2. D. Venous thromboembolism (VTE), which manifests clinically as deep vein thrombosis and pulmonary embolism, typically occurs in patients with risk factors for thrombosis. In most patients with VTE, one or more of Virchow’s triad of thrombotic risk factors (venous stasis, endothelial injury, hypercoagulability) can be identified. Causes of venous stasis include prolonged immobilization, extended air travel, pregnancy, and obesity. Causes of vascular endothelial injury include trauma, surgery, intravenous drug use, vasculitis, and sickle cell anemia. Hypercoagulable states can be acquired or inherited. Acquired hypercoagulable states include pregnancy, oral contraceptive use, hormone replacement therapy, nephrotic syndrome, malignancy, clonal hematologic disorders (including polycythemia vera, essential thrombocythemia, and paroxysmal nocturnal hemoglobinuria), heparin-induced thrombocytopenia (HIT), inflammatory conditions, and antiphospholipid syndrome. Inherited hypercoagulable conditions can be caused by mutations in factor V, prothrombin, methyltetrahydrofolate reductase, protein C and S, fibrinogen, and antithrombin III. This patient does not appear to have venous stasis or a recent vascular injury. Her VTE is therefore likely the result of her oral contraceptive use in addition to, possibly, an inherited hypercoagulable condition.

    The factor V Leiden (FVL) mutation is the most common familial thrombophilia. FVL is present in 4.8% of Caucasians and in 0.05% of Africans and Asians. The frequency of FVL in patients under 50 years of age with a family history of thrombosis or a history of recurrent thrombotic events and no acquired risk factors for thrombosis except pregnancy or oral contraceptive use is 40%. FVL is the result of a missense mutation that changes the arginine at position 506 of factor V to glutamine, which prevents inactivation of factor V by activated protein C. This impairs termination of activation of the coagulation cascade by Protein C.

    The second most common familial thrombophilia is the prothrombin G20210A mutation, which is a mutation in the 3′-untranslated region of prothrombin that results in overproduction of prothrombin. This results in elevated levels of circulating prothrombin. The prothrombin G20210A mutation is present in 2.7% of Caucasians and 0.06% of Africans and Asians, and the frequency of the prothrombin gene mutation in patients less than 50 years of age with a family history of thrombosis or a history of recurrent thrombotic events and no acquired risk factors for thrombosis except pregnancy or oral contraceptive use is 16%.

    Less common familial thrombophilias include antithrombin III deficiency, protein C deficiency, and protein S deficiency, which have a combined frequency of 13% in patients less than 50 years of age with a family history of thrombosis or a history of recurrent thrombotic events and no acquired risk factors for thrombosis except pregnancy or oral contraceptive use. Other, very rare, familial thrombophilias include homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene that results in elevated levels of homocysteine, and mutations in fibrinogen that result in dysfibrinogenemia.

    3. D. The patient’s history is highly suggestive of antiphospholipid syndrome (APLS). APLS is an acquired hypercoagulable state that is characterized by the presence of autoantibodies to phospholipid-binding proteins and by recurrent thrombosis. The thrombotic complications of APLS include venous thrombosis (deep vein thrombosis, pulmonary embolism, portal vein thrombosis), arterial thrombosis (myocardial infarction, limb necrosis), and spontaneous pregnancy loss. APLS can occur in the context of systemic lupus erythematosus, and can also occur in isolation.

    The patient’s prolonged PTT is an additional clue to her diagnosis of APLS. She was treated with low-molecular-weight heparin, which does not affect the PTT. Her prolonged PTT is therefore not due to her therapeutic anticoagulation. Rather, it is due to the presence of antiphospholipid antibodies in her blood. The PTT test requires phospholipid as a cofactor. The antiphospholipid antibodies in patients with APLS bind to the phospholipids and interfere with the in vitro aPTT reaction, resulting in prolongation of the activated PTT (aPTT) in some patients. As her PTT is prolonged due to the presence of an inhibitor and not a factor deficiency, her PTT would not correct upon mixing with normal plasma. Additional testing, including the lupus anticoagulant test and the dRVVT (dilute Russell viper venom time) test, as well as direct serologic testing for the presence of antiphospholipid antibodies (anticardiolipin and anti-beta-2-glycoprotein), would help to confirm the diagnosis.

