. endocarditis. osteomyelitis). has a myelodysplastic syndrome (MDS), a clonal stem cell in[lamnritlory clisorclers (e.g.. rheunratoirl arthritis or rirs disorder rvith ineffective hematopoiesis leading to dys cLllitis), and n.ralignancies. Occasionally it can be seen in plastic bone marrow and peripheral blood cytopenias. The conditions such :rs heart failure and diabetes rnellitus tl'rlt developing trilineage cytopenia supports the diagnosis of 125

Answers and Critiques MDS. No circulating blasts are present, making a hyper and elevated D dimer level. The main diagnostic consider proliferative disorder such as a leukemia or myeloprolif- ations fbr his throntbocytopenia and coagulopath). include erate neoplasm (MPN) less likely. Other reversible causes liver disease and dissenir-ratecl intravascular coagulation of dysplasia that must be ruled out include vitamin B,r, (DIC). l.aboratory orrerlap behr.een these diagnoses is con folate, and copper deflciency; alcohol consumption; med- siderable. making it difficult to dillbrentiate them olt testing ications; and infections such as HIV. The best way to fur alone. Additionallyi they are often present simultaneouslr: )

MDS. No circulating blasts are present, making a hyper and elevated D dimer level. The main diagnostic consider proliferative disorder such as a leukemia or myeloprolif- ations fbr his throntbocytopenia and coagulopath). include erate neoplasm (MPN) less likely. Other reversible causes liver disease and dissenir-ratecl intravascular coagulation of dysplasia that must be ruled out include vitamin B,r, (DIC). l.aboratory orrerlap behr.een these diagnoses is con folate, and copper deflciency; alcohol consumption; med- siderable. making it difficult to dillbrentiate them olt testing ications; and infections such as HIV. The best way to fur alone. Additionallyi they are often present simultaneouslr: ) ther evaluate symptomatic anemia or pancytopenia and to and treatment considerations are heavilf influenced b1' the assess this patient's prognosis is to perform a bone marrow orerall clinical picture. Distinguishing betrreen liver disease biopsy, which will conflrm the histologic diagnosis and and DIC mal be challengir.rg, but measuring the factor VIII provide prognostic information. irctivitf is a theoretical means ot separating these disorders. Testing the ery.thropoietin level is not useful for diag- Factor VIII is often normal or eler.ated in patients \rith li\.er nostic purposes but can be used after diagnosis to predict clisease because factor VIII is procluced in hepatic and non response to ery.thropoietin-based therapy (Option B). Eryth- hepatic endothelial cellsr hou,ever, factor \'il1 is consumed in .A ropoietin deflciency, often associated with chronic kidney DIC. A normal or elevated factor VIII level uill support liver E disease or acute inflammation, is associated with normo- disease as the cause of'this patient's coagulopathr. .D UI cytic anemia; leukocyte and platelet counts are typically Factors II and X are reduced in liver disease. r,itamin K o, normal. deficienc'-ri ancl DIC (Options A. C). \,leasuring these lerels EL lAK2 mutation testing would be used to evaluate for r,r,ould not be helpful in evaluating this patient's coagulopathl: n suspected polycythemia vera or an associated MPN such as Thrombin time measures tl.re final step in coagulation essential thrombocythemia or, more rarely, myelofibrosis (conversion of fibrinogen to fibrin) bv measuritrg the tirne trt lt (Option C). However, this patient has cytopenias rather fibrin clot formation (Option D). This test rvill be prolonged .D UI than elevated cell counts, no splenomegaly, and no systemic in the presence of heparin. lorv fibrinogen level. or abttormal symptoms that would support the presence of an MPN. Tear- tibrinogen (dl,sflbrinogenernia) but is normal in patients drop cells and nucleated erythrocltes would be expected on rtith pure vitamin K deficiencl: A thrombin time \\'ill not the blood smear of patients with myeloflbrosis. distinguish between coagulopathy frorn DIC or liver disease. Parvovirus B19 DNA polymerase chain reaction is not because the fibrinogen level is characteristicalll' lou. result indicated (Option D). Parvovirus B19 is cytotoxic to the ing ir.r prolongation ol the thrombin time, in botl.t conditiorls. erythrocyte precursors in the bone marrow and can cause ItY POIilT pure red cell aplasia (PRCA). Parvovirus infection does not usually cause clinically signiflcant anemia in healthy o Factor VIII is produeed in hepatic and nonhepatic patients. However, patients with chronic hemolysis (such endothelial cells; it is normal or elevated in the ccagu as sickle cell anemia) can have signiflcant anemia with a lopathy of liver disease and is consumed in dissemi- decreased reticulocyte count. PRCA is not associated with nated intravascular coagulation. cytopenias in other cell lines or with the appearance of dysplastic cells on the peripheral blood smear as seen in this Bibliography patient. Tripodi A. Hemostasis in acute and chronic liver disease. Semin l.iver Dis. 2017 :37 :28 32. IPMID: 28201846] doi:l 0. 1055 /s 0036 - 1597770

ther evaluate symptomatic anemia or pancytopenia and to and treatment considerations are heavilf influenced b1' the assess this patient's prognosis is to perform a bone marrow orerall clinical picture. Distinguishing betrreen liver disease biopsy, which will conflrm the histologic diagnosis and and DIC mal be challengir.rg, but measuring the factor VIII provide prognostic information. irctivitf is a theoretical means ot separating these disorders. Testing the ery.thropoietin level is not useful for diag- Factor VIII is often normal or eler.ated in patients \rith li\.er nostic purposes but can be used after diagnosis to predict clisease because factor VIII is procluced in hepatic and non response to ery.thropoietin-based therapy (Option B). Eryth- hepatic endothelial cellsr hou,ever, factor \'il1 is consumed in .A ropoietin deflciency, often associated with chronic kidney DIC. A normal or elevated factor VIII level uill support liver E disease or acute inflammation, is associated with normo- disease as the cause of'this patient's coagulopathr. .D UI cytic anemia; leukocyte and platelet counts are typically Factors II and X are reduced in liver disease. r,itamin K o, normal. deficienc'-ri ancl DIC (Options A. C). \,leasuring these lerels EL lAK2 mutation testing would be used to evaluate for r,r,ould not be helpful in evaluating this patient's coagulopathl: n suspected polycythemia vera or an associated MPN such as Thrombin time measures tl.re final step in coagulation essential thrombocythemia or, more rarely, myelofibrosis (conversion of fibrinogen to fibrin) bv measuritrg the tirne trt lt (Option C). However, this patient has cytopenias rather fibrin clot formation (Option D). This test rvill be prolonged .D UI than elevated cell counts, no splenomegaly, and no systemic in the presence of heparin. lorv fibrinogen level. or abttormal symptoms that would support the presence of an MPN. Tear- tibrinogen (dl,sflbrinogenernia) but is normal in patients drop cells and nucleated erythrocltes would be expected on rtith pure vitamin K deficiencl: A thrombin time \\'ill not the blood smear of patients with myeloflbrosis. distinguish between coagulopathy frorn DIC or liver disease. Parvovirus B19 DNA polymerase chain reaction is not because the fibrinogen level is characteristicalll' lou. result indicated (Option D). Parvovirus B19 is cytotoxic to the ing ir.r prolongation ol the thrombin time, in botl.t conditiorls. erythrocyte precursors in the bone marrow and can cause ItY POIilT pure red cell aplasia (PRCA). Parvovirus infection does not usually cause clinically signiflcant anemia in healthy o Factor VIII is produeed in hepatic and nonhepatic patients. However, patients with chronic hemolysis (such endothelial cells; it is normal or elevated in the ccagu as sickle cell anemia) can have signiflcant anemia with a lopathy of liver disease and is consumed in dissemi- decreased reticulocyte count. PRCA is not associated with nated intravascular coagulation. cytopenias in other cell lines or with the appearance of dysplastic cells on the peripheral blood smear as seen in this Bibliography patient. Tripodi A. Hemostasis in acute and chronic liver disease. Semin l.iver Dis. 2017 :37 :28 32. IPMID: 28201846] doi:l 0. 1055 /s 0036 - 1597770 TTY PQIf,I' . Myelodysplastic syndrome is a clonal stem cell disor- Item 73 Answer: E der with ineffective hematopoiesis leading to dysplas- tic, hypercellular bone marrow and peripheral blood Educational Objective: Manage acute hemolysis associ- ated with glucose-6-phosphate dehydrogenase deficiency. cltopenias. . Bone marrow biopsy is necessary to diagnose myelo- Clinical observation and symptom monitoring are appro- dysplastic syndrome. priate for this patient (Option E). He is experiencing an acute hemolytic event related to glucose 6 phosphate Bibliography dehydrogenase (G6PD) deflciency that was likely trig CazzolaM. Myelodysplastic syndromes. N Engl J Med. 2020;383:1358 1374. gered by recent medication exposure. G6PD deficiency lPMl D: 329979101 doi:10.1056/NUMra19O4794 is an X linked disorder and the most common enzyme deflciency affecting erythrocytes. It is estimated to affect

TTY PQIf,I' . Myelodysplastic syndrome is a clonal stem cell disor- Item 73 Answer: E der with ineffective hematopoiesis leading to dysplas- tic, hypercellular bone marrow and peripheral blood Educational Objective: Manage acute hemolysis associ- ated with glucose-6-phosphate dehydrogenase deficiency. cltopenias. . Bone marrow biopsy is necessary to diagnose myelo- Clinical observation and symptom monitoring are appro- dysplastic syndrome. priate for this patient (Option E). He is experiencing an acute hemolytic event related to glucose 6 phosphate Bibliography dehydrogenase (G6PD) deflciency that was likely trig CazzolaM. Myelodysplastic syndromes. N Engl J Med. 2020;383:1358 1374. gered by recent medication exposure. G6PD deficiency lPMl D: 329979101 doi:10.1056/NUMra19O4794 is an X linked disorder and the most common enzyme deflciency affecting erythrocytes. It is estimated to affect tr Item 72 Answer: B Educational Obiective: Diagnose coagulopathy of liver approximately 11% of Black persons in the United States. Enzyme deflciency results in failure to generate nicotin- amide adenine dinucleotide phosphate (NADPH), leading disease. to reduced glutathione levels and subsequent hemolysis, The most appropriate test to evaluate the patierlt's coagulop which is both intra- and extravascular. Acute hemolytic athy is the factor Vlll level (Option B). In addition to throm events can be triggered by oxidative stress, with medi- bocvtopenia, the patient has a coagulopathy as cviclenced cations and infections among the most common causes. by the prolonged coagulation studies, low fibrinogen level, Nitrofurantoin is one of the medications known to

tr Item 72 Answer: B Educational Obiective: Diagnose coagulopathy of liver approximately 11% of Black persons in the United States. Enzyme deflciency results in failure to generate nicotin- amide adenine dinucleotide phosphate (NADPH), leading disease. to reduced glutathione levels and subsequent hemolysis, The most appropriate test to evaluate the patierlt's coagulop which is both intra- and extravascular. Acute hemolytic athy is the factor Vlll level (Option B). In addition to throm events can be triggered by oxidative stress, with medi- bocvtopenia, the patient has a coagulopathy as cviclenced cations and infections among the most common causes. by the prolonged coagulation studies, low fibrinogen level, Nitrofurantoin is one of the medications known to 125

Answers and Critiques t I I t I cause significant hemolysis in G6PD deflciency. Patients Item 74 Answer: D I' I have signs of hemolysis on laboratory testing, and micro- Educational Objective: Treat a patient with antiphos- I 5 spherocytes, bite cells, and blister cells are seen on the pholipid antibody syndrome. peripheral blood smear. Special stains can demonstrate t denatured globin chains attached to the erythrocyte mem- The most appropriate treatment for this patient is initial low-molecular-weight heparin (LMWH) and transitioning I I brane ("Heinz bodies") as shown. Semiquantitative tests \ are used to evaluate enzyme function through reducing Iater to warfarin (Option D). She has systemic lupus erythe- I \ NADP to NADPH. However, G6PD levels may appear nor matosus and now has a likely diagnosis of antiphospholipid I mal during acute hemolytic episodes when brisk reticu- antibody syndrome (APLAS). APLAS is an autoimmune dis- locytosis occurs because reticulocytes have higher G6PD order in which thrombosis and fetal demise (in pregnancy) I 5 activity than older erythrocytes. may occur. Patients with APLAS are at risk for arterial and venous thrombosis. The diagnosis is based on the clinical \ ..€' iq+ ' ii: criteria of thromboembolism or pregnancy morbidity and t (l, "xm"..-,€* .q. Iaboratory flndings of medium or high-titer antiphospho I ""4. b' tr ^- l " ir.i;6 ET t*, * €"*-_ t"ff.+*" lipid antibodies present on two or more occasions at least t '* 12 weeks apart. A clue to the presence of the lupus antico- (, agulant is activated partial thromboplastin time prolonga t tion that fails to correct with a mixing study. This patient's =, E .' l! I diagnosis of APLAS is based on the presence of an acute UI t o thrombotic event and positive test results for all three anti t phospholipid antibodies (lupus anticoagulant, anticardio- UI = t lipin antibody, and p2-glycoprotein antibody). This patient's I ,u4 antiphospholipid measurements should be repeated after "&# *f r* * *_. 12 weeks for flnal conflrmation. Extended anticoagulation is needed now. The risk for recurrent thrombosis is reported to \ I

t I cause significant hemolysis in G6PD deflciency. Patients Item 74 Answer: D I' I have signs of hemolysis on laboratory testing, and micro- Educational Objective: Treat a patient with antiphos- I 5 spherocytes, bite cells, and blister cells are seen on the pholipid antibody syndrome. peripheral blood smear. Special stains can demonstrate t denatured globin chains attached to the erythrocyte mem- The most appropriate treatment for this patient is initial low-molecular-weight heparin (LMWH) and transitioning I I brane ("Heinz bodies") as shown. Semiquantitative tests \ are used to evaluate enzyme function through reducing Iater to warfarin (Option D). She has systemic lupus erythe- I \ NADP to NADPH. However, G6PD levels may appear nor matosus and now has a likely diagnosis of antiphospholipid I mal during acute hemolytic episodes when brisk reticu- antibody syndrome (APLAS). APLAS is an autoimmune dis- locytosis occurs because reticulocytes have higher G6PD order in which thrombosis and fetal demise (in pregnancy) I 5 activity than older erythrocytes. may occur. Patients with APLAS are at risk for arterial and venous thrombosis. The diagnosis is based on the clinical \ ..€' iq+ ' ii: criteria of thromboembolism or pregnancy morbidity and t (l, "xm"..-,€* .q. Iaboratory flndings of medium or high-titer antiphospho I ""4. b' tr ^- l " ir.i;6 ET t*, * €"*-_ t"ff.+*" lipid antibodies present on two or more occasions at least t '* 12 weeks apart. A clue to the presence of the lupus antico- (, agulant is activated partial thromboplastin time prolonga t tion that fails to correct with a mixing study. This patient's =, E .' l! I diagnosis of APLAS is based on the presence of an acute UI t o thrombotic event and positive test results for all three anti t phospholipid antibodies (lupus anticoagulant, anticardio- UI = t lipin antibody, and p2-glycoprotein antibody). This patient's I ,u4 antiphospholipid measurements should be repeated after "&# *f r* * *_. 12 weeks for flnal conflrmation. Extended anticoagulation is needed now. The risk for recurrent thrombosis is reported to \ I be higher in patients with "triple-positive" APLAS serologic tests when treated with a direct oral anticoagulant (DOAC) \ Managing hemo$sis in a patient with G6PD deflciency compared with LMWH followed by dose-adjusted warfarin. includes removing the offending agent and providing support In general, the preferred treatment of acute venous ive interventions such as packed red blood cell transfusions if thromboembolism in patients with APLAS is LMWH fol t needed (Option A). Patients fypically recover within several lowed by warfarin. DOACs may be associated with a higher days of drug discontinuation. This patient is no longer taking \ risk of thrombosis compared with warfarin in patients with nitrofurantoin, and his hemoglobin level does not necessitate "triple-positive" APLAS or in patients with arterial throm- transfusion, so further intervention is not necessary. \ bosis. Therefore, apixaban and dabigatran would not be the No evidence of microangiopathic hemolytic anemia is ' most appropriate choices for this patient (Options A, B). seen in this patient's examination, with no reported schisto Evidence supporting the use of parenteral anticoag cltes and a normal platelet count; therefore, a diagnosis of I ulants other than LMWH is extremely sparse and consists thrombotic thrombocytopenic purpura is not plausible, and primarily of a few case reports. Fondaparinux cannot be plasma exchange would not be necessary (Option B). \ 'lhis patient shows no evidence of an autoimmune recommended as an alternative to LMWH until sufficient ; data can confirm its effectiveness and safety (Option C). process, including a negative direct antiglobulin test; there Finally, fondaparinux has no reversal agent. Caution should fbre, neither glucocorticoids nor rituximab is indicated be used in patients at risk for bleeding because the half life (Options C, D). i is 17 hours. I(EY POI]IIS TEY POIlIIS \ . In patients with glucose-6 phosphate dehydrogenase deficiency, acute hemoly'tic events can be triggered by o The diagnosis of antiphospholipid antibody syndrome oxidative stress, with medications and infections is based on the clinical criteria of thromboembolism

be higher in patients with "triple-positive" APLAS serologic tests when treated with a direct oral anticoagulant (DOAC) \ Managing hemo$sis in a patient with G6PD deflciency compared with LMWH followed by dose-adjusted warfarin. includes removing the offending agent and providing support In general, the preferred treatment of acute venous ive interventions such as packed red blood cell transfusions if thromboembolism in patients with APLAS is LMWH fol t needed (Option A). Patients fypically recover within several lowed by warfarin. DOACs may be associated with a higher days of drug discontinuation. This patient is no longer taking \ risk of thrombosis compared with warfarin in patients with nitrofurantoin, and his hemoglobin level does not necessitate "triple-positive" APLAS or in patients with arterial throm- transfusion, so further intervention is not necessary. \ bosis. Therefore, apixaban and dabigatran would not be the No evidence of microangiopathic hemolytic anemia is ' most appropriate choices for this patient (Options A, B). seen in this patient's examination, with no reported schisto Evidence supporting the use of parenteral anticoag cltes and a normal platelet count; therefore, a diagnosis of I ulants other than LMWH is extremely sparse and consists thrombotic thrombocytopenic purpura is not plausible, and primarily of a few case reports. Fondaparinux cannot be plasma exchange would not be necessary (Option B). \ 'lhis patient shows no evidence of an autoimmune recommended as an alternative to LMWH until sufficient ; data can confirm its effectiveness and safety (Option C). process, including a negative direct antiglobulin test; there Finally, fondaparinux has no reversal agent. Caution should fbre, neither glucocorticoids nor rituximab is indicated be used in patients at risk for bleeding because the half life (Options C, D). i is 17 hours. I(EY POI]IIS TEY POIlIIS \ . In patients with glucose-6 phosphate dehydrogenase deficiency, acute hemoly'tic events can be triggered by o The diagnosis of antiphospholipid antibody syndrome oxidative stress, with medications and infections is based on the clinical criteria of thromboembolism among the most common causes. or pregnancy morbidity and laboratory findings of medium or high-titer antiphospholipid antibodies o Patients with glucose-6-phosphate dehydrogenase present on two or more occasions at least 12 weeks deficiency have signs of hemolysis on laboratory test- apart. ing, and microspherocytes, bite cells, and blister cells o Patients with "triple-positive" antiphospholipid anti- are seen on the peripheral blood smear. body syndrome (presence of lupus anticoagulant, Bibliography anticardiolipin antibody, and pr-g$coprotein anti Belfield KD, Tichy EM. Review and drug therapy implications of glucose body) should be treated with low-molecular-weight 6 phosphate dehydrogenase deficiency. Am J Health Syst Pharm. heparin followed by warfarin. 2018:75:97 -1O4. IPMIDT 29305344] doi:10.2146lajhpl60961

among the most common causes. or pregnancy morbidity and laboratory findings of medium or high-titer antiphospholipid antibodies o Patients with glucose-6-phosphate dehydrogenase present on two or more occasions at least 12 weeks deficiency have signs of hemolysis on laboratory test- apart. ing, and microspherocytes, bite cells, and blister cells o Patients with "triple-positive" antiphospholipid anti- are seen on the peripheral blood smear. body syndrome (presence of lupus anticoagulant, Bibliography anticardiolipin antibody, and pr-g$coprotein anti Belfield KD, Tichy EM. Review and drug therapy implications of glucose body) should be treated with low-molecular-weight 6 phosphate dehydrogenase deficiency. Am J Health Syst Pharm. heparin followed by warfarin. 2018:75:97 -1O4. IPMIDT 29305344] doi:10.2146lajhpl60961 127

Answers and Critiques Bibliography Item 76 Answer: A Ordi Ros J. Sdez-Comet L. Perez Conesa M, et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: A randomized noninferiority Educational Objective: Treat bleeding in a patient with tr trial. Ann lntern Med. 2019:l7l:685 694. IPMID:31610549] doi:10.7326 acquired hemophilia A. Ml9 0291 lhe most appropriate treatment is actirated factor VII (Option A). A markedly prolonged activatecl partial throrrboplastin time

