The role of protein S in the activation of thrombin activatable fibrinolysis inhibitor (TAFI) and regulation of fibrinolysis

Thrombin activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B- like proenzyme that after activation by thrombin downregulates fibrinolysis . Thrombomodulin stimulates the activation of both TAFI and protein C where as activated protein C inhibits the activation of TAFI by downregulation of thrombin formation, a process in which protein S acts as a cofactor. Here we determined the role of protein S in the activation of TAFI and regulatio n of fibrinolysis. Depletion of protein S from plasma or inhibition of prot ein S by specific antibodies resulted in an increased rate of TAFI activati on and in an increased maximum of TAFIa activity generated. The effect on t he rate of TAR activation could be attributed to the APC-independent antico agulant function of protein S whereas the effect on the maximum activity co uld be attributed to the APC cofactor function of protein S. Therefore it i s concluded that protein S inhibits TAR activation in two ways. On one hand , protein S functions as a cofactor for APC which results in a reduction of the maximum induced TAR activity and on the other band protein S inhibits the initial thrombin formation independently of APC which results in a decr eased rate of TAR activation. The effect of the APC-independent anticoagula nt activity of protein S on the activation of TAR provides a new mechanism for the regulation of fibrinolysis in the early stages of clot formation.