The following cases and commentary, which address thromboembolic disease, are excerpted from ACP's Medical Knowledge Self- Assessment Program (MKSAP14).
Case 1: pulmonary embolism and cancer
A 58-year-old woman is diagnosed with bilateral pulmonary emboli and metastatic uterine adenocarcinoma to the liver. Two years ago, she had a right lower-extremity deep venous thrombosis at the time of her diagnosis of stage II uterine cancer. She underwent anticoagulation therapy with warfarin for 6 months following surgery.
After an initial 7-day course of low-molecular-weight heparin, which of the following is the most appropriate for preventing recurrent venous thromboembolism in this patient?
A. Transition to warfarin with a target INR of 2 to 3
B. Transition to warfarin with a target INR of 3 to 4
C. Continue low-molecular-weight heparin
D. Place an inferior vena cava filter
Case 2: factor V Leiden mutation
A 46-year-old woman (G0P0) is evaluated for follow-up monitoring of pulmonary emboli that developed 13 months ago. The thrombotic event was unprovoked, and anticoagulation was discontinued after 6 months of therapy. The family history is negative for thrombosis.
Genetic analysis performed 3 weeks after the discontinuation of warfarin therapy indicated that she is heterozygous for the factor V Leiden mutation. Five weeks after therapy was discontinued, the patient experienced left lower-extremity pain and swelling in the absence of transient risk factors. A nonocclusive thrombus in the popliteal vein was shown on ultrasonography for which she underwent anticoagulation therapy with lowmolecular- weight heparin followed by warfarin for 6 months.
Which of the following is the most appropriate management of this patient's thrombophilic disorder?
A. Long-term warfarin at a target INR of 2 to 3
B. Long-term warfarin at a target INR of 1.5 to 2
C. Discontinuation of warfarin
D. Daily aspirin therapy
Case 3: post-myocardial infarction
A 55-year-old man was admitted to the hospital with a myocardial infarction. Cardiac catheterization showed an isolated 95% stenosis in the left anterior descending artery for which he underwent a percutaneous intervention with stent placement. His medical regimen will include a β-blocker, a statin, an ACE inhibitor, aspirin 325 mg/d, and clopidogrel for 6 months. His history is significant for a single episode of deep venous thrombosis of the right lower extremity that occurred when he was 40 years of age and was treated with anticoagulant therapy for 6 months. The patient had no known coronary risk factors prior to the myocardial infarction.
Results of a hypercoagulable panel indicate that he is heterozygous for the factor V Leiden mutation.
Which of the following is the most appropriate next step in management of this patient?
A. No change in therapy
B. Add warfarin at a target INR of 2 to 3 to current antiplatelet regimen
C. Add warfarin at a target INR of 3 to 4
D. Add warfarin at a target INR of 3 to 4 and discontinue aspirin and clopidogrel
E. Add warfarin at a target INR of 2 to 3 and discontinue aspirin and clopidogrel
Case 4: pneumonia and history of thrombocytopenia
A 72-year-old man is hospitalized with pneumonia and treated with intravenous antibiotics. His medical history is significant for a right hip replacement 1 year ago, complicated by heparin-induced thrombocytopenia and subsequent deep venous thrombosis in his left popliteal vein. He takes no regular medications.
Which of the following is the most appropriate next step in reducing this patient's risk for venous thromboembolism?
A. Enoxaparin, 40 mg subcutaneously daily
B. Aspirin, 325 mg daily
C. Warfarin adjusted to an INR of 3.5
D. Intermittent pneumatic compression
Case 5: dyspnea after ophthalmologic surgery
A 46-year-old man is evaluated in the emergency department with a 1-day history of progressive dyspnea and nonproductive cough. He does not have hemoptysis, chest pain, or leg discomfort, and no personal or family history of cancer or clotting episodes. He had outpatient ophthalmologic surgery under local anesthesia last week. His medical history includes mild asthma and impaired glucose tolerance, which is controlled by diet. His only medication is a topical optic analgesic.
