Benign hematology: review Questions - Turner White Communications

hematology Board Review Manual Statement of Editorial Purpose The Hospital Physician Hematology Board Review Manual is a study guide for fellows and prac ticing physicians preparing for board exami nations in hematology. Each manual reviews a topic essential to the current practice of hematology.

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Benign Hematology: Review Questions Series Editor: Eric D. Jacobsen, MD Instructor of Medicine, Harvard Medical School, Boston, MA; Attending Physician, Dana-Farber Cancer Institute, Boston, MA

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Contributor: Anaadriana Zakarija, MD Assistant Professor of Medicine, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL

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Table of Contents

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NOTE FROM THE PUBLISHER: This publication has been developed with out involvement of or review by the Amer ican Board of Internal Medicine.

Questions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Answers and Explanations . . . . . . . . . . . . . . . . . . . . . 6 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 Cover Illustration by Kathryn K. Johnson

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www.turner-white.com Hematology Volume 3, Part 3

Hematology Board Review Manual

Benign Hematology: Review Questions Anaadriana Zakarija, MD

QUESTIONS Choose the single best answer for each question. 1. A 28-year-old man presents for follow-up and further evaluation of a recent thrombotic event. Three months ago, the patient presented to the emergency department (ED) with mild shortness of breath occurring at rest that developed a few hours prior to presentation and a 2-day history of dyspnea with exertion. He denied fever and cough, and there was no lower extremity edema. Past medical history was significant for cholecystectomy that occurred 2 weeks before the ED presentation. The patient was not taking any medications. Physical examination conducted in the ED was notable for a heart rate of 102 bpm. On auscultation, crackles were appreciated at the right base of the lungs. Computed tomography scan of the chest demonstrated a thrombus in the right lower lobe segmental pulmonary artery. The patient was admitted to the hospital. Thrombophilia evaluation was subsequently performed, which revealed a positive lupus anticoagulant, anticardiolipin IgM level of 35 MPL (normal, < 12 MPL), and anticardiolipin IgG level of 6 GPL (normal, < 10 GPL) antibodies. The patient was treated with dalteparin, and warfarin was started. His hospital course was uncomplicated, and he was discharged on hospital day 4 with instructions to continue taking dalteparin and warfarin until warfarin reached a therapeutic level with an international normalized ratio (INR) between 2 and 3. At 3-month follow-up, the patient has not experienced any bleeding complications related to warfarin therapy. Repeat thrombophilia evaluation reveals positive lupus anticoagulant, anticardiolipin IgM of 6 MPL, and anticardiolipin IgG of 8 GPL. Which is the best anticoagulation option for this patient at this time? (A) Indefinite warfarin with target INR of 2 to 3 (B) Indefinite warfarin with target INR of 2.5 to 3.5 (C) Warfarin with target INR of 2 to 3 for 3 to 6 months

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(D) Warfarin with target INR of 2.5 to 3.5 for 3 to 6 months 2. A 32-year-old woman is referred for consultation in regards to anticoagulation prophylaxis during pregnancy. Five years ago, the patient experienced a deep vein thrombosis (DVT) of the right popliteal vein 11 days after laparoscopic surgery of the right knee. At that time, the patient was treated initially with enoxaparin and transitioned to warfarin (target INR, 2–3) for 6 months. Thrombophilia evaluation (which included evaluation for lupus anticoagulant; anticardiolipin and β2-glycoprotein I antibodies; factor V Leiden [FVL] and prothrombin G20210A gene mutations; and protein C, protein S, and antithrombin activity) performed at the time of diagnosis was negative. The patient has never taken any hormonal contraceptives. Which of the following is the most appropriate recommendation for this patient during her pregnancy? (A) Aspirin 81 mg/day (B) Prophylactic dose of a low-molecular-weight heparin (LMWH) plus aspirin (C) Prophylactic dose of a LMWH starting at 8 weeks of gestation (D) No treatment antepartum 3. A 64-year-old man is referred by his primary care physician for evaluation of anemia and leukopenia. The patient reports that he has experienced mild fatigue and decreased exercise tolerance for the last 6 months. Both review of systems and physical examination are unremarkable. Past medical history is significant for hypertension, psoriasis, and benign prostatic hypertrophy. The patient’s medications include amlodipine, atenolol, tamsulosin hydrochloride, zinc, a multivitamin, and vitamin E supplement. Laboratory studies are ordered, and notable results are listed in Table 1. Bone marrow biopsy is performed, which reveals a normocellular marrow with adequate megakaryocytes, erythroid, and myeloid precursors. Representative myeloid and erythroid precursors are seen in Figure 1 (see page 4). Cytogenetic analysis reveals normal male

