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Platelet Disorders HIT Suspeaed Calculate 4T score lntermediate/high clinical Low clinical probability probability (4T score )4) (4T score <3) Discontinue heparin; Start nonheparin anticoagulanf Obtain immunoassay Positive Negative Continue to avoid heparin; Continue nonheparin anticoagulant Obtain functional assay Positive Negativeb HIT likely HIT unlikely FIGU RE 2 4. Algorithm to guide the diagnosis and initial management of patients with suspected heparin-induced thrombocytopenia (HlT). 'Argatroban, bivalirudin, danaparoid, Iondaparinux, rivaroxaban. immunoassay. cytopef,ia. Blood Adu 2018;2r3360-3392. IPMID:30482768]. doi: 10.1 182/bloodadvances.201802,t489. Permi$io0 conveyed through CopyrightClearan(e Center, lnc.

FIGU RE 2 4. Algorithm to guide the diagnosis and initial management of patients with suspected heparin-induced thrombocytopenia (HlT). 'Argatroban, bivalirudin, danaparoid, Iondaparinux, rivaroxaban. immunoassay. cytopef,ia. Blood Adu 2018;2r3360-3392. IPMID:30482768]. doi: 10.1 182/bloodadvances.201802,t489. Permi$io0 conveyed through CopyrightClearan(e Center, lnc. A HIT diagnosis requires immediate heparin discon- fEY POITIS tinuation. An alternate anticoagulant should then be . Heparin-induced thromborytopenia should be sus- started (unless the patient is actively bleeding). Argatroban, pected in any patient treated with heparin whose plate- bivalirudin, danaparoid, fondaparinux, or a direct oral Iet count decreases by greater than 50% from baseline anticoagulant (such as rivaroxaban) are alternative options. or is less than 150,000ipl (150 x 10e/L). Warfarin should not be the initial alternate anticoagulant o The 4T scoring algorithm should be used to stratiff the HVC because antithrombotic efficacy requires 3 to 5 days of likelihood of heparin-induced thrombocytopenia, and therapy, during which time declining levels of protein C heparin should be discontinued and an alternate anti- increase the thrombotic risk. Transitioning to warfarin is coagulant started for patients with intermediate or high safe after thrombocytopenia resolves. Anticoagulation risk for disease while awaiting confirrnatory test results. should be continued for 2 to 3 months in patients without documented thromboembolic events or 3 to 6 months for . Most patients taking heparin who develop thrombog'to- HVC penia but have a low 4T score need no further evaluation. patients with associated thrombosis. Patients should be (Continued) instructed to avoid heparin for life.

A HIT diagnosis requires immediate heparin discon- fEY POITIS tinuation. An alternate anticoagulant should then be . Heparin-induced thromborytopenia should be sus- started (unless the patient is actively bleeding). Argatroban, pected in any patient treated with heparin whose plate- bivalirudin, danaparoid, fondaparinux, or a direct oral Iet count decreases by greater than 50% from baseline anticoagulant (such as rivaroxaban) are alternative options. or is less than 150,000ipl (150 x 10e/L). Warfarin should not be the initial alternate anticoagulant o The 4T scoring algorithm should be used to stratiff the HVC because antithrombotic efficacy requires 3 to 5 days of likelihood of heparin-induced thrombocytopenia, and therapy, during which time declining levels of protein C heparin should be discontinued and an alternate anti- increase the thrombotic risk. Transitioning to warfarin is coagulant started for patients with intermediate or high safe after thrombocytopenia resolves. Anticoagulation risk for disease while awaiting confirrnatory test results. should be continued for 2 to 3 months in patients without documented thromboembolic events or 3 to 6 months for . Most patients taking heparin who develop thrombog'to- HVC penia but have a low 4T score need no further evaluation. patients with associated thrombosis. Patients should be (Continued) instructed to avoid heparin for life. 38

