Fibrinolytic Compromise by Synthetic and Recombinant Thrombin Inhibitors: Implications in the Treatment of Thrombotic Disorders

Abstract

Site-directed synthetic and recombinant antithrombin agents are widely used to prevent reocclusion during thrombolytic therapy in acute myocardial infarction and other vascular occlusive disorders. However, minimal studies have been conducted to examine the interactions between these anticoagulant and thrombolytic agents. Because of the structural homology of serine proteases, some of these newly developed antithrombin agents are also capable of inhibiting fibrinolytic enzymes, which may lead to fibrinolytic compromise during thrombolytic therapy. In addition, inhibition of thrombomodutin-bound thrombin may also result in fibrinolytic deficit. Several thrombin inhibitors were studied in in vitro systems to assess whether their inactivating properties extend to fibrinolytic and profibinolytic enzymes, such as kallikrein, plasmin, urokinase, streptokinase, and tissue plasminogen activator. The thrombin inhibitors studied included hirudin, hirulog-I, argatroban, D-MePhe-Pro-Arg-H, and Ac-D-Phe-Pro-boroArg-OH. Their activities were compared with those of aprotinin, which is currently used clinically as an antifibrinolytic agent. Although argatroban, hirulog-I, and hirudin exhibited minimal inhibition of the nonthrombin enzymes studied, the tripeptide derivatives showed variable inhibitory activities, with the boronic acid derivative being the most potent and universal inhibitor. The in vivo antifibrinolytic activities of these thrombin inhibitors were also studied in a rabbit model of jugular vein clot lysis. In agreement with the in vitro studies, argatroban, hirulog-I, and hirudin exhibited minimal antifibrinolytic activities, while Ac-D-Phe-Pro-boroArg-OH and D-MePhe-Pro-Arg-H showed marked inhibition of the thrombolytic process. The results of these studies indicate that newly developed thrombin inhibitors with a broader serine protease spectrum may exhibit fibrinolytic compromise resulting in diminishment of the expected thrombolytic outcome. Key Words: Thrombolysis—Fibrinolysis—Thrombin inhibitors—Argatroban—Hirudin—Hirulog-I—Aprotinin.