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Benign Hematology: Review Questions karyotype, 46,XY. What is the most appropriate initial treatment for this patient? (A) Copper 1 mg orally twice daily (B) Discontinuation of zinc supplement (C) Epoetin alfa once weekly (D) Epoetin alfa and filgrastim weekly 4. A 45-year-old man presents to his hematologist for follow-up. Seven months ago, the patient presented to his primary care physician with a complaint of right lower extremity swelling for 2 weeks. The patient had no other symptoms, and he denied recent surgery, hospitalization, and air travel. The patient underwent colonoscopy approximately 1 year ago, the results of which were normal. Past medical history is significant for hyperlipidemia, which is being treated with simvastatin. Family history is notable for a sister with a pregnancyassociated DVT. Doppler ultrasound was ordered, which demonstrated a right popliteal DVT. The patient was referred to a hematologist, and subsequent thrombophilia evaluation was positive for heterozygous FVL mutation. The remainder of the thrombophilia evaluation (which included assessment for protein C, protein S, and antithrombin activity; prothrombin G20210A gene; lupus antico agulant; and anticardiolipin and β2-glycoprotein I antibodies) was negative. The patient was treated with tinzaparin, followed by warfarin for 6 months. The patient’s physician recommended against contact sports and high-risk activities such as skiing while taking warfarin. As the patient is an avid skier, he did not want to continue warfarin beyond 6 months. Four weeks after warfarin was discontinued, the patient presents for followup assessment. At this visit, the d-dimer level is 676 ng/mL (normal, < 500 ng/mL). Which of the following statements is true about the patient’s risk of recurrent thrombosis? (A) A d-dimer level exceeding 500 ng/mL assessed 4 weeks after discontinuation of anti coagulation is associated with a higher risk of venous thromboembolism (VTE) recurrence as compared with a d-dimer level below 500 ng/mL (B) Patients who have heterozygous FVL mutation are at an increased risk for recurrent VTE as compared with patients who have idiopathic VTE and no FVL mutation (C) In patients with a first episode of idiopathic DVT, treatment with 6 months of warfarin is associated with a higher risk of recurrence as

Table 1. Results of Selected Laboratory Studies for the Patient Described in Question 3 Study (Unit)

Result

Hemoglobin (g/dL) 7.5 Mean corpuscular volume (fL) 84 242,000 Platelet count (cells/µL) 2400 White blood cell count (cells/µL) Segmented neutrophils (%) 10 Lymphocytes (%) 55 Monocytes (%) 23 Basophils (%) 4 Eosinophils (%) 5 Absolute neutrophil count (cells/µL) 200 72 Copper (µg/L) Erythropoietin (IU/L) 88 Lactate dehydrogenase (U/L) 131 Vitamin B12 (pg/mL) 242

Reference Range 14.0–17.0 80–96 150,000–350,000 4500–11,000 34–73 15–50 1–15 0–3 0–8 1500–8000 700–1750 5–36 100–200 180–933

compared with 18 months of treatment with warfarin (D) Women have a threefold higher risk of recurrent VTE as compared with men 5. Which of the following statements about thrombotic thrombocytopenic purpura (TTP) is correct? (A) ADAMTS13 deficiency is found only in patients with thrombotic microangiopathy (TMA) syndromes (B) Presence of ADAMTS13 autoantibodies at presentation and persistence of severe ADAMTS13 deficiency at remission is associated with a higher risk of TTP relapse (C) Rituximab administered at the time of diagnosis of TTP is associated with a decreased risk of future recurrence as compared with patients who do not receive rituximab (D) Severe ADAMTS13 deficiency (ADAMTS13 activity < 10%) is present in all cases of idiopathic TTP (E) Therapeutic plasma exchange is only indicated for patients with severe ADAMTS13 deficiency 6. A 68-year-old man presents to the ED with a swollen left upper extremity and some bruising. Physical examination is notable for left upper extremity edema of the forearm. Approximately 1- to 2-cm ecchymoses are also observed on the left arm. There is no evidence of compartment syndrome, and lymphadenopathy and hepatosplenomegaly are not present. There is no history of bleeding associated


Benign Hematology: Review Questions

Figure 1. Bone marrow aspirate of the patient described in question 3.

