Several new antithrombotic drugs have been introduced into clinical practice over the past 20-year period. However, warfarin remains the drug of choice in many clinical situations for prolonged suppression of the blood coagulation system. Warfarin disrupts the normal metabolism of vitamin K. Vitamin K is a cofactor for γ-carboxylase, a hepatic enzyme that adds a carboxyl group to specific glutamic acid residues located in the aminoterminal region of vitamin K-dependent clotting factors. Table 37.1 lists the vitamin K-dependent coagulation factors. γ-Carboxylation of these factors is necessary for them to bind to phospholipid membranes. Warfarin inhibits vitamin K epoxide reductase, the enzyme responsible for generating the reduced form of vitamin K, which is a required cofactor for γ-carboxylase. In the presence of warfarin, clotting factors are produced; however, their conversion to functional forms by γ-carboxylase is inhibited, thereby producing an anticoagulant effect.

Because warfarin does not inhibit circulating clotting factors present when the drug is started, it typically takes 4 to 5 days for an adequate anticoagulant effect to be achieved. If necessary, heparin is usually used to achieve anticoagulation in the patient during the first several days of warfarin therapy. In general, patients should receive heparin for at least 4 days after starting warfarin, and many experts recommend continuing heparin for an additional 1 to 2 days after therapeutic warfarin anticoagulation is achieved. Loading doses of warfarin should be avoided, because they increase the frequency of excessive anticoagulation, which can result in bleeding (1). Loading doses also cause greater reductions in plasma levels of protein C, an endogenous anticoagulant, which may precipitate thrombotic complications. Current guidelines of the American College of Chest Physicians recommend an initial dose of warfarin for an adult is 5 to 10 mg daily. Further dosing should be based on the response to monitoring after 2 days. Because of increased bleeding risk and susceptibility to warfarin, 2.5 mg per day should be used initially in the elderly. Lower doses should be considered in those taking other drugs known to potentiate warfarin (e.g., amiodarone), and in patients with reduced vitamin K intake.

Warfarin therapy must be monitored carefully because its anticoagulant effect can vary considerably among individuals. The laboratory test used to monitor warfarin is the prothrombin time (PT), because it is sensitive to reductions in factors II (prothrombin), VII, and X. The PT is obtained by adding calcium chloride and a thromboplastin to citrated plasma and then measuring the times required for a clot to form. The results of the PT can vary significantly depending on the type of
thromboplastin that is used. Because different clinical laboratories may use different thromboplastins, a formula was introduced to transform the PT to an index that allows results from different laboratories to be meaningfully compared. This index, the International Normalized Ratio (INR), is routinely used to report PT results. A normal INR (i.e., from a healthy individual not receiving anticoagulant therapy) is approximately 1.0. Warfarin therapy prolongs the PT and increases the INR. The target intensity of anticoagulation for most individuals receiving warfarin is an INR of 2.5 (range, 2.0 to 3.0). For individuals at a higher risk of thrombosis (e.g., a mechanical heart valve in the mitral position), a target INR of 3.0 (range, 2.5 to 3.5) is appropriate. During the first week of warfarin therapy, the INR should be checked at least twice. Depending on the rapidity and stability of the anticoagulant response, the time interval between INR determinations is gradually increased. In the long-term phase of therapy, the INR should be checked at least monthly. Common indications for warfarin and the recommended intensity of anticoagulation are listed in Table 37.2.