On physical examination, he is dyspneic and appears anxious; the temperature is 37.6° C (99.8° F), blood pressure 150/89 mm Hg, heart rate 110/min, and respiration rate 24/min. Cardiac examination discloses tachycardia without murmurs of gallops or evidence of jugular venous distention. Examination of the lungs discloses faint bilateral expiratory wheezes, without rhonchi or rales; the hemi-diaphragms descend normally during inhalation. The abdomen is normal. Extremities are not swollen, nonedematous, nontender, and not cyanotic.
Chest radiograph is normal; electrocardiogram shows tachycardia. Measurement of arterial blood gases with the patient breathing room air show Po2 93 mm Hg, Pco2 36 mm Hg, and pH 7.45. The D-dimer level is 200 mg/dL (normal <250 mg/dL).
Which of the following would most effectively determine the clinical likelihood of this patient's having a pulmonary embolism?
A. Obtaining the report of the patient's ophthalmologic surgery
B. Measuring hemoglobin A1C
C. Determining the effect of bronchodilators on the patient's signs and symptoms
D. Repeating D-dimer after one therapeutic dose of low-molecular- weight heparin
Case 6: anticoagulation before chest tube insertion
A 24-year-old man injures his right leg and the left side of his chest in a motor vehicle accident and is hospitalized. The day after admission he develops worsening pain in the affected leg. An ultrasound shows a deep venous thrombosis in the leg, and therapy with intravenous heparin is begun. The following day he develops left-sided chest pain, and CT scan shows a sub-segmental pulmonary embolism in the right lower lobe. In addition, a moderate-sized pneumothorax is detected on the left side, and the decision is made to insert a chest tube.
Which one of the following anticoagulant regimens would allow the chest tube to be placed most safely?
A. Enoxaparin 1.5 mg/kg subcutaneously, with last dose 6 hours before chest tube insertion
B. Dalteparin, 200 units/kg subcutaneously, with last dose 6 hours before chest tube insertion
C. Fondaparinux, 5 mg subcutaneously, last dose 6 hours before chest tube insertion
D. Continue intravenous heparin, hold infusion for 6 hours before chest tube insertion
Case 7: acute shortness of breath after flight
A 45-year-old man is evaluated in the emergency department for acute shortness of breath with right-sided chest pain. He also has a dry cough with scanty blood streaking of his phlegm. He is a nonsmoker and has no other past medical illnesses; he has just returned by airplane from Japan.
On physical examination his temperature is 37.4° C (99.4° F), blood pressure is 102/76 mm Hg, pulse rate is 98/min, and respiration rate is 32/min. Breath sounds are marginally decreased on the right side with vocal fremitus. There are no rhonchi. The pulmonary component of the second heart sound is accentuated. He feels soreness in the left calf and has trace left ankle edema. All peripheral pulses are intact.
Compression ultrasonography of the lower extremities is positive for the presence of deep vein thrombosis. A follow-up spiral CT scan of the chest confirms the presence of pulmonary emboli and a small right-sided pleural effusion. The patient is hospitalized and therapy with fractionated heparin and warfarin is started. On day 3, the prothrombin time is 14.7 sec; INR is 1.6. Chest radiograph at this time shows a stable right-sided pleural effusion occupying about one fourth of the right hemithorax. Ultrasound guided aspiration of the right pleural effusion is performed.
Laboratory studies are as follows:
- Cell count: Erythrocyte count 100,000/μL (100 × 109/L); leukocyte count 465/μL (0.465 × 109/L) with 70% neutrophils, 25% lymphocytes, 2% mesothelial, and 3% eosinophils.
- Total protein: 3.5 mg/dL (35 g/L)
- Lactate dehydrogenase: 400 U/L
- Glucose: 75 mg/dL (4.16 mmol/L)
- pH: 7.45
Gram stain of pleural fluid shows no organisms.
Which of the following is the most appropriate next step in management?