Table 2. Results of Selected Laboratory Studies for the Patient Described in Question 6 Study (Unit)

Result

Factor VIII assay (%) 99th percentile), present on 2 or more occasions at least 12 weeks apart. Despite the 2 positive tests for lupus anticoagulant in this patient, the diagnosis of


Benign Hematology: Review Questions APS cannot be considered confirmed because the follow-up lupus anticoagulant test was performed while the patient was taking warfarin. Assessment of lupus anticoagulant is problematic because both warfarin and the various heparins can affect the clotting studies that test for lupus anticoagulant,3,4 which must be taken into consideration before committing a patient to long-term anticoagulation. This patient should receive at least 3 months of anticoagulation with standard warfarin therapy (target INR, 2–3) for a pulmonary embolus associated with a transient risk factor (surgery).1 After 3 months, anticoagulation may be interrupted for 2 weeks to retest for lupus anticoagulant. If persistently positive, then longterm anticoagulation could be considered given the high risk of recurrent thrombosis in patients with APS. With respect to intensity of anticoagulation with warfarin for treatment of APS, a retrospective study suggested that the target INR for patients with APS should exceed 3.5 However, recent data from randomized trials that evaluated standard-intensity warfarin (INR, 2–3) with high-intensity warfarin (INR, 3–46 and INR, 3–4.57) in patients with APS and a first thrombotic event revealed that higherintensity warfarin was not associated with a lower risk of recurrence.6,7 Therefore, the target INR should be 2 to 3 in patients with APS and a first thrombotic event. In this case, warfarin was discontinued after 6 months of therapy, and the patient was retested for the presence of the lupus anticoagulant. As this study was negative, there was no indication of APS, and anticoagulation therapy was not resumed. 2. (D) No treatment antepartum. This patient’s first thrombotic event is considered a provoked event because it occurred during the postoperative period. In addition, her thrombophilia evaluation is negative. The risk for a recurrent thrombotic event during pregnancy is considered low in patients who have experienced a prior provoked thrombotic event and who do not have underlying thrombophilia. Brill-Edwards and colleagues8 evaluated 125 women with a prior VTE and followed them during pregnancy. The cohort received only postpartum anticoagulation. The incidence of recurrent events during pregnancy was 0% in those with prior provoked VTE, whereas 5.9% of patients experienced recurrence of VTE when the previous event was idiopathic. Based on this study, antepartum anticoagulation has not been recommended in all patients with a prior thrombotic event. The Eighth American College of Chest Physician evidence-

based clinical practice guidelines also state that antenatal anticoagulation should be considered only in selected patients who experienced a prior provoked VTE, such as those with prior estrogen or pregnancy-provoked thrombosis.9 These guidelines also recommend consideration of postpartum anticoagulation in all patients with a history of provoked or idiopathic thrombosis,9 as the thrombotic risk is highest in the postpartum period.10 Unfortunately, the evidence on which these recommendations are based is not strong, as few studies have been completed in this area. Further well-conducted clinical trials on prevention of thrombosis in pregnancy are necessary. 3. (B) Discontinuation of zinc supplement. Copper deficiency can present with findings similar to myelodysplastic syndrome (MDS) and therefore must be included in the differential diagnosis when assessing patients with MDS.11 Copper deficiency is associated with both neurologic and hematologic abnormalities.12,13 Although not present in this patient, neurologic symptoms include neuropathy and myeloneuropathy. Typical hematologic manifestations of copper deficiency are neutropenia and anemia. Thrombocytopenia occurs in some but not all cases. Bone marrow examination can reveal hypocellularity, dyserythropoiesis, cytoplasmic vacuolization, and ringed sideroblasts.11–13 The bone marrow aspirate in this case demonstrates dyserythropoiesis, megaloblastic erythroid precursors, and cytoplasmic vacuoles in the erythroid and myeloid precursors (Figure 1). Copper is typically absorbed in the intestines, and copper deficiencies have been described in patients receiving parenteral nutrition, patients who underwent gastric bypass surgery, and patients diagnosed with malabsorptive syndromes. In addition, excess zinc ingestion has been recognized as a cause of copper deficiency.12 Zinc ingestion results in upregulation of metallothionein in enterocytes. Metallothionein binds both copper and zinc but has a much greater affinity for copper. Therefore, copper binds to metallothionein in the enterocyte, thus preventing copper from being absorbed into the bloodstream and resulting in copper being excreted when the enterocyte is sloughed.13 As such, oral copper supplementation cannot replete copper stores as long as zinc continues to be ingested. Discontinuation of zinc alone has been shown to be beneficial and improve cytopenias.12 In cases where zinc ingestion is not a contributing factor, copper repletion can be achieved by either oral or