Platelet Disorders (EY P0l llIS (confnuedj TABLE 21 . Clinical Characteristics of Thrombotic o Diagnosis of heparin-induced thrombocytopenia requires Thrombocytopenic Purpura a screening test (enzyme linked immunosorbent assay Clinical Features Laboratory Findings/ for platelet factor 4 antibodies) followed by a confirmatory Pathologic Explanation test (serotonin release assay or heparin-induced platelet Pallor and fever Microangiopathic hemolytic aggregation assay). anemia in 100% of patients t (schistocytes); fever li kely from microinfarcts \ Thrombotic Thrombocytopenic Purpura Bruising, petechiae Thrombocytopenia in 1 00% Patients with TTP present with MAHA and thrombocytopenia. of patients; normal prothrombin time, activated Acquired TTP is caused by a deficiency in the metalloprotease partial thromboplastin time, ADAMTS13, which is responsible for cleaving high molecular- and fibrinogen level weight vWF multimers. These multimers accumulate, gener Kidney injury Mild kidney disease, ating platelet-rich thrombi in small vessels. These thrombi proteinuria, hematuria from microthrombi consume platelets and shear erythrocytes, fragmenting them into schistocytes (see Figure 21) and may cause end-organ Fluctuating neurologic CT scan may demonstrate findings (confusion, cerebrovascu lar accident; injury. Autoantibodies to ADAMTS13 are responsible for the headache, transient transient microthrombi lead deficiency in most patients, but hereditary TTP has been numbness, coma) to reversible findings reported in some. Drugs such as ticlopidine, quinine, cyclo- Nausea, vomiting, diarrhea Bowel ischemia sporine, gemcitabine, and vascular endothelial growth factor Chest pain, arrhythmia Myocardial injury; abnormal inhibitors (such as bevacizumab) can cause TTP Drug abuse findings on electrocardiogram, with oxymorphone, 3,4 methylenedioxymethamphetamine troponin elevation (ecstasy), and cocaine has also been reported to cause TTP. Acquired TTP manifests as MAHA (evidenced by elevated lactate dehydrogenase and decreased haptoglobin levels, aforementioned signs. The mortality rate associated with TTP schistocytes on peripheral blood smear, and a negative direct is high, so treatment must begin immediately without waiting antiglobulin [Coombs] test result) and thrombocytopenia fbr ADAMTS13 test results. Treatment is successful in 85'1, of (with normal coagulation study results). An ADAMTS13 level patients. less than 10'2, supports the diagnosis; an ADAMTS13 level Initial treatment involves therapeutic plasma exchange greater than 50'% should suggest an alternate diagnosis. The (PLEX) to remove the high-molecular weight vWF multi- PLASMIC score is useful in guiding diagnosis while awaiting mers and replace the deficient ADAMTS13 (plasma infusion, ADAMTS 13 level results (Table 2O). The clinical picture is although not a definitive treatment, can be started if PLEX is described in Table 21. All patients have MAHA and thrombo- delayed). Glucocorticoids are added to decrease autoanti cytopenia, but only 5'/" ol patients present with all the body production. Rituximab (a monoclonal anti CD20 B cell antibody) is added to further suppress autoantibody produc- tion and to decrease the risk of recurrence. Caplacizumab TABLE 20. PLASMIC Score" (a monoclonal antibody against vWF) can be used to treat Clinical Feature Points patients with severe hemolysis, severe thrombocytopenia, or significant end organ injury. Caplacizumab is started on the Platelet count <30,000/pL (30 x 1 OelL)b first day of PLEX and continued until 30 days after the final Hemolysis' treatment. Remission is defined by a normalization of the No active cancer platelet count and is usually seen after 7 to 10 PLEX No history of organ or stem cell transplantation treatments. Mean corpuscular volume <90 fL rEY POITTS tNR <1 .5 . AII patients with acquired thrombotic thromboqtopenic Creatinine <2 mg/dL(177 pmol/L) purpura have microangiopathic hemoly.tic anemia and "PLAS[,41C refers to the score's seven components: Platelet count; combined thrombocytopenia; other clinical features may include hemolysis variable; absence of Active cancer; absence of Stem cell or solid organ transplant; MCV; INR; Creatinine. fever, kidney disease, and fluctuating neurologic abnor- blhe presence of schistoc,,tes is a precondition for applying the PLASMIC score. malities. o The mortality rate associated with thrombotic throm 'Reticulocytes >2.5% of er}{hrocytes; indirect bilirubin >2 mg/d L (34.2 gmol/L), haptoglobin <50 mg/dL. bocytopenic purpura is high, so treatment with ther- Low risk:0-4 points. apeutic plasma exchange should be started without lntermediate risk: 5 points. awaiting laboratory results confirming ADAMTSI3 Highrisk:67points. deficiency.

(EY P0l llIS (confnuedj TABLE 21 . Clinical Characteristics of Thrombotic o Diagnosis of heparin-induced thrombocytopenia requires Thrombocytopenic Purpura a screening test (enzyme linked immunosorbent assay Clinical Features Laboratory Findings/ for platelet factor 4 antibodies) followed by a confirmatory Pathologic Explanation test (serotonin release assay or heparin-induced platelet Pallor and fever Microangiopathic hemolytic aggregation assay). anemia in 100% of patients t (schistocytes); fever li kely from microinfarcts \ Thrombotic Thrombocytopenic Purpura Bruising, petechiae Thrombocytopenia in 1 00% Patients with TTP present with MAHA and thrombocytopenia. of patients; normal prothrombin time, activated Acquired TTP is caused by a deficiency in the metalloprotease partial thromboplastin time, ADAMTS13, which is responsible for cleaving high molecular- and fibrinogen level weight vWF multimers. These multimers accumulate, gener Kidney injury Mild kidney disease, ating platelet-rich thrombi in small vessels. These thrombi proteinuria, hematuria from microthrombi consume platelets and shear erythrocytes, fragmenting them into schistocytes (see Figure 21) and may cause end-organ Fluctuating neurologic CT scan may demonstrate findings (confusion, cerebrovascu lar accident; injury. Autoantibodies to ADAMTS13 are responsible for the headache, transient transient microthrombi lead deficiency in most patients, but hereditary TTP has been numbness, coma) to reversible findings reported in some. Drugs such as ticlopidine, quinine, cyclo- Nausea, vomiting, diarrhea Bowel ischemia sporine, gemcitabine, and vascular endothelial growth factor Chest pain, arrhythmia Myocardial injury; abnormal inhibitors (such as bevacizumab) can cause TTP Drug abuse findings on electrocardiogram, with oxymorphone, 3,4 methylenedioxymethamphetamine troponin elevation (ecstasy), and cocaine has also been reported to cause TTP. Acquired TTP manifests as MAHA (evidenced by elevated lactate dehydrogenase and decreased haptoglobin levels, aforementioned signs. The mortality rate associated with TTP schistocytes on peripheral blood smear, and a negative direct is high, so treatment must begin immediately without waiting antiglobulin [Coombs] test result) and thrombocytopenia fbr ADAMTS13 test results. Treatment is successful in 85'1, of (with normal coagulation study results). An ADAMTS13 level patients. less than 10'2, supports the diagnosis; an ADAMTS13 level Initial treatment involves therapeutic plasma exchange greater than 50'% should suggest an alternate diagnosis. The (PLEX) to remove the high-molecular weight vWF multi- PLASMIC score is useful in guiding diagnosis while awaiting mers and replace the deficient ADAMTS13 (plasma infusion, ADAMTS 13 level results (Table 2O). The clinical picture is although not a definitive treatment, can be started if PLEX is described in Table 21. All patients have MAHA and thrombo- delayed). Glucocorticoids are added to decrease autoanti cytopenia, but only 5'/" ol patients present with all the body production. Rituximab (a monoclonal anti CD20 B cell antibody) is added to further suppress autoantibody produc- tion and to decrease the risk of recurrence. Caplacizumab TABLE 20. PLASMIC Score" (a monoclonal antibody against vWF) can be used to treat Clinical Feature Points patients with severe hemolysis, severe thrombocytopenia, or significant end organ injury. Caplacizumab is started on the Platelet count <30,000/pL (30 x 1 OelL)b first day of PLEX and continued until 30 days after the final Hemolysis' treatment. Remission is defined by a normalization of the No active cancer platelet count and is usually seen after 7 to 10 PLEX No history of organ or stem cell transplantation treatments. Mean corpuscular volume <90 fL rEY POITTS tNR <1 .5 . AII patients with acquired thrombotic thromboqtopenic Creatinine <2 mg/dL(177 pmol/L) purpura have microangiopathic hemoly.tic anemia and "PLAS[,41C refers to the score's seven components: Platelet count; combined thrombocytopenia; other clinical features may include hemolysis variable; absence of Active cancer; absence of Stem cell or solid organ transplant; MCV; INR; Creatinine. fever, kidney disease, and fluctuating neurologic abnor- blhe presence of schistoc,,tes is a precondition for applying the PLASMIC score. malities. o The mortality rate associated with thrombotic throm 'Reticulocytes >2.5% of er}{hrocytes; indirect bilirubin >2 mg/d L (34.2 gmol/L), haptoglobin <50 mg/dL. bocytopenic purpura is high, so treatment with ther- Low risk:0-4 points. apeutic plasma exchange should be started without lntermediate risk: 5 points. awaiting laboratory results confirming ADAMTSI3 Highrisk:67points. deficiency. 39

