New Generation Thrombolytic Agents

Abstract

Thrombolytic agents, either approved for clinical use or under clinical investigation, include streptokinase, two chain urokinase (tcu-PA), anisoylated plasminogen streptokinase activator complex (APS AC, eminase), recombinant tissue-type plasminogen activator (rt-PA, alteplase) and recombinant single chain urokinase-type plasminogen activator (rscu-PA, prourokinase, saruplase). These agents are plasminogen activators which activate the fibrinolytic system in the blood. This system contains a proenzyme, plasminogen, which is converted to the active enzyme plasmin by the action of plasminogen activators. Plasmin, in turn, digests fibrin to soluble degradation products. Inhibition of the fibrinolytic system occurs both at the level of the plasminogen activators, by plasminogen activator inhibitors (PAI-1 and PAI-2) and at the level of plasmin, mainly by α2-antiplasmin. Streptokinase, APSAC and two chain urokinase induce extensive systemic activation of the fibrinolytic system, and after saturation of α2- antiplasmin excess plasmin may degrade several plasma proteins. In contrast, the physiologic plasminogen activators, tissue-type plasminogen activator (t-PA) and single chain urokinase-type plasminogen activator (scu-PA), activate plasminogen preferentially at the fibrin surface. Plasmin, associated with the fibrin surface, is protected from rapid inhibition by α2-antiplasmin and may thus efficiently degrade the fibrin of a thrombus (1). This fibrin-specific mechanism of action of t-PA and scu-PA has triggered great interest in the use of these compounds as thrombolytic agents. Staphylokinase, a protein obtained from Staphylococcus aureus, was recently also found to induce fibrin- specific clot lysis in human plasma in vitro (2,3). One approach to further improve thrombolytic therapy consists in the production of new agents with improved thrombolytic profile. An extensive review on the construction and characterization of mutants and variants of plasminogen activators has recently been published (4). This contribution will focus on recent in vivo studies, performed with some of these new thrombolytic agents.KeywordsPlasminogen ActivatorThrombolytic AgentAnisoylated Plasminogen Streptokinase Activator ComplexMinogen ActivatorRecombinant Plasminogen ActivatorThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.