In an open-label, dose-escalation study, soluble thrombomodulin attenuated coagulation abnormalities in patients with disseminated intravascular coagulation. Soluble thrombomodulin has recently been evaluated in a phase II dose-ranging study in patients undergoing elective hip arthroplasty. Patients were given thrombomodulin subcutaneously (dose, 0.3 or 0.45 mg/kg) 2 to 4 h after surgery. Those patients receiving the lower dose of thrombomodulin received a second injection 5 days later. The primary end point, a composite of venographically detected DVT and symptomatic venous thromboembolism, occurred in 4.3% of the 94 patients who received the lower dose of soluble thrombomodulin and in none of the 99 patients receiving the higher dose. Major bleeding occurred in 1.6% and 5.7%, respectively, of patients receiving the low dose or high dose of soluble thrombomodulin. Phase III clinical trials are necessary to compare soluble thrombomodulin with other forms of thromboprophylaxis, such as low-molecular-weight heparin or fondaparinux.

3.2 Inhibitors of fibrin formation

Thrombin, the enzyme that converts fibrinogen to fibrin, can be inhibited indirectly or directly. Indirect thrombin inhibitors act by catalyzing antithrombin and/or heparin cofactor II. In contrast, direct inhibitors bind directly to thrombin and block its interaction with substrates. All of the new agents that block fibrin formation are direct thrombin inhibitors.

Direct thrombin inhibitors have properties that give them potential mechanistic advantages over indirect thrombin inhibitors, such as heparin. First, because direct thrombin inhibitors do not bind to plasma proteins, they produce a more predictable anticoagulant response. Second, unlike heparin, direct thrombin inhibitors do not bind to PF4. Consequently, the anticoagulant activity of direct thrombin inhibitors is unaffected by the large quantities of PF4 released in the vicinity of platelet-rich thrombi. Finally, direct thrombin inhibitors inactivate fibrin-bound thrombin, as well as fluid-phase thrombin.

Three parenteral direct thrombin inhibitors (ie, hirudin, argatroban, and bivalirudin) have been licensed in North America for limited indications. Hirudin and argatroban are approved for the treatment of patients with heparin-induced thrombocytopenia, whereas bivalirudin is licensed as an alternative to heparin in patients undergoing percutaneous coronary interventions. Ximelagatran, a prodrug of melagatran, is the first orally available direct thrombin inhibitor.

3.2.2 Hirudin

A 65-amino acid polypeptide originally isolated from the salivary glands of the medicinal leech Hirudo medici-nalis, hirudin is now available in recombinant form. Hirudin inhibits thrombin in a bivalent fashion. Its globular amino-terminal domain interacts with the active site of thrombin, whereas its anionic carboxy-terminal tail binds to exosite 1 on thrombin, the substrate recognition site. The hirudin/thrombin complex is essentially irreversible, which is a potential drawback because there is no specific antidote.