Platelet Disorders Hemolytic Uremic S5rndrome complement C5 and prevents generation of the membrane Hemolytic uremic sy,ndrome (HUS) is characterized by throm- attack unit, C5b-9) if a[pical HUS is suspected. Drug induced bocytopenia, MAHA, and acute kidney injury. Classic HUS pre HUS is managed supportively with drug avoidance. sents after an acute diarrheal illness caused by enterotoxin- XEY POIXI producing Escherichia coliOIST:H7 (other strains have also been o Classic hemolytic uremic sl,ndrome is usually caused by implicated). Diagnosis is confirmed by stool culture and poly enterotoxin-producing Escherichio coli, and management merase chain reaction for Shiga toxin or O157:H7 antigen testing. is supportive for most patients; antibiotics do not alter Management is supportive with fluids and transfusions as the natural disease course. needed. Antibiotics do not alter the disease course. Patients with classic HUS have a 4% associated mortality rate, and long term sequelae include hypertension and chronic kidney disease. Atypical HUS manifests without diarrhea and may be caused by Oua litative Platelet Disorders complement dysregulation or may occur secondary to drugs (see Acquired Platelet Dysfunction drugs listed in the TTP section previously), systemic lupus ery Patients presenting with mucocutaneous bleeding and nor thematosus, or other infection (HIV Streptococcus pneumo mal complete blood count, prothrombin time, and activated nioe). In severe disease or when the distinction from TTP is partial thromboplastin time should be evaluated for platelet unclear, treatment with plasma exchange should begin immedi- dysfunction, which can result from hereditary or acquired ately, adding eculizumab (a monoclonal antibody that binds to disorders (Table 22). Von Willebrand disease is a common

Hemolytic Uremic S5rndrome complement C5 and prevents generation of the membrane Hemolytic uremic sy,ndrome (HUS) is characterized by throm- attack unit, C5b-9) if a[pical HUS is suspected. Drug induced bocytopenia, MAHA, and acute kidney injury. Classic HUS pre HUS is managed supportively with drug avoidance. sents after an acute diarrheal illness caused by enterotoxin- XEY POIXI producing Escherichia coliOIST:H7 (other strains have also been o Classic hemolytic uremic sl,ndrome is usually caused by implicated). Diagnosis is confirmed by stool culture and poly enterotoxin-producing Escherichio coli, and management merase chain reaction for Shiga toxin or O157:H7 antigen testing. is supportive for most patients; antibiotics do not alter Management is supportive with fluids and transfusions as the natural disease course. needed. Antibiotics do not alter the disease course. Patients with classic HUS have a 4% associated mortality rate, and long term sequelae include hypertension and chronic kidney disease. Atypical HUS manifests without diarrhea and may be caused by Oua litative Platelet Disorders complement dysregulation or may occur secondary to drugs (see Acquired Platelet Dysfunction drugs listed in the TTP section previously), systemic lupus ery Patients presenting with mucocutaneous bleeding and nor thematosus, or other infection (HIV Streptococcus pneumo mal complete blood count, prothrombin time, and activated nioe). In severe disease or when the distinction from TTP is partial thromboplastin time should be evaluated for platelet unclear, treatment with plasma exchange should begin immedi- dysfunction, which can result from hereditary or acquired ately, adding eculizumab (a monoclonal antibody that binds to disorders (Table 22). Von Willebrand disease is a common TABLE 22. Causes of Platelet Dysfunction Comments Severity Treatment Congenital Platelet Defects Glanzmann thrombasthenia Defect in glycoprotein llb-llla Severe Platelets or recombinant factor Vlla, e-aminocaproic acid Bernard-Sou lier syndrome Defect in glycoprotein lb-lX Severe Platelets, e-aminocaproic acid

TABLE 22. Causes of Platelet Dysfunction Comments Severity Treatment Congenital Platelet Defects Glanzmann thrombasthenia Defect in glycoprotein llb-llla Severe Platelets or recombinant factor Vlla, e-aminocaproic acid Bernard-Sou lier syndrome Defect in glycoprotein lb-lX Severe Platelets, e-aminocaproic acid Wi skott-Al d ri ch syn d rome Triad of eczema, Moderate Platelets, e-aminocaproic acid thrombocytopenia im m u nodeficiency

