New approaches to inhibiting thrombin's effect on the blood vessel wall

Abstract

Summary The clinical prevalence of thrombosis and the widespread use, but incomplete effectiveness, of platelet and thrombin inhibitors as therapeutic agents in patients with myocardial infarction, unstable angina, and restenosis following percutaneous transluminal coronary angioplasty has stimulated basic and clinical research into the underlying mechanisms of the thrombotic process. Recent observations that thrombi are quickly formed at sites of vascular injury and thrombin receptor expression is increased in human atherosclerosis, have inspired clinical and laboratory investigations of several novel approaches to limit thrombus formation. This review describes the role of thrombin in the response of the vessel wall to injury and focuses on new approaches, both for inhibiting thrombin with a specific direct thrombin inhibitor and for inhibiting thrombin's effects by inhibiting thrombin receptor activation. The most advanced clinical studies of direct thrombin inhibition are with hirudin. While hirudin has been shown to prevent arterial and venous thrombus formation, and to be synergistic with t-PA in thrombolysis it poses the danger of causing systemic bleeding. An alternative approach is to inhibit thrombin locally, at sites of vascular injury, rather than systemically. The specific approach described here is to target hirudin to fibrin by chemical combination with the high-affinity antifibrin antibody 59D8. Characterization of this conjugate in vitro showed that it was 10-fold more fibrin specific than hirudin alone. Inhibition of thrombin's effects by inhibiting thrombin receptor activation is an attractive approach based on the following two observations: (1) thrombin's effects on the blood vessel wall are likely mediated by activation of the thrombin receptor on the cell surface; and (2) thrombin receptor expression in injured arteries is much greater than in normal arteries. Here we present evidence indicating that thrombin receptor expression is increased following vascular injury and that inhibition of thrombin receptor activation inhibits smooth muscle cell mitogenesis. In summary, thrombosis and thrombin generation are essential components of the proliferative response of blood vessels to injury. Thus, the specific approaches described here offer promise for effectively addressing the clinical problems of thrombosis and restenosis.