TFPI-dependent activities of Protein S

Protein S is an essential anticoagulant protein that acts as a cofactor for full length tissue factor pathway inhibitor (TFPI) and activated protein C (APC) in the down regulation of coagulation. Protein S enhances APC-mediated inactivation of the coagulation factors Va and VIIIa, and it stimulates inhibition of factor (F)Xa by TFPI. Because TFPI is a tight binding, but slow inhibitor of FXa, the TFPI/protein S system fails to regulate FXa generation at high tissue factor/FVIIa concentrations. In this review, we explain how TFPI/protein S can regain its activity at high tissue factor concentrations in the presence of APC, resulting in an intertwinement of TFPI- and APC-cofactor activities of protein S, and making TFPI a major determinant of APC-anticoagulant activity in plasma.