Protein S is a cofactor for platelet and endothelial tissue factor pathway inhibitor-? but not for cell surface-associated tissue factor pathway inhibitor.

ABSTRACT: Tissue factor pathway inhibitor (TFPI) is produced in 2 isoforms: TFPI?, a soluble protein in plasma, platelets, and endothelial cells, and TFPI?, a glycosylphosphatidylinositol-anchored protein on endothelium. Protein S (PS) functions as a cofactor for TFPI?, enhancing the inhibition of factor Xa. However, PS does not alter the inhibition of prothrombinase by TFPI?, and PS interactions with TFPI? are undescribed. Thus, the physiological role and scope of the PS-TFPI system remain unclear.Here, the cofactor activity of PS toward platelet and endothelial TFPI? and endothelial TFPI? was quantified. PS enhanced the inhibition of factor Xa by TFPI? from platelets and endothelial cells and stabilized the TFPI?/factor Xa inhibitory complex, delaying thrombin generation by prothrombinase. By contrast, PS did not enhance the inhibitory activity of TFPI? or a membrane-anchored form of TFPI containing the PS-binding third Kunitz domain (K1K2K3) although PS did function as a cofactor for K1K2K3 enzymatically released from the cell surface.The PS-TFPI anticoagulant system is limited to plasma TFPI? and TFPI? released from platelets and endothelial cells. PS likely functions to localize solution-phase TFPI? to the cell surface, where factor Xa is bound. PS does not alter the activity of membrane-associated TFPI. Because activated platelets release TFPI? and PS, the PS-TFPI? anticoagulant system may act physiologically to dampen thrombin generation at the platelet surface.

SUBMITTER: Wood JP 

PROVIDER: S-EPMC4030531 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature