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Hematology DOT'T BE TRICKED o Treatment of aplastic anemia with hematopoietic growth factors is ineffective. . PNH may present as a DAT-negative hemolytic anemia or as aplastic anemia. Pure Red Cell Aplasia Diagnosis Acquired chronic pure red cell aplasia is characterized by the absence or a marked decrease of erythrocyte production with normal leukocyte and platelet counts. The cause is predominately T-cell autoimmunity (pregnancy, thymoma, malignancy) or direct toxicity to erythrocyte precursors (viral infection, drug toxicity). Testing Bone marrow shows profound erlthroid hypoplasia. The basic evaluation is similar to that for pancytopenia but includes CT of the chest to rule out thymoma. Treatment Patients with pure red cell aplasia are treated with: . transfusion support and immunosuppressive drugs (prednisone, cyclosporine, antithymoqte globulin) o thymectomy for thymoma Neutropenia Diagnosis Isolated neutropenia usually has a hereditary immune, infectious, or drug induced cause: o acute HIV CMV EBV . rickettsial infection . cytotoxicchemotherapies o NSAIDs, carbamazepine, phenytoin, propylthiouracil, cephalosporins, trimethoprim-sulfamethoxazole . SLE, RA Large granular lymphocytes may be identified in Felty syndrome (RA, splenomegaly, neutropenia) Treatment Treat the underlying disorder or remove the offending drug. 192

Hematology I Myel odysplastic Synd rom es I Diagnosis MDS are clonal disorders of hematopoietic stem cells that occur predominantly in patients older than 60 years and are charac terized by ineffective hematopoiesis and peripheral cytopenias. Always rule out vitamin B,, or folate deficiency and an alcohol ; or drug induced cytopenia. The differential diagnosis includes acute leukemia and myeloproliferative syndromes. L Most patients eventuaily progress to acute leukemic syndromes or die of complications of bone marrow failure. t I 1 I I Testing I MDS is suspected in patients with otherwise unexplained cytopenias, especially with dysplastic findings on peripheral blood L I smear. Macrocytic anemia is the most common cytopenia. Bone marrow findings show a hypercellular marrow with dysplastic erythroid precursors. t t Detection of clonal abnormalities supports the diagnosis. Look speciflcally for 5q- syndrome, a subtype of MDS that has a I speciflc therapy. L I t Treatment I I Many patients with a better prognosis require no treatment at all or infrequent transfusions. Choose: . allogeneic HSCT for fit, younger patients i . erythropoiesis stimulating agents (ESAs) decrease transfusion burden . azacytidine and decitabine for those with poor prognosis to decrease transfusion requirements and delay AML . lenalidomide for 5q- syndrome TEST YOURSELF A74-year old man has a hemoglobin concentration of 7.5 gldL,leukocy.te count of 2200/pL, and platelet count of 87,000/pL. The peripheral blood smear shows a few nucleated erythrocytes. Bone marrow shows hypolobulated neutrophils. ANSWER: For diagnosis, choose MDS. Myel o prol iferative N eoplasms The MPNs are caused by acquired genetic defects in myeloid stem cells and are characterized by deregulated production ol leukocy.tes, eosinophils, erythrocytes, or platelets. Although each disorder is named according to the dominant cell line aflected, clinical features may overlap, and all can cause an elevation in several cell lines. MPNs may present with unusual thromboses; massive splenomegaly; or systemic symptoms. Each has a chronic phase that may progress to AML.

Myel o prol iferative N eoplasms The MPNs are caused by acquired genetic defects in myeloid stem cells and are characterized by deregulated production ol leukocy.tes, eosinophils, erythrocytes, or platelets. Although each disorder is named according to the dominant cell line aflected, clinical features may overlap, and all can cause an elevation in several cell lines. MPNs may present with unusual thromboses; massive splenomegaly; or systemic symptoms. Each has a chronic phase that may progress to AML. Chronic Myeloid Leukemia Diagnosis: Myeloid proliferation is associated with translocation of chromosomes 9 and22[t(9;22), the Philadelphia chromo some], which results in an abnormal tyrosine kinase (BCR-ABL) gene. Patients usually present in the chronic phase. CML has three phases: chronic (<10'2, myeloblasts), accelerated (10% l9'7, myeloblasts), and blast (>20'2, myeloblasts). Characteristic findings are splenomegaly, an elevated leukocyte count, and an increased number of granulocytic cells in all phases of maturation on the peripheral blood smear. 193

Hematology Testing: The diagnosis is confirmed through molecular testing for BCR ABL gene in the peripheral blood or bone marrow' Treatment is indicated for all patients with CML. STUDY YABLE: Treatment for CML Treatment Goal Tyrosine kinase inhibitors: imatinib, dasatinib, nilotinib, Disease control with lifelong treatment bosutinib, ponatinib Allogeneic HSCT Potential cure for some patients with accelerated disease or blast crisis DOil'T BETRICKED r All tyrosine kinase inhibitors can prolong the QT interval; periodic ECG monitoring is recommended TEST YOURSELF An asymptomatic s4-year old man has an enlarged spleen. The hemoglobin concentration is 13 g/dl, Ieukocl'te count is 170,000/pL, and platelet count is 47O,OOOI1IL, with mostly segmented and band neutrophils and circulating metamyelocytes and myelocytes. Eosinophilia and basophilia are present. ANSWER: For diagnosis, choose CML. Confirm with BCR-ABL gene detection in the peripheral blood. Polycythemia Vera Diagnosis: PV causes e4,thropoietin-independent (low erythropoietin level) proliferation of erythrocy'tes. PV is suspected when the hemoglobin level is >16.5 g/dl in men or >16 g/dl in women after secondary causes are excluded. Most causes of secondary erythrocytosis are associated with an elevated erythropoietin level.

Polycythemia Vera Diagnosis: PV causes e4,thropoietin-independent (low erythropoietin level) proliferation of erythrocy'tes. PV is suspected when the hemoglobin level is >16.5 g/dl in men or >16 g/dl in women after secondary causes are excluded. Most causes of secondary erythrocytosis are associated with an elevated erythropoietin level. S?UDY TABLE: Causes of Erythrocytosis Disorders Symptoms and Suggestive Physical Examination Laboratory Studies Medical History PV(primary) Pruritus after a warm shower Splenomegaly Low erythropoietin Erythromelalgia" Plethora Leukocytosis TIA Basophilia Thrombosis Thrombocytosis JAK2 positive Mediated by hypoxemia Thrombosis Plethora Normal leukocyte count COPD TIA No splenomegaly Normal platelet count Sleep apnea Erythromelalgia uncommon Findings consistent with No basophilia underlying heart or lung Congenital hea rt disease Pruritus uncommon JAK2 negative disease lntrapulmonary shunting Decreased oxygen saturation High elevation Mediated by ectopic or Thrombosis possible Plethora High erythropoietin excessive erythropoietin TIA uncommon No splenomegaly Microscopic hematuria (renal Renal cell carcinoma cell carcinoma) Erythromelalgia uncommon Renal artery stenosis/other Abnormal finding on kidney Pruritus uncommon kidney pathology ultrasonography Hepatocellular carcinoma No basophilia Uterine fibroids JAK2 negative (Continued on the next page)

S?UDY TABLE: Causes of Erythrocytosis Disorders Symptoms and Suggestive Physical Examination Laboratory Studies Medical History PV(primary) Pruritus after a warm shower Splenomegaly Low erythropoietin Erythromelalgia" Plethora Leukocytosis TIA Basophilia Thrombosis Thrombocytosis JAK2 positive Mediated by hypoxemia Thrombosis Plethora Normal leukocyte count COPD TIA No splenomegaly Normal platelet count Sleep apnea Erythromelalgia uncommon Findings consistent with No basophilia underlying heart or lung Congenital hea rt disease Pruritus uncommon JAK2 negative disease lntrapulmonary shunting Decreased oxygen saturation High elevation Mediated by ectopic or Thrombosis possible Plethora High erythropoietin excessive erythropoietin TIA uncommon No splenomegaly Microscopic hematuria (renal Renal cell carcinoma cell carcinoma) Erythromelalgia uncommon Renal artery stenosis/other Abnormal finding on kidney Pruritus uncommon kidney pathology ultrasonography Hepatocellular carcinoma No basophilia Uterine fibroids JAK2 negative (Continued on the next page) 194

