The following cases and commentary, which focus on preventing venous thromboembolism, are excerpted from ACP's Medical Knowledge Self-Assessment Program (MKSAP 16).
Case 1: Recurrent venous thrombophlebitis
A 35-year-old man is evaluated in the emergency department for a progressive, painful episode of superficial venous thrombophlebitis of the right greater saphenous vein. Three weeks ago, he developed an erythematous, painful, nodular swelling in a distal greater saphenous vein. He has had previous episodes treated with ibuprofen with gradual resolution. On this occasion, his superficial venous thrombophlebitis has progressed to involve the greater saphenous vein in the thigh despite ibuprofen therapy. Family history is positive for venous thromboembolism in his father. He smokes 10 cigarettes daily. His only medication is ibuprofen, 400 mg three times daily.
On physical examination, the right greater saphenous vein is erythematous, warm, and tender along its course from the calf up into the mid-upper thigh.
Duplex ultrasound of the right leg reveals extensive thrombosis of the greater saphenous vein up to within 2 cm of the junction with the common femoral vein.
Which of the following is the most appropriate initial management of this patient?
A. Continue ibuprofen
B. Place an inferior vena cava filter
C. Refer for vein ligation
D. Start therapeutic-dose low-molecular-weight heparin
Case 2: Post-discharge care for pulmonary embolism
A 65-year-old man undergoes follow-up evaluation 2 days after discharge from the hospital for an idiopathic pulmonary embolism that occurred 1 week ago. This was his first thromboembolic event. He was initially treated with low-molecular-weight heparin and was switched to warfarin in the hospital. His INR at the time of hospital discharge was 2.5. He currently takes warfarin, 5 mg/d.
On physical examination, temperature is 36.0°C (96.8°F), blood pressure is 130/80 mm Hg, pulse rate is 80/min, and respiration rate is 20/min. BMI is 34.
His INR is 1.2.
In addition to rechecking the INR in 3 to 5 days, which of the following is the most appropriate management?
A. Increase warfarin to 10 mg/d
B. Increase warfarin to 7.5 mg/d
C. Initiate low-molecular-weight heparin and increase warfarin to 6 mg/d
D. Maintain warfarin at the current dose
Case 3: VTE prophylaxis after stroke
A 65-year-old man is reevaluated 4 days after being hospitalized for an intracerebral hemorrhage of the right putamen diagnosed on a CT scan. He has a history of poorly controlled hypertension, for which he currently takes enalapril and hydrochlorothiazide, and chronic kidney disease. On admission, the dosages of his antihypertensive medications were increased, and labetalol was added.
On physical examination, blood pressure is 118/62 mm Hg, pulse rate is 86/min and regular, and respiration rate is 16/min; his blood pressure has been less than 130/80 mm Hg for the past 36 hours. No lower extremity edema is noted. On neurologic examination, dysarthria and complete paralysis of the left face, arm, and leg are noted.
Laboratory studies show activated partial thromboplastin time 36 s, INR 0.9, platelet count 410,000/µL (410 × 109/L), and creatinine 3.2 mg/dL (283 µmol/L). Two subsequent head CT scans obtained 1 and 3 days after admission showed no expansion of the hematoma. A magnetic resonance angiogram shows no evidence of an aneurysm or a vascular malformation.
Which of the following is the most appropriate prophylaxis for the prevention of venous thromboembolism?
A. Graded elastic pressure stockings
B. Low-dose warfarin
C. Placement of an inferior vena cava filter
D. Subcutaneous unfractionated heparin
Case 4: Transitioning from heparin to warfarin
A 52-year-old man is evaluated in the emergency department for a 5-day history of right leg pain and swelling. He has never had a previous episode of venous thromboembolism.
On physical examination, temperature is 36.5°C (97.7°F), blood pressure is 120/75 mm Hg, pulse rate is 85/min, and respiration rate is 22/min. BMI is 30. The right lower extremity is swollen. Cardiopulmonary examination discloses clear lungs and tachycardia.