A. Discontinue heparin, continue warfarin
B. Discontinue warfarin
C. Continue warfarin and heparin till INR is therapeutic, and then discontinue heparin
D. Discontinue both heparin and warfarin
E. Place an inferior vena cava filter
Case 8: post-partum pulmonary embolism
A 23-year-old woman develops dyspnea and dizziness 2 days after a normal spontaneous vaginal delivery of a healthy child. Her urine output has been less than 20 mL/h for the past 3 hours. On physical examination, the temperature is 37.2° C (99.0° F), blood pressure 80/60 mm Hg, heart rate 125/min, and respiration rate 22/min. The lungs are clear to auscultation. Cardiac examination reveals a fixed split S2, and jugular venous distention. The abdomen and pelvis are soft and nontender. After infusion of 1500 mL of 0.9% saline, the blood pressure is 98/67 mm Hg, the heart rate is 105/min, and she produces 80 mL of urine over the next hour.
Ventilation/perfusion scan shows large unmatched perfusion defects corresponding to the entire right lower lobe, half of the right middle lobe, and the entire left lower lobe. Echocardiogram shows evidence of right ventricular strain. A lower extremity ultrasound shows a noncompressible left superficial femoral vein and left common femoral vein.
In addition to immediate anticoagulation, which of the following therapies would most likely prevent recurrence of pulmonary embolism in the subsequent week?
A. Cardiopulmonary bypass and surgical embolectomy
B. Tissue plasminogen activator
C. Catheter-guided direct removal of the emboli from the pulmonary arteries
D. Immediate insertion of an inferior vena cava filter
Answers and commentary
Correct answer: C. Continue low-molecular-weight heparin
Patients with acute venous thromboembolism in association with metastatic cancer are at higher risk for recurrent venous thrombosis than those without malignancy. In such patients, it has been demonstrated that chronic low-molecular-weight heparin at therapeutic doses reduces the risk for “on treatment” recurrence by approximately 50% at 6 months when compared with standard-intensity anticoagulant therapy (target INR, 2 to 3).
High-intensity warfarin (target INR, 3 to 4) would not be appropriate in this setting because it has not been shown to be more efficacious in preventing recurrent thrombosis than standard- intensity warfarin (target INR, 2 to 3); retrospective studies have also shown that patients with venous thrombosis and active cancer are at increased risk for major bleeding while receiving standard-intensity warfarin.
Placement of an inferior vena cava (IVC) filter in patients with venous thrombosis without anticoagulation is associated with an increased risk for recurrent venous thrombosis; IVC filter placement is generally reserved for patients at high risk for recurrent thrombosis who have sustained major bleeding and cannot undergo anticoagulation.
- Patients with acute venous thromboembolism and metastatic cancer are at higher risk for recurrent venous thrombosis than those without malignancy.
- Chronic low-molecular-weight heparin at therapeutic doses reduces the risk for thrombotic recurrence compared with standard-intensity warfarin in patients with venous thromboembolism and cancer.
Correct answer: A. Long-term warfarin at a target INR of 2 to 3
Although heterozygosity for the factor V Leiden mutation is a risk factor for the development of an initial episode of venous thrombosis, the risk for recurrent venous thrombosis in such a patient is not greater than that in those without an underlying thrombophilic abnormality.
Given that she developed two unprovoked venous thrombotic events over a relatively short period and the absence of risk factors that increase her risk for bleeding during warfarin therapy, this patient should receive long-term warfarin therapy at a target INR of 2 to 3. Although a target INR of 1.5 to 2 has been shown to have efficacy in preventing recurrent venous thrombosis, it is not as efficacious as a target INR of 2 to 3, and the risk for major bleeding is similar for the two target INR ranges. Discontinuing warfarin therapy would not be appropriate because of her high risk for recurrent thrombosis. Aspirin has not been shown to have efficacy in the secondary prevention of venous thromboembolism.
- The risk for recurrent venous thrombosis in patients with the factor V Leiden mutation is not greater than that in those without an underlying thrombophilic abnormality.
- Patients at high risk for recurrent thrombosis should receive long-term anticoagulation therapy with warfarin.
Correct answer: A. No change in therapy
The hereditary thrombophilias, including the prothrombin G20210A mutation, have clearly been shown to predispose patients only to venous thromboembolism. This patient has arterial thrombosis and had a myocardial infarction for which he underwent stent placement; he will require aspirin and clopidogrel for at least 6 months; therefore, no change in his medication regimen is required.