TABLE 22. Causes of Platelet Dysfunction Comments Severity Treatment Congenital Platelet Defects Glanzmann thrombasthenia Defect in glycoprotein llb-llla Severe Platelets or recombinant factor Vlla, e-aminocaproic acid Bernard-Sou lier syndrome Defect in glycoprotein lb-lX Severe Platelets, e-aminocaproic acid Wi skott-Al d ri ch syn d rome Triad of eczema, Moderate Platelets, e-aminocaproic acid thrombocytopenia im m u nodeficiency Gray platelet syndrome Patients may develop myelofibrosis Moderate Platelets, e-ami nocaproic acid Storage pool disease Colleaion of diseases Moderate to mild Platelets, e-a minocaproic acid; characterized by defect in platelet some may respond to granules desmopressin Acquired Platelet Defects Uremia Does not correlate with severity of Mild Dialysis, desmopressin, kidney disease e-aminocaproic acid Liver disease Also associated with Mild to severe Platelets, e-aminocaproic acid hyperfibri nolysis and coagulopathy Myeloproliferative neoplasms lf platelet count is >1-1.5 million/pL Mild to severe Before surgical procedures, (1000-1500 x 10ell), may be normalize the platelet count associated with acquired von Willebrand disease Platelet transfusion may be necessary if bleeding occurs Post-cardiac bypass Mu ltifaaorial, incl uding interaction Mild Platelets, if necessary with bypass machine Antiplatelet drugs llb-llla inhibitors Antiplatelet effects range from Severe Platelets irreversible (abciximab) to reversible (eptifibatide and tirofiban) Aspirin lrreversible Mild Platelets, if necessary Clopidogrel lrreversible Mild Platelets, if necessary NSAIDs Temporary Mild None usually needed Other drugs and herbs (p-lactams, Mild None usually needed vitamin E, ginkgo, turmeric, garlic, Chinese tree fungus)

Gray platelet syndrome Patients may develop myelofibrosis Moderate Platelets, e-ami nocaproic acid Storage pool disease Colleaion of diseases Moderate to mild Platelets, e-a minocaproic acid; characterized by defect in platelet some may respond to granules desmopressin Acquired Platelet Defects Uremia Does not correlate with severity of Mild Dialysis, desmopressin, kidney disease e-aminocaproic acid Liver disease Also associated with Mild to severe Platelets, e-aminocaproic acid hyperfibri nolysis and coagulopathy Myeloproliferative neoplasms lf platelet count is >1-1.5 million/pL Mild to severe Before surgical procedures, (1000-1500 x 10ell), may be normalize the platelet count associated with acquired von Willebrand disease Platelet transfusion may be necessary if bleeding occurs Post-cardiac bypass Mu ltifaaorial, incl uding interaction Mild Platelets, if necessary with bypass machine Antiplatelet drugs llb-llla inhibitors Antiplatelet effects range from Severe Platelets irreversible (abciximab) to reversible (eptifibatide and tirofiban) Aspirin lrreversible Mild Platelets, if necessary Clopidogrel lrreversible Mild Platelets, if necessary NSAIDs Temporary Mild None usually needed Other drugs and herbs (p-lactams, Mild None usually needed vitamin E, ginkgo, turmeric, garlic, Chinese tree fungus) 40 1

Bleeding Disorders a t inherited cause of coagulation factor deficiency leading to platelet dysfunction (see Bleeding Disorders). Management Bleeding Disorders ofl drug induced platelet dysfunction depends on the clinical Normal Hemostasis I situation. The decision to reverse antiplatelet medication Bleeding is controlled through a complex but balanced net must balance the risks of thrombosis against the severity of work of'prothrombotic and fibrinolytic activity called hemo the bleeding; if bleeding is significant, an alternative cause stosis. Hemostasis begins with the formation of a primary plug should be sought because symptoms of drug induced plate of activated platelets, initiated by platelet adhesion to a dis let dysfunction are usually mild. Acute bleeding can be man- rupted vessel wall (mediated by collagen, thrombin, and von aged with platelet transfusions, but complete reversal of Wiltebrand f'actor [vWF]) followed by platelet activation and antiplatelet agents may be detrimental if the therapy is life aggregation (see Platelet Disorders for platelet activation and saving. For example, aspirin fbr primary prevention of ath vWF activity). This platelet plug provides activated phospho erosclerotic cardiovascular disease can be safely discontin lipid membranes to facilitate clot propagation (secondary ued if the patient is bleeding; however, dual antiplatelet hemostasis phase) by activating coagulation factors leading to therapy in patients with recently placed cardiac stents may thrombin formation, fibrinogen conversion to fibrin, and fibrin be lif'esaving, and bleeding management requires cardiology mesh formation. The fibrinolysis system is simultaneously evaluation before reversing the medications. The P2Y12 activated, resulting in dynamic clot remodeling (Figure 25). receptor antagonists can be withheld while aspirin is contin a Although it is now understood that the tissue factor factor Vll ued and resumed after adequate hemostasis is achieved. pathway is the primary initiator of thrombin generation, the When antiplatelet agents are potentially lifesaving, bleeding traditional waterfall coagulation cascade (Figure 26) is still may be controlled by other means (such as endoscopic man used to understand screening tests and the lactors that ,i agement of bleeding ulcers). influence them. Minor dental procedures or menorrhagia can be managed with antifibrinoll.tic agents (tranexamic acid or e aminocaproic acid). Evaluation of Patients With Suspected Bleeding Disorders Platelet Function Testing The patient's bleeding history is the most predictive factor in I Platelet function can be assessed by a variety of laboratory those with a potential bleeding disorder and provides valuable tests. A platelet function analyzer can be used as an initial screening test, replacing the traditional bleeding time. The test is run on a citrated blood sample exposed to collagen INITIATION