Bibliography Item 76 Answer: A Ordi Ros J. Sdez-Comet L. Perez Conesa M, et al. Rivaroxaban versus vitamin K antagonist in antiphospholipid syndrome: A randomized noninferiority Educational Objective: Treat bleeding in a patient with tr trial. Ann lntern Med. 2019:l7l:685 694. IPMID:31610549] doi:10.7326 acquired hemophilia A. Ml9 0291 lhe most appropriate treatment is actirated factor VII (Option A). A markedly prolonged activatecl partial throrrboplastin time tr Item 75 Answer: A Educational Objective: Manage gastrointestinal bleeding (at{T) that fails to correct during a mi-xing stud1'and a lou' fhctor VIII lcrel suggest that thc patieltt's postoperatire bleed 1 in a patient taking dual antiplatelet agents. ing is most likely caused by ar.r acquired inhibitor to fackrr VIII (acquired hemcphilia A). ln this disorder. an autoantibodr- In consulLation lvith cardiolog: clopidogrel should be dis (usualll' lgG) against an epitope of lactor \rlll rreutralizes its continued at this time (Option A). Aspirin and cktpidogrel. ir coagulati<ln function. Acquired factor VIII inhibitors are more P2Y,, receptor antagonist, irrerersibly inhibit difibrerlt steps in D conlrron in patients older than 60 \ears. are slightll' more com platclet acti'uation and rcduce co()nary artery stent thrombosis (a rnon in \{omen than nren. ancl can be associated u'ith under riskr however, they also increase the bleeding risk. Guidelines l1,ing autoimn-rune conditions (systemic lupus crythematosus. = .D recommend treating patients u,ith stable angrna r.t ith dual anti rhcumatoid afi hri ti s) or mal ignancl- (usuall-v llmphoprol i f bra UI platelet therapy (DAPI') ftrr at least 6 rnonths after drug eluting o, tive disorders); houever, they ma1,arise spontaneousll'as u,ell. stent placement, with tl-re option to continue therapy for r EL Patients often present with eccl.rymosis and soft tissue blecdir.rg. n longer duration in thosc rt ith a high risk Ibr thrombosis-related 'l-reatment $,ith acti\ated factor \III or lctirated prothronrbin complications and a fav'orable blceding profile. In patients r'r,ith complex concentrate is recommended because these agents .,,Et significant hemorrhage in whorn DAPT must be cliscontin activate faclur X, located dortnstream fiom facbr Vitl in the .D ued, thc P2Y, rcceptor ilntagonist sl.rould be discontinued ancl UI coagulation cascade. thus bypassing the eflect of the inhibitor. aspirin continuecl. This strate$/' is informed by the results ol a Treiltment udth factor VIll concentrate or fiesh fnrzcn plasn.ra is systematic review of latc stent thrombosis (>:10 days tlut <1 year ineflbctir'e because thc inhibitor neutraliz.es the factor \rlll actir. after stent placement) and rery late stent thrombosis (>1 vcar ity in the adn.rinisterecl product (Options C, D). Prtrcine derired after stent placement). l'}atients who discontinued both aspirin factor VIII is only parliirl\ cnrss- reactire with human fxctor and a P2Y,, receptor lrntagonist had a median time to stent VIII and can be eflective therapy n,hen the inhibitor titer is l<xr,: thrombosis of 7 days. Patients'uvho discontinued a P2Y,, recep hor,r,erer. it is llot ujde\'arailable. Immunosupprcssire therapt tor antagonist but continLled aspirin therapy had a mcdian time should bc inrplen-rented to elirninate thc inhibitor. to thrombotic event of 122 clays. Six percent of stent tlrrombosis Desmopressin is used in the treatment of ron Willc occurred rvithin 10 days oF P2Yrr receptor antagonist cessation. brand diselse (vWI)) and causes end<tthelial cclls to release suggesting short telm discontinuation beM,een 30 da1r5 snfl prefbrmed stores o{' von Willebrand litctor and factor \,'lll 1 year from clrug-eluting coronary stent placement (late ster.rt into the circulation (Option B). Hon'ever. the n.riring studl' thrombosis) might be relatirell,safb but still carries some risk. fbr patients u,ith r,WD u'ith lou' factor \rlll levels u'ould l)iscontinuir.rg both aspirin rnd clopidogrel cannot lte 'lhis paticnt's aPTT did not cor shur.t, complete corrcction. recommendecl becausc of'the high risk of stent thrombosis rcct. n-raking the diagr.rosis of l'WD unlikely and desmopres (Option B). When modifying DAPT. aspirin should be con sin administration unhelp{ul. tinued to recluce the risl< of stent tl-rrombosis. Acute blcecling can be managed with platelet trar.rsfu XEY POIXTS l

tr Item 75 Answer: A Educational Objective: Manage gastrointestinal bleeding (at{T) that fails to correct during a mi-xing stud1'and a lou' fhctor VIII lcrel suggest that thc patieltt's postoperatire bleed 1 in a patient taking dual antiplatelet agents. ing is most likely caused by ar.r acquired inhibitor to fackrr VIII (acquired hemcphilia A). ln this disorder. an autoantibodr- In consulLation lvith cardiolog: clopidogrel should be dis (usualll' lgG) against an epitope of lactor \rlll rreutralizes its continued at this time (Option A). Aspirin and cktpidogrel. ir coagulati<ln function. Acquired factor VIII inhibitors are more P2Y,, receptor antagonist, irrerersibly inhibit difibrerlt steps in D conlrron in patients older than 60 \ears. are slightll' more com platclet acti'uation and rcduce co()nary artery stent thrombosis (a rnon in \{omen than nren. ancl can be associated u'ith under riskr however, they also increase the bleeding risk. Guidelines l1,ing autoimn-rune conditions (systemic lupus crythematosus. = .D recommend treating patients u,ith stable angrna r.t ith dual anti rhcumatoid afi hri ti s) or mal ignancl- (usuall-v llmphoprol i f bra UI platelet therapy (DAPI') ftrr at least 6 rnonths after drug eluting o, tive disorders); houever, they ma1,arise spontaneousll'as u,ell. stent placement, with tl-re option to continue therapy for r EL Patients often present with eccl.rymosis and soft tissue blecdir.rg. n longer duration in thosc rt ith a high risk Ibr thrombosis-related 'l-reatment $,ith acti\ated factor \III or lctirated prothronrbin complications and a fav'orable blceding profile. In patients r'r,ith complex concentrate is recommended because these agents .,,Et significant hemorrhage in whorn DAPT must be cliscontin activate faclur X, located dortnstream fiom facbr Vitl in the .D ued, thc P2Y, rcceptor ilntagonist sl.rould be discontinued ancl UI coagulation cascade. thus bypassing the eflect of the inhibitor. aspirin continuecl. This strate$/' is informed by the results ol a Treiltment udth factor VIll concentrate or fiesh fnrzcn plasn.ra is systematic review of latc stent thrombosis (>:10 days tlut <1 year ineflbctir'e because thc inhibitor neutraliz.es the factor \rlll actir. after stent placement) and rery late stent thrombosis (>1 vcar ity in the adn.rinisterecl product (Options C, D). Prtrcine derired after stent placement). l'}atients who discontinued both aspirin factor VIII is only parliirl\ cnrss- reactire with human fxctor and a P2Y,, receptor lrntagonist had a median time to stent VIII and can be eflective therapy n,hen the inhibitor titer is l<xr,: thrombosis of 7 days. Patients'uvho discontinued a P2Y,, recep hor,r,erer. it is llot ujde\'arailable. Immunosupprcssire therapt tor antagonist but continLled aspirin therapy had a mcdian time should bc inrplen-rented to elirninate thc inhibitor. to thrombotic event of 122 clays. Six percent of stent tlrrombosis Desmopressin is used in the treatment of ron Willc occurred rvithin 10 days oF P2Yrr receptor antagonist cessation. brand diselse (vWI)) and causes end<tthelial cclls to release suggesting short telm discontinuation beM,een 30 da1r5 snfl prefbrmed stores o{' von Willebrand litctor and factor \,'lll 1 year from clrug-eluting coronary stent placement (late ster.rt into the circulation (Option B). Hon'ever. the n.riring studl' thrombosis) might be relatirell,safb but still carries some risk. fbr patients u,ith r,WD u'ith lou' factor \rlll levels u'ould l)iscontinuir.rg both aspirin rnd clopidogrel cannot lte 'lhis paticnt's aPTT did not cor shur.t, complete corrcction. recommendecl becausc of'the high risk of stent thrombosis rcct. n-raking the diagr.rosis of l'WD unlikely and desmopres (Option B). When modifying DAPT. aspirin should be con sin administration unhelp{ul. tinued to recluce the risl< of stent tl-rrombosis. Acute blcecling can be managed with platelet trar.rsfu XEY POIXTS l sions. but this rtill result in complete reversal of'antiplatelct . Acquired hemophilia A is characterizedby a prolonged agent effects, which increases tl.re risk tbr thrombosis simi activated partial thromboplastin time that fails to correct larly kr discontinuing all DAPT (Option C). during a mixing study and by a low factor VIII actMty. (iontinuing both aspirin ancl clopidogrel increases the . Treatment of acquired hemophilia A includes acti- risk of continued gastrointestinal bleeding (Option D). 'll-re vated factor VII, activated prothrombin complex con- risk of stopping clopiclogrel is reasonable b:rsed on the avail able data and. ir.r cor.rsultatior.r ',vith cardiologi is likely the centrate, or porcine derived factor VIII concentrate. best course of irction. Bibliography x[Y POttT Tiede A. Collins P, Knoebl P. et al. International recommendations on the o In patients taking dual antiplatelet therapy following diagnosis and treatment of acquired hemophilia A. Haematologica. 202O:105:1791 1801. IPMID: 32381.574] doi:10.3324/haematol.2019.2ilo771 coronary revascularization with significant hemorrhage, the best strates/ is to discontinue the P2Y,2 receptor antagonist and continue aspirin. llem77 Answer: D Educational Objective: Treat a symptomatic patient Bibliography with 5q- myelodysplastic syndrome. Acosta RD, Abraham NS, Chandrasekhara V, et al.; ASGE Standards of Practice Committee. The management of antithrombotic agents for patients undergoing GI endoscopy. Gastrointest Endosc. 2Ol6;83:3 16. Lenalidomide is the most appropriate treatment for this IPMl D: 266215.18] doi:1O.lol6ij.gie.20l5.09.O35 patient (Option D).The myelodysplastic syndromes (MDS)

sions. but this rtill result in complete reversal of'antiplatelct . Acquired hemophilia A is characterizedby a prolonged agent effects, which increases tl.re risk tbr thrombosis simi activated partial thromboplastin time that fails to correct larly kr discontinuing all DAPT (Option C). during a mixing study and by a low factor VIII actMty. (iontinuing both aspirin ancl clopidogrel increases the . Treatment of acquired hemophilia A includes acti- risk of continued gastrointestinal bleeding (Option D). 'll-re vated factor VII, activated prothrombin complex con- risk of stopping clopiclogrel is reasonable b:rsed on the avail able data and. ir.r cor.rsultatior.r ',vith cardiologi is likely the centrate, or porcine derived factor VIII concentrate. best course of irction. Bibliography x[Y POttT Tiede A. Collins P, Knoebl P. et al. International recommendations on the o In patients taking dual antiplatelet therapy following diagnosis and treatment of acquired hemophilia A. Haematologica. 202O:105:1791 1801. IPMID: 32381.574] doi:10.3324/haematol.2019.2ilo771 coronary revascularization with significant hemorrhage, the best strates/ is to discontinue the P2Y,2 receptor antagonist and continue aspirin. llem77 Answer: D Educational Objective: Treat a symptomatic patient Bibliography with 5q- myelodysplastic syndrome. Acosta RD, Abraham NS, Chandrasekhara V, et al.; ASGE Standards of Practice Committee. The management of antithrombotic agents for patients undergoing GI endoscopy. Gastrointest Endosc. 2Ol6;83:3 16. Lenalidomide is the most appropriate treatment for this IPMl D: 266215.18] doi:1O.lol6ij.gie.20l5.09.O35 patient (Option D).The myelodysplastic syndromes (MDS) 128

Answers and Critiques are clonal stem cell disorders with ineffective hemato- Antithymocyte globulin and cyclosporine are typi- poiesis leading to dysplastic, hypercellular bone marrow cally used to treat aplastic anemia in patients younger than and peripheral blood cytopenias. She has low-risk MDS 65 years to decrease transfusion requirements (Option B). with 5q-. This subtype of MDS typically has a good prog This older adult patient has MDS with 5q- cytogenetic nosis, and patients who are asymptomatic do not require abnormality, not aplastic anemia. therapy. However, this patient is experiencing sympto Intravenous immune globulin would be reasonable for matic anemia requiring frequent transfusions. Lenalid- an immunocompromised patient with pure red cell aplasia omide has been shown to effectively decrease transfu- (PRCA) associated with acute parvovirus infection (Option sion requirements in patients with the 5q- cytogenetic C). PRCA is characterized by anemia with decreased retic- abnormality, and more than 50% of patients can become ulocltes and normal leukocyte and platelet counts. This transfusion independent. By eliminating or lowering patient has anemia and leukopenia that is more compatible the transfusion need, lenalidomide indirectly lowers the with MDS. In addition, she is not immunocompromised as risk of iron overload and alloimmunization. Lenalido- typically seen in patients at risk for PRCA (e.g., HIV infec- (u mide may also delay leukemic transformation, Ieading tion, immunosuppressive therapy, recent chemotherapy). (t to improved survival in patients who respond well to treatment. Patients who do not respond to lenalidomide (J may require salvage therapy with hypomethylating agents o The myelodysplastic Emdromes are clonal stem cell E' such as azacytidine and decitabine. These agents decrease disorders with ineffective hematopoiesis leading to G transfusion dependence and the risk of conversion to dysplastic, hypercellular bone marrow and peripheral la (u acute myeloid leukemia. blood cytopenias. Allogeneic hematopoietic stem cell transplanta- . Patients with the 5q- cytogenetic abnormality who ut = tion (HSCT) is the only potentially curative option for are transfusion dependent can be treated with lena- MDS (Option A). HSCT is performed in patients with Iidomide to decrease transfusion needs. higher risk, symptomatic disease. Despite this, trans- plantation is not an option for most patients with MDS because they are older and therefore not candidates for Bibliography intensive treatment. Lenalidomide is a safer therapy for Giagounidis A. Current treatment algorithm for the management of lower- risk MDS. Hematolos/ Am Soc Hematol Educ Program. 2017;2077:453- this patient. 459. [PMID: 29222293] doi lO.1182/asheducation-2017.1.453

are clonal stem cell disorders with ineffective hemato- Antithymocyte globulin and cyclosporine are typi- poiesis leading to dysplastic, hypercellular bone marrow cally used to treat aplastic anemia in patients younger than and peripheral blood cytopenias. She has low-risk MDS 65 years to decrease transfusion requirements (Option B). with 5q-. This subtype of MDS typically has a good prog This older adult patient has MDS with 5q- cytogenetic nosis, and patients who are asymptomatic do not require abnormality, not aplastic anemia. therapy. However, this patient is experiencing sympto Intravenous immune globulin would be reasonable for matic anemia requiring frequent transfusions. Lenalid- an immunocompromised patient with pure red cell aplasia omide has been shown to effectively decrease transfu- (PRCA) associated with acute parvovirus infection (Option sion requirements in patients with the 5q- cytogenetic C). PRCA is characterized by anemia with decreased retic- abnormality, and more than 50% of patients can become ulocltes and normal leukocyte and platelet counts. This transfusion independent. By eliminating or lowering patient has anemia and leukopenia that is more compatible the transfusion need, lenalidomide indirectly lowers the with MDS. In addition, she is not immunocompromised as risk of iron overload and alloimmunization. Lenalido- typically seen in patients at risk for PRCA (e.g., HIV infec- (u mide may also delay leukemic transformation, Ieading tion, immunosuppressive therapy, recent chemotherapy). (t to improved survival in patients who respond well to treatment. Patients who do not respond to lenalidomide (J may require salvage therapy with hypomethylating agents o The myelodysplastic Emdromes are clonal stem cell E' such as azacytidine and decitabine. These agents decrease disorders with ineffective hematopoiesis leading to G transfusion dependence and the risk of conversion to dysplastic, hypercellular bone marrow and peripheral la (u acute myeloid leukemia. blood cytopenias. Allogeneic hematopoietic stem cell transplanta- . Patients with the 5q- cytogenetic abnormality who ut = tion (HSCT) is the only potentially curative option for are transfusion dependent can be treated with lena- MDS (Option A). HSCT is performed in patients with Iidomide to decrease transfusion needs. higher risk, symptomatic disease. Despite this, trans- plantation is not an option for most patients with MDS because they are older and therefore not candidates for Bibliography intensive treatment. Lenalidomide is a safer therapy for Giagounidis A. Current treatment algorithm for the management of lower- risk MDS. Hematolos/ Am Soc Hematol Educ Program. 2017;2077:453- this patient. 459. [PMID: 29222293] doi lO.1182/asheducation-2017.1.453 129

lndex Note: Page numbers followed by f and t denote figure and table, respectively. Apheresis, 50, 501. See olso Plasmapheresis Test questions are indicated by Q. Apixaban,57,61,611, Q54, Q60, Q64 Aplastic anemia (AA), 2, 3, Q33 A Aplastic crisis, treatment of. 30t Abciximab,36 Arachidonic acid, 36 Abdominal fat pad biopsy, Q32 Argatroban for HII 38 ABO-incompatible transfusion reactions, 47-48 Artinase,29 ABO/Rh blood group,46 l-Asparaginase Acanthrocytes, 28, 28f for ALL management, 10 Activated factor Vll, 47, 48t Aspirin Activated partial prothromboplastin time (aPTT), 42-43,54, Q22, Q76 anticoagulation by, 60 Acute chest syndrome (ACS), 301, Q6 for ET, Q36 Acute febrile neutrophilic dermatosis, 10, lof low dose.6 Acute hemolltic transfusion reaction. 47 -48, Q2l platelet defects in, 40t Acute lung iniury (ALI), transfusion-related, 49 thromboprophylaxis with, 53 Acute lymphoblastic leukemia (ALL),3, 10 11 Autoimmune disorders survivors of pediatric, Q14 neutropenia and, 2 Acute myeloid leukemia (AML),3,9-10, 10f PRCA and,3 high-risk, Q23 Autoimmune hemolytic anemia, 46, Q12 myeloproliferative neoplasms and, 4 Aeascular necrosis, 30t risk in polycythemia vera. 5 Avatrombopag, 37, 44 Acute promyelocytic leukemia (APL), Q8 Azacitidine for AML, 10 Acute venous thromboembolism, 7, 51, Q45 ADAMTS13,45 B ADAMTS13 antibodies. 39 Bobesio antibodies, 45 Albumin, indications for use ol 48t Babesiosis.34 Allergic reactions, transfusion related, 49 Bartonellosis, hemolysis and, 34 crr Antitrypsin,4St Basophils, production of, 2 s-Aminocaproic acid, 43 BCR-ABL translocations, 2 -3 Amyloidoses, 17 -19,17t, Q32 Bendamustine, 16 Anagrelide,6 Benign ethnic neutropenia (BEN), 1 Anaphylaxis, transfusion related, 49 Bemard-Soulier syndrome, 40t Anemia ofchronic disease, 23 24 p-Lactams,3,40t Anemia of inflammation, 23 24,24t,Q24,Q7O Bethesda assay, 45 Anemia ofkidney disease, 25, Q35 Bevacizumab,39 Anemia Birth defects, folate deficiency and, 26 aplastic, Q33 Bisphosphonates, 16 approach to, 19 21 Bite cells, 27 diagnostic algorithm fof 20f Bivalirudin for HIT, 38 gestational, 62 Blackwater fever, 34 hemolytic, 20 Bleeding disorders, 41-45 of inflammation,23,24t congenital, 42-44 management ol Q68 in dabigatran therapy, Q41 medication related, 20 patient evaluatior.in, 41 42, 42t primary myelofibrosis and, 7 Blister cells, 27 reticuloryte count in, Q66 Blood donor screening, 45 Anisopoikilocytosis, 22, 22f Blood group antigens, 46 in thalassemias, 24 Blood management,4T Anthracycline for ALL management, 10 Bone marrow Anticoagulation therapy, 59 62 failure syndromes, 2 decreased factor levels. 52t hematopoiesis and, 2 for DVT, Q64 Bortezomib, 16 indications for, 6, 7 Brisk hemolysis, 28 \ oral,61 62, 61t Bronze diabetes, 34 : parenteral,59 60 Bruising, thrombocytopenia and, 36 fbr superficial vein thrombosis, Q67 Budd-Chiari syndrome, 54 \\ in unprovoked DVT, Q43 Burr cells. 25f for upper extremity DVI, Q58 for venous thromboembolism, 58t c Anti EPO antibodies, 3 Cl-esterase inhibitors. 48t Antifibrinolltic agents, 43 Calreticulin receptors, 6 Antimyelin associated glycoprotein, 19 Cancer, thrombophilias in, 53 Antiphospholipid antibody syndrome (APtAS), 54, 541, Q9, Q74 Caplacizumab for TTP, 39 Antiplatelet drugs, 401, Q75 CAR T cells, 11 Antipyretics,49 Carfilzomib, 16 Antithrombin Catheter-related thrombosis, Q58 conditions associated with deflciency, 52t Celiac disease, parenteml iron in, 23 indications fbr use of, 48t Cellular transfusion product modifications, 46t Antithrombin deficiency, 51 52 Chemotherapy, macrocytic anemia and, Q10 Antithrombin Ill (ATIII),51 52 Child Pugh liver disease, 62 Antithymocyte globulin, 3 Chimeric antigen receptor (CAR) T cells, Q50