    In this patient the diagnosis of HIT is not consistent with her presentation or with the time course of her mild thrombocytopenia. HIT is a highly prothrombotic state that presents 5–10 days after initiation of heparin therapy in patients who develop autoantibodies to platelet factor 4–heparin complexes. The patient was on heparin for only 1 day when her blood tests were done, which is insufficient time for her to have developed HIT antibodies. Answer A is therefore incorrect. Peripheral blood flow cytometry for CD55 and CD59 is done to evaluate patients suspected of having paroxysmal nocturnal hemoglobinuria (PNH). PNH is an acquired clonal disorder of red cell membranes in which red cells lack surface expression of GPI-anchored proteins, including proteins that protect red cells from complement-mediated lysis. Patients with PNH have recurrent episodes of intravascular hemolysis and, for unclear reasons, are predisposed to venous thrombosis, in particular Budd-Chiari syndrome (hepatic vein thrombosis). The patient’s normal haptoglobin level argues against the presence of any significant intravascular hemolysis, and the diagnosis of PNH would not explain her prolonged PTT or her history of spontaneous pregnancy loss. Answer B is therefore incorrect. Serologic testing for autoantibodies to ADAMTS13 is done in patients with suspected thrombotic thrombocytopenic purpura (TTP) to confirm the diagnosis, although ADAMTS13 serologic testing is not a sensitive test for TTP. TTP is classically characterized by a pentad of signs and symptoms—fever, neurological changes, renal insufficiency, microangiopathic hemolytic anemia, and thrombocytopenia. Patients with TTP typically present with severe thrombocytopenia and very elevated LDH levels. This patient’s mild thrombocytopenia, mildly elevated LDH, and normal haptoglobin are not consistent with the extensive platelet destruction and intravascular hemolysis that are hallmarks of TTP. In addition, TTP typically causes microvascular, not macrovascular, thrombosis, and the diagnosis of TTP would not explain her prolonged PTT or her history of spontaneous pregnancy loss. Answer C is therefore incorrect.

    4. D. This patient meets the clinical criteria for thrombotic thrombocytopenia purpura (TTP). TTP is classically characterized by a pentad of signs and symptoms—fever, neurologic changes, renal insufficiency, microangiopathic hemolytic anemia, and thrombocytopenia—although, in the appropriate clinical context, only microangiopathic hemolytic anemia and thrombocytopenia are required to make the diagnosis. Figure 20.1 shows a typical blood smear with Schistocytes.

    Under normal physiological conditions, endothelial cells secrete unusually large multimers of vWF, which are tethered to the endothelial cell surface. These large multimers are cleaved into smaller fragments by the vWF–cleaving metalloprotease ADAMTS13. Cleavage releases the small vWF fragments into the circulation, where they help mediate platelet aggregation and clotting. In TTP, the activity of ADAMTS13 is impaired by the presence of autoantibodies to the metalloprotease. The lack of ADAMTS13 activity results in the accumulation of membrane-bound, unusually large vWF multimers. These large multimers inappropriately bind to and activate circulating platelets, resulting in in situ microvascular thrombus formation and tissue ischemia. If left untreated, TTP can cause irreversible kidney damage and stroke. The primary treatment for TTP is plasmapheresis, which is thought to work both by removing anti-ADAMTS13 antibodies as well as by providing a large infusion of active ADAMTS13 enzyme. Ninety percent of cases of TTP improve with plasmapheresis, although about 30% of patients will subsequently relapse and require additional courses of plasmapheresis. About 10% of patients have refractory disease and require additional therapeutic interventions, which may include splenectomy, cytotoxic agents, and/or rituximab (anti–B-cell therapy).