t inherited cause of coagulation factor deficiency leading to platelet dysfunction (see Bleeding Disorders). Management Bleeding Disorders ofl drug induced platelet dysfunction depends on the clinical Normal Hemostasis I situation. The decision to reverse antiplatelet medication Bleeding is controlled through a complex but balanced net must balance the risks of thrombosis against the severity of work of'prothrombotic and fibrinolytic activity called hemo the bleeding; if bleeding is significant, an alternative cause stosis. Hemostasis begins with the formation of a primary plug should be sought because symptoms of drug induced plate of activated platelets, initiated by platelet adhesion to a dis let dysfunction are usually mild. Acute bleeding can be man- rupted vessel wall (mediated by collagen, thrombin, and von aged with platelet transfusions, but complete reversal of Wiltebrand f'actor [vWF]) followed by platelet activation and antiplatelet agents may be detrimental if the therapy is life aggregation (see Platelet Disorders for platelet activation and saving. For example, aspirin fbr primary prevention of ath vWF activity). This platelet plug provides activated phospho erosclerotic cardiovascular disease can be safely discontin lipid membranes to facilitate clot propagation (secondary ued if the patient is bleeding; however, dual antiplatelet hemostasis phase) by activating coagulation factors leading to therapy in patients with recently placed cardiac stents may thrombin formation, fibrinogen conversion to fibrin, and fibrin be lif'esaving, and bleeding management requires cardiology mesh formation. The fibrinolysis system is simultaneously evaluation before reversing the medications. The P2Y12 activated, resulting in dynamic clot remodeling (Figure 25). receptor antagonists can be withheld while aspirin is contin a Although it is now understood that the tissue factor factor Vll ued and resumed after adequate hemostasis is achieved. pathway is the primary initiator of thrombin generation, the When antiplatelet agents are potentially lifesaving, bleeding traditional waterfall coagulation cascade (Figure 26) is still may be controlled by other means (such as endoscopic man used to understand screening tests and the lactors that ,i agement of bleeding ulcers). influence them. Minor dental procedures or menorrhagia can be managed with antifibrinoll.tic agents (tranexamic acid or e aminocaproic acid). Evaluation of Patients With Suspected Bleeding Disorders Platelet Function Testing The patient's bleeding history is the most predictive factor in I Platelet function can be assessed by a variety of laboratory those with a potential bleeding disorder and provides valuable tests. A platelet function analyzer can be used as an initial screening test, replacing the traditional bleeding time. The test is run on a citrated blood sample exposed to collagen INITIATION f X and either epinephrine or adenosine diphosphate. It is a PRlf\rlNG sensitive test for von Willebrand disease and will detect abnormalities caused by antiplatelet medications. A modi fied platelet aggregometry device using a platelet activator TF can measure the amount of GPIIb/lla receptor blockade by TF Tis$ue Fsctor Bearing Cell x aspirin or P2Y12 inhibitors. Classic platelet aggregometry tests platelet reactions to a variety of agonists and captures Vlla the primary and secondary aggregation waves. It is labor d xS { tx intensive and requires technical expertise, so it is not avail- lla able in all hospitals. Thromboelastography and rotational d"c thromboelastometry are bedside devices that analyze plate *,3r*s- g ;' Xla Iet function. coagulation, and clot stability; these may be .,3,s "3..{ Xa useful as screening tests in patients with unexplained bleeding. * "".,r",f ;ld * PROPAGATION F IG U R E 2 5. The cell'based model of hemostasis is useful for understanding I(EY POIilTS coagulation as it occurs in vivo. Ihe initiation of coagulation takes place on the o Patients presenting with mucocutaneous bleeding and surface of a tissue fattor-bearing cell, such as a macrophage, a tumor cell, or an

f X and either epinephrine or adenosine diphosphate. It is a PRlf\rlNG sensitive test for von Willebrand disease and will detect abnormalities caused by antiplatelet medications. A modi fied platelet aggregometry device using a platelet activator TF can measure the amount of GPIIb/lla receptor blockade by TF Tis$ue Fsctor Bearing Cell x aspirin or P2Y12 inhibitors. Classic platelet aggregometry tests platelet reactions to a variety of agonists and captures Vlla the primary and secondary aggregation waves. It is labor d xS { tx intensive and requires technical expertise, so it is not avail- lla able in all hospitals. Thromboelastography and rotational d"c thromboelastometry are bedside devices that analyze plate *,3r*s- g ;' Xla Iet function. coagulation, and clot stability; these may be .,3,s "3..{ Xa useful as screening tests in patients with unexplained bleeding. * "".,r",f ;ld * PROPAGATION F IG U R E 2 5. The cell'based model of hemostasis is useful for understanding I(EY POIilTS coagulation as it occurs in vivo. Ihe initiation of coagulation takes place on the o Patients presenting with mucocutaneous bleeding and surface of a tissue fattor-bearing cell, such as a macrophage, a tumor cell, or an normal complete blood count, prothrombin time, and activated endothelial cell.TF and a small amount ofiactorVlla generate factor Xa, which joins with factorVa to form a small amount of thrombin (factor ll). Excess activated partial thromboplastin time should be evalu thrombin generation is avoided through the antagonistic role ofTFPl. ln the ated for von Willebrand disease or acquired platelet priming step, this small amount of thrombin proceeds to activate platelets and dysfunction. facto r Vl I l, wh ch joi ns with factor lX to generate factor Xa. 0 n the p latelet su rface, i

normal complete blood count, prothrombin time, and activated endothelial cell.TF and a small amount ofiactorVlla generate factor Xa, which joins with factorVa to form a small amount of thrombin (factor ll). Excess activated partial thromboplastin time should be evalu thrombin generation is avoided through the antagonistic role ofTFPl. ln the ated for von Willebrand disease or acquired platelet priming step, this small amount of thrombin proceeds to activate platelets and dysfunction. facto r Vl I l, wh ch joi ns with factor lX to generate factor Xa. 0 n the p latelet su rface, i o The platelet function ana\zer is a useful screening test the prothrombinase complex can generate a large thrombin burst in the propagation step, allowing for cleavage o{ fibrinogen into fibrin. TF= tissue iactor; TFPI = tissue for assessing qualitative platelet disorders. factor pathway inhibitor. 41

i I Bleeding Disorders t The intrinsic The extrinsic or TABLE 23. Differential Diagnoses for Patients "PTT" pathway "PT" pathway Experiencing Bleeding Clotting Assay Differential Diagnoses Abnormality Vll + Tissue Prolonged PT, FactorVll deficiency factor normal aPTT Drc X+V Liver disease Vitamin K deficiency J Warfarin ingestion Prothrombin ----) thrombin (il)

