[A new cause of familial thrombophilia: resistance to the effect of activated protein C].
An examination of the cascade of events leading to coagulation emphasizes the importance of protein inhibitors. Deficiencies in these proteins have been implicated as playing a possible causal role in familial thrombo-embolic diseases. Recently the discovery of a probable deficiency in protein C cofactor, different from protein S, stimulated much research in this area. Protein C is a 461 amino acid vitamin K-dependent protein with a molar mass of 62,000 Daltons. After transduction the precursor protein is modified into an active form. Circulating protein C is then activated by proteolysis on the endothelial surface under the control of thrombomodulin-bound thrombin. Thus thrombin affects both procoagulation by activating factors V and VIII (and XI) and anticoagulation after being bound to thrombomodulin. Inactivation of factors V and VIII requires calcium, phospholipids and a C-protein cofactor, protein S. On the basis of clinical observations, it was hypothesized then confirmed that deficiency in a non-identified cofactor of protein C could explain resistance to the anticoagulating action of activated protein C. Purification of the plasma fraction carrying the cofactor activity led to the isolation of a protein which has all the biochemical properties of factor V. In addition, adding factor V to affected plasma has been shown to correct for resistance to activated protein C. But paradoxically, patients with resistance to the action of activated protein C have a normal level of factor V. The mutation responsible for activated protein C resistance was found to be a Gln for Arg mutation at position 506 of factor V. The implication of this mutation has been very recently confirmed and led rapidly to the development of molecular biology methods allowing its identification. At present, this new cause of familial hypercoagulable states can thus be identified with polymerase chain reaction and denaturing gradient gel electrophoresis. These advances have increased the number of identifiable hypercoagulable states, yet further work is needed since currently less than 10% of these diseases can be explained by deficiencies in one of the inhibitor proteins, antithrombin III, protein C or protein S.