    Without immediate treatment the morbidity and mortality of TTP is very high, and it is important to initiate therapy before permanent tissue damage occurs. Answers B and C are therefore incorrect. Answer A incorrectly presumes that the patient has hemolytic uremic syndrome. Hemolytic uremic syndrome (HUS) is another thrombotic microangiopathy that is characterized by renal failure, microangiopathic hemolytic anemia, and thrombocytopenia, but it is caused by a strain of E. coli (E. coli 0157) that produces shiga toxin, a toxin that interferes with ADAMTS13 activity. HUS is classically a disease of childhood and is rare in adults, and it is a self-limited condition for which plasmapheresis is not required. The age of the patient and the fact that she did not present with an antecedent diarrheal illness makes HUS unlikely. Given the high morbidity and mortality of TTP and the lack of a rapid diagnostic test to differentiate HUS from TTP, adult patients who present with microangiopathic hemolytic anemia and thrombocytopenia should be presumed to have TTP and should be treated accordingly.

    Other causes of microangiopathic hemolytic anemia and thrombocytopenia that should be considered in the differential diagnosis of this patient include DIC (disseminated intravascular coagulation), HELLP syndrome of pregnancy (hemolysis, elevated liver enzymes, and low platelets), systemic vasculitides, malignant hypertension, advanced cancer, and drug effects. The patient is not on any medications and does not appear ill, and these conditions are therefore all less likely than TTP.

    5. B. Immune thrombocytopenic purpura (ITP) is an acquired disorder in which platelets are destroyed in the peripheral circulation by an autoimmune mechanism. ITP is characterized by isolated thrombocytopenia with otherwise normal blood counts, no other abnormalities on peripheral blood smear, and the absence of an identifiable alternative cause for the low platelet count. ITP is commonly associated with other autoimmune diseases and can also occur in the setting of HIV infection, although the majority of cases are idiopathic. Patients with ITP can also present with Evans syndrome, in which ITP and Coombs’-positive autoimmune hemolytic anemia occur concomitantly. ITP is a diagnosis of exclusion; there are no laboratory tests that can reliably confirm or rule out the diagnosis of ITP. Although antiplatelet antibody levels can be measured, the antibodies are neither sensitive nor highly specific for the diagnosis of ITP and are therefore of limited clinical utility.

    The differential diagnosis of thrombocytopenia in ITP includes TTP (although microangiopathic hemolytic anemia is not present in ITP), DIC (although patients with DIC are typically ill-appearing and have abnormalities of coagulation, which are not present in ITP), drug-associated thrombocytopenia (commonly implicated drugs include alcohol, anticonvulsants, sulfonamides, quinine, penicillins), HIT, acute viral infections (HIV, Epstein-Barr virus [EBV], cytomegalovirus [CMV], hepatitis), hypersplenism, and primary bone marrow disorders (although other hematologic abnormalities are typically present).

    The choice of first-line treatment for ITP depends primarily on the presence or absence of active bleeding. In ITP, megakaryocytes respond to thrombocytopenia by producing larger-than-normal platelets that have enhanced function, and spontaneous bleeding is therefore rare at platelet counts above 10,000/mm³. However, when thrombocytopenia is very severe (platelet counts <10,000/mm³) and/or when patients with ITP are taking medications that interfere with platelet function (aspirin, nonsteroidal antiinflammatory drugs (NSAIDs), clopidogrel), they can be at risk for spontaneous and even life-threatening bleeding. In patients who are not bleeding, ITP can be treated with dexamethasone, 40 mg by mouth for 4 days, or with prednisone, 1 mg/kg followed by a slow taper. Splenectomy, intravenous immunoglobulin, Rh_o(D) immune globulin, cytotoxic agents (cyclophosphamide, vincristine), and rituximab are reserved for second-line treatment of refractory ITP. In patients who are actively bleeding, intravenous immunoglobulin in combination with steroids is a highly effective first-line treatment, although intravenous immunoglobulin is contraindicated in patients with renal insufficiency. Rh_o(D) immune globulin can also be used to treat ITP in Rh+ patients, but because Rh_o(D) immune globulin binds the patients’ red blood cells it can precipitate an autoimmune hemolytic episode and is therefore contraindicated in Rh+ ITP patients with anemia. Platelet transfusions are typically not effective at raising the platelet count of patients with ITP and should therefore be reserved for cases of life-threatening hemorrhage.