Note: Page numbers followed by f and t denote figure and table, respectively. Apheresis, 50, 501. See olso Plasmapheresis Test questions are indicated by Q. Apixaban,57,61,611, Q54, Q60, Q64 Aplastic anemia (AA), 2, 3, Q33 A Aplastic crisis, treatment of. 30t Abciximab,36 Arachidonic acid, 36 Abdominal fat pad biopsy, Q32 Argatroban for HII 38 ABO-incompatible transfusion reactions, 47-48 Artinase,29 ABO/Rh blood group,46 l-Asparaginase Acanthrocytes, 28, 28f for ALL management, 10 Activated factor Vll, 47, 48t Aspirin Activated partial prothromboplastin time (aPTT), 42-43,54, Q22, Q76 anticoagulation by, 60 Acute chest syndrome (ACS), 301, Q6 for ET, Q36 Acute febrile neutrophilic dermatosis, 10, lof low dose.6 Acute hemolltic transfusion reaction. 47 -48, Q2l platelet defects in, 40t Acute lung iniury (ALI), transfusion-related, 49 thromboprophylaxis with, 53 Acute lymphoblastic leukemia (ALL),3, 10 11 Autoimmune disorders survivors of pediatric, Q14 neutropenia and, 2 Acute myeloid leukemia (AML),3,9-10, 10f PRCA and,3 high-risk, Q23 Autoimmune hemolytic anemia, 46, Q12 myeloproliferative neoplasms and, 4 Aeascular necrosis, 30t risk in polycythemia vera. 5 Avatrombopag, 37, 44 Acute promyelocytic leukemia (APL), Q8 Azacitidine for AML, 10 Acute venous thromboembolism, 7, 51, Q45 ADAMTS13,45 B ADAMTS13 antibodies. 39 Bobesio antibodies, 45 Albumin, indications for use ol 48t Babesiosis.34 Allergic reactions, transfusion related, 49 Bartonellosis, hemolysis and, 34 crr Antitrypsin,4St Basophils, production of, 2 s-Aminocaproic acid, 43 BCR-ABL translocations, 2 -3 Amyloidoses, 17 -19,17t, Q32 Bendamustine, 16 Anagrelide,6 Benign ethnic neutropenia (BEN), 1 Anaphylaxis, transfusion related, 49 Bemard-Soulier syndrome, 40t Anemia ofchronic disease, 23 24 p-Lactams,3,40t Anemia of inflammation, 23 24,24t,Q24,Q7O Bethesda assay, 45 Anemia ofkidney disease, 25, Q35 Bevacizumab,39 Anemia Birth defects, folate deficiency and, 26 aplastic, Q33 Bisphosphonates, 16 approach to, 19 21 Bite cells, 27 diagnostic algorithm fof 20f Bivalirudin for HIT, 38 gestational, 62 Blackwater fever, 34 hemolytic, 20 Bleeding disorders, 41-45 of inflammation,23,24t congenital, 42-44 management ol Q68 in dabigatran therapy, Q41 medication related, 20 patient evaluatior.in, 41 42, 42t primary myelofibrosis and, 7 Blister cells, 27 reticuloryte count in, Q66 Blood donor screening, 45 Anisopoikilocytosis, 22, 22f Blood group antigens, 46 in thalassemias, 24 Blood management,4T Anthracycline for ALL management, 10 Bone marrow Anticoagulation therapy, 59 62 failure syndromes, 2 decreased factor levels. 52t hematopoiesis and, 2 for DVT, Q64 Bortezomib, 16 indications for, 6, 7 Brisk hemolysis, 28 \ oral,61 62, 61t Bronze diabetes, 34 : parenteral,59 60 Bruising, thrombocytopenia and, 36 fbr superficial vein thrombosis, Q67 Budd-Chiari syndrome, 54 \\ in unprovoked DVT, Q43 Burr cells. 25f for upper extremity DVI, Q58 for venous thromboembolism, 58t c Anti EPO antibodies, 3 Cl-esterase inhibitors. 48t Antifibrinolltic agents, 43 Calreticulin receptors, 6 Antimyelin associated glycoprotein, 19 Cancer, thrombophilias in, 53 Antiphospholipid antibody syndrome (APtAS), 54, 541, Q9, Q74 Caplacizumab for TTP, 39 Antiplatelet drugs, 401, Q75 CAR T cells, 11 Antipyretics,49 Carfilzomib, 16 Antithrombin Catheter-related thrombosis, Q58 conditions associated with deflciency, 52t Celiac disease, parenteml iron in, 23 indications fbr use of, 48t Cellular transfusion product modifications, 46t Antithrombin deficiency, 51 52 Chemotherapy, macrocytic anemia and, Q10 Antithrombin Ill (ATIII),51 52 Child Pugh liver disease, 62 Antithymocyte globulin, 3 Chimeric antigen receptor (CAR) T cells, Q50 131

lndex Chloroquine, hemolysis and, 28 Epstein-Barr virus, 2 Cholelithiasis in SCD, 30t Eptifibatide,36 Chronic kidney disease, in SCD,30t Erlthroclte disorders, 19- 34 Chronic lymphocytic leukemia (CLL), 3, 36 Erythroclte exchange, 501, Q6 Chronic myeloid leukemia (CML),4,5,4l Q20 Erythroclte membrane defects, 27 28 Chronic myelomonocytic leukemia, 9 Erythroclte transfu sions, Q52 Chronic obstructive pulmonary disease (COPD), 6t Erythrocltes, nucleated, Tl 91 24 Circulatory overload, transfusion-related, 49 Erlthrocytosis, 5, 6t, Q44 Cirrhosis,1,28 Erythropoiesis,20, Q40 Clonal hematopoiesis of indeterminate potential (CHIP), 9 Erlthropoiesis-stimulating agents (ESAs), 25 Clopidogrel, 401, 60, Q75 Erythropoietin, 2, 6t, 25 Clost rid ium perfingens, 33 Escherichio mli Ol57:H7, 40 Coagulation cascade, 41, 42f Essential thromboclthemia (ET), 5 7, Q36 Coagulation factors, 41 - 42 Estrogens, 53 plasma transfusions and, 46 Ethylenediaminetetraacetic acid, 36 recombinant.4T Exercise tolerance, 22 vitamin K dependent,42, 45 Extracorporeal photopheresis, 50t Coagulopathy cytokine release syndrome and, 1l t of liver disease, Q72 Factor IX, 48t Cobalamin,26 Factor Ix deficiency, 42 43 Cobalamin defi ciency, 2, 26 Factor V t€iden. 51 Cocaine, TTP related to, 39 Factor \rll, activated, Q76 Cold agglutinin disease, 27, 32 33, 32t, 33[ Q55 Factor VIII. 48t Complete blood counts (CBCS), 19-20 concentrates, 45 Conjunctival pallor, 22 deficiency ol 42-44 Contraceptives, VTE risk and, 53 Factor XI deficiency, Q15 Coombs test, 32, 46 Fatigue, iron deficiency and, 22 Copper deficiency, 2 Fedratinib. T Corticosteroids, for ALL management, l0 Ferric carborymaltose, 23 Crizanlizumab, 30 Ferric gluconate, 23 Cryoglobulinemia, l9 Ferritin values, 22, 25, 34 Cryoprecipitate, 44, 46-47, 48t Ferroportin expression, 34 Cyclophosphamide, 3, 16, 45 Ferumoxytol,23 Cyclosporine,3, 39 Fibrinogen concentrate, 48t Cltarabine for AML, 10 Fibrinolysis, DIC and,44 45 Cltokine release syndrome (CRS), U, Q50 FLC assay, 12, 15 Cltoreductive therapies, 6 FIT3-ITD gene, 10 Folate D deflciency of, 2,20,26 27 Dabigatran therapy, 61 62, 61t, Q4l dietary sources of,26 Danaparoid for HIT, 38 supplementation of, 25 Dapsone, hemolysis and, 28 Folic acid supplementation, 25, Q18 Daratumumab, 16 Fondaparinux,38, 60 Decitabine for AML 10 Foot ulcers in SCD, 30t Decreased absolute lymphoclte count (ALC), r 4-Factor prothrombin complex concentmte (4f PCC) , 47, Q62 Deep tissue hematomas, 42 Fragmentation hemolysis, 33 Deep venous thrombosis (DVT),50, 53, 56f Fragmentation hemolltic anemia, 33t anticoagulant therapy, Q64 Fresh frozen plasma, 44,481 diagnosis,55 56 long-term complications, 58 G prevention ol 55 Gemcitabine, TTP related to, 39 treatment ol 57, Q60 Gestational anemia, 62 unprovoked, Q43 Gilteritinib. 10 upper extremity, 59, Q58 Glanzmann thrombasthemia, 40t Wells criteria for, 551, Q47 Glucocorticoids Desmopressin,44, 45 for ITP management, Q25 Dexamethasone. 16 lymphopenia and, I Diabetes, inflammatory cytokines in, 23 medication related,36 Diabetes mellitus, screening for, Q14 neutrophilia and, 2 Dialysis, parenteral iron in, 23 Glucose 6 phosphate dehydrogenase (G6PD) deficiency, 27, 28, 29f, Q7 3 Digital cyanosis, 19 L Glutamine in SCD.30 Direct antiglobulin test (DAT), Q12 Graft -uersus-host disease (GVHD), 49 Direct oral anticoagulants (DOACS), 61t, Q27 Granuloclte colony stimulating factor (G-CSF), 2 Dislipidemia, screening fot Q14 Granulopoiesis, 7f Disseminated intravascular coagulation (DIC), 44 45, Q26, Q49 Gray platelet syndrome, 40t Dystrophic nails, u H 2 Helicobocte r py lort, 22, 36 Ecchymoses, 36, 42 Hematocrit levels. 5 Echinocytes,25f Hematopoiesis, 2,7 Ecstasy, TTP related to, 39 Hematopoietic growth factors, 11 Edoxaban,61,611 Hematopoietic stem cell transplantation (HSCT) Electrolyte disturbances, 50 allogeneic, 3, 11, Q23, Q33 Eliptocytosis, 28 autologous, 11, 16 Elotuzumab, l6 Hematopoietic stem cells (HSCs), 2-3 Eltrombopag, 3, 37 Hemochromatosis, 34-35 Enasidenib, l0 Hemoglobin, structure ol 24 Enoxaparin,60 Hemoglobin C (Hb C), 29 Eosinophilia, 7-8,7t Hemoglobin S (Hb S), 29 \, Eosinophilic myocarditis, 8 Hemoglobin F,25 Eosinophils, production of, 2 Hemoglobin levels, 5 l t I 132 I I I a

