[Physiologie and cellular regulation of the protein C system]

The protein C (PC) pathway is a major anticoagulant system, the role of which is evidenced by the incidence of thrombotic events occurring in patients presenting PC or PS deficiencies. However, the regulation mechanism of this system is not yet well understood. A part of the thrombin produced during the coagulation process interacts with the protein thrombomodulin on the endothelium surface. This thrombin-thrombomodulin complex converts PC to activated PC (APC). APC then interacts with its cofactor protein S on phospholipid surfaces, and proteolytically inactivates factors Va and VIIIa, thus limiting the thrombin formation. Factor V mutation at position 506 (replacement of an Arg by a Gln) results in a decrease of factor Va inactivation rate by APC and has been recently described as a thrombosis risk factor. This "APC resistance" has been found in 15 to 20% of patients with antecedents of thromboembolic events. The PC pathway is also linked to the inflammatory reaction. A fraction of circulating PS is complexed to a regulatory protein of the complement system, the C4b binding protein (C4bBP) and only the free PS is active. An increase in the C4bBP level results in an elevation of bound PS, and as a consequence in a decrease of the free active form of PS. Moreover, endotoxins and cytokins inhibit the expression of both TM and the recently described PC cellular receptor. Under these conditions, a stimulation of tissue factor expression occurs on activated monocytes and endothelials cells surface. APC also modulates inflammatory response, through preventing tumor necrosis factor production. Thus, in the absence of PC, inflammation leads to an increased thrombin formation. This suggests that functions of PC system components are not only implicated in the regulation of the coagulation process, but also in inflammatory reactions and cellular proliferative responses.