The Role of Lipid Mediators in Blood Fibrinolysis

Abstract

The fibrinolytic system is the physiological counterpart of the coagulation system. Formed from fibrinogen by thrombin after activation of the coagulation cascade, fibrin is not meant to be a permanent structure in the body, but a temporary one bound to be removed by proteolytic enzymes. The most important of these enzymes is plasmin that, by limited proteolytic cleavage, degrades the insoluble polymer fibrin into soluble fragments, the fibrin degradation products. As plasmin is a broad spectrum protease and can degrade many plasma proteins, it will not normally be present in the blood in its active form, but as an inactive pro-enzyme (plasminogen). Plasminogen is activated into plasmin by other specific proteases: the plasminogen activators. Of the three types of plasminogen activators present in the blood, tissue-type plasminogen activator (t-PA) is considered to be the most important for intravascular fibrinolysis. The role of the other two plasma plasminogen activators in intravascular fibrinolysis (plasma pro-urokinase, and the Factor Xll-dependent plasminogen pro-activator, both circulating in blood as pro-enzymes) is still obscure. Not only is fibrin the substrate for plasmin, but it also dramatically accelerates plasminogen activation by t-PA, thus virtually limiting plasmin formation to the surface of its substrate fibrin. Moreover, fibrin protects plasmin from inactivation by protease inhibitor α2-antiplasmin, which rapidly inactivates plasmin in the fluid phase. Plasminogen activator activity is regulated by other specific protease inhibitors, the plasminogen activator inhibitors (PA inhibitors). The fibrinolytic system is schematically depicted in Fig. 1. For more detailed descriptions of the fibrinolytic system, the reader is referred to recent reviews (1–5).