Index Hemoglobinopathy, 24 Ischemic stroke, 30t Hemoiuvelin,2l Isoniazid,3 Hemolysis,33, Q73 Ivosidenib, l0 Hemolytic anemias, 27 -34, 27 f lxazomib, 16 Hemolltic disease of the newbom, 46 J Hemolytic transfusion reactions, 47-48 Hemolytic uremic syndrome (HUS), 40 lAK2 EXONi2 mutation. 5 Hemophilia, acquired, 45, Q76 "IAK2 tyrosine kinase mutation, 54, Q30 Hemophilia A, 42 -43, 47 , Q76 lAK2 (lAK2 Y617F) mutation, 3t Hemophilia B, 42-43,47 in essential thrombocythemia, 5 Hemostasis, 41, 4lf, 42f in myeloproliferative neoplasms, 3 Heparin-induced thrombocytopenia (HIT), 37 38, 37t, 381 Q31 in polycythemia vera, 5 Hepatic crisis, in SCD, 30t in primary myelofibrosis, 7 Hepatitis B, 45, 49 Joint effusions. 42 Hepatitis C, 36, 45, 49, Q39 t( Hepatocellular carcinoma, 6t Khorana Score, 53, 531, Q37 Hepatosplenomegaly, l9 Kidney disease Hepcidin,21, 23 anemia ol 25, Q35 Hereditary hemochromatosis (HH), 34-35, 351 Q63 deep venous thrombosis in, Q60 Hereditary spherocytosis (HS), 28, 28f, Q18 Kupffer cells, 33 Herpes zoster virus, Q4 HFEgene, Q63 t High elevations, erythrocltosis and, 6t Lactate dehydrogenase, 24 HIV Leg ulcers in SCD, 30t blood donor screening, 45 Lenalidomide, 16, Q77 immune thrombocltopenic purpura and, 36 Leukapheresis, 5ot screening in ITB Q39 Leukoclte counts, 7 transfusion-related infections, 49 Leukopenia,36 Homocysteine levels, 26 Leukoreduction. 49 Human T-cell lymphotropic virus I/ll, 45 Liver disease Hydroxyurea acanthrocltes and, 28 for AML, 10 coagulopathy of, 44 45, Q72 anemia and. 20 platelet defects in, 40t contraindications, 63 Liver failure, cytokine release syndrome and, 11 cytoreductive therapy with, 6 Low-molecular weight heparin (LMWH), 53, 60, Q74 fbr ET, Q36 Lymphocltosis, 1t, 2 macrocytic anemia induced by, Q48 Lymphoid leukemias, 3 fbr polycythemia vera, 5 Lymphomas,3 in sickle cell disease. 29 Lymphopenias, l 2, lt Hypercalcemia, 16 Lymphoplasmacytic cell dyscrasias, t4t Hlpereosinophilic syndrome (HES), 8 Hyperhemolytic crisis, 30t il Hlperkalemia,50 M protein, 12, 13, 19 Hyperviscosity syndrome, 19, 501, Q53 Macrocltic anemla,2,8 9, Q10, Q48 Hypocalcemia, S0 Macroglossia, 17,17f Hypochromia,22t Q17 Malaria, hemolysis and, 34 Hypofibrinogenemia, 50 Mastocytosis, 4, 8 Hypokalemia,50 Matriptase 2, 21 Hypotension, cltokine release syndrome and, 11 Mean corpuscular volume (MCV), 19 20 Megaloblastic anemia, Q40 I Melphalan, 16 Idarucizumab,62, Q41 Mercaptopurine, 11 IgA deficiency,49 Metabolic alkalosis, 50 IgM, removal ol 19 Methyldopa,20 lmatinib for CML, Q20 Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms, 52-53 Immune thrombocytopenic purpura (lTP), 36 37, 63, Q19, Q25, Q39 3,4-Methylenedioxymethamphetamine, 39 Immune mediated hemolysis,32 33 Microangiopathic hemolytic anemia (MAHA), 33, 36, 39, Q61 lmmune-mediated hemolytic anemia, 33 Microangiopathy of pregnancy, 64, 64t lmmunoglobulin light-chain (AL) amyloidosis, 17-19, 18t Microcytic anemia, Q17 lnferior lena cava (lVC) filters, 57 Microcytosis, 22, 22f , 24, 25 lnflammatory bowel disease, 23,53 Midostaurin, l0 lnterferon-cr. 5 Monoclonal B cell lymphocytosis, 2 lnterleukin 6,23 Monoclonal gammopathies, 12-13, 12t lntrapulmonary shunting. 6t disorders associated with, 12t I lntravenous immune globulin (IVIG), 481, Q2 lron Monoclonal gammopathy of undetermined significance (MGUS), 12-15, l2t, 1st, Qs1 absorption ol 21f, 22 Monocytes, production of, 2 dietary sources of, 22 Monocytosis,2 parenteral, 25 Moyamoya disease, 31 lron chelation therapy, 35, Q69 MPL receptors, 6 lron deficiency Mucocutaneous bieeding, 40 anemia,24t Multiorgan system failure, 11, 3ot causes of anemia related to. 22t Multiple myeloma (MM), 12 19 management of, 23 bone lesions. 15f platelet counts and, 6 clinical findings, l5 in pregnancy, 62 diagnosis, 15-17 lron deficiency anemia, 20 23, 22t, Q59 herpes zoster virus prevention in, Q4 lron dextran. 23 MRI oI Ql lron overload, Q38, Q69 plasmapheresis fo1 50t lron overload syndromes, 34-35 prognosis, 15-17 lron sucrose, 23 treatment of. l6 lsatuximab, 16 vaccinations in, Q42

Hemoglobinopathy, 24 Ischemic stroke, 30t Hemoiuvelin,2l Isoniazid,3 Hemolysis,33, Q73 Ivosidenib, l0 Hemolytic anemias, 27 -34, 27 f lxazomib, 16 Hemolltic disease of the newbom, 46 J Hemolytic transfusion reactions, 47-48 Hemolytic uremic syndrome (HUS), 40 lAK2 EXONi2 mutation. 5 Hemophilia, acquired, 45, Q76 "IAK2 tyrosine kinase mutation, 54, Q30 Hemophilia A, 42 -43, 47 , Q76 lAK2 (lAK2 Y617F) mutation, 3t Hemophilia B, 42-43,47 in essential thrombocythemia, 5 Hemostasis, 41, 4lf, 42f in myeloproliferative neoplasms, 3 Heparin-induced thrombocytopenia (HIT), 37 38, 37t, 381 Q31 in polycythemia vera, 5 Hepatic crisis, in SCD, 30t in primary myelofibrosis, 7 Hepatitis B, 45, 49 Joint effusions. 42 Hepatitis C, 36, 45, 49, Q39 t( Hepatocellular carcinoma, 6t Khorana Score, 53, 531, Q37 Hepatosplenomegaly, l9 Kidney disease Hepcidin,21, 23 anemia ol 25, Q35 Hereditary hemochromatosis (HH), 34-35, 351 Q63 deep venous thrombosis in, Q60 Hereditary spherocytosis (HS), 28, 28f, Q18 Kupffer cells, 33 Herpes zoster virus, Q4 HFEgene, Q63 t High elevations, erythrocltosis and, 6t Lactate dehydrogenase, 24 HIV Leg ulcers in SCD, 30t blood donor screening, 45 Lenalidomide, 16, Q77 immune thrombocltopenic purpura and, 36 Leukapheresis, 5ot screening in ITB Q39 Leukoclte counts, 7 transfusion-related infections, 49 Leukopenia,36 Homocysteine levels, 26 Leukoreduction. 49 Human T-cell lymphotropic virus I/ll, 45 Liver disease Hydroxyurea acanthrocltes and, 28 for AML, 10 coagulopathy of, 44 45, Q72 anemia and. 20 platelet defects in, 40t contraindications, 63 Liver failure, cytokine release syndrome and, 11 cytoreductive therapy with, 6 Low-molecular weight heparin (LMWH), 53, 60, Q74 fbr ET, Q36 Lymphocltosis, 1t, 2 macrocytic anemia induced by, Q48 Lymphoid leukemias, 3 fbr polycythemia vera, 5 Lymphomas,3 in sickle cell disease. 29 Lymphopenias, l 2, lt Hypercalcemia, 16 Lymphoplasmacytic cell dyscrasias, t4t Hlpereosinophilic syndrome (HES), 8 Hyperhemolytic crisis, 30t il Hlperkalemia,50 M protein, 12, 13, 19 Hyperviscosity syndrome, 19, 501, Q53 Macrocltic anemla,2,8 9, Q10, Q48 Hypocalcemia, S0 Macroglossia, 17,17f Hypochromia,22t Q17 Malaria, hemolysis and, 34 Hypofibrinogenemia, 50 Mastocytosis, 4, 8 Hypokalemia,50 Matriptase 2, 21 Hypotension, cltokine release syndrome and, 11 Mean corpuscular volume (MCV), 19 20 Megaloblastic anemia, Q40 I Melphalan, 16 Idarucizumab,62, Q41 Mercaptopurine, 11 IgA deficiency,49 Metabolic alkalosis, 50 IgM, removal ol 19 Methyldopa,20 lmatinib for CML, Q20 Methylene tetrahydrofolate reductase (MTHFR) gene polymorphisms, 52-53 Immune thrombocytopenic purpura (lTP), 36 37, 63, Q19, Q25, Q39 3,4-Methylenedioxymethamphetamine, 39 Immune mediated hemolysis,32 33 Microangiopathic hemolytic anemia (MAHA), 33, 36, 39, Q61 lmmune-mediated hemolytic anemia, 33 Microangiopathy of pregnancy, 64, 64t lmmunoglobulin light-chain (AL) amyloidosis, 17-19, 18t Microcytic anemia, Q17 lnferior lena cava (lVC) filters, 57 Microcytosis, 22, 22f , 24, 25 lnflammatory bowel disease, 23,53 Midostaurin, l0 lnterferon-cr. 5 Monoclonal B cell lymphocytosis, 2 lnterleukin 6,23 Monoclonal gammopathies, 12-13, 12t lntrapulmonary shunting. 6t disorders associated with, 12t I lntravenous immune globulin (IVIG), 481, Q2 lron Monoclonal gammopathy of undetermined significance (MGUS), 12-15, l2t, 1st, Qs1 absorption ol 21f, 22 Monocytes, production of, 2 dietary sources of, 22 Monocytosis,2 parenteral, 25 Moyamoya disease, 31 lron chelation therapy, 35, Q69 MPL receptors, 6 lron deficiency Mucocutaneous bieeding, 40 anemia,24t Multiorgan system failure, 11, 3ot causes of anemia related to. 22t Multiple myeloma (MM), 12 19 management of, 23 bone lesions. 15f platelet counts and, 6 clinical findings, l5 in pregnancy, 62 diagnosis, 15-17 lron deficiency anemia, 20 23, 22t, Q59 herpes zoster virus prevention in, Q4 lron dextran. 23 MRI oI Ql lron overload, Q38, Q69 plasmapheresis fo1 50t lron overload syndromes, 34-35 prognosis, 15-17 lron sucrose, 23 treatment of. l6 lsatuximab, 16 vaccinations in, Q42 133

