Clinical Pharmacology of Drugs Used to Prevent Clotting

CLINICAL PHARMACOLOGY OF DRUGS USED TO PREVENT CLOTTING

VENOUS THROMBOSIS

Risk Factors

A. Inherited Disorders

The inherited disorders characterized by a tendency to form thrombi (thrombophilia) derive from either quantitative or quali-tative abnormalities of the natural anticoagulant system. Deficiencies (loss of function mutations) in the natural anticoagu-lants antithrombin, protein C, and protein S account for approxi-mately 15% of selected patients with juvenile or recurrent thrombosis and 5–10% of unselected cases of acute venous throm-bosis. Additional causes of thrombophilia include gain of function mutations such as the factor V Leiden mutation and the prothrom-bin 20210 mutation, elevated clotting factor and cofactor levels, and hyperhomocysteinemia that together account for the greater number of hypercoagulable patients. Although the loss of function mutations is less common, they are associated with the greatest thrombosis risk. Some patients have multiple inherited risk factors or combinations of inherited and acquired risk factors as discussed below. These individuals are at higher risk for recurrent thrombotic events and are often considered candidates for lifelong therapy.

B. Acquired Disease

The increased risk of thromboembolism associated with atrial fibrillation and with the placement of mechanical heart valves has long been recognized. Similarly, prolonged bed rest, high-risk surgical procedures, and the presence of cancer are clearly associ-ated with an increased incidence of deep venous thrombosis and embolism. Antiphospholipid antibody syndrome is another important acquired risk factor. Drugs may function as synergistic risk factors in concert with inherited risk factors. For example, women who have the factor V Leiden mutation and take oral contraceptives have a synergistic increase in risk.

Antithrombotic Management

A. Prevention

Primary prevention of venous thrombosis reduces the incidence of and mortality rate from pulmonary emboli. Heparin and warfarin may be used to prevent venous thrombosis. Subcutaneous admin-istration of low-dose unfractionated heparin, LMWH, or fonda-parinux provides effective prophylaxis. Warfarin is also effective but requires laboratory monitoring of the prothrombin time.

B. Treatment of Established Disease

Treatment for established venous thrombosis is initiated with unfractionated or LMWH for the first 5–7 days, with an overlap with warfarin. Once therapeutic effects of warfarin have been established, therapy with warfarin is continued for a minimum of 3–6 months. Patients with recurrent disease or identifiable, non-reversible risk factors may be treated indefinitely. Small thrombi confined to the calf veins may be managed without anticoagulants if there is documentation over time that the thrombus is not extending.

Warfarin readily crosses the placenta. It can cause hemorrhage at any time during pregnancy as well as developmental defects when administered during the first trimester. Therefore, venous thromboembolic disease in pregnant women is generally treated with heparin, best administered by subcutaneous injection.

ARTERIAL THROMBOSIS

Activation of platelets is considered an essential process for arterial thrombosis. Thus, treatment with platelet-inhibiting drugs such as aspirin and clopidogrel or ticlopidine is indicated in patients with TIAs and strokes or unstable angina and acute myocardial infarc-tion. Prasugrel is an alternative to clopidogrel for patients with acute coronary syndromes managed with percutaneous coronary interventions. In angina and infarction, these drugs are often used in conjunction with β blockers, calcium channel blockers, and fibrinolytic drugs.