    ITP rarely resolves spontaneously and, without treatment, patients can be at risk for severe, even life-threatening bleeding. Answer A is therefore incorrect. As this patient has not failed primary therapy with steroids and is not actively bleeding, answers C and D are incorrect as well.

    6. D. This patient meets the clinical criteria for heparin-induced thrombocytopenia (HIT). HIT is characterized clinically by the development of thrombocytopenia in patients on heparin, and the diagnosis should be considered in any patient whose platelet count drops by 50% or more within 5–10 days of initiation of heparin. HIT occurs in 1–10% of patients exposed to unfractionated heparin and in 0.1–0.5% of patients exposed to low-molecular-weight heparin. The incidence of HIT is highest in surgical patients undergoing cardiac and orthopedic procedures and lowest in obstetric patients.

    HIT is an immune-mediated disorder in which autoantibodies develop to complexes of heparin and platelet factor 4, a factor secreted by activated platelets. The antibodies bind to the heparin-PF4 complexes and bind to the Fc receptors on the surface of platelets, which causes activation of the platelets and uncontrolled release by the platelets of procoagulant platelet microparticles. The activated platelets are cleared from the circulation by the spleen, resulting in thrombocytopenia, and the released procoagulant platelet microparticles bind to sites of endothelial injury and initiate uncontrolled thrombosis. The morbidity and mortality associated with HIT are not consequences of thrombocytopenia, which is rarely severe, but from arterial and venous thrombosis, which occurs in as many as 50% of patients with HIT. Common thrombotic complications of HIT include DVT/PE, cerebral vein thrombosis, lower-limb ischemia and limb loss, stroke, and myocardial infarction. Untreated HIT has a mortality of 20–30%.

    There are two diagnostic tests for HIT. The immunoassay that detects the presence of antibodies to the heparin-PF4 complex is highly sensitive but only moderately specific, whereas the platelet activation assay that detects the presence of heparin-PF4 antibodies that can bind to platelets and cause platelet degranulation is both highly sensitive and highly specific. However, HIT remains a clinical diagnosis and, given the high morbidity and mortality of HIT, appropriate management of patients suspected of having HIT should never await results of laboratory tests.

    Management of suspected HIT consists of immediate cessation of all heparin products and immediate initiation of alternative anticoagulants. Alternative anticoagulants that are FDA-approved for the treatment of HIT include the direct thrombin inhibitors argatroban, bivalirudin, and lepirudin (which are intravenous), and dabigatran (which is oral). Simple cessation of heparin is not adequate intervention in patients suspected of having HIT because patients continue to be significantly hypercoagulable after discontinuation of heparin and are at continued risk for catastrophic thrombosis. Although low-molecular-weight heparin has a lower incidence of causing HIT than unfractionated heparin, it is absolutely contraindicated in patients with HIT. Answers A and B are therefore incorrect. Anticoagulation with warfarin should not be started in patients with HIT until they are fully anticoagulated with a direct thrombin inhibitor and their platelet count has recovered. Premature initiation of anticoagulation with warfarin can result in the development of venous gangrene. Answer C is therefore incorrect.

    7. D. The patient’s clinical presentation is consistent with DIC, likely secondary to acute mesenteric ischemia. DIC is a condition in which uncontrolled activation of the coagulation cascade in response to severe physiological stress results in intravascular fibrin deposition and microvascular thrombosis, as well as consumption of platelets and clotting factors. DIC can occur in a number of different clinical settings in which large amounts of tissue factor are released into the circulation including sepsis, obstetric complications, malignancy, and trauma. Patients with DIC typically have prolonged clotting times (PT and PTT), inappropriately low/normal fibrinogen levels (fibrinogen, as an acute phase reactant, should be elevated in acute illness), and elevated D-dimer levels. Clinically, patients with DIC present with varying degrees of intravascular hemolysis, bleeding, tissue ischemia, and end-organ damage including renal failure, hepatic dysfunction, acute respiratory distress syndrome (ARDS), stroke, and shock. Treatment of DIC is supportive and involves maintaining organ perfusion and, in patients who are bleeding, transfusing blood products (red blood cells, platelets, fresh frozen plasma, cryoprecipitate) until the underlying cause of the DIC can be treated and reversed.

