Thrombin activatable fibrinolysis inhibitor and an antifibrinolytic pathway

Coagulation and fibrinolysis are processes that form and dissolve fibrin, r espectively. These processes are exquisitely regulated and protect the orga nism from excessive blood loss or excessive fibrin deposition. Regulation o f these cascades is accomplished by a variety of mechanisms involving cellu lar responses, flow, and protein-protein interactions. With respect to regu lation mediated by protein-protein interaction, the coagulation cascade app ears to be more complex than the fibrinolytic cascade because it has more c omponents. Yet each cascade is regulated by initiators, cofactors, feedback reactions, and inhibitors. Coagulation is also controlled by an anticoagul ant pathway composed of (minimally) thrombin, thrombomodulin, and protein C .(1) Protein C is converted by the thrombin/thrombomodulin complex to activ ated protein C (APC), which catalyzes the proteolytic inactivation of the e ssential cofactors required for thrombin formation, factors Va and VIIIa. A n analogous antifibrinolytic pathway has been identified recently. This pat hway provides an apparent symmetry between coagulation and fibrinolysis and is also composed of thrombin, thrombomodulin, and a zymogen that is activa ted to an enzyme. The enzyme proteolytically inactivates a cofactor to atte nuate fibrinolysis. However, unlike APC, which is a serine protease, the an tifibrinolytic enzyme is a metalloprotease that exhibits carboxypeptidase B -like activity. Within a few years of each other, 5 groups independently de scribed a molecule that accounts for this antifibrinolytic activity. We ref er to this molecule as thrombin activatable fibrinolysis inhibitor (TAFI), a name that is based on functional properties by which it was identified, a ssayed, and purified. (Because of the preferences of some journals "activat able" is occasionally referred to as "activable.") This review will encompa ss a historical account of efforts to isolate TAFI and characterize it with respect to its activation, activity, regulation, and potential function in vivo.