Regulation of Fibrinolysis by Thrombin Activatable Fibrinolysis Inhibitor, an Unstable Carboxypeptidase B That Unites the Pathways of Coagulation and Fibrinolysis

Abstract

Abstract-The coagulation and fibrinolytic systems safeguard the patency of the vasculature and surrounding tissue. Cross regulation of coagulation and fibrinolysis plays an important role in preserving a balanced hemostatic process. Identification of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) as an inhibitor of fibrinolysis and one of the main intermediates between coagulation and fibrinolysis, greatly improved our understanding of cross regulation of coagulation and fibrinolysis. As TAFI is an enzyme that is activated by thrombin generated by the coagulation system, its activation is sensitive to the dynamics of the coagulation system. Defects in coagulation, such as in thrombosis or hemophilia, resonate in TAFI-mediated regulation of fibrinolysis and imply that clinical symptoms of coagulation defects are amplified by unbalanced fibrinolysis. Thrombomodulin promotes the generation of both antithrombotic activated protein C (APC) and prothrombotic (antifibrinolytic) activated TAFI, illustrating the paradoxical effects of thrombomodulin on the regulation of coagulation and fibrinolysis. This review will discuss the role of TAFI in the regulation of fibrinolysis and detail its regulation of activation and its potential therapeutic applications in thrombotic disease and bleeding disorders. Key Words: coagulation Ⅲ fibrinolysis Ⅲ carboxypeptidase B Ⅲ TAFI Ⅲ thrombomodulin Ⅲ APC Ⅲ hemophilia T hrombin Activatable Fibrinolysis Inhibitor (TAFI) is an enzyme that is activated by thrombin generated by the coagulation system and which downregulates fibrinolysis. It is, therefore, considered to play an important role in the regulation of fibrinolysis by the coagulation system. Independent identification of TAFI by different groups resulted in different nomenclature for the same protein. Consequently, activated TAFI (TAFIa), plasma carboxypeptidase B (pCPB), carboxypeptidase U (CPU), or carboxypeptidase R (CPR) are all used in literature to denote the active enzyme TAFIa, whereas TAFI, procarboxypeptidase U (pro-CPU), plasma procarboxypeptidase B (pro-pCPB), or procarboxypeptidase R (pro-CPR) are used to denotes the zymogen, TAFI. [1][2][3][4] In this review TAFI will be used to indicate the zymogen and TAFIa to indicate the enzyme.Activation of TAFI by thrombin is greatly enhanced in the presence of thrombomodulin and this presents two distinct pathways for TAFI activation: (1) by relative low concentrations of thrombin in the presence of thrombomodulin, and (2) by relative high concentrations of thrombin generated via the intrinsic pathway of coagulation in the absence of thrombomodulin. Activation of TAFI is therefore sensitive to the dynamics of coagulation and so is its inhibition of fibrinolysis. The fact that TAFIa inhibits fibrinolysis by modulating the fibrin cofactor function for plasmin generation, rather than by direct irreversible inhibition, and the fact that the activity of TAFIa is short-lived contribute to the dynamics of this system.The discovery of TAFI greatly facilitated our understanding of cr...

Plasma clot formation and clot lysis to compare effects of different anticoagulation treatments on hemostasis in patients with atrial fibrillation

“…5c). Thrombin forms a complex with rThm with great affinity for thrombin-activatable fibrinolysis inhibitor (TAFI) [24], which inhibits fibrinolysis and thus may be responsible for the prolongation of the clot lysis time in our experiment (Fig. 5d), as well as a previous report [25].…”

Activated factor V is a cofactor for the activation of factor XI by thrombin in plasma

“…At high thrombin concentrations, thrombin is able to activate TAFI. This carboxypeptidase helps to protect fibrin polymers from enzymatic degradation through removal of C-terminal lysine residues that are important in tPA-mediated plasminogen activation (21). Our studies suggest that the cofactor function of FVa in feedback activation of the intrinsic pathway plays a role in this mechanism by stimulating thrombin formation to levels that promote TAFI activation.…”

Simvastatin Ameliorates Radiation Enteropathy Development After Localized, Fractionated Irradiation by a Protein C-Independent Mechanism

“…Hence, while the Gly(404)→Pro substitution affects protein C activation, other aspects of TM function are retained. These include activation of TAFI, that plays important roles in coagulation, inflammation, and extracellular matrix remodeling (47,48), and binding of the highly pro-inflammatory HMGB1 DNA binding protein (sometimes referred to as the "nuclear weapon in the immune system's arsenal"). HMGB1 binds to the cell surface receptor for advanced glycation endproducts (RAGE), which is involved in induction of fibrosis and intestinal inflammation and mucosal barrier loss (49)(50)(51).…”