Comparative Studies on the Anticoagulant and Protease Generation Inhibitory Actions of Newly Developed Site-Directed Thrombin Inhibitory Drugs

Abstract

Site-directed thrombin inhibitors are being currently assessed clinically for their antithrombotic efficacy. Although these agents are claimed to be specific and direct thrombin inhibitors, their mechanism of inhibition varies. The objective of these studies was to compare four such agents in in vitro systems and to assess their relative anticoagulant efficacy. The four agents utilized in these studies were argatroban, Efegatran^®, hirulog, and hirudin. While hirulog and hirudin are specific irreversible inhibitors of thrombin, argatroban and Efegatran^® are reversible. All four agents were found to have a concentration-dependent anticoagulant effect when supplemented into normal human plasma, as assessed in the global clotting tests (PT, APTT, and Heptest). The most potent anticoagulant on a molar basis was hirudin in all three tests. The other three agents had similar anticoagulant actions. All four agents were also capable of inhibiting the generation of thrombin and factor Xa as determined by an amidolytic method after intrinsic or extrinsic activation of fibrinogen-deficient human plasma. Except for hirulog, all agents inhibited the extrinsic generation of thrombin, with hirudin being the most potent agent. The intrinsic generation of thrombin was blocked by the reversible thrombin inhibitors (argatroban and Efegatran^®) but not by the irreversible inhibitors (hirulog and hirudin). While all agents were capable of inhibiting the intrinsic generation of factor Xa at very low concentrations, only Efegatran^® was capable of blocking the extrinsic generation of the same factor. While all agents have comparable anticoagulant profiles in the global clotting systems, Efegatran^® appears to be more effective in blocking the generation of thrombin and factor Xa, while hirulog appears to have minimal activities in the same systems. The clinical relevance of these observations awaits the outcomes of current clinical trials.

Key words:

Anticoagulants - antithrombins - hirudin - hirulog