Modulation of fibrin cofactor activity in plasminogen activation.

Fibrin is a cofactor for the formation of plasmin from plasminogen as catalyzed by tissue plasminogen activator. Initial cleavages of fibrin by plasmin upregulates the cofactor activity of fibrin by exposing carboxyl terminal lysine residues. This effect is eliminated by a carboxypeptidase B-like enzyme generated from the precursor, thrombin activatable fibrinolysis inhibitor (TAFI) that is generated by thrombin during the formation of fibrin. Thus, TAFI and its activation to TAFIa create a link between the coagulation and fibrinolytic cascade, such that activation of the former suppresses the latter. Complete solubilization of fibrin results in a family of very large fibrin degradation products. These also have very substantial tissue plasminogen activator cofactor activity that is very highly downregulated by TAFIa.