Case 1: Pulmonary emboli
A 46-year-old woman with no history of pregnancy is evaluated for follow-up monitoring of pulmonary emboli that developed 13 months ago. The thrombotic event was unprovoked, and anticoagulation was discontinued after six months of therapy. The family history is negative for thrombosis.
Genetic analysis performed three 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 low-molecular-weight heparin followed by warfarin for six 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 2: 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 ß-blocker, a statin, an angiotensin-converting enzyme inhibitor, aspirin (325 mg/d) and clopidogrel for six months.
The patient's 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 six 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 3: Sinus thrombosis
A previously healthy 40-year-old man is hospitalized for a sagittal sinus thrombosis after presenting with a five-day history of nausea, vomiting and lethargy. Laboratory studies indicate a normal prothrombin time and an activated partial thromboplastin time (aPTT) of 50 seconds. The presence of a lupus anticoagulant is confirmed, and the serum cardiolipin IgG antibody concentration is elevated at 43 U/mL (reference range, <16 U/mL), with a normal serum IgM antibody concentration. The patient undergoes anticoagulation therapy with unfractionated heparin followed by warfarin. One month later, the INR is 3.0, aPTT is 70 seconds, and repeated serum cardiolipin antibody IgG concentration is 35 U/mL.
Which of the following is the most appropriate antithrombotic therapy and target INR for this patient?
A. Warfarin with a target INR of 2 to 3 and daily aspirin
B. Warfarin with a target INR of 3 to 4
C. Warfarin with a target INR of 2 to 3
D. Warfarin with a target INR of 2 to 3 and clopidogrel
Case 4: Pregnancy
A 24-year-old woman with a mechanical bileaflet aortic valve prosthesis presents 14 weeks after her last menstrual period. A pregnancy test is positive. She takes 4 mg of warfarin daily to maintain her INR between 2 and 3.
Which is the most appropriate therapy to prevent valve thrombosis at this point in the patient's pregnancy?
A. Continue warfarin to maintain an INR of 2 to 3
B. Replace warfarin with aspirin, 325 mg daily
C. Replace warfarin with subcutaneous unfractionated heparin, 5000 U twice daily
D. Add clopidogrel, 75 mg daily, to current warfarin dose
E. Increase warfarin to maintain an INR of 3 to 4
Case 5: Pre-surgery
A 59-year-old man undergoes cardiac evaluation prior to radical prostatectomy for recently diagnosed prostate cancer. Two years ago, he received a diagnosis of symptomatic aortic stenosis and underwent aortic valve replacement with a bileaflet tilting disk valve.
Since his valve replacement, the patient has done very well. He has no angina, exertional dyspnea, palpitations, syncope or symptoms of congestive heart failure. His current medications include warfarin and a low-dose angiotensin-converting enzyme inhibitor.
The only significant findings on physical examination are a nonradiating grade 2/6 systolic murmur heard over the left upper sternal border and a mechanical S2 on auscultation of his heart.
Which preoperative recommendation regarding management of this patient's anticoagulation regimen is the most appropriate?
A. Continue warfarin through the surgery without interruption
B. Discontinue warfarin three days prior to surgery
C. Give 5 mg of oral vitamin K on the day of surgery
D. Start full-dose aspirin in lieu of warfarin three days prior to surgery
E. Start intravenous heparin and discontinue warfarin three days prior to surgery
Case 6: Post-surgery
A 62-year-old woman is evaluated after total knee replacement surgery complicated by postoperative pneumonia. She is now beginning to ambulate. While she was bedridden, a sequential compression device was used for prophylaxis of deep venous thrombosis. The patient is overweight.
Now that she is ambulating, which of the following is the best approach to ongoing prophylaxis during hospitalization?
A. Standard support hose, in bed and ambulating
B. Sequential compression device while in bed
C. High-dose low-molecular-weight heparin
D. High-dose unfractionated heparin
E. Warfarin with a target INR of 1.5 to 2.0
Answers and commentary
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 six 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 hyperhomocysteinemia.
- Factor V Leiden mutation is associated with venous, not arterial, thromboses.
Correct answer: C. Warfarin with a target INR of 2 to 3.
This patient has the antiphospholipid antibody syndrome characterized by cerebral venous thrombosis associated with a persistently elevated serum cardiolipin IgG antibody concentration. Although a lupus anticoagulant was detected on initial presentation, the test was not repeated at one month when he was still receiving warfarin because of the potential for false-positive values. However, it is likely that a lupus anticoagulant was still present at this time because an aPTT of 70 seconds is quite prolonged for an accompanying INR of 3.0.
Although retrospective studies have suggested that warfarin at a target INR greater than 3 is required to adequately prevent recurrent thrombotic events in patients with the antiphospholipid antibody syndrome, two recent prospective trials indicate that warfarin with a target INR of 2 to 3 is adequate for preventing recurrent venous thrombosis in this population. Antiplatelet therapy with aspirin, clopidogrel or both has not been shown to add to the antithrombotic efficacy of warfarin.
- Warfarin with a target INR of 2 to 3 is adequate for preventing recurrent venous thrombosis in patients with the antiphospholipid antibody syndrome.
Correct answer: A. Continue warfarin to maintain an INR of 2 to 3.
Pregnant women with a mechanical heart valve have a high risk of valve thrombosis, and the management of anticoagulation in this situation remains controversial. The ideal therapy would maintain continuous effective anticoagulation with an agent that does not harm the fetus; unfortunately, this ideal regimen does not exist.