A right popliteal vein deep venous thrombosis is confirmed by venous duplex compression ultrasonography. The patient is given low-molecular-weight heparin (LMWH).
Which of the following is the most appropriate management of this patient's transition to warfarin therapy?
A. At least 3 days of LMWH plus warfarin with a target INR of 1.5 or higher for 24 hours
B. At least 3 days of LMWH plus warfarin with a target INR of 2 or higher for 24 hours
C. At least 5 days of LMWH plus warfarin with a target INR of 2 or higher for 24 hours
D. At least 5 days of LMWH plus warfarin with a target INR of 1.5 or higher for 24 hours
Case 5: Evaluation after radical hysterectomy
A 45-year-old woman is evaluated in the hospital after radical hysterectomy for cervical carcinoma. Aside from postoperative pain, she has no symptoms. She has no history of venous thromboembolism or excessive bleeding. Her only current medication is morphine as needed.
On physical examination, temperature is normal, blood pressure is 110/72 mm Hg, and pulse rate is 84/min. There is trace edema in the legs. Prothrombin time, activated partial thromboplastin time, and INR are normal.
In addition to early ambulation, which of the following interventions is the most appropriate in this patient for thromboembolism prophylaxis?
A. Enoxaparin for 5 weeks
B. Inferior vena cava filter placement
C. Unfractionated heparin until discharge
D. Warfarin for 3 months
Case 6: Managing DVT in a cancer patient
A 49-year-old woman is evaluated for a right lower extremity deep venous thrombosis (DVT). Medical history is significant for metastatic breast cancer but no previous DVT. Current medications are intermittent chemotherapy for her active breast cancer.
Which of the following is the most appropriate management for the long-term therapy of this patient's DVT?
A. Inferior vena cava filter plus unfractionated heparin and warfarin
B. Low-molecular-weight heparin
C. Unfractionated heparin
Answers and commentary
Correct answer: D. Start therapeutic-dose low-molecular-weight heparin.
The most appropriate management is to initiate low-molecular-weight heparin and transition the patient to warfarin (INR, 2-3). Superficial venous thrombophlebitis is traditionally managed with NSAIDs or compression stockings. However, recent studies indicate that superficial venous thrombophlebitis shares many similarities with deep venous thrombosis (DVT), including recurrence risk factors (intravenous catheters, thrombophilia, cancer) and the potential to progress and cause DVT and pulmonary embolism. Therefore, serious consideration of conventional anticoagulation therapy should be given to patients with progressive or extensive superficial venous thrombophlebitis. This patient's superficial venous thrombophlebitis has progressed to involve most of the greater saphenous vein and is close to entering the common femoral vein. Therefore, he is at high risk for DVT and pulmonary embolism and requires therapeutic anticoagulation.
Continuation of ibuprofen therapy would not be appropriate because it would be unlikely to prevent progressive thrombosis and possible thromboembolism.
An inferior vena cava filter is not necessary in this patient because he does not have a contraindication to anticoagulation.
Vein ligation may be useful in preventing symptomatic recurrent episodes in a particular target vessel but should not be used for treatment in the setting of progressive superficial venous thrombophlebitis with near involvement of the deep venous system.
- Patients with progressive or extensive superficial venous thrombophlebitis may require conventional anticoagulation therapy to avoid involvement of the deep venous system.
Correct answer: C. Initiate low-molecular-weight heparin and increase warfarin to 6 mg/d.
The most appropriate management is administration of low-molecular-weight heparin (LMWH) and an increased warfarin dosage. In addition, the INR should be rechecked in 3 to 5 days. In the first month after an episode of venous thromboembolism (VTE), the recurrence risk in the absence of anticoagulation is 40%. Therefore, patients who have subtherapeutic INR values during this period are at increased risk for recurrent VTE and should be treated with LMWH and increased dosages of warfarin until the INR returns to the therapeutic range. Ideally, this should be confirmed by two INR determinations at least 24 hours apart. With an INR of 1.2, a warfarin dose increase of 10% to 20% would be appropriate. It takes at least 3 days for the dose increase to begin to take effect, whereas the complete impact of a dose change can take as long as 7 to 10 days. Rechecking the INR in 3 to 5 days allows enough time for the patient to respond to the change in dose and to determine whether additional dose increases may be necessary.