The presence of the factor V Leiden mutation and distant history of venous thrombosis should not affect his antithrombotic management, and there is no indication in this patient for anticoagulation therapy with warfarin at this time. It would be appropriate to consider adding warfarin at an INR of 2 to 3 to the antiplatelet regimen if the patient were also in atrial fibrillation or warfarin at an INR of 2.5 to 3.5 if he had a prosthetic heart valve. However, neither of these scenarios is applicable in this case, and warfarin is therefore not required. The combination of aspirin and clopidogrel confers an increased risk for major bleeding when compared with the risk associated with each of these agents alone; the addition of warfarin to these two drugs would increase the hemorrhagic risk even further. An increased risk for myocardial infarction has been reported in young female smokers who are heterozygous for factor V Leiden. Other hypercoagulable states that are associated with arterial thrombosis are the antiphospholipid antibody syndrome and hyperhomocystinemia.
Correct answer: D. Intermittent pneumatic compression
Although the clinical evidence for reducing risk for venous thromboembolism with intermittent pneumatic compression is not as strong as that for heparin and low-molecular-weight heparin, it carries a very low risk of adverse effects and has been associated with substantial reductions in the incidence of embolism in populations at risk. Intermittent pneumatic compression is recommended for patients at moderate to high risk in whom heparin and low-molecular-weight heparin are contraindicated.
This patient's history of heparin-induced thrombocytopenia with thrombosis (HITT) is a contraindication for the use of heparin and all low-molecular-weight heparins, because the antibodies that cause HITT cross-react with both medication classes. Warfarin has not been as well studied for prophylaxis in medical patients, but there is no evidence to support the use of high-dose warfarin in therapy for venous thrombosis, let alone for prophylaxis. Aspirin alone is not recommended for prophylaxis against venous thrombosis. The left popliteal vein would have about a 50% chance of showing some residual noncompressibility on ultrasound, even a year after treatment. The ultrasound findings described would not necessarily indicate the presence of a new venous thrombosis, especially in the absence of symptoms.
- Intermittent pneumatic compression is effective prophylaxis in patients at moderate to high risk for venous thrombosis in whom heparin and low-molecular-weight heparin are contraindicated.
- D-dimer reflects the presence of thrombosis (or inflammation), but does not reflect the activity of thrombosis.
Correct answer: C. Determining the effect of bronchodilators on the patient's signs and symptoms
The likelihood of pulmonary embolism after a negative CT scan is determined by the negative likelihood ratio of the scan as well as the pretest likelihood of pulmonary embolism. This patient with dyspnea has no specific symptoms, family history, or physical examination findings that suggest pulmonary embolism. The patient has expiratory wheezing on examination and a history of asthma; therefore, resolution of the dyspnea and physical findings after administration of bronchodilators would provide strong evidence of an asthma exacerbation as the cause of his symptoms and thereby decrease the likelihood of his having pulmonary embolism.
The extent of the patient's recent ophthalmologic surgery may affect the risk/benefit relationship of anticoagulation. However, there is no evidence that a more extensive surgery (done under local anesthesia for a relatively brief time) would substantially influence the probability for pulmonary embolism. An elevated hemoglobin A1C may reflect recent episodes of hyperglycemia due to his diabetes, but wouldn't indicate an elevated risk for venous thromboembolism.
The D-dimer fragment is shed into the blood when crosslinked fibrin, present within thrombi and within many areas of inflammation, is digested by fibrinolytic enzymes. D-dimer reflects the presence of thrombosis (or inflammation), but does not reflect the activity of thrombosis and would not decrease acutely in response to anticoagulation.
- Factor V Leiden mutation is associated with venous, not arterial, thromboses.