Warfarin provides the most effective anticoagulation for the mother but is associated with a risk of fetal defects, particularly between weeks six and 12 of pregnancy. The risk of embryopathy is lower when effective anticoagulation can be maintained with a daily warfarin dose of below 5 mg. Because this woman presented after the 12th week of pregnancy and requires only 4 mg of warfarin daily, continuation of warfarin at this point in pregnancy is reasonable. The recommended INR range is the same during pregnancy as in nonpregnant patients, with the recommended INR being 2 to 3 for a patient with a bileaflet mechanical aortic valve and with no other risk factors.
Aspirin alone is not an effective therapy to prevent thrombosis of mechanical valves, and there is no evidence that clopidogrel alone is effective for mechanical valves. Heparin has the advantage that it does not cross the placenta and thus is safer for the fetus. However, when heparin is used either subcutaneously or intravenously, the dose must be adjusted to achieve a therapeutic partial thromboplastin time (for unfractionated heparin) or factor Xa level (for low-molecular-weight heparin). Some centers use heparin throughout pregnancy, and all centers use heparin after 36 weeks in preparation for delivery.
- Continuous effective anticoagulation is needed throughout pregnancy in women with mechanical heart valves.
Correct answer: B. Discontinue warfarin three days prior to surgery.
Mechanical valves are durable but require lifelong anticoagulation for prophylaxis against valve thrombosis and embolism. Preoperative management of anticoagulation is dependent on the risk factors for thrombosis and embolism. This patient had a bileaflet prosthesis in the aortic position with no other high-risk characteristics, and can therefore have his warfarin discontinued three days prior to surgery.
Patients at higher risk of thrombosis or embolic complications include those with slower transvalvular blood velocities, in whom pooling or turbulent flow may lead to thrombus formation. This is the case with any mechanical valve in the mitral position. Other high-risk patients include those in atrial fibrillation and those who have had previous thromboembolic events.
The older ball-and-cage mechanical valves, such as the Starr-Edwards valve, pose a significant thrombotic risk in any valvular position and warrant hospitalization with a heparin bridge until surgery. However, bileaflet mechanical valves in the aortic position are subjected to higher transvalvular blood velocities with less blood stasis and are less prone to thrombotic complications. Therefore, patients with bileaflet prostheses, such as the St. Jude's valve, in the aortic position can have warfarin discontinued as an outpatient several days prior to surgery and restarted postoperatively as soon as surgical control of bleeding allows, without use of a heparin bridge.
Continuation of warfarin at therapeutic doses throughout the surgery poses a significant perioperative bleeding risk and increases the potential need for blood transfusions. Sudden reversal of warfarin therapy on the day of surgery with oral vitamin K therapy increases the chances of valve thrombosis and will lengthen the postoperative time interval between restarting warfarin and achieving therapeutic anticoagulation. Aspirin is an antiplatelet agent and is not a sufficient anticoagulation surrogate for warfarin. Aspirin is used only as a chronic adjunct therapy in patients who manifest systemic emboli despite adequate anticoagulation.
- High-risk patients who require a heparin anticoagulation bridge after stopping warfarin prior to surgery include those with a mitral mechanical valve, atrial fibrillation or previous embolism.
- Low-risk patients do not require a heparin bridge after stopping warfarin prior to surgery and include patients with a bileaflet aortic valve and no other high-risk features.
- Aspirin alone is not a sufficient replacement for warfarin, and is used only as a chronic adjunct in patients who manifest systemic emboli despite therapeutic warfarin therapy.
Correct answer: C. High-dose low-molecular-weight heparin.
Recommended prophylaxis for elective total knee replacement before the patient is ambulating consists of high-dose low-molecular-weight heparin (subcutaneous enoxaparin, 30 mg twice daily), fondaparinux, adjusted-dose warfarin with a target INR of 2.5 or use of a continuous sequential compression device. High-dose low-molecular-weight heparin is currently the only specifically recommended venous thromboembolism prophylaxis among the options listed earlier for patients who have begun ambulating after knee arthroplasty. Other options include fondaparinux and adjusted-dose warfarin with a target INR of 2.5.
Low-dose low-molecular-weight heparin (subcutaneous enoxaparin, 30 mg daily) and low- or high-dose unfractionated heparin (5000 U subcutaneously twice or three times daily) are effective prophylaxis for patients undergoing general surgery but are not adequate for those undergoing major orthopedic surgery. Single-modality use of unfractionated heparin, a foot sequential compression device or compression stockings is not recommended. Compared with higher-gradient, fitted compression hose, lower-gradient standard-issue support hose offer protection only when patients are supine because the elastic does not have a sufficient pressure gradient to override gravity once patients sit or stand. Patient compliance with sequential compression devices is variable, and the devices are effective only if worn continuously while patients are not ambulating.
Unfractionated heparin is less effective than low-molecular-weight heparin for prophylaxis in major orthopedic surgery. Although prophylaxis is not recommended for patients who have undergone elective knee arthroplasty after discharge, the risk for deep venous thrombosis is increased for months after elective hip arthroplasty or hip fracture repair surgery, and extended prophylaxis is recommended for approximately one month after these procedures.
- Recommended prophylaxis for elective total knee replacement before the patient is ambulating consists of high-dose low-molecular-weight heparin, fondaparinux, adjusted-dose warfarin with a target INR of 2.5 or use of a continuous sequential compression device.
- Low-dose low-molecular-weight heparin (subcutaneous enoxaparin, 30 mg daily) and low- or high-dose unfractionated heparin (5000 U subcutaneously twice or three times daily) are effective prophylaxis for patients undergoing general surgery but are not adequate for those undergoing major orthopedic surgery.