Direct Thrombin Inhibitors
The pivotal role of thrombin in all phases of coagulation, cellular proliferation, and cellular interactions involved centrally in inflammatory processes provides an attractive target for pharmacologic inhibition. The development of direct thrombin inhibitors has evolved rapidly to include both intravenous and oral preparations. Hirudin is extracted from the parapharyngeal gland of the medicinal leech Hirudo medicinalis. Several derivatives and recombinant preparations have been developed, including the most widely used agent lepirudin (Refludan). Hirudin binds to both the catalytic and fibrinogen-binding sites of thrombin and thus is considered a bivalent inhibitor. The plasma half-life of hirudin is 50 to 65 minutes, with a biologic half-life of 2 hours (Verstraete et al., 1993). The properties of heparin, hirudin, and bivalirudin are highlighted in Table 16.1. The predominant renal clearance of hirudin must be emphasized for safe clinical use. Hirudin forms a tight complex with thrombin, inhibiting the conversion of fibrinogen to fibrin as well as thrombin-induced platelet aggregation (Verstraete, 1997). These actions are independent of the presence of antithrombin, and also affect thrombin bound to fibrin. On the downside, the ability of thrombin to complex with thrombomodulin, activating protein C, is also inhibited. Hirudin does not bind to platelet factor , nor does it elicit antibodies that induce platelet and endothelial cell activation; thus, it can be safely administered to patients with heparin induced thrombocytopenia (HIT). Hirudin does have weak immunogenicity, so diminished (or rarely increased) responsiveness after repeated dosing is possible. The use of hirudin in the management of heparin-induced thrombocytopenia is discussed in Chapter 29.