Correct answer: D. Continue intravenous heparin, hold infusion for 6 hours before chest tube insertion
The patient has symptomatic venous thromboembolism and would likely benefit from immediate anticoagulation. Heparin, the low-molecular-weight heparins and fondaparinux all enhance the activity of antithrombin, which has the immediate effect of neutralizing activated clotting enzymes such as factor Xa and (in the case of heparin and low-molecular-weight-heparin) thrombin. In the case of intravenous heparin, the onset of action is immediate and has a half-life of under an hour after discontinuation. However, the low-molecular-weight heparins and fondaparinux become effective within about a half hour of subcutaneous administration, and the effect lasts throughout much of the subsequent day. The long duration of effect makes the subcutaneous more convenient to administer, but would necessitate a longer delay between the last dose and any planned invasive procedures.
Warfarin interferes with the final step of synthesis of clotting enzymes (thrombin and factors VII, IX and X). It has no immediate effect on clotting enzymes that are already in the blood (or within a thrombus). Therefore, warfarin is not recommended as the sole immediate treatment for venous thrombosis. Vitamin K counteracts the inhibitory effect of warfarin, allowing clotting factor production to resume. Clinical reversal of anticoagulation, however, would take several hours to begin.
- Intravenous heparin has immediate onset of action and has a half-life of under an hour after discontinuation.
- Low-molecular-weight heparins and fondaparinux have onset of action within about a half hour of subcutaneous administration, and the effect lasts throughout much of the subsequent day.
Case 7 Correct answer: C. Continue warfarin and heparin till INR is therapeutic, and then discontinue heparin
The INR in this patient is not yet therapeutic, and therefore, the warfarin dose needs to be adjusted and the patient requires ongoing anticoagulation that relies on continuation of heparin. The patient's acute presentation following a prolonged air trip is not uncommon in this era of long-distance travel. The mechanism of effusion formation in pulmonary embolism involves both increased hydrostatic pressure in the pulmonary circulation and increased permeability in the visceral pleural vasculature. Approximately 80% of effusions associated with pulmonary emboli are therefore exudative. They are also usually small (<1/3 of the hemithorax) and unilateral and tend not to be progressive. The effusion in pulmonary embolism usually does not persist beyond 7 to 10 days after formation in the presence of underlying embolism.
The presence of a sanguineous or bloody effusion (erythrocyte count >100,000 cells/μL [100 × 109/L]) associated with pulmonary emboli is not a contraindication to anticoagulant therapy. If a pleural effusion clearly increases in size during anticoagulant therapy, the development of hemothorax or an underlying infection should be excluded by thoracentesis. Insertion of an inferior vena cava filter should also be considered in such patients; however, in this patient anticoagulation should be maintained and placement of a vena cava filter is not indicated as the next management step in this case.
- Approximately 80% of effusions associated with pulmonary emboli are exudative, usually small and unilateral, and tend not to be progressive or to persist beyond 7 days after formation.
Correct answer: D. Immediate insertion of an inferior vena cava filter
All four options are reasonable approaches to prevent death resulting from hemodynamically significant pulmonary embolism, and none of them has been shown to be superior in randomized clinical trials. However, insertion of an inferior vena cava filter has been shown to reduce the short-term incidence of pulmonary embolism in patients who are being anticoagulated for deep venous thrombosis, and may, in this case, prevent a devastating recurrent embolization.
Cardiopulmonary bypass and surgical embolectomy will remove the proximally located pulmonary emboli, but will not prevent further embolization. It must be performed by experienced surgical teams that can be rapidly mobilized. Even under these circumstances, embolectomy carries significant risks of morbidity and mortality. Thrombolytic therapy may decrease the size of the emboli and reduce right heart strain more rapidly than that which occurs with anticoagulation alone. However, there is no evidence that such therapy would protect the lungs from embolization of preexisting lower extremity thrombi.
Furthermore, thrombolytic therapy carries a significant risk of serious bleeding and may not, in the long run, resolve emboli more completely than would therapy with heparin alone. Catheter-guided direct emboli removal has been performed successfully in a few specialized centers, but it has not been widely adopted for treatment of pulmonary embolism. It would not decrease the risk of emboli from the left leg thromboses.
- Insertion of an inferior vena cava filter reduces the short-term incidence of pulmonary embolism in patients being anticoagulated for deep venous thrombosis.