Benign Hematology: Review Questions intravenous administration. In this patient, treatments for MDS such as epoetin alfa and filgrastim are not warranted. 4. (A) A d-dimer level exceeding 500 ng/mL assessed 4 weeks after discontinuation of anticoagulation is associated with a higher risk of VTE recurrence as compared with a d-dimer level below 500 ng/mL. In general, all patients with a history of an idiopathic VTE are at higher risk for recurrence than patients with provoked VTE.1,14 Patients who have heterozygous mutations in FVL gene or the G20210A prothrombin gene do not have a higher risk for VTE recurrence as compared with individuals who experienced an idiopathic VTE event and do not have these mutations; this risk is equivalent between these patient populations.14,15 Therefore, the presence of such a mutation should not be used to determine length of anticoagulation. A longer duration of anticoagulation beyond the standard 6- to 12-month period is not associated with a lower recurrence risk once therapy is concluded. When anticoagulation is discontinued, the relapse rate steadily increases over time.16 As demonstrated by 1 study of 826 patients who experienced their first VTE and completed anticoagulation, men had a higher VTE recurrence rate (31%) after 5 years of follow-up as compared with women (9%).17 The reasons for this difference are not clear. Since the risk of recurrence is elevated in many patients with idiopathic events, current studies have focused on identifying other markers of risk. Recent data demonstrates that d-dimer level measured using enzyme-linked immunoabsorbent assay 1 month after discontinuation of anticoagulation can be predictive of recurrent VTE.18,19 In patients with a d-dimer level exceeding 500 ng/mL, the risk of recurrence after 1.5 years was 15%, whereas the risk was only 6% if the d-dimer level was normal.19 Additional studies are being conducted to confirm this finding. It should be noted that these data refer only to measurement of d-dimer at 1 specific point in time. Studies are needed to evaluate whether repeat testing of d-dimer levels over time is useful for assessing ongoing risk for recurrent thrombosis. 5. (B) Presence of ADAMTS13 autoantibodies at presentation and persistence of severe ADAMTS13 deficiency at remission is associated with a higher risk of TTP relapse. Idiopathic TTP is a TMA without an obvious precipitating cause. The microvascular thrombi are caused by platelet aggre-

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gation, and they result in the classic findings of microangiopathic hemolytic anemia and thrombocytopenia. Organ dysfunction commonly includes renal failure or neurologic abnormalities (eg, mental status changes, confusion, seizures), although these abnormalities are not present in all cases of TTP. In the past 2 decades, significant progress has been made in understanding the pathophysiology of idiopathic TTP. Ultra large von Willebrand multimers were found to be present in patients with relapsing TTP.20 In 1996, 2 groups described a von Willebrand factor (vWF) cleaving protease that was responsible for cleavage of vWF under shear stress.21,22 This metalloprotease was subsequently named ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1–like domains). Patients with familial and acquired TTP have ADAMTS13 deficiency,21,23 and some patients with acquired TTP have autoantibodies to this metalloprotease.21,22 ADAMTS13 levels have been found to be decreased in several situations where TMA is not present, including sepsis, liver disease, and diffuse intravascular coagulation, although severe deficiency is reportedly found only in TTP.24 Severe ADAMTS13 deficiency has been reported in 30% to 80% of idiopathic TTP cases,25–27 and up to 80% of patients with severe ADAMTS13 deficiency will have a detectable neutralizing autoantibody.26 Yet, deficient activity of ADAMTS13 or the presence of an autoantibody inhibitor does not occur in all cases of idiopathic TTP, and a proportion of patients with idiopathic disease and normal levels of ADAMTS13 will still respond to therapeutic plasma exchange.25,28 At this time, treatment of all cases of idiopathic TTP, regardless of ADAMTS13 activity, should include therapeutic plasma exchange. Severe ADAMTS13 deficiency and autoantibodies may have prognostic significance. TTP patients presenting with high-titer ADAMTS13 neutralizing antibodies have high mortality rates, persistent ADAMTS13 deficiency during remission, and higher relapse rates.27,29 Therefore, an autoimmune etiology appears to be important in this patient subset, and treatment with immunosuppressive therapy appears to be a promising option. Immunosuppressive therapy that has been utilized for these patients includes corticosteroids, rituximab, and cyclosporine. The experience to date with rituximab is published in case series.27 These data demonstrate that rituximab is efficacious in patients with refractory or relapsing TTP, and relapse rates appear to be low after rituximab


