Protein S is a cofactor for platelet and endothelial tissue factor pathway inhibitor-α but not for cell surface-associated tissue factor pathway inhibitor.
OBJECTIVE
Tissue factor pathway inhibitor (TFPI) is produced in 2 isoforms: TFPIα, a soluble protein in plasma, platelets, and endothelial cells, and TFPIβ, a glycosylphosphatidylinositol-anchored protein on endothelium. Protein S (PS) functions as a cofactor for TFPIα, enhancing the inhibition of factor Xa. However, PS does not alter the inhibition of prothrombinase by TFPIα, and PS interactions with TFPIβ are undescribed. Thus, the physiological role and scope of the PS-TFPI system remain unclear.


RESULTS
Here, the cofactor activity of PS toward platelet and endothelial TFPIα and endothelial TFPIβ was quantified. PS enhanced the inhibition of factor Xa by TFPIα from platelets and endothelial cells and stabilized the TFPIα/factor Xa inhibitory complex, delaying thrombin generation by prothrombinase. By contrast, PS did not enhance the inhibitory activity of TFPIβ 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.


CONCLUSIONS
The PS-TFPI anticoagulant system is limited to plasma TFPIα and TFPIα released from platelets and endothelial cells. PS likely functions to localize solution-phase TFPIα to the cell surface, where factor Xa is bound. PS does not alter the activity of membrane-associated TFPI. Because activated platelets release TFPIα and PS, the PS-TFPIα anticoagulant system may act physiologically to dampen thrombin generation at the platelet surface.
From the Blood Research Institute, Blood Center of Wisconsin, Milwaukee, WI (J.P.W., P.E.R.E., S.A.M., A.E.M.); and Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI (A.E.M.).
Jeremy P
JP
Wood
Paul E R
PE
Ellery
Susan A
SA
Maroney
Alan E
AE
Mast
D000818:Animals; D001777:Blood Coagulation; D001792:Blood Platelets / Q000378:metabolism*; D016466:CHO Cells; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D015951:Factor Xa / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism*; D015539:Platelet Activation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017293:Protein S / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000378:metabolism; D014162:Transfection
D008074:Lipoproteins; D017293:Protein S; C051928:lipoprotein-associated coagulation inhibitor; D013925:Thromboplastin; D013917:Thrombin; D015951:Factor Xa
blood coagulation; hemorrhage; thromboplastin; thrombosis