Question 1

A 38-year-old white woman comes to your outpatient clinic after returning from a 4-week trip to Patagonia. She complains of persistent shortness of breath, which she has been experiencing since her return 2 days ago. The flight back to the United States was 9 hours long. She reports experiencing mild shortness of breath while in Patagonia. She attributed it to increased exercise (hiking) and the high altitude. She takes atenolol, 25 mg q.d., for mild hypertension. Results of physical examination are as follows: temperature, 99.0° F (37.2° C); respiratory rate, 26 breaths/min; heart rate, 95 beats/min; and blood pressure, 122/78 mm Hg. The lungs are clear. The heart rate and rhythm are regular, and there is no murmur, rub, or gallop. A chest x-ray is clear. Results of a D-dimer assay are positive. The patient's ventilation-perfusion scan is positive. Laboratory work to assess for thrombophilia is sent.

Please choose the single most appropriate answer to the question

1. A family history that includes a grandmother with a history of deep vein thrombosis after hip replacement surgery at 80 years of age
   
   Sorry, this is incorrect. Try again!
   
   
2. A family history that includes a father with a history of skin necrosis after treatment with warfarin for atrial fibrillation at 48 years of age
   
   This is correct.
   
   

   Key Concept/Objective: To understand the importance of the patient's medical history and family history in the assessment of thrombotic risk

   
   

   Most commonly, thromboses involve the deep veins of the lower extremities. Thrombosis at an atypical site, such as the hepatic, mesenteric, or cerebral veins (or skin necrosis after warfarin administration), increases the likelihood of an underlying hypercoagulable state. Objectively documented venous thromboembolism before 50 years of age in a first-degree family member strongly suggests a hereditary thrombotic disorder. Common triggers of thrombosis are surgery, trauma, pregnancy, malignancy, prolonged immobilization, and infection. Those circumstances can provoke thrombosis even in persons with a normal coagulation system. In acute thrombosis, many inhibitors of the clotting cascade (e.g., antithrombin and protein C) are consumed. Immediately after the episode, plasma levels may be decreased, even in patients who do not have a hereditary deficiency.
   
   

   
   
   
3. An abnormally low protein C level, with blood drawn today
   
   Sorry, this is incorrect. Try again!
   
   
4. A positive ?-human chorionic gonadotropin (?-hCG) test, with blood drawn today
   
   Sorry, this is incorrect. Try again!
   
   

Question 2

A 28-year-old African-American woman presents to your clinic complaining of unilateral lower extremity swelling, which began 3 days ago. Her medications include a multivitamin with folic acid. On examination, the patient's right lower extremity is warm, and there is pitting edema to the knee. Her right calf is 3 cm larger than her left calf. A right lower extremity Doppler ultrasound reveals a nonocclusive thrombus in her right common femoral vein. She is treated acutely with low-molecular-weight heparin (LMWH), followed by warfarin therapy.

Please choose the single most appropriate answer to the question

1. She should be tested for both the heterozygous and the homozygous forms of antithrombin deficiency
   
   Sorry, this is incorrect. Try again!
   
   
2. She should not be tested for factor V Leiden, because the defect is almost absent in nonwhite ethnic groups
   
   Sorry, this is incorrect. Try again!
   
   
3. She should be tested for the mutation in methylene-tetrahydrofolate reductase (MTHFR) that leads to hyperhomocysteinemia, because she reports eating an average American diet
   
   Sorry, this is incorrect. Try again!
   
   
4. She should be tested for protein C and S deficiencies after the acute event has resolved and when she is no longer on warfarin therapy
   
   This is correct.
   
   

   Key Concept/Objective: To be able to recognize the most common heritable hypercoagulable states

   
   

   Functional and antigenic assays for protein C and protein S are preferable for diagnosis of deficiency. Warfarin reduces protein C and S levels because these are vitamin K- dependent factors. These assays should not be used in patients with acute thrombosis, because many inhibitors of the clotting cascade are consumed during this time. Antithrombin deficiency is transmitted in an autosomal dominant pattern. Homozygous antithrombin deficiency has not been reported, presumably because the condition is incompatible with normal fetal development. Factor V Leiden is now considered the most common hereditary hypercoagulable state. Its prevalence in patients with thrombophilia is as high as 20% to 50%. Approximately 5% of the general white population are heterozygous for factor V Leiden; the defect is very low in nonwhite ethnic groups. However, citizens of the United States often have diverse ethnic heritages; therefore, it is inappropriate to exclude testing for factor V Leiden testing on the basis of ethnicity. Hyperhomocysteinemia may be secondary to a defect in the remethylation pathway resulting from a thermolabile mutant of the MTHFR enzyme. The homozygous MTHFR mutation has a prevalence of 5% in the general population. However, the homozygous form of the MTHFR thermolabile enzyme isoform is not clinically relevant in patients whose diet includes adequate folate.
   
