Lower Extremity Deep Vein Thrombosis: Treatment

Treatment of deep vein thrombosis of the lower extremities is aimed primarily at preventing pulmonary embolism, and secondarily at reducing symptoms, preventing chronic venous insufficiency and postphlebitic syndrome. Treatment of deep vein thrombosis of the lower and upper extremities is generally the same.

All patients are given anticoagulants, initially injectable heparin (unfractionated or low molecular weight), then warfarin (in the first 24-48 hours). Insufficient anticoagulant therapy in the first 24 hours may increase the risk of pulmonary embolism. Acute deep vein thrombosis can be treated on an outpatient basis if there is no suspicion of pulmonary embolism, severe symptoms (in which case parenteral analgesics are indicated), other nuances that prevent safe outpatient treatment, and some specific factors (e.g., dysfunction, socioeconomic aspect). General measures include pain relief with analgesics (except aspirin and NSAIDs due to their antiplatelet properties) and elevation of the legs during periods of rest (with a pillow or other soft surface under the legs to avoid compression of the veins). Limitation of physical activity is not indicated because there is no evidence that early activity increases the risk of thrombus dislodgement and pulmonary embolism.

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Anticoagulants

Low molecular weight heparins (eg, enoxaparin sodium, dalteparin sodium, reviparin, tinzaparin) are the initial therapy of choice because they can be administered on an outpatient basis. LMWHs are as effective as unfractionated heparin (UFH) in reducing the risk of recurrent deep vein thrombosis, thrombus dissemination, and death due to pulmonary embolism. Like UFH, LMWHs enhance the activity of antithrombin III (which inhibits coagulation factor proteases), leading to inactivation of coagulation factor Xa and (to a lesser extent) Na. LMWHs also have some antithrombin III-mediated anti-inflammatory properties that promote thrombus organization and resolution of symptoms and inflammation.

LMWH is administered subcutaneously in a standard dose depending on body weight (eg, enoxaparin sodium 1.5 mg/kg subcutaneously once a day or 1 mg/kg subcutaneously every 2 hours to a maximum dose of 200 mg per day or dalteparin sodium 200 U/kg subcutaneously once a day). Higher doses may be required in obese patients, and lower doses may be required in cachexia. UFH is more effective in patients with renal failure. Coagulation system monitoring is not necessary because LMWHs do not significantly prolong activated partial thromboplastin time (APTT), the reactions are predictable, and there are no reliable relationships between LMWH overdose and bleeding. Treatment is continued until the full anticoagulant effect of warfarin is achieved. However, previous experience suggests that LMWH is effective for long-term treatment of deep vein thrombosis in high-risk patients, so LMWH may be an acceptable alternative to warfarin in some cases, although warfarin is likely to be the drug of choice due to its low cost and ease of administration.

UFH can be prescribed instead of LMWH in hospitalized patients and patients with renal failure (creatinine clearance 10-50 ml/min), because UFH is not excreted by the kidneys. UFH is prescribed by bolus and infusion (see Table 50-3 on p. 419) to achieve adequate hypocoagulation, defined as an increase in APTT by 1.5-2.5 times compared with reference values (or the minimum serum amount of heparin of 0.2-0.4 U/ml, determined by the protamine sulfate titration test). UFH at 3.5-5 thousand U subcutaneously every 8-12 hours can replace parenteral administration of UFH and thus increase the patient's motor activity. The dose can be selected on the basis of APTT determined before administration of the drug. Treatment is continued until adequate hypocoagulation is achieved when taking warfarin.

Complications of heparin therapy include bleeding, thrombocytopenia (sometimes with LMWH), urticaria, and, less commonly, thrombosis and anaphylaxis. Long-term use of UFH causes hypokalemia, increased liver function tests, and osteoporosis. Occasionally, UFH given subcutaneously causes skin necrosis. Inpatients and possibly outpatients should be screened for bleeding (serial blood counts and stool tests for occult blood). Bleeding due to overheparinization can be controlled with protamine sulfate. The dose is 1 mg of protamine sulfate for each milligram of LMWH, given as 1 mg of protamine sulfate in 20 mL of normal saline, given slowly intravenously over 10 to 20 minutes or longer. If a second dose is needed, it should be half the first. However, the exact dose is not defined because protamine sulfate only partially neutralizes the inactivation of factor Xa by low-molecular-weight heparins. During all infusions, the patient should be monitored for possible arterial hypotension and anaphylactic-like reactions.

