Protein C Inhibitor Regulates the Thrombin-Thrombomodulin Complex in the Up- and Down Regulation of TAFI Activation

Abstract

SummaryThrombin Activatable Fibrinolysis Inhibitor (TAFI) is a carboxypeptidase B-like proenzyme that after activation by thrombin down regulates fibrinolysis. Thrombomodulin (TM) stimulates the activation of both TAFI and protein C whereas activated protein C (APC) inhibits the activation of TAFI by down regulating thrombin generation. Recently, protein C inhibitor (PCI) was identified as a potent inhibitor of thrombin bound to TM and it can thereby regulate the balance between TAFI activation, and inhibition of TAFI activation by APC. Both in a purified system and in plasma, activation of TAFI and protein C by IIa-TM could be inhibited by PCI. Previously we found in plasma that at low concentrations (~1 nM), TM predominantly stimulated the activation of TAFI whereas at higher concentrations of TM (~10 nM) the activation of protein C resulted in inhibition of the activation of TAFI. In agreement with this, PCI inhibited the activation of TAFI at 1 nM TM whereas at 10 nM TM PCI inhibited the activation of protein C resulting in an increase in the activation of TAFI. This suggests that PCI can up regulate TAFI activation by inhibiting the protein C activation. PCI may therefore be an important regulator in the balance between coagulation and fibrinolysis by differentially inhibiting the activation of TAFI and of protein C. The local TM concentration plays an important role in the outcome of this process.

Thrombomodulin Enhances the Reactivity of Thrombin with Protein C Inhibitor by Providing Both a Binding Site for the Serpin and Allosterically Modulating the Activity of Thrombin

“…Activated thrombin-activable fibrinolysis inhibitor is a carboxypeptidase B-like enzyme that can downregulate fibrinolysis by cleaving carboxyl-terminal basic residues of fibrin. Thus, plasma PCI may play an important role in the regulation of both coagulation and fibrinolytic pathways (16).…”

Association of functional thrombin‐activatable fibrinolysis inhibitor (TAFI) with conventional cardiovascular risk factors and its correlation with other hemostatic factors in a Spanish population

“…This implies that part of the thrombin needed for the activation of TAFI may be mediated by the extrinsic pathway [7]. Another point to take into account in the activation of TAFI is the role of the physiological anticoagulant pathway, including protein S, protein C, and antithrombin, since these enzymes also regulate the formation of thrombin [8][9][10]. Therefore, TAFI is important in the balance between coagulation and fibrinolysis.…”

“…It is also important to determine the possible correlation of TAFI with other hemostatic factors, since different coagulation and fibrinolytic factors influence the activation of TAFI such as Factor XI, protein C, and others and may allow us to understand the complex interactions of TAFI with other hemostatic factors [3,[7][8][9][10].…”

Thrombomodulin-dependent effect of factor V Leiden mutation on the cross-linking of α2-plasmin inhibitor to fibrin and its consequences on fibrinolysis

“…8). Its concentration-dependent effect on TAFI activation is complex in itself and implicates two opposing mechanisms [17, 40,41]. On one hand TM can down-regulate fibrinolysis by stimulating thrombin-induced TAFI activation, on the other hand this effect is diminished by the TM-promoted activation of PC, which decreases the generation of thrombin required for TAFI activation.…”