Management of INR values that are out-of-range differs for patients treated chronically with warfarin who have had stable therapeutic levels. If a single INR is less than or equal to 0.5 below the desired therapeutic level, it is recommended that the current dose be continued and that the INR be rechecked in 1-2 weeks without bridging LMWH. This would not be appropriate in this patient whose initial therapeutic dose has not been established following his acute thromboembolic event.
Increasing the warfarin dosage to 7.5 mg/d or to 10 mg/d would represent a dose increase of 50% and 100%, respectively, which is excessive and would likely result in a supratherapeutic INR. Furthermore, without concomitant coverage with LMWH, the patient would be at increased risk for recurrent thrombosis.
- In the first month following a thromboembolic episode, patients who have subtherapeutic INR values should be treated with low-molecular-weight heparin and a warfarin dose adjustment until the INR returns to the therapeutic range.
Correct answer: D. Subcutaneous unfractionated heparin.
This patient should receive subcutaneous unfractionated heparin. He is at high risk for venous thromboembolism (deep venous thrombosis and pulmonary embolism) because of his recent stroke and subsequent hemiparesis and immobility. He had an intracerebral hemorrhage, but CT scans of the head have remained stable, and no active source of bleeding in the brain has been identified. Thromboembolism prophylaxis is safe in this setting and should be administered by hospital day 4. Although low-molecular-weight heparin may be slightly superior to unfractionated heparin in preventing deep venous thrombosis, this patient's chronic kidney disease is a relative contraindication to using low-molecular-weight heparin.
Graded elastic pressure stockings without pneumatic compression have been shown to be ineffective in reducing the risk of deep venous thrombosis in patients with stroke.
Although commonly used to prevent deep venous thrombosis in patients who have orthopedic surgery, low-dose warfarin has not been shown to have this effect in patients with stroke.
An inferior vena cava filter is inappropriate for this patient with hemorrhagic stroke because no ongoing bleeding has been identified and because heparinoids are safe and effective in preventing deep venous thrombosis. Inferior vena cava filters for prevention of venous thromboemboli are reserved for patients with an active source of uncontrolled intracranial bleeding and for patients with severe traumatic brain injury to whom anticoagulants cannot be administered.
- Low-dose low-molecular-weight or unfractionated heparin is recommended in patients at high risk for venous thromboembolism after an intracerebral hemorrhage by hospital day 4.
Correct answer: C. At least 5 days of LMWH plus warfarin with a target INR of 2 or higher for 24 hours.
The best management of this patient's transition from parenteral low-molecular-weight heparin (LMWH) to warfarin therapy requires at least 5 days of overlap with LMWH and warfarin therapy and an INR of 2 or more for 24 hours. Randomized clinical trials have demonstrated that 5 to 7 days of unfractionated heparin is as effective as 10 to 14 days when transitioning to warfarin therapy. Shorter durations of parenteral anticoagulation in the transition to vitamin K antagonists have not been tested and, theoretically, could confer a higher risk for recurrent thromboembolism. Warfarin acts as an anticoagulant by impairing hepatic synthesis of vitamin K-dependent coagulation factors rather than by directly inhibiting the function of already synthesized factors. Therefore, once an appropriate warfarin dose is initiated, the onset of therapeutic anticoagulation is dictated by the half-life of the coagulation factors. If a patient is receiving an adequate warfarin dose, it takes at least 5 days for vitamin K-dependent factor activity levels to decrease sufficiently for therapeutic anticoagulation (INR of 2-3) to occur. Consequently, parenteral anticoagulant therapy (low-molecular-weight heparin) should be continued along with warfarin for at least 5 days and until a therapeutic INR of 2 or more for 24 hours is achieved to avoid an increased risk for recurrent thromboembolism.
