OVERVIEW ON FIBRINOLYSIS - PLASMINOGEN ACTIVATION PATHWAYS ON FIBRIN AND CELL-SURFACES

Plasminogen activation at the surface of fibrin or of cell membranes is a sophisticated specialized system for localized extracellular proteolysis implicated in a large variety of biological functions (fibrinolysis, cell migration and extracellular matrix degradation). Assembly of plasminogen and/or activators at specific binding sites induces conformational changes that make accessible the scissile peptide bond of plasminogen and exposes the active centre of the tissue-type plasminogen activator. The mechanism of activation by pro-urokinase, a second type of activator that binds to cell membrane but not to fibrin, is far from being understood. It may be able, however, in contrast to urokinase, to specifically activate plasminogen bound to partially degraded fibrin. An extremely low K-m and high catalytic rate are characteristic of the process of activation at surfaces. In contrast, activation in liquid phase by tissue-type plasminogen activator proceeds at an extremely low catalytic rate. The initiation and amplification of plasminogen activation depend on specific interactions between the modular constitutive units of these proteins and binding sites present on cell or fibrin surfaces. Thus, the most important mechanism for the acceleration of fibrinolysis and pericellular proteolysis is the unveiling of carboxy-terminal lysine residues on these surfaces, to which plasminogen may bind. Since plasminogen bound to carboxy-terminal lysines of progressively degraded firbrin dr membranes is readily transformed into plasmin by fibrin-bound t-PA, this mechanism represents the most important pathway for the acceleration and amplification of fibrinolysis. Alpha-2-antiplasmin, by inhibiting plasmin release from surfaces, regulates the extent and rate of this process but has no effect on fibrin-bound or membrane-bound plasmin. Lipoprotein(a), a particle possessing a plasminogen-like apolipoprotein, apo(a), may interfere with this mechanism by inhibiting the specific binding of plasminogen to lysine residues in membrane or fibrin surfaces.