Protein S and protein C Biochemistry, physiology, and clinical manifestation of deficiencies.

Protein C and protein S are two plasma proteins that participate in an anticoagulant pathway. Protein C circulates as an inactive precursor that is converted to an active serine protease by a complex between thrombin and the endothelial cell-surface protein thrombomodulin. Activated protein C and protein S form an anticoagulant complex on cell surfaces that inactivates two of the regulatory proteins of coagulation, factors Va and VIIIa. Activated protein C is then cleared from the circulation by a relatively slow inactivation by α(1) antitrypsin and the protein C inhibitor. Deficiencies in protein C and protein S are associated with thrombotic complications. With protein S, this can arise as the result of a deficiency in protein S synthesis, proteolytic cleavage, and/or due to an increase in binding to the complement regulatory protein C4bBP, which behaves like an acute phase reactant. Inflammatory mediators not only elevate C4bBP levels, but also lead to downregulation of thrombomodulin expression. Animal experiments suggest that activated protein C and protein S may be effective and safe antithrombotic agents.