Thrombin Activatable Fibrinolysis Inhibitor and an Antifibrinolytic Pathway

Abstract

Abstract-Coagulation and fibrinolysis are processes that form and dissolve fibrin, respectively. These processes are exquisitely regulated and protect the organism from excessive blood loss or excessive fibrin deposition. Regulation of these cascades is accomplished by a variety of mechanisms involving cellular responses, flow, and protein-protein interactions. With respect to regulation mediated by protein-protein interaction, the coagulation cascade appears to be more complex than the fibrinolytic cascade because it has more components. Yet each cascade is regulated by initiators, cofactors, feedback reactions, and inhibitors. Coagulation is also controlled by an anticoagulant pathway composed of (minimally) thrombin, thrombomodulin, and protein C. 1 Protein C is converted by the thrombin/thrombomodulin complex to activated protein C (APC), which catalyzes the proteolytic inactivation of the essential cofactors required for thrombin formation, factors Va and VIIIa. An analogous antifibrinolytic pathway has been identified recently. This pathway provides an apparent symmetry between coagulation and fibrinolysis and is also composed of thrombin, thrombomodulin, and a zymogen that is activated to an enzyme. The enzyme proteolytically inactivates a cofactor to attenuate fibrinolysis. However, unlike APC, which is a serine protease, the antifibrinolytic enzyme is a metalloprotease that exhibits carboxypeptidase B-like activity. Within a few years of each other, 5 groups independently described a molecule that accounts for this antifibrinolytic activity. We refer to this molecule as thrombin activatable fibrinolysis inhibitor (TAFI), a name that is based on functional properties by which it was identified, assayed, and purified.(Because of the preferences of some journals "activatable" is occasionally referred to as "activable.") This review will encompass a historical account of efforts to isolate TAFI and characterize it with respect to its activation, activity, regulation, and potential function in vivo. Discovery of TAFIOur initial efforts were directed toward understanding the apparent profibrinolytic effect of the anticoagulant APC, which had been reported previously. 2,3 In the work of Taylor and Lockhart, 2 the modest acceleration of fibrinolysis evoked by APC in a cell-free system was more pronounced in clots formed from either whole blood or platelet-poor plasma supplemented with leukocytes. Other investigators showed that APC can consume plasminogen activator inhibitor-1 (PAI-1), thereby sparing tissue plasminogen activator (tPA), and this was offered as an explanation for the apparent profibrinolytic properties of APC. 4 -6 Consumption of PAI-1 by APC, however, is a kinetically unfavorable reaction when it is compared with inhibition of tPA by PAI-1. 7 Alternative explanations included APC inhibition of thrombin production, which would otherwise inhibit fibrinolysis either by the stimulation of PAI-1 release from platelets 8 or by some unknown mechanism. 9 We investigated the profibrinolytic effect of A...

Metabolic Syndrome Accompanied by Hypercholesterolemia Is Strongly Associated With Proinflammatory State and Impairment of Fibrinolysis in Patients With Type 2 Diabetes

“…TAFI is thought to be another potent inhibitor of fibrinolysis, acting by a removal of COOHterminal lysine and arginine residues from partially degraded fibrin. This reduces plasminogen binding to the surface of fibrin and impedes plasmin generation (7)(8)(9). However, since we found no significant correlation between plasma TAFI and PAP in diabetic patients, PAI-1 appears to be the more important determinant of fibrinolytic activity rather than TAFI.…”

“…TAFI proved to be identical with plasma procarboxypeptidase B, U, or R (8). TAFI removes COOHterminal lysine or arginine residues from partially degraded fibrin, decreasing plasminogen binding to the fibrin surface (9). Since TAFI is associated with coagulation/ fibrinolysis and inflammation, plasma TAFI may participate in arterial thrombosis in CVD (10) or in venous thrombosis (11).…”

The Effect of Hormone Replacement Treatment on Thrombin-Activatable Fibrinolysis Inhibitor Activity Levels in Patients with Hashimoto Thyroiditis

“…These residues are important for binding and activating plasminogen. Thus, TAFI leads to a potent inhibitor of tissue plasminogen activator-induced fibrinolyis (11).…”

Increased circulating levels of thrombin‐activatable fibrinolysis inhibitor in lung cancer patients

“…It is well known that C-terminal lysines on cell-surface proteins and partially degraded fibrin enhance fibrinolysis by providing binding sites for plasminogen, which, once bound, adopts a more activatable conformation. Activated TAFI inhibits activation of plasminogen to plasmin by removing these C-terminal lysine residues [19]. In addition, activated TAFI may also directly inactivate plasmin further impairing fibrinolysis [19].…”

“…Activated TAFI inhibits activation of plasminogen to plasmin by removing these C-terminal lysine residues [19]. In addition, activated TAFI may also directly inactivate plasmin further impairing fibrinolysis [19]. The possibility that TAFI also participates in the pathogenesis of hypercoagulable state in patients with lung cancer has not yet been appraised.…”