Warfarin is the drug of choice for long-term anticoagulant therapy for all patients except pregnant women (who require heparin therapy) and patients who have had new or worsening venous thromboembolism during warfarin therapy (such patients may be candidates for placement of a cava filter). Warfarin 5-10 mg may be administered simultaneously with heparin preparations, except for patients with protein C deficiency who have achieved adequate hypocoagulation with heparins (APTT 1.5-2.5 times the reference value) before starting warfarin therapy. Elderly patients and patients with impaired liver function usually require lower doses of warfarin. The therapeutic goal is to achieve an INR of 2.0-3.0. INR is monitored weekly during the first 1-2 months of warfarin therapy, then monthly. The dose is increased or decreased by 0.5 to 3 mg to maintain the INR within this range. Patients taking warfarin should be advised of potential drug interactions, including interactions with over-the-counter herbal medicines.

Patients with transient risk factors for deep vein thrombosis (such as immobilization or surgery) may discontinue warfarin after 3 to 6 months. Patients with permanent risk factors (eg, hypercoagulability), spontaneous deep vein thrombosis without known risk factors, recurrent deep vein thrombosis, and patients with a history of pulmonary embolism should continue warfarin for at least 6 months and probably for life if there are no complications from therapy. In low-risk patients, low-dose warfarin (to maintain an INR of 1.5 to 2.0) may be safe and effective for at least 2 to 4 years, but such treatment requires further evidence of safety before it can be widely recommended.

Bleeding is the most common complication. Risk factors for major bleeding (defined as life-threatening bleeding or loss of > 2 units of blood volume in < 7 days) are as follows:

• age 65 years and older;
• history of previous gastrointestinal bleeding or stroke;
• recent acute myocardial infarction;
• concomitant anemia (Ht < 30%), renal failure [serum creatinine concentration > 132.5 μmol/L (1.5 mg/dL)] or diabetes mellitus.

The anticoagulant effect can be completely reversed with menadione sodium bisulfite (vitamin K). The dose is 1-4 mg daily if the INR is 5-9; 5 mg daily if the INR is >9; 10 mg intravenously (administered slowly to avoid anaphylaxis) if bleeding occurs. In severe bleeding, coagulation factors, fresh frozen plasma, or prothrombin complex concentrate are transfused. Excessive hypocoagulation (IN >3-4) without bleeding can be corrected by skipping several doses of the anticoagulant while monitoring the INR more frequently, and then prescribing warfarin at a lower dose. Warfarin occasionally causes skin necrosis in patients with protein C or S deficiency.

Other anticoagulants, such as direct thrombin inhibitors (eg, subcutaneous hirudin, lepirudin, bivalirudin, desirudin, argatroban, ximelagatran) and selective factor Xa inhibitors (eg, fondaparinox), are under study for use in the treatment of acute DVT. Ximelagatran is an oral prodrug that is metabolized to melegetran (a difficult-to-use direct thrombin inhibitor); ximelagatran does not require patient monitoring and appears to be comparable in efficacy to LMWH and warfarin.

Inferior vena cava filter (vena cava filter)

An inferior vena cava filter (IVCF) may help prevent pulmonary embolism in patients with deep vein thrombosis of the lower extremity and contraindications to anticoagulation or with recurrent deep vein thrombosis (or embolism) despite adequate anticoagulation. IVCFs are placed in the inferior vena cava below the renal veins by catheterization of the internal jugular or femoral vein. IVCFs reduce the risk of acute and subacute thrombotic complications but have delayed complications (eg, venous collaterals may develop, providing a route for emboli that bypasses the IVCF). In addition, the IVCF may migrate. Thus, patients with recurrent deep vein thrombosis or non-modifiable risk factors for deep vein thrombosis may require anticoagulation. NPVs provide some protection until contraindications to anticoagulant treatment are reduced or disappear. Despite widespread use of NPVs, their effectiveness in preventing PE has not been studied or proven.

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Thrombolytic drugs

Streptokinase, urokinase, and alteplase dissolve thrombi and are probably more effective in preventing postphlebitic syndrome than sodium heparin alone, but the risk of bleeding is higher. Their use is under study. Thrombolytics may be used for large proximal thrombi, especially in the iliac and femoral veins, and for circulatory white venous or blue gangrene. Local administration using an indwelling catheter is preferred to intravenous administration.

Surgical treatment of deep vein thrombosis of the lower extremities

Surgical treatment is rarely indicated. However, thrombectomy, fasciotomy, or both are mandatory for white or blue phlegmasia that is resistant to thrombolytic therapy to prevent the development of gangrene of the limb.