PROTEIN-C INHIBITOR ACTS AS A PROCOAGULANT BY INHIBITING THE THROMBOMODULIN-INDUCED ACTIVATION OF PROTEIN-C IN HUMAN PLASMA

Protein C inhibitor (PCI), which was originally identified as an inhib itor of activated protein C, also efficiently inhibits coagulation fac tors such as factor Xa and thrombin. Recently it was found, using puri fied proteins, that the anticoagulant thrombin-thrombomodulin complex was also inhibited by PCI. The paradoxical inhibitory effect of PCI on both coagulant and anticoagulant proteases raised questions about the role of PCI in plasma. We studied the role of thrombomodulin (TM)-dep endent inhibition of thrombin by PCI in a plasma system. Clotting was induced by addition of tissue factor to recalcified plasma in the abse nce or presence of TM, and clot formation was monitored using turbidim etry. In the absence of TM, PCI-deficient plasma showed a slightly sho rter coagulation time compared with normal plasma. Reconstitution with a physiologic amount of PCI gave normal clotting times. Addition of P CI to normal plasma and protein C-deficient plasma resulted in a minor prolongation of the clotting time. This suggested that PCI can act as a weak coagulation inhibitor in the absence of TM. TM caused a strong anticoagulant effect in normal plasma due to thrombin scavenging and activation of the protein C anticoagulant pathway. This effect was les s pronounced when protein C-deficient plasma was used, but could be re stored by reconstitution with protein C, When PCI was added to protein C-deficient plasma in the presence of TM, a strong anticoagulant effe ct of PCI was observed. This anticoagulant effect was most likely caus ed by the TM-dependent thrombin inhibition by PCI. However, when PCI w as added to normal plasma containing TM, a strong procoagulant effect of PCI was observed, due to the inhibition of protein C activation. PC I-deficient plasma was less coagulant in the presence of TM. A concent ration-dependent increase in clotting time was observed when PCI-defic ient plasma was reconstituted with PCI. The combination of these resul ts suggest that the major function of PCI in plasma during coagulation is the inhibition of thrombin. A decreased generation of activated pr otein C is a procoagulant consequence of the TM-dependent thrombin inh ibition by PCI. We conclude that TM alters PCI from an anticoagulant i nto a procoagulant during tissue factor-induced coagulation. (C) 1998 by The American Society of Hematology.