THE ENDOTHELIAL-CELL PROTEIN-C RECEPTOR - INHIBITION OF ACTIVATED PROTEIN-C ANTICOAGULANT FUNCTION WITHOUT MODULATION OF REACTION WITH PROTEINASE-INHIBITORS

A soluble form of the endothelial cell protein C receptor (EPCR) was a nalyzed for the ability to modulate the functional properties of prote in C and activated protein C (APC). in a plasma clotting system initia ted with factor Xa, EPCR blocked the anticoagulant activity of APC in a dose-dependent fashion. EPCR had no influence on clotting in the abs ence of APC. Consistent with the plasma results, EPCR slowed the prote olytic inactivation of factor Va by slowing both of the key proteolyti c cleavages in the heavy chain of factor Va. EPCR did not prevent prot ein C activation by the soluble thrombin-thrombomodulin complex, did n ot alter the inactivation of APC by alpha(1)-antitrypsin or protein C inhibitor, and did not influence the kinetics of peptide paranitroanil ide substrate cleavage significantly. We conclude that EPCR binds to a n exosite on APC that selectively modulates the enzyme specificity in a manner reminiscent of the influence of thrombomodulin on thrombin.