Defects in the protein C pathway

Activated protein C functions as an anticoagulant by enzymatically degrading factors Va and Villa in the clotting cascade. Protein C may be converted to its enzymatically active form bythrombin. The rate at which thrombin cleavage of the zymogen occurs is greatly enhanced when thrombin is bound to an endothelial cell receptor protein, thrombomodulin. Activated proteinC has a relatively long half-life in vivo and the formation of activated protein C in response to low level thrombin infusion suggests that the protein C system may provide a feedback mechanism to limit blood clotting. Clinical support for such a physiologic role for activated protein C includes an increased incidence of thrombophlebitis and pulmonary emboli in heterozygous deficient individuals, and severe, often fatal, cutaneous thrombosis in homozygous deficient newborns. A third thrombotic condition associated with protein C deficiency is coumarin induced skin (tissue) necrosis. This localized skin necrosis occurs shortly after the initiation of coumarin therapy and is hypothesized to bedue to the rapid disappearance of protein C activity in the plasma beforean adequate intensity of anticoagulation is achieved. Recent estimates of heterozygous protein C deficiency range as high as 1 in 300 individuals in the general population. Since coumarin compounds are in routine clinical use throughout the world and skin necrosis remains a relatively rare clinical finding, this suggests that factors other than protein C deficiency alone may be involved in the pathogenesis of the skin necrosis.The anticoagulant properties of activated protein C are greatly enhanced by another vitamin K-dependent plasma protein, protein S. Protein S functions by increasing the affinity of activated protein C for cell surfaces.Protein S is found in two forms in plasma: free and in complex with C4b-binding protein, "an inhibitor of the complement system. Free protein S is functionally active and the complexed protein S is not active. Individuals congenitally deficient in protein S ae subject to recurrent thromboembolicevents. At least two classes of protin S deficiency occur.Some patienshavedecreased levels of protein S antigen and reduced protein S functional activity. A second group of deficient individuals have normal levels of protein S antigen but most or all their protein S is complexed to C4b-binding protein and they have little or no functional protein S activity. Such a protein S distribution could result from abnormal forms of protein S or C4b-binding protein or some other abnormal plasma or cellular component. Patients with functionally inactive forms of protein S have yet to be identified. Identification of protein S deficient individuals is complicated by thepossible effect of sex hormones on plasma protein S levels. Total protein S antigen is reduced during pregnancyand during oral contraceptive administration. This finding is of practicalclinical importance since the decrease in protein S which occurs during pregnancy may be an added risk factor for congenitally protein S deficient women and may explain why some proteinS deficient women experience their first episode of thrombosis during pregnancy.In addition to having anticoagulant properties, activated protein C enhances fibrinolysis, at least in part,by inhibiting the inhibitor of tissueplasminogen activator. This profibrinolytic effect is enhanced by protein S and cell surfaces. This protection of plasminogen activator activity suggests that the combination of tissue plasminogen activator and activated protein C may be useful in the treatment of coronary artery thrombi. Tissueplasminogen activator would promote clot lysis while activated protein C protected the plasminogen activatorfrom inhibition and also prevented further clot deposition. There is no evidence at present that fibrinolytic activity is reduced in protein C deficient individuals. The possible clinical relevance of this aspect of protein Cfunction in the predisposition of protein C deficient individuals to thrombosis remains to be defined.