A STUDY OF THE MECHANISM OF INHIBITION OF FIBRINOLYSIS BY ACTIVATED THROMBIN-ACTIVABLE FIBRINOLYSIS INHIBITOR

TAFI (thrombin-activable fibrinolysis inhibitor) is a recently describ ed plasma zsmogen that, when exposed to the thrombin-thrombomodulin co mplex, is converted by proteolysis at Arg(92) to a basic carboxypeptid ase that inhibits fibrinolysis (TAFIa). The studies described here wer e undertaken to elucidate the molecular basis for the inhibition of fi brinolysis. When TAFIa is included in a clot undergoing fibrinolysis i nduced by tissue plasminogen activator and plasminogen, the time to ac hieve lysis is prolonged, and free arginine and lysine are released ov er time. In addition, TAFIa prevents a 2.5-fold increase in the rate c onstant for plasminogen activation which occurs when fibrin is modifie d by plasmin in the early course of fibrin degradation. The effect is specific for the Glu- form of plasminogen, TAFIa prevents or at least attenuates positive feedback expressed through Lys-plasminogen formati on during the process of fibrinolysis initiated by tissue plasminogen activator and plasminogen. TAFIa also inhibits plasmin activity in a c lot and prolongs fibrinolysis initiated with plasmin, We conclude that TAFIa suppresses fibrinolysis by removing COOH-terminal lysine and ar ginine residues from fibrin, thereby reducing its cofactor functions i n both plasminogen activation and the positive feedback conversion of Glu-plasminogen to Lys-plasminogen. At relatively elevated concentrati ons, it also directly inhibits plasmin.