I I { lndex I

I I { lndex I Myeloblasts,9 production of, 2 \ I Myelodysplastic syndromes (MDS), 8 9, 9f transfusions ol 41, 47. Q28 sq-, Q77 Pneumococcal vaccinations, Q42 1 diagnosis of, Q71 POEMS syndrome, l2t, 13t WHO classiflcation of, 8t Polycythemia vera (PV),5, 6t, Q11 Myelofibrosis, 5, 36 Polymorphonuclear (PMN) cells, 26f ; Myeloid cells, maturation of, 1 Polymyalgia rheumatica, Q24 Myeloproliferative neoplasms (MPNs), 2-3, 54 Porphyria cutanea tarda, 35 classiflcation of, 4f Portal hlrpertension, 1 definition of, 3-4 Portal vein thrombosis. 1 platelet counts and, 6 : Post cardiac b,?ass platelet defects, 40t platelet defects in, 40t Prednisone,3, Q24 splanchnic vein thrombosis and, Q3O Pregnanry dilutional anemia in, 20 il gestational anemia in, 62 Nails, dystrophic, lT interferon o for CML during, 5 Neonatal purpura fulminans, 52 iron deficienry in, 22 Nephrotic syndrome, 53 managing leukemia during, 9 Neutropenia microangiopathy of, 64, 64t aplastic anemia and, 3 PRCA and. 3 causes of, 1, lt sickle cell disease in, 63 chemotherapy induced, Q13 thrombocytopenia in, 63-64, Q19 i diagnosis of, Q29 thrombophilia in, 64 65 drug-induced, Q29 venous thromboembolism in.64 65 medication induced.2 Priapism in SCD, 30t nonmalignant, 1-2 Primary myelofibrosis (PMF), 7, 7f Neutrophitia,1t,2, Q7 Progesterone,53 Nicotinamide adenine dinucleotide phosphate (NADPH), 28 Promalidomide, 16 Nitrofurantoin, 28 Protamine, 60, Q16 Nonsteroidal antiinflammatory drugs (NSAIDs), 40t, 60 Protein C concentrate, 48t Nutritional deficiencies, neutropenia and, 2 Protein C deflciency, 52t ,

Myeloblasts,9 production of, 2 \ I Myelodysplastic syndromes (MDS), 8 9, 9f transfusions ol 41, 47. Q28 sq-, Q77 Pneumococcal vaccinations, Q42 1 diagnosis of, Q71 POEMS syndrome, l2t, 13t WHO classiflcation of, 8t Polycythemia vera (PV),5, 6t, Q11 Myelofibrosis, 5, 36 Polymorphonuclear (PMN) cells, 26f ; Myeloid cells, maturation of, 1 Polymyalgia rheumatica, Q24 Myeloproliferative neoplasms (MPNs), 2-3, 54 Porphyria cutanea tarda, 35 classiflcation of, 4f Portal hlrpertension, 1 definition of, 3-4 Portal vein thrombosis. 1 platelet counts and, 6 : Post cardiac b,?ass platelet defects, 40t platelet defects in, 40t Prednisone,3, Q24 splanchnic vein thrombosis and, Q3O Pregnanry dilutional anemia in, 20 il gestational anemia in, 62 Nails, dystrophic, lT interferon o for CML during, 5 Neonatal purpura fulminans, 52 iron deficienry in, 22 Nephrotic syndrome, 53 managing leukemia during, 9 Neutropenia microangiopathy of, 64, 64t aplastic anemia and, 3 PRCA and. 3 causes of, 1, lt sickle cell disease in, 63 chemotherapy induced, Q13 thrombocytopenia in, 63-64, Q19 i diagnosis of, Q29 thrombophilia in, 64 65 drug-induced, Q29 venous thromboembolism in.64 65 medication induced.2 Priapism in SCD, 30t nonmalignant, 1-2 Primary myelofibrosis (PMF), 7, 7f Neutrophitia,1t,2, Q7 Progesterone,53 Nicotinamide adenine dinucleotide phosphate (NADPH), 28 Promalidomide, 16 Nitrofurantoin, 28 Protamine, 60, Q16 Nonsteroidal antiinflammatory drugs (NSAIDs), 40t, 60 Protein C concentrate, 48t Nutritional deficiencies, neutropenia and, 2 Protein C deflciency, 52t , 0 Protein S deficiency, 52t Obesiry neutrophilia and, 2 Proteinuria,30t \ Osteopenia in SCD, 30t Prothrombin complex concentrate, 48t, Q62 Osteoporosis in SCD, 30t Prothrombin G202IoA mutation, 51 Oxidative stress, hemolysis and, 28 Prothrombin time ([rI), 42 .

0 Protein S deficiency, 52t Obesiry neutrophilia and, 2 Proteinuria,30t \ Osteopenia in SCD, 30t Prothrombin complex concentrate, 48t, Q62 Osteoporosis in SCD, 30t Prothrombin G202IoA mutation, 51 Oxidative stress, hemolysis and, 28 Prothrombin time ([rI), 42 . Orygen supplementation, 31 Pruritus, transfusion related, 49 1 Oxymorphone,39 Pseudothrombocltopenia, 36, 36f Pulmonary embolism P patient evaluation for, 55 56, Q3 P2Y12 receptor antagonists, 41 severity index, 57t Packed red blood cells (PRBCs), 46 treatment of, 57, Q27, Q54 Pamidronate, 16 Wells criteria for. 55t Pancytopenia,3 YEARS criteria, 38, 381, Q3 \ Panobinostat, l6 Pulmonary Embolism Rule Out Criteria (PERC),55,561, Q56 Parasitic infections, 7, 34 Pulmonary Embolism Severity Index (PESI), simplified, 57t, Q54 Parorysmal nocturnal hemoglobinuria, 3, 31 32,54 Pulmonary hypertension in SCD, 30t Parvovirus 819 infections, 3, 3t Pure red cell aplasia (PRCA), 3, 3t Patent ductus arteriosus. 63 Pyruvate kinase deficiency. 28 Penicillin, anemia and, 20 Periorbital purpura, 17f R Peripheral blood smears (PBS) "Raccoon eyes," 17 reticulocyte count in, Q66 Radiation therapy, macrocJ,tic anemia and, Q10 thrombocltopenia diagnosis, Q65 Rasburicase, hemolysis and, 28 Pemicious anemia, 26, 26f, Q5 Raynaud phenomenon, 19 Petechiae.42 Red cell distribution width (RDW),19 20 Phenazopyridine, 28 Reticuloclte counts, 20, Q66 Philadelphia chromosome, 4, 10, Q20 Reticulocltosis, oral iron and, 23 Phlebotomy, therapeutic, 34 Retinopathy, in SCD, 30t Pica, iron deficiency and, 22 Rh status.46 PIGA gene, 31-32 Rituximab, 33, 39,45 Pinch purpura, 17 Rivaroxaban. 38, 57, 61, 6lt Plasma, 46, 47,481 Romiplostim,3T Plasma cell dyscrasias (PCDs), 12, 131, 14t, 15t Rotational thromboelastometry, 41 Plasma-derived therapeutic products, 48t Ruxolitinib,5 Plasma exchange (PLEX), 39, 50t, Q61 for primary myeloflbrosis, 7 Plasmapheresis, 19, 501, Q53 PLASMIC score,39t s Plosmodium folciporum, 28, 34 Schistocytes, 27, 33f Platelet disorders, 35 41 Selective blood component removal, 50t Platelet dysfunction, causes of, 40t Sepsis Platelet factor 4 antibodies, 37 DIC and. 44-45 Platelet function testing, 41 disseminated intravascular coagulation and, Q26 Platelet transfusions, 41, 47, Q28 hemolysis and, 33 Platelet derived gowth factor receptor-a (PDGFR-a) mutations, 8 Serum protein electrophoresis (SPEP), 12 Platelet-derived growth factor receptor p (PDGFR-p) mutations, 8 Shiga toxin, 40 Plateletpheresis, 50t Sickle cell disease (SCD) Platelets characteristics of, 29 aggregation of, 36 complications of, 29-31, 30t causes of dysfunction in, 40t erythrocyte exchange, sot elevated in essential thromboc),themia, 5 7 management ol 311, Q57 normal physiologr of, 35-36 in pregnanry. 63

Orygen supplementation, 31 Pruritus, transfusion related, 49 1 Oxymorphone,39 Pseudothrombocltopenia, 36, 36f Pulmonary embolism P patient evaluation for, 55 56, Q3 P2Y12 receptor antagonists, 41 severity index, 57t Packed red blood cells (PRBCs), 46 treatment of, 57, Q27, Q54 Pamidronate, 16 Wells criteria for. 55t Pancytopenia,3 YEARS criteria, 38, 381, Q3 \ Panobinostat, l6 Pulmonary Embolism Rule Out Criteria (PERC),55,561, Q56 Parasitic infections, 7, 34 Pulmonary Embolism Severity Index (PESI), simplified, 57t, Q54 Parorysmal nocturnal hemoglobinuria, 3, 31 32,54 Pulmonary hypertension in SCD, 30t Parvovirus 819 infections, 3, 3t Pure red cell aplasia (PRCA), 3, 3t Patent ductus arteriosus. 63 Pyruvate kinase deficiency. 28 Penicillin, anemia and, 20 Periorbital purpura, 17f R Peripheral blood smears (PBS) "Raccoon eyes," 17 reticulocyte count in, Q66 Radiation therapy, macrocJ,tic anemia and, Q10 thrombocltopenia diagnosis, Q65 Rasburicase, hemolysis and, 28 Pemicious anemia, 26, 26f, Q5 Raynaud phenomenon, 19 Petechiae.42 Red cell distribution width (RDW),19 20 Phenazopyridine, 28 Reticuloclte counts, 20, Q66 Philadelphia chromosome, 4, 10, Q20 Reticulocltosis, oral iron and, 23 Phlebotomy, therapeutic, 34 Retinopathy, in SCD, 30t Pica, iron deficiency and, 22 Rh status.46 PIGA gene, 31-32 Rituximab, 33, 39,45 Pinch purpura, 17 Rivaroxaban. 38, 57, 61, 6lt Plasma, 46, 47,481 Romiplostim,3T Plasma cell dyscrasias (PCDs), 12, 131, 14t, 15t Rotational thromboelastometry, 41 Plasma-derived therapeutic products, 48t Ruxolitinib,5 Plasma exchange (PLEX), 39, 50t, Q61 for primary myeloflbrosis, 7 Plasmapheresis, 19, 501, Q53 PLASMIC score,39t s Plosmodium folciporum, 28, 34 Schistocytes, 27, 33f Platelet disorders, 35 41 Selective blood component removal, 50t Platelet dysfunction, causes of, 40t Sepsis Platelet factor 4 antibodies, 37 DIC and. 44-45 Platelet function testing, 41 disseminated intravascular coagulation and, Q26 Platelet transfusions, 41, 47, Q28 hemolysis and, 33 Platelet derived gowth factor receptor-a (PDGFR-a) mutations, 8 Serum protein electrophoresis (SPEP), 12 Platelet-derived growth factor receptor p (PDGFR-p) mutations, 8 Shiga toxin, 40 Plateletpheresis, 50t Sickle cell disease (SCD) Platelets characteristics of, 29 aggregation of, 36 complications of, 29-31, 30t causes of dysfunction in, 40t erythrocyte exchange, sot elevated in essential thromboc),themia, 5 7 management ol 311, Q57 normal physiologr of, 35-36 in pregnanry. 63 134