Benign Hematology: Review Questions therapy; however, no controlled clinical trials have been completed and rituximab therapy cannot be recommended routinely at this time. An ongoing clinical trial in the United States is being conducted to assess the efficacy of early rituximab therapy in patients presenting with idiopathic TTP. Future treatment recommendations may be guided by the results of such studies. 6. (D) Recombinant factor VIIa 7.2 mg IV. Acquired factor VIII inhibitor presents in patients with a negative history of bleeding and is associated with various medical conditions (eg, pregnancy, autoimmune diseases, malignancies), although many cases are idiopathic.30 Bleeding complications are common and can be life-threatening in 8% to 22% of cases.31 The most common sites of bleeding are mucosal or soft tissue sites, as seen in this case patient. Treatment must include (1) management of any bleeding complications and (2) immunosuppression of the autoantibody. Options for treatment of bleeding depend on severity of the inhibitor as measured by the Bethesda unit (BU) titer.31,32 Appropriate hemostatic agents may include desmopressin, activated prothrombin complex concentrates, or recombinant factor VIIa. Hemostasis occasionally may be achieved with factor VIII products alone when low-titer inhibitors (< 5 BU) are present. In this case, desmopressin or cryoprecipitate is unlikely to be effective given that the patient’s Bethesda titer is 16 BU. Antifibrinolytic therapy with aminocaproic acid would not be effective in achieving hemostasis alone in an intramuscular bleed but can be a useful adjunct in patients with acquired factor VIII inhibitor. Therefore, recombinant factor VIIa is the most appropriate therapy in this patient, and the typical effective dose is 90 µg/kg IV.33 Given the location of the hematoma and potential for development of compartment syndrome, this 80-kg patient should receive a 7.2-mg dose of recombinant factor VIIa. 7. (B) Acquired von Willebrand syndrome. In this patient, the elevated PTT corrected in a 1:1 mixing study, which suggests a factor deficiency. If this patient’s bleeding was caused by an acquired factor VIII inhibitor, the PTT would be expected to prolong after 1-hour incubation.31 The detailed bleeding history then further narrows the differential diagnosis. As this patient’s history does not suggest a congenital bleeding disorder (previous surgeries were unremarkable), hemophilia A and