Hematology STUDY TABLE: Causes of Erythrocytosis (Continued) Disorders Symptoms and Suggestive Physical Examination Laboratory Studies Medical History Unusual causes Thrombosis Plethora High erythropoietin High oxygen affinity TIA No splenomegaly No basophilia hemoglobin Erythromelalgia uncommon Age <30 years No leukocytosis Pruritus uncommon Family history of JAK2 negative erythrocytosis Abnormal hemoglobin electrophoresis Low P50b 'lntermittently red, hot, painful extremities. hP50 is the point on the oxyhemoglobin dissociation curve where the hemoglobin molecule is half saturated with oxygen, indicating an increased hemoglob,in afinity for oxygen and reduced oxygen delivery to tissues. Characteristic findings are thrombosis or bleeding, facial plethora, erythromelalgia, pruritus exacerbated by bathing in hot water, and splenomegaly. Serious complications may include TIA, MI or stroke, DVT, and Budd Chiari syndrome. Testing: Patients have a low semm erythropoietin level in the setting of erythrocltosis. An activating mutation of -IAK2 is present in 97% of patients with PV Treatment is indicated for all patients with PV:

Characteristic findings are thrombosis or bleeding, facial plethora, erythromelalgia, pruritus exacerbated by bathing in hot water, and splenomegaly. Serious complications may include TIA, MI or stroke, DVT, and Budd Chiari syndrome. Testing: Patients have a low semm erythropoietin level in the setting of erythrocltosis. An activating mutation of -IAK2 is present in 97% of patients with PV Treatment is indicated for all patients with PV: . therapeutic phlebotomy to hematocrit level <45'1, o low dose aspirin for all patients unless strong contraindications exist . hydroxyurea or interferon cr for patients at highest risk for thrombosis (age >60 years; history of MI, CVA, VTE) DOil'T BE TRICKED . Hepatic vein thrombosis (the Budd-Chiari syndrome) or portal vein thrombosis should prompt consideration of PV even if erythrocytosis is absent. . Do not prescribe high-dose aspirin, which may cause increased bleeding. TESTYOURSELF A67 year old man has intolerable pruritus. He does not smoke and takes no medications. The hematocrit value is 60u1,, and he has splenomegaly. ANSWER: For diagnosis, choose PV. For management, order PCR for lAK2 mutation and measure the erythropoietin level. For treatment, perform phlebotomy to hematocrit <45'7, and administer hydroxyurea and low dose aspirin. Essential Throm bocythemia Diagnosis: Essential thrombocy'themia is characterized by thrombotic and hemorrhagic complications. It is marked by a pre dominant increase in megakaryocytes and platelet counts greater than 450,000/pL in the absence of more common secondary thrombocythemia, including iron deficiency, bleeding, cancer, infection, and chronic inflammatory disease. Many patients are asymptomatic. When they occur, symptoms include: o erythromelalgia (red and painful hands or feet with warmth and swelling) . bleeding (when platelet count >1 million/pl) o headache o vision symptoms . arterial or venous thromboses 195

Hematology Splenomegaly (up to 50%) may be present. The lAK2 mutation is found in about half of patients (other mutations occur in the calreticulin tCAL-Rl or MPLreceptors) and helps distinguish essential thrombocythemia from secondary thromboclthemia' Treatment depends on risk factors and complications: . low risk patients (age <60 Years; IAK2 negative; no previous MI, stroke, or VTE) -+ low dose aspirin, which reduces vasomotor symptoms (such as erythromelalgia) o high risk patients (age >60 years, JAK2 positive + previous MI, CVA, VTE) -+ hydroxyurea plus aspirin o pregnant high risk patients r interferon-cr . acute, serious thrombotic or hemorrhagic events and platelet count >1 million/pl + plateletpheresis DON'T BE TRICKED . The most common causes of thrombocythemia are iron deflciency anemia and infection, and platelet counts will improve within a couple of weeks following treatment of the underlying condition. o A negative JAK2 test does not exclude the diagnosis of essential thrombocythemia. TEST YOURSELF A 67-year-old man is evaluated because of red, warm, painful feet and a platelet count of 975,000/pL. Medical history is positive for previous MI. ANSWER: For diagnosis, choose essential thrombocythemia. For management, prescribe hydroxyurea and low dose aspirin. Primary Myelofibrosis r{y Diagnosis: Primary myelofibrosis results from clonal proliferation 6 of abnormal hematopoietic stem cells that release fibrosis , promoting cytokines. The disorder is characterized by massive splenomegaly, normocytic anemia, circulating erythroblasts and immature myeloid precursors, giant platelets, and teardrop eryth P rocltes. Bone marrow biopsy confirms fibrosis because the aspi rate is a "dry tap." Splenomegaly and hepatomegaly result from extramedullary hematopoiesis, and patients can develop portal hypertension. lAK2, CAL-R, and MPL mutations are common. Death commonly results from bone marrow failure, transforma- tion to acute leukemia, or portal hypertension complications. Myelofibrosis: Peripheral blood smear showing teardrop erythrocytes, nucleated Treatment is usually supportive. erythrocytes, and giant platelets characteristic of myelolibrosis.

Primary Myelofibrosis r{y Diagnosis: Primary myelofibrosis results from clonal proliferation 6 of abnormal hematopoietic stem cells that release fibrosis , promoting cytokines. The disorder is characterized by massive splenomegaly, normocytic anemia, circulating erythroblasts and immature myeloid precursors, giant platelets, and teardrop eryth P rocltes. Bone marrow biopsy confirms fibrosis because the aspi rate is a "dry tap." Splenomegaly and hepatomegaly result from extramedullary hematopoiesis, and patients can develop portal hypertension. lAK2, CAL-R, and MPL mutations are common. Death commonly results from bone marrow failure, transforma- tion to acute leukemia, or portal hypertension complications. Myelofibrosis: Peripheral blood smear showing teardrop erythrocytes, nucleated Treatment is usually supportive. erythrocytes, and giant platelets characteristic of myelolibrosis. Hydroxyurea and ruxolitinib or fedratinib (JAK2 inhibitors) may alleviate splenomegaly and constitutional symptoms. Allogeneic HSCT is indicated for patients <60 years of age with high risk disease. DOil'T BE TRICKED . Splenectomy should be avoided because it is associated with hemorrhagic and thrombotic complications, increased risk of progression to leukemia, and no effect on survival. Eosinophilia and Hypereosinophilic Syndromes HES are characterized by eosinophil counts greater than 1500/pL; eosinophilic infiltrates of the liver, spleen, heart, and lymph nodes; and systemic symptoms. HES may have a reactive or primary cause. Primary HES is an MPN with molecular activation of platelet derived growth factor receptor (PDGFR) cr or F. 195

Hematology For patients with activating mutations of PDGFR, imatinib leads to durable responses. Otherwise, glucocorticoid therapy is used. STUDY ?AEIE: Causes of Eosinophilia (...500/pL) (CHINA) Collagen vascular disease (eosinophilic granulomatosis with polyangiitis is prototypical) Helminthic (parasitic worm) infection ldiopathic (no cause after extensive investigation) Neoplasia (lymphomas are most common) Allergy, atopy, asthma Acute Lymphoblastic Leukemia Diagnosis ALL is an extremely rggressive disease of precursor T or B cells. The usual presenting clinical features include rapidly rising blast cells in the blood and bone marrow bulky lymphadenopathy (especially in the mediastinum), a younger age at onset, and cytopenia secondary to bone marrow involvement. Patients with ALL may have CNS involvement. Treatment Induction therapy involves intensive combination chemotherapy often followed by allogeneic HSCT. CNS prophylaxis (intrathecal chemotherapy with or without radiation) is also indicated. Patients who are positive for the Philadelphia chromosome [t(9;22)] can be treated with the tyrosine kinase inhibitor imatinib or dasatinib in addition to chemotherapy and allogeneic HSCT. Follow-up Adult survivors of childhood leukemia are at high risk of secondary cancer, CVD, and metabolic syndrome. Screening for dys lipidemia, diabetes, and hypertension is recommended. Echocardiography should be performed periodically if anthracycline exposure was high. Acute Myeloid Leukemia Diagnosis AML is a malignant clonal proliferation of myeloid cells that do not fully mature. AML can appear de novo; arise after exposure to radiation, benzene, or chemotherapy; or occur as a result of transformation of an MPN. Of all the leukemias, AML will most likely involve significant bleeding, bruising, petechiae, and inf'ection. Patients with AML seldom develop lymphadenopathy or hepatosplenomegaly; if present, these flndings suggest an alternative or concomitant diagnosis. When the leukocyte count is very high, patients may present with leukostasis syndrome characterized by CNS manifestations, hypoxia, and diffuse infiltrates on chest x ray. The diagnosis of AML is suggested by an elevated leukocyte count, low absolute neutrophil count, anemia, thrombocy'topenia, and blasts on peripheral blood smear.

Of all the leukemias, AML will most likely involve significant bleeding, bruising, petechiae, and inf'ection. Patients with AML seldom develop lymphadenopathy or hepatosplenomegaly; if present, these flndings suggest an alternative or concomitant diagnosis. When the leukocyte count is very high, patients may present with leukostasis syndrome characterized by CNS manifestations, hypoxia, and diffuse infiltrates on chest x ray. The diagnosis of AML is suggested by an elevated leukocyte count, low absolute neutrophil count, anemia, thrombocy'topenia, and blasts on peripheral blood smear. Gingival hylpertrophy and leukemia cutis (violaceous, nontender cutaneous plaques) are commonly encountered' Pathognomonic Auer rods may be seen on a peripheral blood smear. 197

I l l i tl Hematology l I l Testing The diagnosis is confirmed by bone marrow aspiration and biopsy showing >20% myeloblasts' : Cytogenetic studies can classifli patients into risk (for relapse) and prognostic categories. Acute promyelocytic leukemia is a special case marked by the t(15;17) translocation' Patients with acute promyelocytic leukemia have signiflcant bleeding because of flbrinolysis and DIC. Tumor lysis syndrome may develop in treated patients and causes hyperuricemia, hyperkalemia, hyperphosphatemia, hypo- calcemia, and AKI. DON'T BE TRICKED . In older patients, acute leukemia may present with pancytopenia, but bone marrow examination will demonstrate a hypercellular marrow with 20% or more blasts. Treatment Platelet transfusion is indicated for patients with hemorrhage or a platelet count <10,000/pL. ATRA is the backbone of treatment for acute promyelocytic ffiit= I5 t, leukemia. Patients taking ATRA or arsenic trioxide are at risk for developing differentiation syndrome. Characteristic findings are fever, pulmonary infiltrates, hypoxemia, and, occasionally, hyper leukocytosis. Treatment is dexamethasone. tsg o Because of the high rate of early mortality in patients with acute promyelocytic leukemia, it is critical to start ATRA therapy as soon as the diagnosis is suspected.

ATRA is the backbone of treatment for acute promyelocytic ffiit= I5 t, leukemia. Patients taking ATRA or arsenic trioxide are at risk for developing differentiation syndrome. Characteristic findings are fever, pulmonary infiltrates, hypoxemia, and, occasionally, hyper leukocytosis. Treatment is dexamethasone. tsg o Because of the high rate of early mortality in patients with acute promyelocytic leukemia, it is critical to start ATRA therapy as soon as the diagnosis is suspected. Intensive combination chemotherapy is used for induction ther- DO & $ & I I *t -. $ # apy of non-promyelocl.tic leukemia. Leukapheresis is used for symptoms of leukostasis syndrome \ r-^ .l (rypical leukoclte count >50,000/pL). Auer Rod: This myeloblast has findings associated with Al\ilL: a large nucleus, dis- placed nuclear chromatin, azurophile cytoplasmic granules, and a rod-shaped Allogeneic and autologous HSCT is used for high-risk patients. inclusion (Auer rod). DON'T BE TRICKED . Tumor lysis syndrome may be the first manifestation of AML.

Leukapheresis is used for symptoms of leukostasis syndrome \ r-^ .l (rypical leukoclte count >50,000/pL). Auer Rod: This myeloblast has findings associated with Al\ilL: a large nucleus, dis- placed nuclear chromatin, azurophile cytoplasmic granules, and a rod-shaped Allogeneic and autologous HSCT is used for high-risk patients. inclusion (Auer rod). DON'T BE TRICKED . Tumor lysis syndrome may be the first manifestation of AML. Plasma Cell Dyscrasias Plasma cell dyscrasias consist of abnormal clonal proliferation of immune globulin-secreting differentiated B lymphocl.tes and plasma cells. Multiple myeloma is the most common malignant plasma cell dyscrasia. Other common plasma cell dyscrasias include MGUS, Waldenstrdm macroglobulinemia, and light-chain-associated amyloidosis (AL amyloidosis). MGUS and multi ple myeloma are characterized by a serum monoclonal protein. Patients with MGUS should be periodically reassessed after initial diagnosis for development of multiple myeloma or AL amyloidosis. 198

Hematology Findings in AL amyloidosis include: . nephrotic syndrome with enlarged kidneys on ultrasound . delayed gastric emptying, intestinal pseudo-obstruction, malabsorption . hepatomegaly, elevated alkaline phosphatase, and portal hypertension . distal sensorimotor polyneuropathy o restrictive cardiomyopathy with granular appearance on echocardiography . LVH by echocardiography, low voltage ECG . bleeding diathesis, periorbital purpura, factor X deficiency with prolonged PT and aPTT . macroglossia Testing: Confirmation of AL amyloidosis requires: . abdominal fat pad aspirate or bone marrow biopsy demonstrating apple green birefringence under polarized light with Congo red staining . r/), light chain detection and typing . presence of an M protein on serum or urine testing or clonal plasma cells in the marrow Treatment: Treatment algorithms for AL amyloidosis are similar to those for multiple myeloma. DOil'T BE TRICKED . Abdominal fat pad or bone marrow biopsy has a high yield and is safer than liver, kidney, or heart biopsy in establishing the diagnosis of AL amyloidosis. Wa ldenstrtim Macrog lobulinemia Diagnosis: Waldenstr6m macroglobulinemia is a neoplastic infiltrate consisting of: . clonal lymphocytes, plasmacltoid lymphocytes, plasma cells, and immunoblasts comprising >10% of the bone marrow cellularity or o M protein level >3 gldL and o presence of disease related signs, symptoms, or organ dysfunction Fatigue and B symptoms (fever, night sweats, weight loss) are present. One third of patients will have hyperviscosity symptoms, including headache, blurred vision, hearing loss, dizziness, altered mental status, and nasal and mucosal bleeding. Lymphadenopathy, hepatomegaly, and splenomegaly are found on physical examination. Funduscopic evaluation may reveal hyperviscosity related findings (dilated retinal veins, papilledema, flame hemorrhages). Treatment: Waldenstrdm macroglobulinemia hyperviscosity syndrome is a medical emergency treated with plasmapheresis to rapidly reduce IgM levels and with chemotherapy to decrease new production. Normocytic Anemia Diagnosis Normocltic anemia is associated with a normal MCV of 80 to 100 fL. The reticulocyte count can help differentiate the cause.

Treatment: Waldenstrdm macroglobulinemia hyperviscosity syndrome is a medical emergency treated with plasmapheresis to rapidly reduce IgM levels and with chemotherapy to decrease new production. Normocytic Anemia Diagnosis Normocltic anemia is associated with a normal MCV of 80 to 100 fL. The reticulocyte count can help differentiate the cause. Increased reticuloc5rte count: Normocytic anemia with an increased absolute reticulocyte count (>100,000/pL) reflects either erythrocyte loss (bleeding or hemolysis) or response to therapy (iron, folate, or cobalamin). 200

Hematology Decreased reticuloc5rte count: Normocytic anemia with a lower than expected reticulocyte count indicates underproduction anemia: o inflammation with deficient erythropoietin (most frequent cause) o nutritional deficiencies (iron, folate, cobalamin) . hypometabolism (hypothyroidism, testosterone deficiency) o a primary hematopoietic disorder (pure red cell aplasia or myelodysplasia) Anemia from iron deficiency and inflammation are often confused (see Study Table). A serum ferritin level >100 ng/ml rules out iron deflciency. S?UOY TABLE: Differentiating lron Deficiency and Anemia of lnflammation Test lron Deficiency Anemia Anemia of lnflammation Serum iron Low Low Ferritin Low High TIBC High Low Transferrin saturation Low (<10%) Low/Normal Testing S?UDY TABLE: Diagnostic Studies for Normocytic Anemia Test Comments Serum iron, TIBC, ferritin 337o of patients with iron deficiency have a normal MCV Peripheral blood smear Used to detect spherocytes, fragmented erythrocytes (schistocytes), or blister cells with associated hemolysis DAT lf spherocytes are found Hemoglobin electrophoresis lf target or sickle cells are found Lead level lf basophilic stippling is found Bone marrow aspiration and biopsy lf leukopenia, thrombocytopenia, myelocytes, or nucleated erythrocytes (in normocytic, microcytic, or macrorytic anemias) are found; if patient has lymphadenopathy or splenomegaly

Lead level lf basophilic stippling is found Bone marrow aspiration and biopsy lf leukopenia, thrombocytopenia, myelocytes, or nucleated erythrocytes (in normocytic, microcytic, or macrorytic anemias) are found; if patient has lymphadenopathy or splenomegaly ,a t a o Spherocytes: This peripheral blood smear shows small erythrocytes with loss ol Erythrocyte tragmentation: The erythrocytes show marked anisocytosis and poi ki locytosis with prom i nent frag me ntation. Consider D I C, TTP, or other th rom botic usual central pallor. Consider acquired immune hemolytic anemia or hereditary m icroa ng iopathy. sphe rocytosis. 201

Hematology STUDY TABLE: Common Complications and Treatments in Adults With Sickle Cell Disease Complications Treatment Vaso-occlusive pain episode Acute: rest, relaxation, warmth, NSA|Ds, oral and lV hydration, opioid analgesia Recurringr hydroxyurea for more than 3 episodes/year, pain that interferes with daily activities; avoidance of triggers; nonopioid (preferred) or opioid analgesia Acute chest syndrome Acute: oxygen, incentive spirometry, analgesics, empiric antibiotics, lV fluids, simple or e ryth rocyte excha nge tra nsf usions

STUDY TABLE: Common Complications and Treatments in Adults With Sickle Cell Disease Complications Treatment Vaso-occlusive pain episode Acute: rest, relaxation, warmth, NSA|Ds, oral and lV hydration, opioid analgesia Recurringr hydroxyurea for more than 3 episodes/year, pain that interferes with daily activities; avoidance of triggers; nonopioid (preferred) or opioid analgesia Acute chest syndrome Acute: oxygen, incentive spirometry, analgesics, empiric antibiotics, lV fluids, simple or e ryth rocyte excha nge tra nsf usions Preventive: hydroxyurea for recurrent acute chest syndrome, incentive spirometry in hospitalized patients Aplastic crisis Acute: supportive care, blood transfusions as needed lnfection Acute: appropriate and immediate antibiotic management (particular concern for encapsulated bacteria) Prevention: influenza, COVID-1 9, pneumococcal, and meningococcal vaccines Hyperhemolytic crisis Acute: supportive care, avoid further blood transfusions, immunosuppression might be helpful Preventive: avoid blood transfusions if possible, extended antibody screen can lessen but not eliminate recurrence Multiorgan failure Acute: eryth rocyte exchange transfusions lschemic stroke Acute: erythrocyte excha n ge transfusions, aspi ri n Preventive: chronic simple transfusions or erythrocyte exchange transfusions (target Hb s <30%-50%) Hepatic crisis Acute: supportive, transfusion or exchange transfusion if anemia is symptomatic Cholelithiasis Acute: if symptomatic, cholecystectomy with preoperative transfusions to hemoglobin of 10 g/dl Chronic kidney disease/proteinuria Preventive: BP controlto <130/80 mm Hg Secondary preventive: ACE inhibitor orARB in patients with microalbuminuria Priap tsm Acute: relaxation, hydration, opioid analgesics, aspiration of blood {rom corpora cavernosa and irrigation with dilute epinephrine, transfusions, shunt procedure Preventive: ora I cr-ad renerg ic a gon ists, hyd roxyu rea Pulmonary hypertension No proven therapy established for prevention or treatment Retinopathy Annual ophthalmologic examination, laser phototherapy for retinopathy Osteo pe n ialoste o po rosis Supplementation with calcium and vitamin D, bone mineral density measurements Avascular necrosis Ana gesics and physica I therapy, a rthroplasty I

Preventive: hydroxyurea for recurrent acute chest syndrome, incentive spirometry in hospitalized patients Aplastic crisis Acute: supportive care, blood transfusions as needed lnfection Acute: appropriate and immediate antibiotic management (particular concern for encapsulated bacteria) Prevention: influenza, COVID-1 9, pneumococcal, and meningococcal vaccines Hyperhemolytic crisis Acute: supportive care, avoid further blood transfusions, immunosuppression might be helpful Preventive: avoid blood transfusions if possible, extended antibody screen can lessen but not eliminate recurrence Multiorgan failure Acute: eryth rocyte exchange transfusions lschemic stroke Acute: erythrocyte excha n ge transfusions, aspi ri n Preventive: chronic simple transfusions or erythrocyte exchange transfusions (target Hb s <30%-50%) Hepatic crisis Acute: supportive, transfusion or exchange transfusion if anemia is symptomatic Cholelithiasis Acute: if symptomatic, cholecystectomy with preoperative transfusions to hemoglobin of 10 g/dl Chronic kidney disease/proteinuria Preventive: BP controlto <130/80 mm Hg Secondary preventive: ACE inhibitor orARB in patients with microalbuminuria Priap tsm Acute: relaxation, hydration, opioid analgesics, aspiration of blood {rom corpora cavernosa and irrigation with dilute epinephrine, transfusions, shunt procedure Preventive: ora I cr-ad renerg ic a gon ists, hyd roxyu rea Pulmonary hypertension No proven therapy established for prevention or treatment Retinopathy Annual ophthalmologic examination, laser phototherapy for retinopathy Osteo pe n ialoste o po rosis Supplementation with calcium and vitamin D, bone mineral density measurements Avascular necrosis Ana gesics and physica I therapy, a rthroplasty I Foot and leg ulcers Acute: early ag gressive treatment, debridement, compression

Preventive: hydroxyurea for recurrent acute chest syndrome, incentive spirometry in hospitalized patients Aplastic crisis Acute: supportive care, blood transfusions as needed lnfection Acute: appropriate and immediate antibiotic management (particular concern for encapsulated bacteria) Prevention: influenza, COVID-1 9, pneumococcal, and meningococcal vaccines Hyperhemolytic crisis Acute: supportive care, avoid further blood transfusions, immunosuppression might be helpful Preventive: avoid blood transfusions if possible, extended antibody screen can lessen but not eliminate recurrence Multiorgan failure Acute: eryth rocyte exchange transfusions lschemic stroke Acute: erythrocyte excha n ge transfusions, aspi ri n Preventive: chronic simple transfusions or erythrocyte exchange transfusions (target Hb s <30%-50%) Hepatic crisis Acute: supportive, transfusion or exchange transfusion if anemia is symptomatic Cholelithiasis Acute: if symptomatic, cholecystectomy with preoperative transfusions to hemoglobin of 10 g/dl Chronic kidney disease/proteinuria Preventive: BP controlto <130/80 mm Hg Secondary preventive: ACE inhibitor orARB in patients with microalbuminuria Priap tsm Acute: relaxation, hydration, opioid analgesics, aspiration of blood {rom corpora cavernosa and irrigation with dilute epinephrine, transfusions, shunt procedure Preventive: ora I cr-ad renerg ic a gon ists, hyd roxyu rea Pulmonary hypertension No proven therapy established for prevention or treatment Retinopathy Annual ophthalmologic examination, laser phototherapy for retinopathy Osteo pe n ialoste o po rosis Supplementation with calcium and vitamin D, bone mineral density measurements Avascular necrosis Ana gesics and physica I therapy, a rthroplasty I Foot and leg ulcers Acute: early ag gressive treatment, debridement, compression L Preventive: p roper footwea r to preve nt pressu re poi nts

Preventive: hydroxyurea for recurrent acute chest syndrome, incentive spirometry in hospitalized patients Aplastic crisis Acute: supportive care, blood transfusions as needed lnfection Acute: appropriate and immediate antibiotic management (particular concern for encapsulated bacteria) Prevention: influenza, COVID-1 9, pneumococcal, and meningococcal vaccines Hyperhemolytic crisis Acute: supportive care, avoid further blood transfusions, immunosuppression might be helpful Preventive: avoid blood transfusions if possible, extended antibody screen can lessen but not eliminate recurrence Multiorgan failure Acute: eryth rocyte exchange transfusions lschemic stroke Acute: erythrocyte excha n ge transfusions, aspi ri n Preventive: chronic simple transfusions or erythrocyte exchange transfusions (target Hb s <30%-50%) Hepatic crisis Acute: supportive, transfusion or exchange transfusion if anemia is symptomatic Cholelithiasis Acute: if symptomatic, cholecystectomy with preoperative transfusions to hemoglobin of 10 g/dl Chronic kidney disease/proteinuria Preventive: BP controlto <130/80 mm Hg Secondary preventive: ACE inhibitor orARB in patients with microalbuminuria Priap tsm Acute: relaxation, hydration, opioid analgesics, aspiration of blood {rom corpora cavernosa and irrigation with dilute epinephrine, transfusions, shunt procedure Preventive: ora I cr-ad renerg ic a gon ists, hyd roxyu rea Pulmonary hypertension No proven therapy established for prevention or treatment Retinopathy Annual ophthalmologic examination, laser phototherapy for retinopathy Osteo pe n ialoste o po rosis Supplementation with calcium and vitamin D, bone mineral density measurements Avascular necrosis Ana gesics and physica I therapy, a rthroplasty I Foot and leg ulcers Acute: early ag gressive treatment, debridement, compression L Preventive: p roper footwea r to preve nt pressu re poi nts Treatment The three common disease altering strategies are hydroxyurea therapy, prophylactic exchange transfusion, and HSCT.

Foot and leg ulcers Acute: early ag gressive treatment, debridement, compression L Preventive: p roper footwea r to preve nt pressu re poi nts Treatment The three common disease altering strategies are hydroxyurea therapy, prophylactic exchange transfusion, and HSCT. . Hydroxyurea is used for patients with three or more vaso-occlusive crises per year, for those with pain or chronic anemia interfering with daily activities, or those with recurrent acute chest syndrome. Additional approved agents for the treat- ment and prevention of painful events include L glutamine and the P selectin inhibitor crizanlizumab. . Exchange transfusion is indicated for patients with an acute stroke, fat embolism, or ACS. Use prophylactic exchange transfusion for patients with a history of ischemic stroke. Because of transfusion-related complications, persons with sickle cell disease should not receive transfusion unless they have signiflcant symptoms from their anemia orsigns of end-organ failure (acute neurologic symptoms, ACS, multiorgan failure). The transfusion target is hemoglobin level <10 g/dl (hemoglobin A level >70%). Do not transfuse patients with simple vaso- occlusive pain. 206

Hematology Simple transfusion to a hemoglobin level of l0 g/dl has been shown to be equivalent to exchange transfusions in low- to medium-risk surgeries (e.g., adenoidectomy, inguinal hernia repair, cholecystectomy, joint replacement). Erythropoietin is used for patients with severe anemia, low retic- ulocyte counts, and CKD. DOil'T BE TRICKED . Hydroxyurea is contraindicated in pregnancy and kidney failure. . Do not use meperidine to treat painful crises because the accumulation of the metabolite normeperidine can lead to seizures. Skkle Cells: Erythrocyte anisocytosis and poikilocytosis involving several sickle . Iron overload resulting from multiple transfusions may cells. require chelation therapy. TESTYOURSETF A 32-year-old woman with sickle cell disease has a low-grade fever and exertional dyspnea. Hemoglobin concentration is 4.2 g/dl, and the reticuloclte count is 0.2%. ANSWER: For diagnosis, choose aplastic crisis caused by parvovirus B19 infection. Thalassemia Diagnosis Hemoglobin is a tetrameric molecule. The two cr globin chains and two p-globin chains are linked to heme (iron and protopor- phldn) and reversibly bind one molecule of oxygen. The thalassemic syndromes result from defects in synthesis of cr or p chains and lead to ineffective erythropoiesis and hemolysis. Patients with q,-thalassemia or p-thalassemia have microcytosis and target cells on the peripheral blood smear and may have splenomegaly. S?UDY TABLE: ri-Thalassemia Gene Deletion Clinical Syndrome Treatment (-olctct) [si n gle-gene deletion] Silent carrier state that is clinically normal None (- -/aa; or -al-o) [two-gene deletion] cr-Thalassemia trait, mild microcytic anemia, normal or elevated None erythrocyte count, normal hemoglobin electrophoresis (- -/-o) [three-gene deletion] Hemoglobin H (pa), severe anemia and usually early death lntermittent transfusion (- -/- -) [four-gene deletion] Hydrops fetalis, fetal death ln utero transfusion

S?UDY TABLE: ri-Thalassemia Gene Deletion Clinical Syndrome Treatment (-olctct) [si n gle-gene deletion] Silent carrier state that is clinically normal None (- -/aa; or -al-o) [two-gene deletion] cr-Thalassemia trait, mild microcytic anemia, normal or elevated None erythrocyte count, normal hemoglobin electrophoresis (- -/-o) [three-gene deletion] Hemoglobin H (pa), severe anemia and usually early death lntermittent transfusion (- -/- -) [four-gene deletion] Hydrops fetalis, fetal death ln utero transfusion B-Thalassemia is most common among persons from the Mediterranean, Southeast Asia, India, and Pakistan. p Thalassemia results from several abnormalities in the p-gene complex. Decreased B-chain synthesis leads to impaired production of hemo- globin A (azFJ and resultant increased synthesis of hemoglobin A, (o16r) and/or hemoglobin p (crzyJ. 2tJ7

Hematology STUDY TABLE: f3-Thalassemia Condition Characteristics Treatment B-Thalassemia major Two-gene deletion leading to either no production or Transfusion, iron chelation; consider (Cooley anemia) severely limited production of p-globin splenectomy and HSCT p-Thalassemia minor A single B-gene deletion leading to reduced B globin None (p-thalassemia trait) production with no or mild anemia p-Thalassemia intermedia lntermediate severity, such as in those who are compound lntermittent trans{usion, iron _h.,"r"1y9 9E_' "f ,'9jh ulg:1.I l! yqry l!. chelation p Thalassemia trait and o thalassemia trait are commonly confused with iron deflciency anemia S?UDY TAB[E: lron Deficiency Anemia and Thalassemia Trait lron DeficiencyAnemia o-Thatassemia Trait p-Thalassemia Trait Low serum ferritin level Normal serum ferritin level Normal serum ferritin level Low erythrocyte count Normal or high erythrocyte count Normal or high erythrocyte count High RDW Normal RDW Normal RDW Normal hemoqlobin elect rophoresis Normal hemoglobin electrophoresis Elevated hemoglobin 42 and fetal hemoglobin RDW = red cell distribution width. DON'T BE TRICKED ' B-Thalassemia can be associated with iron overload even in the absence of transfusion therapy Treatment 'l'halassemia treatment varies with the type of disease: ,ro j:". : rl. . fblilte supplementation o no iron replacement unless iron deficiency is documented , . genetic counseling

Treatment 'l'halassemia treatment varies with the type of disease: ,ro j:". : rl. . fblilte supplementation o no iron replacement unless iron deficiency is documented , . genetic counseling TEST YOURSEtF An asymptomatic 18-year old man has a hemoglobin concentra tion of 13 g/dl, an MCV of 64 fL, and a reticulocyte count of 4',4, of erythrocytes. ANSWER: The diagnosis is p thalassemia or cr thalassemia trait. Fbr m:rnagement, select serum t.erritin measurement and hemo Thalassemia: Microcytosis, hypochromia, and target cells consistent with thalas globi r.r electrophoresis. sem ia. Hemochromatosis Diagnosis Hereditary hemochromatosis is an autosomal recessive disorder characterized by increased intestinal absorption of iron and iron deposition in multiple organs. r '['he most common symptoms are erectile dysfunction; fatigue; and OA involving unusual joints, such as the shoulders, ankles. and elbows. . Less commonly, patients may have diabetes, HF, hyperpigmentation (skin bronzing), and panhypopituitarism. . Hand radiograph may show distinctive hook like osteophytes of the second and third MCp joints. 208

Hematology Testing The most appropriate screening tests for hemochromatosis are transferrin saturation and serum ferritin level, with HFEgenotype testing if abnormal. DOil'T BE TRIGKED . Advanced liver disease commonly causes an elevated ferritin level, but the iron saturation is usually normal. . A nondiagnostic HFEgenotype does not rule out a diagnosis of hemochromatosis. Treatment Patients who are C282Y homozygous but have normal serum ferritin levels can be monitored without treatment. Patients with hemochromatosis and an elevated ferritin level should be treated with phlebotomy. Hemorhromatosis: These hook-like osteophyles (atowsl are characteristic of hemoch romatosis. Family Screening First degree relatives of patients with hemochromatosis should undergo screening. Follow-up Su rveil lance Screen for HCC with ultrasonography every 6 months in patients with cirrhosis. TESTYOURSETF A 68-year old man has increasing pain in the second and third MCP joints of both hands. Medical history is significant for type 2 diabetes mellitus and HF. ANSWER: For diagnosis, select hemochromatosis. For management, order transferrin saturation and serum ferritin measurement. Approach to Bleeding Disorders Diagnosis and fiesting Bleeding disorders are characterized by defects in primary and secondary hemostasis. Primary hemostasis involves the forma tion of a platelet plug at the site of vascular disruption. Secondary hemostasis is initiated by the exposure of tissue factor at the site of vascular damage and the initiation of the coagulation cascade. . Primary hemostasis failure is characterized by mucocutaneous bleeding (epistaxis, gingival bleeding, easy bruising, and menorrhagia). . Secondary hemostasis failure is characterized by bleeding into muscles and joints as well as delayed bleeding. . Excessive bleeding after childbirth, surgery or trauma can occur in either category. t 209

Hematology The following tests are used when evaluating bleeding disorders: o PT and aPTT monitor for factor deficiencies and factor inhibitors. o Mixing study differentiates factor deficiency from factor inhibitor by mixing patient plasma with normal plasma and retesting the PT and aPTT. . Bleeding time identifies platelet disorders and vessel-wall integrity; a commercially available platelet function test also assesses platelet function. o Thrombin time tests the conversion of fibrinogen to fibrin. o Fibrinogen, fibrinogen degradation products, and D-dimer are used to identi$r excessive fibrinolysis. Common Acquired Bleeding Disorders Diag nosis and Treatment Liver disease: Patients with liver failure have prolonged PT and aPTT values owing to decreased levels ofcoagulation factors. Despite this, patients are not protected against thrombosis, because protein C and S levels and antithrombin levels are low as well. Fibrinogen levels are low, and the fibrinogen may be dysfunctional. Patients experiencing bleeding may require vitamin K, cryoprecipitate (increases fibrinogen), FFP, or platelets. Vitamin K deficiency: Patients with liver disease and a prolonged PT require oral or lV vitamin K. Factor inhibitors: Bleeding mimics hemophilia A (most common) and B. A factor inhibitor is diagnosed a mixing study "r,ith that fails to correct the coagulation abnormality. This disorder may be associated with an underlying condition such as preg- nancy, postpartum state, SLE, or malignancy (either lymphoproliferative or solid tumor). Bleeding is treated with activated factor concentrate, and the patient should receive immunosuppression to decrease the inhibitor levels. DIC: Characteristic findings are thrombocltopenia, prolonged PT and aPTT, decreased plasma fibrinogen level, and elevated serum D-dimer. Schistocytes are seen on a peripheral blood smear. Treatment for active bleeding is platelet and coagulation factor replacement and management of the underlying disorder.

Factor inhibitors: Bleeding mimics hemophilia A (most common) and B. A factor inhibitor is diagnosed a mixing study "r,ith that fails to correct the coagulation abnormality. This disorder may be associated with an underlying condition such as preg- nancy, postpartum state, SLE, or malignancy (either lymphoproliferative or solid tumor). Bleeding is treated with activated factor concentrate, and the patient should receive immunosuppression to decrease the inhibitor levels. DIC: Characteristic findings are thrombocltopenia, prolonged PT and aPTT, decreased plasma fibrinogen level, and elevated serum D-dimer. Schistocytes are seen on a peripheral blood smear. Treatment for active bleeding is platelet and coagulation factor replacement and management of the underlying disorder. STUDY TABLE: Differential Diagnoses for Patients Experiencing Bleeding Clotting Assay Abnormality Differential Diagnoses Prolonged PT, normal aPTT Factor Vll deficiency or inhibitor DIC Liver disease Vitamin K deficiency Warfarin ingestion Normal PT, prolonged aPTT Deficiency of factors Vlll, lX, Xl, or Xll vWD (if severe and factorVlll level is quite low) Heparin exposure Prolonged PT and aPTT Deficiency of factors V X, ll, or fibrinogen Severe liver disease, DlC, vitamin K deficiency, or warfarin toxicity Heparin overdose Normal PT and aPTT Platelet dysfunction (acquired and congenital) vWD (if mild and factorVlll level is nottoo low) Scurvy Eh lers-Danlos synd rome Hereditary hemorrhagic telangiectasia l Deficiency of factor Xlll 210

Hematology Testing Diagnostic testing includes a prolonged bleeding time, normal PT, and a normal or prolonged aPTT. Definitive diagnosis is based on the vWF antigen level (low), vWF activity assay (reduced vWF ristocetin cofactor activity), factor VIII level (may be low), and a multimer study used to diagnose subtypes of vWD. Treatment For mild symptoms, estrogen containing oral contraceptives can regulate menstrual bleeding and increase vWF levels in women. Desmopressin (rype f vWO) is used for mild-to-moderate bleeding or before minor invasive procedures (e.g., dental procedures). DOiI'I BE TRICKED . Do not use cryoprecipitate to treat vWD because of its increased transfusion infection risk. TESTYOURSELF A 33 year old man is evaluated for continued bleeding following a tooth extraction. His mother has easy bruising, and his sister required a transfusion following the birth of her flrst child. The hemoglobin concentration is 13 g/dl, and the platelet count is 210,000/gL. ANSWER: The diagnosis is vWD. For management, select an aPTT and bleeding time as initial diagnostic studies. Thrombocytopenia Thrombocy.topenia is caused by decreased platelet production, accelerated destruction from consumptive disorders (such as TTP) or autoimmune-mediated destruction, or sequestration of platelets in conditions causing splenomegaly. Disorders associ ated with decreased bone marrow production often affect other cell lines, causing additional cytopenias. Common causes of nonimmune thromboqtopenia include: o toxins (alcohol) o idiosyncratic drug reactions . metastatic cancer r infections o vitamin B,, or folate deficiency . acute leukemia o MDS DOil'T BE TRICKED . Pseudothrombocytopenia occurs if patients have antibodies to EDTA, causing platelets to clump together in vitro; an accurate count can be obtained from blood drawn in citrate or heparin. Consumptive thrombocytopenia: Thrombocytopenia and the presence of schistocy.tes on the peripheral blood smear suggest disorders such as DIC, TTB and HUS.

DOil'T BE TRICKED . Pseudothrombocytopenia occurs if patients have antibodies to EDTA, causing platelets to clump together in vitro; an accurate count can be obtained from blood drawn in citrate or heparin. Consumptive thrombocytopenia: Thrombocytopenia and the presence of schistocy.tes on the peripheral blood smear suggest disorders such as DIC, TTB and HUS. Immune thrombocytopenia occurs when antibodies targeting platelet antigens mediate accelerated destruction. Diagnosis requires a platelet count <100,000/pL. The characteristic flnding is isolated thrombocytopenia in a patient without other apparent causes for the reduced platelets. Antibodies arise in three distinct clinical settings: drug induced, disease associated, and idiopathic. Drug-induced ITP: . most often linked to heparin and certain antibiotics r discontinuation of the offending drug should result in platelet recovery 212

Hematology Disease associated immune thrombocytopenia: . common causes include HIV and hepatitis C infection (testing always indicated) . other causes include hyperthyroidism, hypothyroidism, SLE (testing based on compatible findings) ITP: o peripheral blood smear shows reduced numbers of platelets; some platelets may be large . normal erythroid and myeloid cells . bone marrow biopsy/aspiration indicated only in older patients with new onset ITP or if the peripheral blood smear is abnormal DOI{'T BE TRICKED . Anemia does not exclude a diagnosis of ITP if the anemia can be explained by bleeding. r Measurement of platelet-associated antibody is not helpful because the test lacks both sensitivity and specificity STUDY TABIE: Thrombocytopenia Associations lf you see this. Think this... Schistocytes DIC,TTP-HUS, HELLP Platelet clumps Pseudoth rom bocytope n ia Teardrop (erythrocyte) cells and/or leukopenia with dysplastic leukocytes MDS Anemia, leu kopenia, lymphocytosis Aplastic anemia Pancytopenia, macrocytosis, macro-ovalocytes, hypersegmented neutrophils Vitamin B12 or folate deficiencies Thrombocytopenia following heparin administration orthrombocytopenia and thrombosis HIT Thrombocytopenia 5-10 days after blood transfusion Posttransfusion purpura Cirrhosis and thrombocytopenia Splenic sequestration Treatment Initiate therapy for ITP when the platelet count is <30,000/pL or with evidence of bleeding.

Thrombocytopenia 5-10 days after blood transfusion Posttransfusion purpura Cirrhosis and thrombocytopenia Splenic sequestration Treatment Initiate therapy for ITP when the platelet count is <30,000/pL or with evidence of bleeding. . Glucocorticoids are first-line therapy. . IVIG is indicated for severe thrombocytopenia and life-threatening bleeding. . Splenectomy or rituximab is indicated for patients who are unresponsive to drug therapy or who relapse after glucocorticoids are tapered. Pseudothrombocytopenia: Platelet clu mps on r Thrombopoiesis stimulating agents (romiplostim, eltrombopag) may be attempted peripheral blood smear associated with pseudo' in refractory illness. th rom bocytopenia. Th ro m boti c Th ro m bocyto pe n i c Pu rp u ra - H e m o lytic Uremic Syndrome Diagnosis TTP and HUS are difficult to differentiate and are sometimes considered as an overlap syndrome. TTP-HUS is a clinical diagnosis present with thromboqtopenia and microangiopathic hemolytic anemia: . elevated LDH . decreased haptoglobin level 213

Hematology . negative DAT . schistocytes on peripheral blood smear . decreased ADAMTSI3 activity and positive ADAMST13 inhibitor Fever, kidney disease, and fluctuating neurologic abnormalities may occur but are seldom all present during earlier phases of the illness. Patients with TTP have been found to have unusually large multimers of vWF in their plasma and also have ADAMTS13 (vWF-cleaving protease) deficiency. TTP can also occur in patients with cancer, in transplant recipients, and following administration of chemotherapeutic agents and other drugs (quinine, clopidogrel, ticlopidine, cyclosporine, gemcitabine). Escherichia coliOLST:H7 or Shigello infections are more common in patients with HUS. Infection leads to the development of abdominal pain and bloody diarrhea. DOI{'T BE TRICKED . Do not wait to initiate therapy until ADAMTS13 activity and inhibitor results are available if clinical features suggest TTP; results may be delayed, and these tests have poor sensitivity and speciflcity in the diagnosis of TTP. Treatment TTP caused by immune mediated drug hypersensitivity requires immediate discontinuation of the causative drug. Treat TTP with plasma exchange (removes inhibitor and replaces deficient ADAMST13). HUS is typically managed with supportive therapy. Antibiotics for underlying enterotoxigenic E. coli infection are not indicated. DOil'T BE TRIGKED . Do not order platelet transfusion in TTP-HUS because it can exacerbate the microvascular occlusion o PT, aPTT, D-dimer, and fibrinogen levels are normal in TTP-HUS and abnormal in DIC. . Plasma exchange is superior to simple plasma infusion for TTP. Heparin-lnduced Thrombocytopenia and Thrombosis Diagnosis The characteristic findings of HIT and HITT are a platelet decrease >150,000/pL or >507, decrease from baseline in a patient taking heparin or a thromboembolic event 5 to 10 days after starting heparin. Patients with recent past exposure to heparin may experience the onset of HIT more rapidly after re-exposure to heparin. The 4T scoring algorithm is used to stratify the likelihood of HIT. Testing Diagnostic testing for HIT includes ELISA for heparin/PF4 antibodies and the functional assays, of which the serotonin release assay is the gold standard. 214

Hematology Treatment Iherapy is instituted before the results ofdiagnostic testing are returned ifclinical suspicion is high (elevated 4T score). Heparin must be discontinued immediately. Use a nonheparin anticoagulant (e.g., argatroban, fondaparinux, bivalirudin, danaparoid, or DOAC) to stabilize the patient. DOil'T BE TRICKED r For HIT or HITT, warfarin or LMWH cannot be substituted for UFH. TESTYOURSELF A 75-year old man who has been hospitalized several times for ischemic heart disease is admitted with increasing chest pain. The morning after admission, he has a painful, cold left lower leg. The platelet count is 30,000/pL. ANSWER: For diagnosis, choose HITT. For management, stop heparin and begin argatroban. Transfusion Medicine Transfusions Erythrocytes, platelets, plasma, cryoprecipitates, and (rarely) whole blood may be used for transfusion. . Each unit of packed red blood cells results in a hemoglobin level increase of 1 g/dl. . Each unit of platelets transfused results in a 20,000 to 30,000/pL increase in platelets. In emergencies: . Group O erythrocytes can be transfused to anyone. o Group AB plasma and platelets can be transfused to anyone. r Patients who are Rh(D) positive can safely receive either D positive or D-negative blood, but patients who are Rh(D) negative must receive D-negative blood and platelets. Replacement of Coagu lation Factors FFP is used to replace coagulation factors. FFP is not needed for treating mild coagulopathies characterized by an INR <1.9. Cryoprecipitates (factor VIII, fibrinogen, vWF) are an adjunct to FFP replacement therapy and are used mainly for their flbrino- gen content in patients with DIC. STUDY TABLE: Threshold Values for Prophylactic Transfusion Condition Threshold to Transfuse Platelet transfusion; no other risk faaors for bleeding 1 0,000-20,00Oip1 Platelet tra nsfusion for neu rosu rgery or intracra n ia I b leed ing 100,000/pL Platelettransfusion; bleeding or planned surgery 50,000/pL Hemoglobin for most medical and surgical patients 7 g/dL I tr 215

Hematology Tran#usion Complications An acute hemolytic transfusion reaction results from ABO incompatibility. Characteristic findings are: . fever and chills . flank and abdominal pain . dyspnea . hypotension and tachycardia . red plasma and urine . free hemoglobin in the plasma o positive DAT (Coombs test) Treatment of acute hemolytic transfusion reaction consists of transfusion discontinuation, IV hydration, and appropriate car diovascular support. A delayed hemolytic transfusion reaction results from delayed emergence of an alloantibody that causes rapid extravascular clearance of transfused erythrocytes 2 to 10 days after transfusion. Characteristic findings are low grade fever and an unex plained drop in hemoglobin concentration, elevated serum bilirubin and LDH levels, increased reticulocl'te count, decreased haptoglobin concentration, and the presence of a new alloantibody. A febrile nonhemo\rtic transfusion reaction can occur during or after a transfusion; it is caused by donor leukocyte cytokines or recipient alloantibodies directed against donor leukocltes. The translusion should be stopped, hemolytic transfusion reaction ruled out, and antipyretic agents given. Transfusion-related acute lung injury (TRALD is a rare, severe reaction caused by donor antileukocyte antibodies reacting with recipient leukocytes and causing leukocyte aggregation in the pulmonary capillary bed, usually during or within 6 hours of transfusing ery.throcltes, platelets, or FFP Characteristic flndings are hypoxemia and noncardiogenic pulmonary edema. The transfusion should be stopped and respiratory support provided. Transfusion-associated circulatory overload (TACO) is the most common serious complication of blood transfusion and is more likely in patients with underlying heart or kidney disease but should be considered in any patient with new respiratory symp toms during or within 6 hours of transfusion. Management is the same as cardiogenic pulmonary edema. An allergic transfusion reaction occurs when donor plasma constituents react with a recipient's IgE on mast cells. Characteristic findings are rash, hives, wheezing, and mucosal edema. Treatment includes antihistamines and glucocorticoids. Patients with IgA deflciency are at high risk because ofthe presence ofanti-lgA antibodies.

An allergic transfusion reaction occurs when donor plasma constituents react with a recipient's IgE on mast cells. Characteristic findings are rash, hives, wheezing, and mucosal edema. Treatment includes antihistamines and glucocorticoids. Patients with IgA deflciency are at high risk because ofthe presence ofanti-lgA antibodies. Transfusion-associated GVHD is a rare but fatal complication in which donor lymphocytes engraft in an immunocompro- mised or HlA-similar recipient and cause reactions that affect the bone marrow liver, skin, and GI tract. Patients at risk are immunosuppressed. STUDY TABLE: Cellular Transfusion Product Modifications Modification Notes Leukoreduction Reduces the number of leukocytes present in the transfused product. Reduces platelet transfusion refractoriness, febrile nonhemolytic transfusion reactions, and transmission of CMV. lrradiation Used to prevent transfusion-associated GVHD, which is mediated by donor lymphocytes. Washing Removes the proteins residing in the small amount of plasma in erythrocyte and platelet transfusions and is used in patients with a history o{ allergic reactions, lgA deficiency, or complement-dependent autoimmune hemolytic anemia. 216

Hematology Deep Venous Thrombosis and Pulmonary Embolism Screening Routine extensive screening for underlying cancer or thrombophilia in all patients with unprovoked VTE is not recommended. Prevention Pharmacologic prophylaxis is recommended in most hospitalized patients without a contraindication' VTE prophylaxis with graduated compression stockings is not recommended. In the absence of increased bleeding risk, intermittent pneumatic com- pression devices are not recommended as the only prophylaxis. VTE prophylaxis is often only given during a patient's hospi- talization with the exception of postdischarge prophylaxis (up to 5 weeks) following hip fracture, hip and knee replacement, and major cancer surgery. Diagnosis Use the Wells criteria for DVT or PE scores for all patients. . In patients with low pretest probability for DVT (score <1) or PE (score <4), obtain a D dimer blood test. . If the D-dimer is negative, no further testing is needed. . If the D-dimer is positive or the Wells score indicates that a DVT or PE is likely (Wells DVT score >1; Wells PE score >4), obtain an imaging study. Duplex ultrasonography and CTA are the diagnostic tests ofchoice for DVT and PE, respectively. A PERC (Pulmonary Embolism Rule-Out Criteria) score of zero eliminates the need for D dimer testing or CTA. Treatment Hospital admission is unnecessary for most patients with DVT; in selected, stable patients, outpatient therapy can be initiated with apixaban or rivaroxaban.