II i t Index t t Sickle cell syndromes, 29t infectious complications, 49 t Sildenafil.3l Simplified Pulmonary Embolism Severity Index (PESI), 57, 57t massive,50 nonhemolytic reactions to, 49 Skin necrosis, 37, 52f in SCD.31 Sleep apnea, 6t for sickle cell anemia, Q57 Smoking special circumstances, 50 neutrophilia and, 2, Q7 unnecessary Q68 secondary erythrocytosis and, Q44 Trimethoprim-sulfamethoxazole, 20 Spherocltosis, hereditary 28, 281 Q18 Trypanosomo cruzi antibodies, 45 Splanchnic vein thrombosis, 5, 54, Q30 Turmeric, platelet defects and, 40t Splenectomy,6, 32 Tyrosine kinase inhibitors (TKls), 5 Splenomegaly ery,throclte membrane defects and, 28 u in polycythemia vera, 5 Unfractionated heparin (UFH), 57, 59, Q16 primary myeloflbrosis and, 7 Uremia, platelet defects in, 40t thromboctopenia and, 36 Urine protein electrophoresis (UPEP), 12 Stomatocltosis, 28 Urticaria, transfusion related, 49 Storage pool disease, 40t Stronguloides infection, 8 v Sulfonamides, hemolysis and, 28 Vaccinations Superficial vein thrombosis (SVT), 58-59, Q67 in multiple myeloma, Q42 Sweet syndrome, 10, 10f Valacyclovir, Q4 Syphilis, blood donor screening, 45 Vascular endothelial growth lactor inhibitors, 39 Systemic lupus erythematosus, 2, 36 Vascular leak, 11 Vasculitis, 19 T Vaso occlusive events, 30, 30t Target cells, 24, 24f, Q17 Venous thromboembolic disease, 50 Testosterone supplements, 5 anticoagulant therapy, 58t, Q64 Thalassemias, 24-25 nosocomial,53 diagnosis of, QU risk for, Q37 iron overload in, Q38 Venous thromboembolism (VTE), 50 target cells in, 24f nosocomial, 50 Thalidomide, 16 in pregnancy, 64-65 Thrombin, indications for use of,48t Vincristine. l0 Thromboclthemia, Q36 Vitamin B,2 deficiency, 26 Thrombocytopenia, 50 anemia and, 20 aplastic anemia and, 3 diagnosis ol 26, Q5, Q40 approach to patients with, 36 presentation of, Q5 \ diagnosis of Q65 Vitamin E, platelet defects and,40t heparin-induced, 37, 371, 381 59 Vitamin K antagonists (VKA), 60 platelet transfusions in, 47 Vitamin K deficiency,45 t in pregnancy,63 64, Q19 Von Willebrand disease. 40-44 primary myeloflbrosis and, 7 acquired,45 treatment of, Q28 diagnosis of, Q46 Thromboelastognphy, 41 hereditary 43 Thrombophilia, 51-55 types ol 43t acquired, S3-55 Von WilIebrand factor (vWF),36 factor V Leiden, 51 Von Willebrand protein-rich factor VII[, 48t inappropriate testing in, Q45 inherited.51 w in pregnancy, 64 65 Waldenstrom macroglobinemia (WM),13, 19, Q53 testing, 51 Warfarin.54 Thrombophlebitis, 58-59 for APLAS, Q9 Thrombopoietin, 2 elevated INR in, Q34 Thrombopoietin agonists, 44 for HIT, 38 L Thrombosis oral,60-62 pathophysiolog/ of 51 thromboprophylaxis with, 53 risk in polycythemia vera, 5 toxicity, Q62 sites of, 58 62 Warfarin-induced skin necrosis, 52f Thrombotic disorders, 50-62 Warm autoimmune hemolytic anemia (WAIHA), 32, 32t, Q52 Thrombotic thrombocytopenic purpura (TTP), Wells criteria, 551, Q47 39, 39t West Nile virus, 45, 49 apheresis for, 50 Wiskott Aldrich syndrome, 40t plasmapheresis for, 50t treatment ol Q61 x Thromboxane Ar, 36 Xa inhibitor, 62 Thymomas, PRCA and, 3 X-linked hereditary bleeding disorders, 42 43 Tirofiban,36 Tissue factor-factor VII pathway, 4l Y Tranexamic acid, 43 YEARS criteria, 65, 651, Q3 Transferrin, low saturation of, 22 Yellow wary papules, 17 Transferrin receptors, 21 Yersinia,49 Tmnsfusion medicine. 45-50 Transfusion-related acute lung injury (TRALI), 49 z Transfusions Zieve s,.ndrome, 28 complications of, 47 50, Q21 Zika virus antibodies. 45 hemolytic reactions, 47 -48 Zoledronic acid, 16

II i t Index t t Sickle cell syndromes, 29t infectious complications, 49 t Sildenafil.3l Simplified Pulmonary Embolism Severity Index (PESI), 57, 57t massive,50 nonhemolytic reactions to, 49 Skin necrosis, 37, 52f in SCD.31 Sleep apnea, 6t for sickle cell anemia, Q57 Smoking special circumstances, 50 neutrophilia and, 2, Q7 unnecessary Q68 secondary erythrocytosis and, Q44 Trimethoprim-sulfamethoxazole, 20 Spherocltosis, hereditary 28, 281 Q18 Trypanosomo cruzi antibodies, 45 Splanchnic vein thrombosis, 5, 54, Q30 Turmeric, platelet defects and, 40t Splenectomy,6, 32 Tyrosine kinase inhibitors (TKls), 5 Splenomegaly ery,throclte membrane defects and, 28 u in polycythemia vera, 5 Unfractionated heparin (UFH), 57, 59, Q16 primary myeloflbrosis and, 7 Uremia, platelet defects in, 40t thromboctopenia and, 36 Urine protein electrophoresis (UPEP), 12 Stomatocltosis, 28 Urticaria, transfusion related, 49 Storage pool disease, 40t Stronguloides infection, 8 v Sulfonamides, hemolysis and, 28 Vaccinations Superficial vein thrombosis (SVT), 58-59, Q67 in multiple myeloma, Q42 Sweet syndrome, 10, 10f Valacyclovir, Q4 Syphilis, blood donor screening, 45 Vascular endothelial growth lactor inhibitors, 39 Systemic lupus erythematosus, 2, 36 Vascular leak, 11 Vasculitis, 19 T Vaso occlusive events, 30, 30t Target cells, 24, 24f, Q17 Venous thromboembolic disease, 50 Testosterone supplements, 5 anticoagulant therapy, 58t, Q64 Thalassemias, 24-25 nosocomial,53 diagnosis of, QU risk for, Q37 iron overload in, Q38 Venous thromboembolism (VTE), 50 target cells in, 24f nosocomial, 50 Thalidomide, 16 in pregnancy, 64-65 Thrombin, indications for use of,48t Vincristine. l0 Thromboclthemia, Q36 Vitamin B,2 deficiency, 26 Thrombocytopenia, 50 anemia and, 20 aplastic anemia and, 3 diagnosis ol 26, Q5, Q40 approach to patients with, 36 presentation of, Q5 \ diagnosis of Q65 Vitamin E, platelet defects and,40t heparin-induced, 37, 371, 381 59 Vitamin K antagonists (VKA), 60 platelet transfusions in, 47 Vitamin K deficiency,45 t in pregnancy,63 64, Q19 Von Willebrand disease. 40-44 primary myeloflbrosis and, 7 acquired,45 treatment of, Q28 diagnosis of, Q46 Thromboelastognphy, 41 hereditary 43 Thrombophilia, 51-55 types ol 43t acquired, S3-55 Von WilIebrand factor (vWF),36 factor V Leiden, 51 Von Willebrand protein-rich factor VII[, 48t inappropriate testing in, Q45 inherited.51 w in pregnancy, 64 65 Waldenstrom macroglobinemia (WM),13, 19, Q53 testing, 51 Warfarin.54 Thrombophlebitis, 58-59 for APLAS, Q9 Thrombopoietin, 2 elevated INR in, Q34 Thrombopoietin agonists, 44 for HIT, 38 L Thrombosis oral,60-62 pathophysiolog/ of 51 thromboprophylaxis with, 53 risk in polycythemia vera, 5 toxicity, Q62 sites of, 58 62 Warfarin-induced skin necrosis, 52f Thrombotic disorders, 50-62 Warm autoimmune hemolytic anemia (WAIHA), 32, 32t, Q52 Thrombotic thrombocytopenic purpura (TTP), Wells criteria, 551, Q47 39, 39t West Nile virus, 45, 49 apheresis for, 50 Wiskott Aldrich syndrome, 40t plasmapheresis for, 50t treatment ol Q61 x Thromboxane Ar, 36 Xa inhibitor, 62 Thymomas, PRCA and, 3 X-linked hereditary bleeding disorders, 42 43 Tirofiban,36 Tissue factor-factor VII pathway, 4l Y Tranexamic acid, 43 YEARS criteria, 65, 651, Q3 Transferrin, low saturation of, 22 Yellow wary papules, 17 Transferrin receptors, 21 Yersinia,49 Tmnsfusion medicine. 45-50 Transfusion-related acute lung injury (TRALI), 49 z Transfusions Zieve s,.ndrome, 28 complications of, 47 50, Q21 Zika virus antibodies. 45 hemolytic reactions, 47 -48 Zoledronic acid, 16 135