von Willebrand’s disease type 2N are unlikely. However, this diagnosis should be confirmed. Therefore, vWF antigen and ristocetin cofactor activity ratio (vWF:RCo) were measured in this case. In a patient with mild hemophilia A, the vWF antigen and ristocetin cofactor activity are normal. In patients with type 2N von Willebrand’s disease, the vWF antigen and vWF:RCo would be normal or only mildly decreased.34 Assays of factor VIII-vWF binding may be required to make the diagnosis. In this patient, further testing revealed vWF antigen of 19% and vWF:RCo below 5%, which confirms that an acquired factor VIII inhibitor is not present. Acquired von Willebrand syndrome results from 1 of 3 mechanisms: autoimmune clearance of vWF, increased shear-induced proteolysis of vWF, or increased binding of vWF to platelets or other cells.34,35 The autoimmune etiology is seen in patients with lymphoproliferative disorders, other cancers, or autoimmune diseases such as systemic lupus erythematosus.34 Valvular disorders, particularly aortic stenosis, can result in increased fluid shear stress with subsequent unfolding of vWF multimers and therefore increased proteolysis by ADAMTS13. Repair of the underlying valvular disorder frequently results in correction of the bleeding diathesis. Finally, increased binding of vWF to platelets may be a possible explanation for the bleeding diathesis seen in patients with myeloproliferative disorders.36 The normal level of von Willebrand propeptide, as seen in this case, suggests normal production of vWF antigen but accelerated clearance of the vWF antigen. The von Willebrand multimer profile also should be obtained in evaluation of these patients. Occasionally, the multimer pattern is normal, but frequently large multimers are absent. Treatment of bleeding in patients with acquired von Willebrand syndrome can include desmopressin or vWF/factor VIII concentrates. Intravenous IgG is also effective in about one third of patients with acquired von Willebrand syndrome, although the duration of response is typically only a few weeks.35 8. (C) Vitamin B12 deficiency. This patient has pancytopenia, macrocytosis, indirect hyperbilirubinemia, and decreased reticulocyte count, which are most consistent with severe vitamin B12 deficiency. In both TTP and autoimmune hemolytic anemia, the reticulocyte levels would be elevated. Aplastic anemia does not present with hyperbilirubinemia or severe macrocytosis. Vitamin B12 deficiency typically is a result of impaired absorption or decreased


Benign Hematology: Review Questions intake. If absorption of vitamin B12 ceases, the body has stores sufficient for 3 to 6 years. Vitamin B12 is an essential coenzyme for a variety of important enzymes, including folate-dependent enzymes that are necessary for purine and pyrimidine synthesis. Hematologic manifestations of vitamin B12 deficiency include macrocytic anemia and hypersegmented neutrophils. Due to ineffective erythropoiesis, intramedullary hemolysis occurs and therefore indirect hyperbilirubinemia and elevated lactate dehydrogenase levels can be seen.37 With severe deficiency, pancytopenia can be seen. The hematologic manifestations are reversible with repletion of vitamin B12. 9. (A) Congenital TTP. The laboratory results in this case reveal anemia, thrombocytopenia, indirect hyperbilirubinemia, and reticulocytosis. The peripheral smear demonstrates profound thrombocytopenia and frequent schistocytes (Figure 2), which is consistent with a microangiopathic hemolytic anemia. Therefore, the clinical and laboratory findings are most consistent with the diagnosis of TTP. Congenital TTP, or Upshaw-Schulman syndrome, is a rare disorder that often presents in childhood, but adult cases have been reported.38,39 Patients with congenital TTP have severe ADAMTS13 deficiency that is typically caused by a homozygous or double heterozygous mutation in the ADAMTS13 gene on chromosome 9 (see the answer to question 5 for more information). Treatment for patients diagnosed with congenital TTP includes therapeutic plasma exchange during an acute episode, but relapses are common and can occur at 3-week intervals.38,39 Prophylactic infusion of fresh frozen plasma, which repletes the deficient ADAMTS13 metalloprotease, has been effective in patients to prevent relapses.27,39 The presence of schistocytes on the smear is not consistent with any of the other answers in this question. In cases of autoimmune hemolytic anemia, spherocytes would be the classic finding on peripheral smear.

was normal (> 70%). Glanzmann thrombasthenia is caused by a defect in the glycoprotein IIb/IIIa receptor. Clinical severity is variable, as there is either complete absence (type I) or decreased number (type II) of receptors. The disorder is autosomal recessive, and heterozygote carriers are typically asymptomatic. Therefore, this patient’s lack of family history is typical.41 Treatment of bleeding includes either platelet transfusions and/or antifibrinolytic therapy. Recombinant activated factor VII can also be effective42 but is not approved by the US Food and Drug Administration for this indication. Platelet aggregation curves are distinct for each of the other disorders presented and are not consistent with those presented in Figure 3. Bernard-Soulier syndrome is characterized by absent ristocetin-induced aggregation but normal aggregation to all other agonists. Platelet aggregations studies may be variable in storage pool disorder, but classically there is lack of a secondary wave of aggregation when stimulated by adenosine diphosphate or epinephrine. Finally, low-dose concentrations of ristocetin (0.3–0.6 mg/mL) do not result in platelet aggregation in normal patients, but patients with type 2B von Willebrand’s disease characteristically have platelet aggregation at this dose of ristocetin. Curves for low-dose ristocetin aggregation are not presented in Figure 3.

10. (B) Glanzmann thrombasthenia. Glanzmann thrombasthenia is characterized by abnormal platelet aggregation in response to all agonists, with the exception of ristocetin.40 The platelet aggregation curves presented here (Figure 3) demonstrate no platelet aggregation to adenosine diphosphate, arachidonic acid, or epinephrine. Aggregation to collagen is abnormal (< 50% of normal [normal, > 70%]), whereas ristocetin-induced aggregation

11. (B) Peak anti-Xa levels are similar in nonobese and obese patients when a weight-based LMWH is administered. In patients weighing more than 100 kg, weight-based dosing with a LMWH appears to be effective and safe. Therefore, obesity is not a contraindication to LMWH therapy.43 A pharmacokinetic study of enoxaparin in obese volunteers measured anti-Xa levels during 4 days of therapy with LMWH. After 4 days of therapy, the time to maximum anti-Xa activity was 1 hour longer in obese volunteers (4 hours versus 3 hours in nonobese subjects), but the peak anti-Xa activity was similar in both groups.44 Formal clinical trials have not been conducted to assess the safety or efficacy of LMWH in the obese population, but data from some clinical trials provide evidence of outcomes similar to those of a normal weight cohort. Barba et al45 reviewed data from the Italian Registry (RIETE) from 8845 patients treated for acute VTE that included 294 (3.3%) patients whose weight exceeded 100 kg. The incidence of recurrent VTE, fatal pulmonary embolism, or major bleeding was similar among patients who weighed between 50 and 100 kg and patients whose weight exceeded

10 Hospital Physician Board Review Manual


Benign Hematology: Review Questions 100 kg. In addition, data on efficacy of LMWH in obese patients are available from 2 clinical trials that compared enoxaparin to unfractionated heparin in patients with myocardial infarction.46 The results of this subgroup analysis demonstrated that treatment outcomes and bleeding events were comparable in obese and nonobese patients. The peak weight in the RIETE registry was 160 kg, whereas the cardiac trials included patients up to 158 kg. Further study in this patient population is warranted, but current data support use of LMWH in this population. The advantage of using LMWHs for anticoagulation in patients with VTE include a more reliable and predictable anticoagulant effect due to less binding to plasma protein. Even when algorithms for weight-adjusted unfractionated heparin dosing are employed, only 50% of patients achieve therapeutic levels 24 hours after initiation of the drug.47 In contrast, the peak effect of LMWHs occurs about 4 to 6 hours after the dose is administered.43 The other disadvantages to use of unfractionated heparin include binding to plasma proteins, requirement for hospitalization, frequent monitoring, and higher incidence of heparininduced thrombocytopenia.43 Monitoring of antiXa activity during LMWH therapy may be necessary in special populations, such as those with renal insufficiency or obesity.43 If anti-Xa monitoring is performed, then the level should be drawn when steady state is achieved, which is typically after 3 to 4 doses have been administered. Then, the anti-Xa level should also be drawn 4 to 6 hours after the last dose is administered.

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Kearon C, Kahn SR, Agnelli G, et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6 Suppl):454S–545S. Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006;4: 295–306. Tripodi A. More on: criteria to define the antiphospholipid syndrome [letter]. J Thromb Haemost 2008;6:1049–50. Tripodi A. Laboratory testing for lupus anticoagulants: a review of issues affecting results. Clinical Chem 2007;53:1629–35. Ruiz-Irastorza G, Khamashta MA, Hunt BJ, et al. Bleeding and recurrent thrombosis in definite antiphospholipid syndrome: analysis of a series of 66 patients treated with oral anticoagulation to a target international normalized ratio of 3.5. Arch Intern Med 2002;162:1164–9. Crowther MA, Ginsberg JS, Julian J, et al. A comparison of two in-

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Benign Hematology: Review Questions