- In patients with acute venous thromboembolism, parenteral anticoagulation should be administered concomitantly with warfarin for at least 5 days and until an INR of 2 or more has been achieved for 24 hours.
Correct answer: A. Enoxaparin for 5 weeks.
The most appropriate treatment for this patient is venous thromboembolism (VTE) prophylactic therapy for up to 5 weeks with a low-molecular-weight heparin (LMWH), such as enoxaparin. VTE is a major preventable postoperative complication, and nearly all surgical patients should receive some VTE prophylaxis postoperatively. Patients at high risk for VTE, including patients with previous VTE, patients who have undergone orthopedic surgery, and patients with some cancers (especially gynecologic malignancy) should receive extended (up to 5 weeks) prophylaxis with LMWH.
Nonpharmacologic prophylaxis against VTE, such as early ambulation, should be encouraged in all postsurgical patients. Other nonpharmacologic treatments include elastic compression stockings and pneumatic compression devices. However, these treatments are only suitable as the sole modality when either the risk of VTE is very low (outpatient surgery) or the morbidity from excess bleeding is unacceptably high (such as in patients undergoing neurosurgery). This patient's surgery for a gynecologic malignancy places her in a high-risk category, and pharmacologic prophylaxis is indicated.
Inferior vena cava (IVC) filters are sometimes used perioperatively, especially in patients with known VTE or patients with a high risk for VTE who cannot receive prophylaxis because of bleeding risk. This patient does not have an excessive bleeding risk, and IVC placement is not indicated. Although newer IVC filters are thought to be extractable following a procedure, the retrieval rate is not typically 100%, and a filter that cannot be removed postoperatively may complicate ongoing care.
Unfractionated subcutaneous heparin is an accepted medication to prevent VTE. However, in this high-risk patient, extended prophylaxis is indicated; therefore, providing prophylaxis only until the patient is discharged is incorrect.
Warfarin, in both fixed doses and adjusted doses, has been studied for VTE prophylaxis, primarily in the orthopedic setting, and been found to be effective in preventing venous thromboembolism in the perioperative period. However, 3 months of prophylaxis would not be indicated and would substantially increase the risk of bleeding once the perioperative thromboembolism risk has resolved.
- Surgical patients at high risk for venous thromboembolism, including those with previous venous thromboembolism, patients who have undergone orthopedic surgery, and patients with some cancers (especially gynecologic malignancy), should receive extended (up to 5 weeks) prophylaxis.
Correct answer: B. Low-molecular-weight heparin.
Cancer-associated venous thromboembolism (VTE) confers a high risk for recurrence. Heparin therapy (unfractionated or low-molecular-weight heparin [LMWH]) is currently recommended for initial therapy for VTE in patients with cancer. In patients with an active malignancy, extended treatment (greater than 3 months and continuing while the malignancy is active) with LMWH is indicated instead of vitamin K antagonist therapy, which is frequently used in individuals without cancer requiring long-term treatment. Although there may ultimately be viable alternatives to LMWH in patients with active malignancy, the role of newer oral anticoagulant medications, such as dabigatran or rivaroxaban, remains to be established.
The traditional indications for an inferior vena cava (IVC) filter are the inability to use an anticoagulant (usually because the risk of bleeding is too high) or the failure of an anticoagulant. Neither of these situations exists in this patient; therefore, the use of an IVC filter is unnecessary.
Although UFH is commonly used for acute therapy for VTE, it is infrequently used for chronic therapy because of the requirement for laboratory monitoring of intravenous UFH and the large injection volumes required for subcutaneous administration. A randomized controlled trial demonstrated that unmonitored subcutaneous UFH was equivalent to subcutaneous LMWH for acute therapy, but no study of chronic therapy has been conducted. Long-term UFH has been associated with an increased risk of osteoporosis compared with LMWH; consequently, it is not a particularly attractive agent for chronic VTE treatment.
- Cancer-associated deep venous thrombosis confers a high risk for recurrence, and extended treatment with low-molecular-weight heparin while the malignancy remains active is recommended.