. In patients with low pretest probability for DVT (score <1) or PE (score <4), obtain a D dimer blood test. . If the D-dimer is negative, no further testing is needed. . If the D-dimer is positive or the Wells score indicates that a DVT or PE is likely (Wells DVT score >1; Wells PE score >4), obtain an imaging study. Duplex ultrasonography and CTA are the diagnostic tests ofchoice for DVT and PE, respectively. A PERC (Pulmonary Embolism Rule-Out Criteria) score of zero eliminates the need for D dimer testing or CTA. Treatment Hospital admission is unnecessary for most patients with DVT; in selected, stable patients, outpatient therapy can be initiated with apixaban or rivaroxaban. STUDY TABLE: Duration of Anticoagulant Therapy for WE Type of Thrombotic Event Duration of Anticoagulant Therapf Superficial vein thrombophlebitis No anticoagulation suggested Treat with supportive care (analgesia, warm compresses, and NSAIDs) and image if symptoms progress Superficial vein thrombosis Anticoagulate for 6 weeks if >5 cm in length, close to the deep venous system, or other thrombophilic risk factors exist lf not anticoagulated, {ollow-up in 1 week and image if symptoms are persistent or worseni ng Distal leg DW Provoked or unprovoked, asymptomatic or mild No anticoagulation suggested in healthy patients, but monitor with symptoms serial duplex ultrasonography within 1-2 weeks Provoked or unprovoked, moderate-severe symptoms 3-6 months Proximal leg DW or PE Provoked (by surgery, trauma, immobility) 3-6 months Unprovoked Extendedb Recurrent Duration of therapy depends on whether VTE events were provoked or unprovoked Upper extremity DW, proximal 3 months or as long as a central venous catheter remains in place

STUDY TABLE: Duration of Anticoagulant Therapy for WE Type of Thrombotic Event Duration of Anticoagulant Therapf Superficial vein thrombophlebitis No anticoagulation suggested Treat with supportive care (analgesia, warm compresses, and NSAIDs) and image if symptoms progress Superficial vein thrombosis Anticoagulate for 6 weeks if >5 cm in length, close to the deep venous system, or other thrombophilic risk factors exist lf not anticoagulated, {ollow-up in 1 week and image if symptoms are persistent or worseni ng Distal leg DW Provoked or unprovoked, asymptomatic or mild No anticoagulation suggested in healthy patients, but monitor with symptoms serial duplex ultrasonography within 1-2 weeks Provoked or unprovoked, moderate-severe symptoms 3-6 months Proximal leg DW or PE Provoked (by surgery, trauma, immobility) 3-6 months Unprovoked Extendedb Recurrent Duration of therapy depends on whether VTE events were provoked or unprovoked Upper extremity DW, proximal 3 months or as long as a central venous catheter remains in place (Continued on the nert page) 218

Hematology STUDY TABLE: Duration of Anticoagulant Therapy for VTE (Continued) Type of Thromboti< Event Duration of Anticoagulant Therapy. Cancer-associated DW or PE As long as the cancer is active or being treated LMWH or DOACs are the preferred anticoagulants' CTEPH Extended uDecisions regarding duration of anticoagulation must always weigh the risk of VTE recurrence, risk of bleeding, and patient preference. clinical study results and new anticoagulant drugs. 'Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol. 2020:38:496-520. lPMl D: 3 1 381 4641 doi:1 0.1 200/JCO.1 9.01 46 1 Data from Ortel TL, Neumann l, Ageno W, et al. American Society of Hematology 2020 guidelines for management o{ venous thromboembolism: treatment of deep vein throm bosis and pulmonary embolism. Blood Adv.2020;4:4693 4738. IPMID: 33007077] doi:1 0.1 1 82lbloodadvances.2020001 830 Thromboly-tic therapy indications: . massive VTE leading to impaired venous drainage, severe edema, and acute limb ischemia . massive PE and shock from low cardiac output Anticoagulant treatment options for VTE include initial parenteral administration of LMWH, UFH, or fondaparinux, followed by oral administration of dabigatran, edoxaban, or warfarin or monotherapy (oral anticoagulant started without initial paren- teral anticoagulant) with apixaban or rivaroxaban. The only clear indication for an IVC filter is in patients with an acute proximal DVT or an acute PE with an absolute contraindi cation to anticoagulat ion. DOil'T BE TRICKED . lf DVT is diagnosed, a CTA is not needed because the treatment is the same. . Parenteral anticoagulant administration must overlap with warfarin for at least 5 days and until the INR is >2 for 24 hours. Warfarin r€v€rsal: . INR 4.5 10 -+ withhold warfarin . INR >10 without bleeding + oral vitamin K . Iife threatening bleeding -+ vitamin K and 4f PCC DOAC life threatening bleeding reversal:

DOil'T BE TRICKED . lf DVT is diagnosed, a CTA is not needed because the treatment is the same. . Parenteral anticoagulant administration must overlap with warfarin for at least 5 days and until the INR is >2 for 24 hours. Warfarin r€v€rsal: . INR 4.5 10 -+ withhold warfarin . INR >10 without bleeding + oral vitamin K . Iife threatening bleeding -+ vitamin K and 4f PCC DOAC life threatening bleeding reversal: . stop drug . dabigatran -+ idarucizumab o apixaban, rivaroxaban, edoxaban -+ either 4f PCC or andexanet alfa Anemia and Thrombocytopenia in Pregnancy Diagnosis Anemia: Pregnancy results in a normal dilutional anemia. Hemoglobin values less than 1l g/dl in the first trimester or less than 10 g/dl in the second and third trimesters should prompt a search for other causes of anemia; iron and folate deflciency are the most common causes. Thrombocytopenia: The most common cause is gestational thrombocytopenia. 219

Hematology HELLP syndrome, preeclampsia, and AFLP can cause thrombocytopenia and are part of a spectrum of disorders referred to as the "thrombotic microangiopathy of pregnancy." S)"rnptoms and laboratory features for each overlap. Making the distinction between the disorders may not be critical, because the most effective therapy for each is emergent delivery of the fetus. STUDY TABL€: Thrombocytopenia during Pregnancy Disorder Characteristics Gestational throm bocytopenia Benign thrombocytopenia typically >100,000/pL; late second orthird trimester; no schistocytes on peripheral blood smear No treatment needed ITP May present early in pregnancy Treatment with glucocorticoids or lVlG for platelet count <30,000/pL (<50,000/pLfor delivery) TTP.HUS See TTP-HUS section; develops at >20 weeks' gestation; not affected by pregnancy termination Preeclampsia Hypertension, proteinuria, and thrombocytopenia developing at >20 weeks' gestation Treatment is delivery HELLP syndrome Microangiopathic hemolytic anemia; AST >70 U/1, platelet count <100,000/pL developing at >20 weeks'gestation Treatment is delivery AFLP Microangiopathic hemolytic anemia, liver failure, hypoglycemia, and coagulopathy at >20 weeks' gestation Treatment is delivery Drc ln setting of obstetric emergency, elevated levels of fibrin degradation products and/or D-dimers, decreased fibrinogen level, possible prolongation of the PTand aPTT, and thrombocytopenia DO]I'T BE TRICKED . Mild thrombocytopenia (platelet count >100,0OO/pL) occurring late in pregnancy is likely to be gestational thromboc5rtopenia, not ITP, and requires no therapy. 220