title: Thrombin-activable fibrinolysis inhibitor zymogen does not play a significant role in the attenuation of fibrinolysis.
abstract: Activated thrombin-activable fibrinolysis inhibitor (TAFIa) plays a significant role in the prolongation of fibrinolysis. During fibrinolysis, plasminogen is activated to plasmin, which lyses a clot by cleaving fibrin after selected arginine and lysine residues. TAFIa attenuates fibrinolysis by removing the exposed C-terminal lysine residues. It was recently reported that TAFI zymogen possesses sufficient carboxypeptidase activity to attenuate fibrinolysis through a mechanism similar to TAFIa. Here, we show with a recently developed TAFIa assay that when thrombin is used to clot TAFI-deficient plasma supplemented with TAFI, there is some TAFI activation. The extent of activation was dependent upon the concentration of zymogen present in the plasma, and lysis times were prolonged by TAFIa in a concentration-dependent manner. Potato tuber carboxypeptidase inhibitor, an inhibitor of TAFIa but not TAFI, abolished the prolongation of lysis in TAFI-deficient plasma supplemented with TAFI zymogen. In addition, TAFIa but not TAFI catalyzed release of plasminogen bound to soluble fibrin degradation products. The data presented confirm that TAFI zymogen is effective in cleaving a small substrate but does not play a role in the attenuation of fibrinolysis because of its inability to cleave plasmin-modified fibrin degradation products.
authors.affiliation: Departments of Biochemistry and Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Foley
authors.forename: Paula
authors.initials: P
authors.lastname: Kim
authors.forename: Michael E
authors.initials: ME
authors.lastname: Nesheim
mesh_terms: D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D002268:Carboxypeptidases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000737:chemistry; D005341:Fibrinolysin / Q000737:chemistry* / Q000378:metabolism; D005342:Fibrinolysis / Q000502:physiology*; D006801:Humans; D010940:Plant Proteins / Q000737:chemistry / Q000494:pharmacology; D010958:Plasminogen / Q000737:chemistry* / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D005338:Fibrin Fibrinogen Degradation Products; D010940:Plant Proteins; D011480:Protease Inhibitors; D010958:Plasminogen; D002268:Carboxypeptidases; D025901:Carboxypeptidase B2; D005341:Fibrinolysin