Extrinsic plasminogen activator: a new principle in fibrinolysis

Abstract

Fibrinolysis in the blood seems to be regulated by specific molecular interactions between plasminogen activator, plasmin(ogen), fibrin and alpha 2-antiplasmin. Plasmin(ogen) contains structures, called lysine-binding sites, which mediate its interaction with fibrin and with alpha 2-antiplasmin. In plasma normally no systemic plasminogen activation by plasminogen activator occurs and plasmin, if formed, is efficiently neutralized by alpha 2-antiplasmin. When fibrin is formed in plasma a small amount of plasminogen is bound via its lysine-binding sites. Plasminogen activator present or released in the blood is strongly adsorbed to the fibrin and activates bound plasminogen in situ. The formed plasmin, which remains transiently complexed to fibrin, both by its lysine-binding site(s) and active center, is only slowly inactivated by alpha 2-antiplasmin, while plasmin which is released from digested fibrin is rapidly and irreversibly neutralized. The fibrinolytic process thus seems to be triggered by and confined to fibrin. An important consequence of this molecular model for fibrinolysis is that specific thrombolysis is only expected with the use of a specific activator, like the physiological extrinsic plasminogen activator, which confines the activation of plasminogen to the fibrin surface. Recent in vitro and in vivo studies have confirmed that the extrinsic plasminogen activator (tissue-type) might constitute a superior thrombolytic agent compared to urokinase or streptokinase.