X+V Liver disease Vitamin K deficiency J Warfarin ingestion Prothrombin ----) thrombin (il) Fibrinogen I ---) fibrin Normal PT, prolonged aPTT Deficiency of factors Vlll, lX, Xl, or Xll von Willebrand disease (if severe and factorVlll level is quite low) The common Heparin exposure pathway Prolonged PT Deficiency of factors V X, ll, or fibrinogen F 1G U R E 2 6. The "waterfall" model of hemostasis is useful for teasing out and aPTT coagulation disorders affecting the PI and the aPTT. ln this model, factors common Severe liver disease, DlC, vitamin K to the PI and the aPTIare X, V ll, and fibrinogen. FactorVll is unique to the PT, and deficiency, warfa rin toxicity factors Xll, Xl, Vlll, and lX are unique to the aPTT. aPIT= activated partial Heparin overdose thromboplastin time; PT= prothrombin time. Normal PT and Platelet dysfunction (acquired and aPTT congenita l) information to guide management, including in patients undergoing an invasive procedure. Laboratory testing provides von Willebrand disease (if mild and faaor Vlll level is not too low) supplementary information to the clinical history but inde- Scurvy pendently is insufficient to predict bleeding risk (e.g., patients may have a contact factor deficiency or a lupus anticoagulant Ehlers-Danlos syndrome with an elevated activated partial thromboplastin time [aPTT] Hereditary hemorrhagic telangiectasia but no increased risk of bleeding). Patients with bleeding dis- Deficiency of faaor Xlll orders may have a history or new symptoms of easy bruising, aPTT = activated panial thromboplastin time; DIC = disseminated intravascular joint or soft tissue bleeding, mucocutaneous bleeding (includ coaqulation; PT . prothrombin trme. ing epistaxis, bleeding following dental extractions, menstrual and postpartum bleeding, gastrointestinal bleeding), or post- operative bleeding. Family bleeding history and medication Differential diagnoses for patients experiencing bleeding use (including over the-counter medications and supple and who have abnormal findings on specific clotting assays are ments) must be documented. The physical examination outlined in Table 23. fbcuses on finding evidence of petechiae, ecchymoses, deep TEY POIilIS tissue hematomas, or joint effusions. o The clinical history and bleeding symptoms are the Laboratory tests used to measure hemostasis include most important predictive factors to guide management the complete blood count, prothrombin time (PT), and aPTT. for patients with a suspected bleeding disorder. The PT, expressed as the INR, is more sensitive to the eflects of the vitamin K dependent factors (ll, VII, and X), whereas the . Basic laboratory tests, including the complete blood aPTT is a more sensitive measurement of factors VIII, IX, XI, count, prothrombin time, and activated partial throm- and XII. Specialized tests include the thrombin time (measures boplastin time, help guide additional diagnostic testing fibrinogen convergence to fibrin clot), platelet aggregation if required. tests, mixing studies to evaluate for factor deficiencies or inhibitors, specific factor level assays, and tests for fibrin deg radation products and D-dimers. Congenital Bleeding Disorders Mixing studies combine equal parts of the patient's plasma Hemophilia A and B and Other with control plasma. The aPTT is measured immediately fol Factor Deficiencies lowing the mix and again after an incubation period. The Hemophilia A and B (deficiency of factors VIII and IX, respec immediate mixing study will not correct in the presence of most tively) are X linked hereditary bleeding disorders primarily factor inhibitors (e.g., lupus anticoagulant). Characteristically, found in male patients. Daughters of men with hemophilia are the aPTT will correct immediately following mixing when a obligate carriers. Hemophilia A is more common than hemo factor VIII inhibitor is present, but it becomes prolonged again philia B, but both are rare. They manifest in a similar fashion, after incubation. Therefore, mixing study results should always with spontaneous hemarthrosis or bleeding into deep muscles be reported immediately and after incubation. or with excessive or delayed bleeding after trauma. Hemophilia

Fibrinogen I ---) fibrin Normal PT, prolonged aPTT Deficiency of factors Vlll, lX, Xl, or Xll von Willebrand disease (if severe and factorVlll level is quite low) The common Heparin exposure pathway Prolonged PT Deficiency of factors V X, ll, or fibrinogen F 1G U R E 2 6. The "waterfall" model of hemostasis is useful for teasing out and aPTT coagulation disorders affecting the PI and the aPTT. ln this model, factors common Severe liver disease, DlC, vitamin K to the PI and the aPTIare X, V ll, and fibrinogen. FactorVll is unique to the PT, and deficiency, warfa rin toxicity factors Xll, Xl, Vlll, and lX are unique to the aPTT. aPIT= activated partial Heparin overdose thromboplastin time; PT= prothrombin time. Normal PT and Platelet dysfunction (acquired and aPTT congenita l) information to guide management, including in patients undergoing an invasive procedure. Laboratory testing provides von Willebrand disease (if mild and faaor Vlll level is not too low) supplementary information to the clinical history but inde- Scurvy pendently is insufficient to predict bleeding risk (e.g., patients may have a contact factor deficiency or a lupus anticoagulant Ehlers-Danlos syndrome with an elevated activated partial thromboplastin time [aPTT] Hereditary hemorrhagic telangiectasia but no increased risk of bleeding). Patients with bleeding dis- Deficiency of faaor Xlll orders may have a history or new symptoms of easy bruising, aPTT = activated panial thromboplastin time; DIC = disseminated intravascular joint or soft tissue bleeding, mucocutaneous bleeding (includ coaqulation; PT . prothrombin trme. ing epistaxis, bleeding following dental extractions, menstrual and postpartum bleeding, gastrointestinal bleeding), or post- operative bleeding. Family bleeding history and medication Differential diagnoses for patients experiencing bleeding use (including over the-counter medications and supple and who have abnormal findings on specific clotting assays are ments) must be documented. The physical examination outlined in Table 23. fbcuses on finding evidence of petechiae, ecchymoses, deep TEY POIilIS tissue hematomas, or joint effusions. o The clinical history and bleeding symptoms are the Laboratory tests used to measure hemostasis include most important predictive factors to guide management the complete blood count, prothrombin time (PT), and aPTT. for patients with a suspected bleeding disorder. The PT, expressed as the INR, is more sensitive to the eflects of the vitamin K dependent factors (ll, VII, and X), whereas the . Basic laboratory tests, including the complete blood aPTT is a more sensitive measurement of factors VIII, IX, XI, count, prothrombin time, and activated partial throm- and XII. Specialized tests include the thrombin time (measures boplastin time, help guide additional diagnostic testing fibrinogen convergence to fibrin clot), platelet aggregation if required. tests, mixing studies to evaluate for factor deficiencies or inhibitors, specific factor level assays, and tests for fibrin deg radation products and D-dimers. Congenital Bleeding Disorders Mixing studies combine equal parts of the patient's plasma Hemophilia A and B and Other with control plasma. The aPTT is measured immediately fol Factor Deficiencies lowing the mix and again after an incubation period. The Hemophilia A and B (deficiency of factors VIII and IX, respec immediate mixing study will not correct in the presence of most tively) are X linked hereditary bleeding disorders primarily factor inhibitors (e.g., lupus anticoagulant). Characteristically, found in male patients. Daughters of men with hemophilia are the aPTT will correct immediately following mixing when a obligate carriers. Hemophilia A is more common than hemo factor VIII inhibitor is present, but it becomes prolonged again philia B, but both are rare. They manifest in a similar fashion, after incubation. Therefore, mixing study results should always with spontaneous hemarthrosis or bleeding into deep muscles be reported immediately and after incubation. or with excessive or delayed bleeding after trauma. Hemophilia 42

