Recent developments in thrombolytic therapy

Abstract

Abstract One approach to the treatment of thrombosis consists of infusing thrombolytic agents to dissolve the blood clot and to restore tissue perfusion and oxygenation. Thrombolytic agents are plasminogen activators which activate the blood fibrinolytic system by activation of the proenzyme, plasminogen, to the active enzyme plasmin. 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, and at the level of plasmin, mainly by α2-antiplasmin. Streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC) and two-chain urokinase-type plasminogen activator (tcu-PA) induce extensive systemic plasmin generation; α2-antiplasmin inhibits circulating plasmin but may become exhausted during thrombolytic therapy, since its plasma concentration is only about half that of plasminogen. As a result plasmin, which has a broad substrate specificity, will degrade several plasma proteins, such as fibrinogen, coagulation factors V, VIII and XII, and von Willebrand factor. These thrombolytic agents are, therefore, considered to be non-fibrin-specific. In contrast, the physiologic plasminogen activators, tissue-type plasminogen activator (t-PA) and single-chain u-PA (scu-PA), as well as the bacterial plasminogen activator staphylokinase, are more fibrin-specific because they activate plasminogen preferentially at the fibrin surface and less in the circulation, albeit via different mechanisms. Plasmin, associated with the fibrin surface, is protected from rapid inhibition by α2-antiplasmin because its lysine-binding sites are not available, and may thus efficiently degrade the fibrin of a thrombus. Several mutants and variants, mainly of fibrin-specific plasminogen activators, are being evaluated in clinical trials in patients with acute myocardial infarction.