The fibrinolytic system

The plasminogen system plays a central role in the maintenance of vascular patency and cell migration. The binding of plasminogen to surfaces (fibrin or cells) is of importance in regulating the system. Plasmin(ogen) binds to cells with low affinity and high capacity via its lysine binding sites associated with kringle domains and also recognizes carboxy-terminal lysines of cell surface proteins. Plasminogen circulates in inactive forms as glu-plasminogen. This is converted by proteolytic activation to lys-plasminogen which binds with fibrin via lysine binding sites (antagonized by e-aminocaproic acid). The final conversion to plasmin, which has fibrinolytic and other activities, is mediated by tissue plasminogen activator and/or urokinase.

Tissue plasminogen activator, which is produced by endothelial cells and other tissues, contains similar kringle domains to plasmin which slowly converts plasminogen to plasmin; this action is dramatically potentiated with binding of tissue plasminogen activator to fibrin. This fibrin specificity for plasmin and tissue plasminogen activator results in an ideal complex of fibrin, tissue plasminogen activator, and plasminogen, in which fibrin-bound tissue plasminogen activator converts fibrin-associated plasminogen to plasmin 'on site'. The fibrin-associated plasmin generated is protected from the inhibitory action of a 2-antiplasmin. In the urokinase system, pro-urokinase can exist as either the single-chain urinary plasminogen activator, which is proteolysed to urokinase which has specificity for fibrin, or the two-chain urinary plasminogen activator, which lacks fibrin specificity in converting plasminogen to plasmin.

There are natural inhibitors of fibrinolysis which block the plasminogen activators or plasmin. Free plasmin is inhibited by interaction of its lysine site a 2-antiplasmin, but while bound to fibrin its lysine site is blocked, allowing partial protection against the action of a 2-antiplasmin. Plasminogen activator inhibitors 1, 2, and 3 inhibit tissue plasminogen activator and urokinase. Plasminogen activator inhibitor is the most important of these agents.

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