Elements of the Fibrinolytic System

The blood fibrinolytic system comprises an inactive proenzyme, plasminogen, that can be converted to the active enzyme, plasmin. Plasmin degrades fibrin into soluble fibrin degradation products, by two physiological plasminogen activators (PA), the tissue type PA (t-PA) and the urokinase type PA (u-PA). t-PA mediated plasminogen activation is mainly involved in the dissolution of fibrin in the circulation. u-PA binds to a specific cellular receptor (u-PAR), resulting in enhanced activation of cell bound plasminogen. Inhibition of the fibrinolytic system may occur either at the level of the PA, by specific plasminogen activator inhibitors (PAI), or at the level of plasmin, mainly by alpha 2-antiplasmin. Several molecular interactions have been observed between the fibrinolytic and the matrix metalloproteinase (MMP) system; both systems may cooperate in generating proteolytic activity. Thus, stromelysin-1 (MMP-3) cleaves a 55-kDa kringle 1-4 fragment, containing the lysine binding site(s) involved in cellular binding, from plasminogen and removes a 17-kDa NH2-terminal fragment, containing the cellular receptor binding site, from urokinase (u-PA). Thereby, MMP-3 may downregulate cell associated plasmin activity by decreasing the amount of activatable plasminogen, without affecting cell bound u-PA activity.