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the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 2001;413:488–94. George JN. Clinical insights from observations on ADAMTS13 deficiency in liver cirrhosis. Thromb Haemost 2008;99:987–8. Vesely SK, George JN, Lammle B, et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 2003;102:60–8. Zheng XL, Kaufman RM, Goodnough LT, Sadler JE. Effect of plasma exchange on plasma ADAMTS13 metalloprotease activity, inhibitor level, and clinical outcome in patients with idiopathic and nonidiopathic thrombotic thrombocytopenic purpura. Blood 2004;103:4043–9. Sadler JE. von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 2008;112:11–8. Veyradier A, Obert B, Houllier A, et al. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood 2001;98:1765–72. Ferrari S, Scheiflinger F, Rieger M, et al; Frencg Clinical and Biological Network on Adult Thrombotic Microangiopathies. Prognostic value of anti-ADAMTS 13 antibody features (Ig isotype, titer, and inhibitory effect) in a cohort of 35 adult French patients undergoing a first episode of thrombotic microangiopathy with undetectable ADAMTS 13 activity. Blood 2007;109:2815–22. Green D, Lechner K. A survey of 215 non-hemophilic patients with inhibitors to factor VIII. Thromb Haemost 1981;45:200–3. Ma AD, Carrizosa D. Acquired factor VIII inhibitors: pathophysiology and treatment. Hematology Am Soc Hematol Educ Program 2006:432–7. Aggarwal A, Grewal R, Green RJ, et al. Rituximab for autoimmune haemophilia: a proposed treatment algorithm. Haemophilia 2005; 11:13–9. Hay CR, Negrier C, Ludlam CA. The treatment of bleeding in acquired haemophilia with recombinant factor VIIa: a multicentre study. Thromb Haemost 1997;78:1463–7. Nichols WL, Hultin MB, James AH, et al. von Willebrand disease (VWD): evidence-based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA). Haemophilia 2008;14:171–232. Federici AB, Rand JH, Bucciarelli P, et al; Subcommittee on von Willebrand factor. Acquired von Willebrand syndrome: data from an international registry [published erratum appears in Thromb Haemost 2000;84:739]. Thromb Haemost 2000;84: 345–9.

36. van Genderen PJ, Budde U, Michiels JJ, et al. The reduction of large von Willebrand factor multimers in plasma in essential thrombocythaemia is related to the platelet count. Br J Haematol 1996;93:962–5. 37. Hartong SC, Steegers EA, Visser W. Hemolysis, elevated liver enzymes and low platelets during pregnancy due to vitamin B12 and folate deficiencies [letter]. Eur J Obstet Gynecol Reprod Biol 2007;131:241–2. 38. Moake JL. Thrombotic microangiopathies. N Engl J Med 2002; 347:589–600. 39. George JN, Sadler JE, Lämmle B. Platelets: thrombotic thrombocytopenic purpura. Hematology Am Soc Hematol Educ Program 2002:315–34. 40. Hayward CP. Diagnostic approach to platelet function disorders. Transfus Apher Sci 2008;38:65–76. 41. Handin RI. Inherited platelet disorders. Hematology Am Soc Hematol Educ Program 2005:396–402. 42. Poon MC, D’Oiron R, Von Depka M, et al; International Data Collection on Recombinant Factor VIIa and Congenital Platelet Disorders Study Group. Prophylactic and therapeutic recombinant factor VIIa administration to patients with Glanzmann’s thrombasthenia: results of an international survey. J Thromb Haemost 2004;2:1096–103. 43. Hirsh J, Bauer KA, Donati MB, et al. Parenteral anticoagulants: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6 Suppl):141S– 159S. 44. Sanderink GJ, Le Liboux A, Jariwala N, et al. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers. Clin Pharmacol Ther 2002;72:308–18. 45. Barba R, Marco J, Martin-Alvarez H, et al; RIETE investigators. The influence of extreme body weight on clinical outcome of patients with venous thromboembolism: findings from a prospective registry (RIETE). J Thromb Haemost 2005;3:856–62. 46. Spinler SA, Inverso SM, Cohen M, et al; ESSENCE and TIMI 11B Investigators. Safety and efficacy of unfractionated heparin versus enoxaparin in patients who are obese and patients with severe renal impairment: analysis from the ESSENCE and TIMI 11B studies. Am Heart J 2003;146:33–41. 47. Becker RC, Ball SP, Eisenberg P, et al. A randomized, multicenter trial of weight-adjusted intravenous heparin dose titration and point-of-care coagulation monitoring in hospitalized patients with active thromboembolic disease. Antithrombotic Therapy Consortium Investigators. Am Heart J 1999;137:59–71.

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12 Hospital Physician Board Review Manual