Bleeding Disorders is classified as mild, moderate, or severe according to the cir require intervention (e.g., before surgery); symptomatic culating factor levels (mi]d, 5'1,-40'1,; moderate, 1% 5%; severe, patients require plasma infusions for bleeding episodes and <1'l,). Patients with mild disease may not present with symp surgical procedures. toms until adulthood. t(EI P0l]tIS Diagnosis requires a prolonged aPTT (that corrects in mixing studies) and a normal PT and complete blood count. . Patients with hemophilia A (factor VIII deficiency) or B (factor IX deficiency) have a prolonged activated partial Assay of individual factors (Vlll and lX) confirms the diagno- sis. ln hemophilia A, vWF must be measured to rule out type thromboplastin time with a normal prothrombin time 3 von Willebrand disease (see next section). Arthropathy of the and complete blood count. knees, ankles, and elbows occurs as a late sequela in S0'1, of . Factor replacement infusions (factor concentrates or patients as a result of recurrent hemarthroses. recombinant factor) can help prevent and control Managing bleeding in hemophilia A and B varies based on bleeding in patients with hemophilia A or B; some severity. Patients with mild hemophilia A can be treated with patients with mild hemophilia A may also be treated desmopressin, which stimulates the release of preformed with desmopressin to stimulate the release of pre- tactor VIII from endothelial cells. Patients with moderate or formed factor VIII from stores in endothelial cells. severe hemophilia often require virally inactivated factor con . Patients with factor XI deficiency who are asympto- HVC centrates or recombinant factor replacement. Antifibrinolytic matic do not require prophylactic intervention for most agents (such as e-aminocaproic acid and tranexamic acid) are surgeries. useful in controlling bleeding from dental procedures. Inhibitors are neutralizing antibodies to infused factors that can develop in up to 257, ol patients with hemophilia A and 3% Von Willebrand Disease to 5'1, of patients with hemophilia B who undergo recombi- Von Willebrand disease (vWD), the most common hereditary nant factor replacement therapy. An inhibitor should be sus- bleeding disorder, is caused by deficiency or inef'I'ectiveness pected when a patient with hemophilia who is receiving of vWF. In hemostasis, vWF promotes platelet adhesion and adequate factor replacement experiences a marked increase in functions as a protective carrier protein for factor VIII, so bleeding frequency and severity. mucocutaneous bleeding symptoms that mimic thrombocyto Factor XI deficiency (also known as hemophilia C) is a penia and a mild secondary decrease in factor VIII levels are rare autosomal hereditary disorder seen predominantly in common manifestations of vWD. persons of Ashkenazi lewish heritage. Patients typically do not Hereditary vWD is subclassified into three broad groups experience spontaneous bruising, muscle hematomas, or (Table 24); type 1 is the most common. Patients become symp hemarthroses but tend to have postsurgical bleeding, particu- tomatic when vWF levels decrease to less than 30'2,. Clinical larly from sites with high endogenous fibrinolytic activity features influence vWF levels, including type O blood (decreased (dental, nasal, oropharyngeal, genitourinary), or menorrhagia levels) and pregnancy or oral contraceptive use (increased lev and postpartum hemorrhage. Asymptomatic patients do not els). The aPTT may be prolonged or normal. The diagnosis is

