Venous Thromboembolism

Introduction

Venous thromboembolism (VTE) results from clot formation in the venous circulation and is manifested as deep vein thrombosis (DVT) and pulmonary embolism (PE).

CLINICAL PRESENTATION

• Many patients never develop symptoms from the acute event.
• Symptoms of DVT:

Unilateral leg swelling, pain, tenderness, erythema, and warmth. Physical signs may include a palpable cord and a positive Homan sign.

• Symptoms of PE: Cough, chest pain or tightness, shortness of breath palpitations, hemoptysis, dizziness, or lightheadedness. Signs of PE include tachypnea, tachycardia, diaphoresis, cyanosis, hypotension, shock, and cardiovascular collapse.
• Postthrombotic syndrome may produce chronic lower extremity swelling, pain, tenderness, skin discoloration, and ulceration.

DIAGNOSIS

• Assessment should focus on identifying risk factors (e.g., increased age, major surgery, previous VTE, trauma, malignancy, hypercoagulable states, drug therapy).
• Radiographic contrast studies (venography, pulmonary angiography) are the most accurate and reliable method for VTE diagnosis. Noninvasive tests (e.g., compression ultrasound, computed tomography scan, ventilation-perfusion scan) are often used for initial evaluation of patients with suspected VTE.
• Elevated d-dimer blood levels occur in acute thrombosis but also with other conditions (eg, recent surgery or trauma, pregnancy, cancer). Therefore, a negative test can help exclude VTE, but a positive test is not conclusive evidence of the diagnosis.
• Clinical assessment checklists can be used to determine whether a patient has a high, moderate, or low probability of DVT or PE.

TREATMENT

• Goals of Treatment: The goals are to prevent development of PE and postthrombotic syndrome, reduce morbidity and mortality from the acute event, and minimize adverse effects and cost of treatment.

Nonpharmacologic Therapy

• Graduated compression stockings and intermittent pneumatic compression (IPC) devices improve venous blood flow and reduce risk of VTE.
• Inferior vena cava filters can provide short-term protection against PE in very high-risk patients with contraindications to anticoagulation therapy or in whom anticoagulant therapy has failed.
• Encourage patients to ambulate as much as symptoms permit.
• Consider thrombectomy in life- or limb-threatening DVT. For acute PE, catheter-based embolectomy might be suitable for patients who have contraindications to thrombolytic therapy, have failed thrombolytic therapy, or in whom death is likely before onset of thrombolysis. Reserve surgical embolectomy for massive PE and hemodynamic instability when thrombolysis is contraindicated, has failed, or will have insufficient time to take effect.

Pharmacologic Therapy

Unfractionated Heparin

Unfractionated heparin (UFH) prevents growth and propagation of a formed thrombus and allows endogenous thrombolytic systems to degrade the clot. Because some patients fail to achieve an adequate response, IV UFH has largely been replaced by LMWH or fondaparinux. UFH continues to have a role in patients with creatinine clearance less than 30 mL/min.

Low-Molecular-Weight Heparin

• Advantages of LMWHs over UFH include:

(1) predictable anticoagulation dose response,

(2) improved SC bioavailability,

(3) dose-independent clearance,

(4) longer biologic half-life,

(5) lower incidence of thrombocytopenia, and

(6) less need for routine laboratory monitoring

• Recommended doses (based on actual body weight) of LMWH for treatment of DVT with or without PE include the following: ✓ Enoxaparin (Lovenox): 1 mg/kg SC every 12 hours or 1.5 mg/kg every 24 hours ✓ Dalteparin (Fragmin): 100 units/kg every 12 hours or 200 units/kg every 24 hours (not approved by the U.S. FDA [Food and Drug administration] forthis indication) ✓ Tinzaparin (Innohep): 175 units/kg SC every 24 hours

Fondaparinux

• Fondaparinux sodium (Arixtra) prevents thrombus generation and clot formation by indirectly inhibiting factor Xa activity through its interaction with antithrombin. It is approved for prevention of VTE following orthopedic (hip fracture, hip and knee replacement) or abdominal surgery and for the treatment of DVT and PE (in conjunction with warfarin).
• Fondaparinux is a safe and effective alternative to LMWH for treatment of DVT or PE.
• Fondaparinux is dosed once daily via weight-based subcutaneous injection: 5 mg if less than 50 kg, 7.5 mg if 50 to 100 kg, and 10 mg if greater than 100 kg. Fondaparinux is contraindicated if creatinine clearance is less than 30 mL/min

Direct Anti-Xa Inhibitors

• Rivaroxaban (Xarelto) and apixaban (Eliquis) are selective inhibitors of both free and clot-bound factor Xa that do not require antithrombin to exert their anticoagulant effect.
• Neither agent is FDA approved for VTE treatment in the United States, but rivaroxaban is approved for prevention of VTE following hip or knee replacement surgery; the rivaroxaban dose is 10 mg orally once daily with or without food. Rivaroxaban should be initiated at least 6 to 10 hours after surgery once hemostasis has been established and continued for 12 days (knee replacement) or 35 days (hip replacement).

Warfarin

• Warfarin inhibits enzymes responsible for cyclic interconversion of vitamin K in the liver. Reduced vitamin K is a cofactor required for the carboxylation of the vitamin K–dependent coagulation proteins prothrombin (II); factors VII, IX, and X; and the endogenous anticoagulant proteins C and S. By reducing the supply of vitamin K, warfarin indirectly slows their rate of synthesis. By suppressing the production of clotting factors, warfarin prevents initial formation and propagation of thrombi. Warfarin has no direct effect on previously circulating clotting factors or previously formed thrombi. The time required to achieve its anticoagulant effect depends on the elimination half-lives of the coagulation proteins. Because prothrombin has a 2- to 3-day half-life, warfarin’s full antithrombotic effect is not achieved for 8 to 15 days after initiation of therapy.

Thrombolytics

• Thrombolytic agents are proteolytic enzymes that enhance conversion of plasminogen to plasmin, which subsequently degrades the fibrin matrix.
• Removal of the occluding thrombus by fibrinolytic therapy (or surgical means) is rarely warranted. Patients who present within 14 days of symptom onset with extensive proximal DVT, good functional status, low bleeding risk, and a life expectancy of a year or more are candidates for thrombolysis
• Dosage regimens of thrombolytic agents for treatment of DVT and/or PE: ✓ Alteplase (Activase): For PE, 100 mg by IV infusion over 2 hours ✓ Streptokinase (Streptase): 250,000 units IV over 30 minutes, followed by a continuous IV infusion of 100,000 units/h for 24 hours (PE) or 24 to 72 hours (DVT) ✓ Urokinase (Abbokinase): For PE, 4400 IU/kg IV over 10 minutes, followed by 4400 IU/kg/h for 12 to 24 hours