Direct thrombin inhibitors in acute coronary syndromes: present and future.

Most acute coronary syndromes are caused by intracoronary thrombus superimposed on disrupted atherosclerotic plaque. Platelets adhere to subendothelial proteins exposed at sites of plaque disruption where they become activated, release vasoactive and procoagulant substances, and aggregate.1 Tissue factor in the lipid-rich core of the plaque initiates coagulation, which leads to thrombin generation. A potent platelet agonist, thrombin recruits additional platelets to the site of vascular injury. Thrombin also converts fibrinogen to fibrin, which serves to stabilize platelet-rich thrombi formed at sites of plaque disruption. Depending on the extent and duration of coronary artery obstruction, clinical manifestations range from unstable angina to acute myocardial infarction.1 Aspirin and heparin, the cornerstones of therapy for acute coronary syndromes, reduce the risk of myocardial infarction and death.2,3 Despite the widespread use of these treatments, however, patients with unstable angina or acute myocardial infarction remain at risk for recurrent ischemic events, suggesting that intracoronary thrombus formation is incompletely attenuated by aspirin and heparin. High concentrations of thrombin are generated by tissue factor exposed at sites of arterial injury.4 When bound to fibrin,5,6 fibrin degradation products,7 or subendothelial matrix,8 thrombin is resistant to inactivation by the heparin/antithrombin complex. Bound thrombin, which remains enzymatically active, triggers thrombus growth by activating factors V, VIII, and XI,9 thereby amplifying thrombin generation. Bound thrombin also activates platelets,10 at least in part, via thromboxane A2-independent pathways that are not blocked by aspirin. Because thrombin plays a central role in arterial thrombogenesis, the goal of most treatment regimens is to block thrombin generation or inhibit its activity. Direct thrombin inhibitors were developed to overcome the inability of the heparin/antithrombin complex to inactivate bound thrombin. In contrast to heparin and low-molecular-weight heparin, which catalyze the inactivation of thrombin by antithrombin,11,12 direct thrombin inhibitors bind to the enzyme and block its interaction with its substrates. This paper will outline the mechanisms responsible for protection of fibrinbound thrombin from inhibition by the heparin/antithrombin complex, describe the potential advantages of direct thrombin inhibitors over heparin and low-molecular-weight heparin, review the clinical data with hirudin, bivalirudin (formerly known as Hirulog), and argatroban, and outline the opportunities and challenges for direct thrombin inhibitors in the face of new anticoagulant drugs currently under development.