is classified as mild, moderate, or severe according to the cir require intervention (e.g., before surgery); symptomatic culating factor levels (mi]d, 5'1,-40'1,; moderate, 1% 5%; severe, patients require plasma infusions for bleeding episodes and <1'l,). Patients with mild disease may not present with symp surgical procedures. toms until adulthood. t(EI P0l]tIS Diagnosis requires a prolonged aPTT (that corrects in mixing studies) and a normal PT and complete blood count. . Patients with hemophilia A (factor VIII deficiency) or B (factor IX deficiency) have a prolonged activated partial Assay of individual factors (Vlll and lX) confirms the diagno- sis. ln hemophilia A, vWF must be measured to rule out type thromboplastin time with a normal prothrombin time 3 von Willebrand disease (see next section). Arthropathy of the and complete blood count. knees, ankles, and elbows occurs as a late sequela in S0'1, of . Factor replacement infusions (factor concentrates or patients as a result of recurrent hemarthroses. recombinant factor) can help prevent and control Managing bleeding in hemophilia A and B varies based on bleeding in patients with hemophilia A or B; some severity. Patients with mild hemophilia A can be treated with patients with mild hemophilia A may also be treated desmopressin, which stimulates the release of preformed with desmopressin to stimulate the release of pre- tactor VIII from endothelial cells. Patients with moderate or formed factor VIII from stores in endothelial cells. severe hemophilia often require virally inactivated factor con . Patients with factor XI deficiency who are asympto- HVC centrates or recombinant factor replacement. Antifibrinolytic matic do not require prophylactic intervention for most agents (such as e-aminocaproic acid and tranexamic acid) are surgeries. useful in controlling bleeding from dental procedures. Inhibitors are neutralizing antibodies to infused factors that can develop in up to 257, ol patients with hemophilia A and 3% Von Willebrand Disease to 5'1, of patients with hemophilia B who undergo recombi- Von Willebrand disease (vWD), the most common hereditary nant factor replacement therapy. An inhibitor should be sus- bleeding disorder, is caused by deficiency or inef'I'ectiveness pected when a patient with hemophilia who is receiving of vWF. In hemostasis, vWF promotes platelet adhesion and adequate factor replacement experiences a marked increase in functions as a protective carrier protein for factor VIII, so bleeding frequency and severity. mucocutaneous bleeding symptoms that mimic thrombocyto Factor XI deficiency (also known as hemophilia C) is a penia and a mild secondary decrease in factor VIII levels are rare autosomal hereditary disorder seen predominantly in common manifestations of vWD. persons of Ashkenazi lewish heritage. Patients typically do not Hereditary vWD is subclassified into three broad groups experience spontaneous bruising, muscle hematomas, or (Table 24); type 1 is the most common. Patients become symp hemarthroses but tend to have postsurgical bleeding, particu- tomatic when vWF levels decrease to less than 30'2,. Clinical larly from sites with high endogenous fibrinolytic activity features influence vWF levels, including type O blood (decreased (dental, nasal, oropharyngeal, genitourinary), or menorrhagia levels) and pregnancy or oral contraceptive use (increased lev and postpartum hemorrhage. Asymptomatic patients do not els). The aPTT may be prolonged or normal. The diagnosis is TABLE 24. Types of von Willebrand Disease and Associated Features Type of vWD Basic Defect Symptoms Diagnostic Test Treatment Type 1' Low vWF (<30%) but normal Mucocutaneous bleeding RCoF'vWAs 0.6-0.7 Desmopressin function Prolonged closure time on platelet funaion analysis Iype 2 Abnormal vWF function Mucocutaneous bleeding RCoF:vWAg <0.6-0.7 lype2A Selective deficiency oi high- Desmopressin molecular-weight fragments vWF concentrates of vWF fype28 lncreased binding of high- vWF concentrates molecula r-weig ht fragments (desmopressin o{ vWF to platelet receptors contrai ndicated) Type 3 Severe deficiency Joint and deep muscle vWAg: unmeasurable vWF concentrates bleeding RCoF activity: very low Factor Vl I I activity: 1 o/o- 1 07o of normal RCoF = ristocetin cofactor; vWAg = von Willebrand antigen; vWF = von Willebrand factor

TABLE 24. Types of von Willebrand Disease and Associated Features Type of vWD Basic Defect Symptoms Diagnostic Test Treatment Type 1' Low vWF (<30%) but normal Mucocutaneous bleeding RCoF'vWAs 0.6-0.7 Desmopressin function Prolonged closure time on platelet funaion analysis Iype 2 Abnormal vWF function Mucocutaneous bleeding RCoF:vWAg <0.6-0.7 lype2A Selective deficiency oi high- Desmopressin molecular-weight fragments vWF concentrates of vWF fype28 lncreased binding of high- vWF concentrates molecula r-weig ht fragments (desmopressin o{ vWF to platelet receptors contrai ndicated) Type 3 Severe deficiency Joint and deep muscle vWAg: unmeasurable vWF concentrates bleeding RCoF activity: very low Factor Vl I I activity: 1 o/o- 1 07o of normal RCoF = ristocetin cofactor; vWAg = von Willebrand antigen; vWF = von Willebrand factor "80% of cases. I

TABLE 24. Types of von Willebrand Disease and Associated Features Type of vWD Basic Defect Symptoms Diagnostic Test Treatment Type 1' Low vWF (<30%) but normal Mucocutaneous bleeding RCoF'vWAs 0.6-0.7 Desmopressin function Prolonged closure time on platelet funaion analysis Iype 2 Abnormal vWF function Mucocutaneous bleeding RCoF:vWAg <0.6-0.7 lype2A Selective deficiency oi high- Desmopressin molecular-weight fragments vWF concentrates of vWF fype28 lncreased binding of high- vWF concentrates molecula r-weig ht fragments (desmopressin o{ vWF to platelet receptors contrai ndicated) Type 3 Severe deficiency Joint and deep muscle vWAg: unmeasurable vWF concentrates bleeding RCoF activity: very low Factor Vl I I activity: 1 o/o- 1 07o of normal RCoF = ristocetin cofactor; vWAg = von Willebrand antigen; vWF = von Willebrand factor "80% of cases. I l

TABLE 24. Types of von Willebrand Disease and Associated Features Type of vWD Basic Defect Symptoms Diagnostic Test Treatment Type 1' Low vWF (<30%) but normal Mucocutaneous bleeding RCoF'vWAs 0.6-0.7 Desmopressin function Prolonged closure time on platelet funaion analysis Iype 2 Abnormal vWF function Mucocutaneous bleeding RCoF:vWAg <0.6-0.7 lype2A Selective deficiency oi high- Desmopressin molecular-weight fragments vWF concentrates of vWF fype28 lncreased binding of high- vWF concentrates molecula r-weig ht fragments (desmopressin o{ vWF to platelet receptors contrai ndicated) Type 3 Severe deficiency Joint and deep muscle vWAg: unmeasurable vWF concentrates bleeding RCoF activity: very low Factor Vl I I activity: 1 o/o- 1 07o of normal RCoF = ristocetin cofactor; vWAg = von Willebrand antigen; vWF = von Willebrand factor "80% of cases. I l 43