Trials and tribulations of thrombin inhibition.

Trials and tribulations of thrombin inhibition Thrombin is a central component in the molecular and cellular response to plaque rupture and therefore pertinent to the entire spectrum of acute coronary syndromes. This serine protease not only promotes the deposition of fibrin strands and further activation of the coagulation cascade, but is also a potent stimulus for platelet activation, induction of adhesion molecules by neutrophils and monocytes, and proliferation of vascular smooth muscle cells. The current regimen of combined antithrombin and antiplatelet therapy with heparin and aspirin, respectively, across the spectrum of acute coronary syndromes is based on the pivotal role played by thrombin as well as activated platelets (to whose activation thrombin also contributes). However, this is not an ideal regimen. Aspirin is a relatively weak antiplatelet agent and the promise of more potent agents is being fulfilled by the platelet glycoprotein Ilbllla receptor inhibitors. Heparin also leaves much to be desired. It is an indirectly acting drug that catalyzes the inactivation of fluid phase thrombin by antithrombin III, but is unable to inhibit clot-bound thrombin, which therefore remains enzymatically active. In addition to this deficiency, heparin has several other theoretical disadvantages including inhibition by platelet factor IV and marked heterogeneity of its pharmaco-kinetic and pharmacodynamic properties. Considerable effort has been expended in identifying a safe and effective antithrombin that can inhibit both fluid phase and clot-bound thrombin. The medicinal leech, hirudo medicinalis, is the source of hirudin, a 65 amino acid compound that binds directly in a 1:1 fashion via its carboxy terminus to the substrate recognition site of thrombin and via its amino terminus to the catalytic centre of thrombin. Nonsulfated forms of hirudin have been produced by recombinant technology by Ciba-Geigy (CGP 39393 also referred to as REVASC® or desi-rudin) and Hocchst Behringwerke (HBW 023) that are nearly identical in structure and activity to the naturally occurring compound 1 ' 1. In experimental studies of coronary thrombosis, hirudin was superior to heparin in facilitating thrombolysis with both tPA and streptokinase' 2 ' 31. Additionally, hirudin was more effective than heparin in preventing thrombus deposition in animal models of deep arterial injury 141. Pilot studies of patients with stable angina, unstable angina, and acute MI consistently observed that hirudin was more likely than heparin to maintain a stable aPTT in the target range, thus potentially avoiding the periods of inadequate and excessive anticoagulation frequently seen with heparin. Angio-graphic …