   

   
   
   

Question 3

A 32-year-old white woman with systemic lupus erythematosus presents to your clinic with a painful great toe. She reports a history of two first-trimester miscarriages and a second-trimester miscarriage. Her medications include plaquenil and prednisone. On examination, the patient's toe is pale and cool, and there is a 1 cm ulcer at the tip.

Please choose the single most appropriate answer to the question

1. Lupus anticoagulant is an antiphospholipid antibody associated with an abnormally shortened activated partial thromboplastin time (aPTT)
   
   Sorry, this is incorrect. Try again!
   
   
2. The majority of patients with antiphospholipid antibodies and thrombosis present with venous thromboses
   
   This is correct.
   
   

   Key Concept/Objective: To be able to recognize the common antiphospholipid antibody syndromes and their clinical and serologic presentations

   
   

   Thrombotic events occur in approximately 30% of patients with antiphospholipid antibodies. Thirty-seven percent of patients present with venous thrombosis, 27% with arterial thrombosis, 15% with both venous and arterial thrombosis, and 12% with fetal loss only. The general criteria for the diagnosis of lupus anticoagulant are (1) prolongation of at least one phospholipid-dependent clotting assay (i.e., aPTT), (2) proof, by mixing studies, that the prolongation is caused by an inhibitor and not a clotting factor deficiency, and (3) confirmation that the inhibitor is phospholipid dependent. The clotting tests commonly used are aPTT and dilute Russell viper venom time. High titers of anticardiolipin IgG antibodies (> 33 IgG phospholipid [GPL] units) are associated with an approximately fivefold increase in overall thrombotic risk. The importance of low titers of IgG antibodies (< 20 GPL), isolated IgM antibodies, and IgA antibodies has not been established. Antiphospholipid antibodies should be measured in patients with a history of unexplained second- or third-trimester loss, fetal demise, early-onset severe preeclampsia, and intrauterine growth retardation. In contrast, antiphospholipid antibodies are not associated with sporadic early pregnancy loss, which is frequently the result of genetic abnormalities in the fetus.
   
   

   
   
   
3. An increased thrombotic risk is associated with anticardiolipin IgM antibodies
   
   Sorry, this is incorrect. Try again!
   
   
4. Antiphospholipid antibodies are associated with early (first-trimester) miscarriage
   
   Sorry, this is incorrect. Try again!
   
   

Question 4

A 76-year-old African-American man undergoes elective four-vessel coronary artery bypass grafting (CABG). On day six after surgery, his platelet count is found to be 150,000/µl, which is down from the previous day's count of 350,000/µl. His hospital medications include metoprolol, 50 mg q.d., and unfractionated heparin, 5,000 units S.C., t.i.d. On examination, the patient is afebrile. His blood pressure is 132/67 mm Hg; his pulse is 65 beats/min; and his respiratory rate is 16 breaths/min. Cardiac examination reveals an irregularly irregular rhythm. His chest wound is 10 cm long, with staples; it is clean, dry, and intact. His saphenous vein retrieval site is also clean, dry, and intact, with staples. Further laboratory testing reveals the presence of heparin platelet antibodies.

Please choose the single most appropriate answer to the question

1. He should be switched from unfractionated heparin to LMWH because LMWH rarely causes heparin-induced thrombocytopenia (HIT)
   
   Sorry, this is incorrect. Try again!
   
   
2. He can continue taking heparin because, with a platelet count of 150,000/µl, he is not technically thrombocytopenic
   
   Sorry, this is incorrect. Try again!
   
   
3. He can continue taking heparin because false positive HIT laboratory values are common after CABG
   
   Sorry, this is incorrect. Try again!
   
   
4. He should be switched from unfractionated heparin to an alternative anticoagulant agent such as lepirudin, argatroban, or fondaparinux because these agents are not associated with HIT
   
   This is correct.
   
   

   Key Concept/Objective: To know the clinical signs of HIT and the appropriate treatment

   
   

   Management of HIT consists of stopping heparin immediately and starting alternative anticoagulation therapy; alternative anticoagulant agents include lepirudin, argatroban, and fondaparinux. Although LMWH is much less immunogenic than unfractionated heparin in causing HIT, it cannot be used as a safe substitute when a patient develops HIT caused by unfractionated heparin. LMWH and unfractionated heparin have extensive cross-reactivity (> 90%) in terms of antibody recognition. LMWH is not an appropriate choice in patients with HIT. HIT typically develops 5 to 10 days after the initiation of heparin therapy. HIT is generally defined as a platelet count below 150 ( 109/L or a drop in the platelet count by more than 50% from the postoperative peak, occurring 5 to 14 days after starting heparin. An HIT seroconversion rate as high as 50% has been reported in patients undergoing cardiopulmonary bypass surgery, limiting its usefulness in that situation; however, diagnosis of HIT should be based primarily on clinical findings.