Fibrinolysis

After the haemostatic plug has served its purpose by preventing blood loss during the vessel repair process, it is cleared from the site by an enzymatic process termed fibrinolysis. The fibrinolytic system is a short enzyme cascade system, which ends in the degradation of the fibrin network into soluble products by the function of the key enzyme plasmin. Initiation of the fibrinolytic system can be accomplished by either tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA). tPA is secreted by endothelial cells and is in the presence of fibrin a strong activator that converts the zymogen plasminogen to its active form, plasmin. uPA is mainly found in urine, but has been shown to be secreted by several different cell types. uPA, in contrast to tPA, is not dependent on the presence of fibrin to convert plasminogen into plasmin [74, 75]. Both tPA and uPA exist in single chain precursor molecules (sctPA and scuPA) that can undergo enzymatic cleavage by plasmin. scuPA behaves as a zymogen and its enzymatic activity is increased by ~200% by the cleavage, whereas both sctPA and tPA functions with approximately the same efficiency. Interestingly, scuPA can also be activated by the contact activation enzymes factor XIIa and kallikrein in the intrinsic pathway of coagulation [76]. The architecture of the fibrin network has been shown to affect the fibrinolytic process, and the degradation process proceeds drastically slower for thinner fibrin structures than for thicker fibrin structures [77]. The fibrinolytic system has to be constrained by regulatory mechanisms to prevent it from interfering with the vital process of haemostatic plug formation. This is accomplished in numerous ways but the principal inhibitors are plasminogen activator inhibitor (PAI-1) [78],  a2-macroglobulin [79], C1-inhibitor [80] and thrombin activated fibrinolysis inhibitor (TAFI) [81].

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