Binding of plasminogen activators to fibrin: characterization and pharmacological consequences.

The fibrinolytic pathway maintains vascular patency by the proteolytic degradation of fibrin, the end-product of coagulation. Formation of a fibrin mesh during haemostasis is part of the physiological response to vascular injury, whereas thrombosis is a pathological obstruction of blood flow, but the biochemical and cellular participants are believed to be similar. Physiological fibrinolysis is co-ordinated by an interaction of enzymes, zymogens and inhibitors to produce the local lysis of fibrin deposits. Plasminogen activators are serine proteases with restricted substrate specificity, catalysing the hydrolysis of the Arg-561-Val-562 bond in the zymogen, plasminogen (Fig. 1). The resultant two-chain enzyme, plasmin, which is also a serine protease, has a trypsin-like specificity so that the physiological function of fibrinolysis requires some localization of plasminogen activation within the fibrin matrix. Fibrin can act as a cofactor, as well as substrate, increasing the catalytic efficiency of plasmin production by forming a ternary complex with plasminogen and the endogenous plasminogen activator, t-PA (tissue-type plasminogen activator) (Hoylaerts et al., 1982). Fibrin also interacts with a second type of endogenous plasminogen activator, scu-PA (single chain urokinase-type plasminogen activator), possibly by nullifying the effect of a plasma inhibitor (Lijnen et al., 1986) or by inducing a conformational change in plasminogen, enhancing activation (Pannell et al., 1988). Hence, although scu-PA may have no specific affinity for fibrin, it may, like t-PA, at physiological concentrations have some selectivity for the activation of plasminogen bound to fibrin. These mechanisms, together with the relative protection of fibrin-bound plasmin from the principal inhibitor, a2antiplasmin, provide a molecular rationale to substantiate the original concept (Alkjaersig et al., 1959) of fibrinolysis as the local activation of fibrin-bound plasminogen in an inhibitor-free environment.