Heparin Enhances the Inhibition of Factor Xa by Protein C Inhibitor in the Presence but Not in the Absence of Ca²⁺

Protein C inhibitor (PCI) is a versatile serine protease inhibitor with both pro- and anticoagulant and other properties. Interactions of certain ligands with PCI, including heparin, affect its specificity for proteases. In this study, heparin was found to enhance PCI inhibition of factor Xa up to 42-fold in the presence of a physiological Ca(2+) concentration, whereas no heparin-induced activation was observed in the absence of Ca(2+). These results thus show that factor Xa adds to the group of proteases whose inhibition by PCI is enhanced by heparin and that such inhibition contributes to the anticoagulant properties of PCI by a Ca(2+)-dependent mechanism.