    The morbidity and mortality of DIC are high, and resolution of DIC requires treatment of the underlying condition. It is therefore important to distinguish DIC from other thrombotic microangiopathies and from other causes of coagulopathy and thrombocytopenia that might need different specific treatments. The principal conditions from which DIC must be distinguished are TTP and the coagulopathy of liver failure. In differentiating DIC from TTP it is important to remember that whereas DIC results from the dysregulated activation and depletion of both platelets and clotting factors, TTP results from the inappropriate activation of platelets by uncleaved vWF without perturbation of the coagulation cascade. Clotting times as well as fibrinogen and D-dimer levels are therefore normal in TTP. In addition, TTP is a primary autoimmune disorder that typically occurs in patients who are otherwise well, whereas DIC occurs as a consequence of severe underlying physiological stress, and patients are typically ill. Differentiating DIC from severe liver failure can be difficult and frequently relies largely on patient history and patient presentation. Liver failure, like DIC, is frequently associated with thrombocytopenia, due in the case of liver failure to portal hypertension, splenomegaly, and splenic sequestration of platelets. Also, as the liver synthesizes most of the coagulation factors, patients with severe liver disease frequently have elevated clotting times. Moderate elevations in D-dimer levels are also frequently seen in patients with liver cirrhosis because D-dimer products are cleared by the liver, and clearance is impaired in the setting of liver failure. Of note: although the liver does synthesize fibrinogen, fibrinogen levels are typically maintained within the normal range in patients with liver disease until their liver failure becomes extremely severe, and a low fibrinogen level should therefore raise the suspicion for DIC even in patients with hepatic synthetic dysfunction.

    In the above question, although it is not clear from the patient’s history whether he might be taking medications that are associated with drug-induced thrombocytopenia, a drug effect would not explain his overall presentation. Similarly, the diagnosis of ITP would not explain most of his laboratory findings or the severity of his presentation. Answers A and B are therefore incorrect. And although fever, acute renal failure, mental status changes, peripheral blood schistocytosis, and thrombocytopenia are all features of TTP, the diagnosis of TTP would not explain his abnormal coagulation studies, and the patient is too acutely ill for TTP to be the underlying cause of his presentation. Answer C is therefore incorrect. The patient does have elevated liver enzymes, but this is likely due to hepatic hypoperfusion, and there is nothing in his history to suggest that he has underlying liver cirrhosis, portal hypertension, or splenomegaly. Answer E is therefore incorrect.

    8. D. Even in people who have no apparent medical problems the majority of cases of thrombocytosis are reactive, where the elevated platelet count is secondary to an underlying medical condition. Common causes of reactive thrombocytosis include iron deficiency, acute and chronic infections, inflammatory conditions, allergic reactions, occult malignancies, hyposplenism, recent trauma or surgery, and count recovery after episodes of thrombocytopenia (such as post-chemotherapy, post–vitamin B₁₂/folate repletion, and post–alcohol cessation). Reactive thrombocytosis is rarely, even at very elevated platelet counts, associated with thrombosis or bleeding, and appropriate therapy for reactive thrombocytosis consists of treating the underlying medical condition, not the platelet count.

    The initial workup of an elevated platelet count should include a careful patient history, measurement of iron saturation levels to rule out iron deficiency (which is very common in premenopausal women), and measurement of markers of inflammation such as the erythrocyte sedimentation rate and ferritin and C-reactive protein levels. In patients whose elevated platelet counts are sustained and who have none of the above-mentioned medical conditions, a workup for primary causes of thrombocytosis is indicated. Causes of autonomous platelet production include the chronic myeloproliferative disorders (chronic myelogenous leukemia, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis), the 5q– myelodysplastic syndrome, and hereditary thrombocythemias (which are caused by activating mutations in thrombopoietin and the thrombopoietin receptor). Many of these thrombocythemias are associated with increased risk of thrombotic complications, including DVT/PEs and the Budd-Chiari syndrome, and varying degrees of risk of progression to acute leukemia.

    Essential thrombocythemia (ET) is one of the Philadelphia chromosome-negative chronic myeloproliferative disorders. It is characterized by a sustained elevated platelet count in the absence of evidence of reactive thrombocytosis or other causes of primary thrombocytosis. There is no single diagnostic laboratory test for ET. Although 30–50% of patients with ET test positive for the presence of the JAK2V617F mutation, the mutation is found in over 90% of patients with polycythemia vera and 30–50% of patients with idiopathic myelofibrosis and is therefore not diagnostic of ET. ET is associated with a low risk of thrombosis and bleeding and a very low risk of progression to marrow failure or acute leukemia, and the median survival of patients with ET approaches that of normal subjects. Many patients with ET do not require treatment, although elderly patients and patients who have risk factors for vascular disease are typically treated with low-dose aspirin even if they are asymptomatic. Indications for treatment with platelet-lowering agents include a platelet count >1,500,000/mm³; symptoms of vasomotor instability (headaches, flushing); bleeding, arterial, venous and/or microvascular thrombosis; and recurrent fetal loss. The most commonly used platelet-lowering agent in ET is hydroxyurea, which effectively lowers the platelet count and the risk of thrombosis in the majority of ET patients. The principal dose-limiting toxicity of hydroxyurea is leukopenia, and anagrelide is frequently used to treat symptomatic patients who cannot tolerate hydroxyurea.

    In the above question, until reactive thrombocytosis is ruled out the initiation of any antiplatelet therapy would be premature. Answers A and C are therefore incorrect. The thrombosis in ET and the other primary thrombocythemias are platelet-mediated and warfarin, which targets the coagulation cascade, is therefore not an effective drug to decrease the risk of ET-associated thrombosis. Answer B is therefore incorrect. Finally, given the lack of a clear etiology for the patient’s thrombocytosis, any discussion of her risk of developing leukemia would be premature. Answer E is therefore incorrect.

    9. A. This patient has glucose-6-phosphate dehydrogenase (G6PD) deficiency. G6PD deficiency is an X-linked enzymatic disorder of red blood cells that results in a decreased ability of red blood cells to generate NADPH, a metabolic intermediate that is essential for the conversion of oxidized intracellular proteins to their reduced forms. When G6PD-deficient red blood cells are exposed to oxidative stress, the hemoglobin in the cells denatures and precipitates resulting in the formation of Heinz bodies (see Figure 20.2) that can be detected on peripheral blood smear. The oxidized red blood cells become rigid and nondeformable and are destroyed by the reticuloendothelial system of the liver, spleen, and bone marrow.

    There are more than 100 mutations that are associated with G6PD deficiency, but the two most common mutations are the A-variant, which is present in 10% of African Americans, and the Mediterranean variant, which is present in 5% of people of Mediterranean descent. The A-variant has normal enzymatic activity but is unstable and has a shorter half-life than the wild-type enzyme. When A-variant red blood cells are exposed to oxidative stress, only the older cells have insufficient G6PD and hemolyze whereas reticulocytes and newly generated mature red blood cells survive. The A-variant is therefore generally associated with a mild, self-limited hemolysis. The Mediterranean variant is a mutation that results in very low baseline G6PD enzymatic activity and is associated with more severe hemolysis.

    There are several diagnostic tests that quantify, with varying degrees of sensitivity, the level of G6PD activity in red blood cells. These include the dye decolorization test, the rapid fluorescence screening test, the G6PD-tetrazolium cytochemical test, and spectrophotometric tests that determine the rate of NADPH production by red blood cells. The ability of all of these tests to diagnose A-variant G6PD deficiency during or immediately after an acute hemolytic episode is limited due to the fact that the older G6PD-deficient red blood cells are preferentially hemolyzed, whereas the younger cells that have near-normal levels of G6PD activity survive. These diagnostic tests should therefore be performed in patients with suspected A-variant G6PD deficiency only after they have recovered from their hemolytic episode, when their hematocrit and reticulocyte count have normalized. The red blood cells of patients with the Mediterranean variant of G6PD, on the other hand, will have abnormal G6PD activity throughout their lifespan and will test positive even during an acute hemolytic episode.

    Common oxidative stresses that have been associated with hemolytic crises in patients with G6PD deficiency include the following:

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