Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism.

V ENOUS THROMBOEMBOLISM, with an annual incidence of 1/1,000, is a serious medical problem causing considerable suffering and occasional death.‘-3 Thrombosis tends to occur in conjunction with surgery, fractures, inflammatory states, immobilization, pregnancy, and the use of oral contraceptives, demonstrating circumstantial risk factors to be of importance in the pathogenesis. In addition, thrombosis is often familial, suggesting genetic risk factors to be involved.3-6 The genetic defects previously known to be associated with thrombophilia were deficiencies of protein C, protein S , antithrombin 111, and dysfibrinogenemia, though together they accounted for only 5% to 10% of case^.^-^.' Recently, however, inherited resistance to the anticoagulant action of activated protein C (APC) was found to be a factor involved in thrombophilia.’ In most cases, APC resistance is caused by a single point mutation in the factor V gene, predicting replacement of Arg506 with Glr~.~”’ Arg506 is located at one of the APC cleavage sites in factor Va, and mutated factor Va is less sensitive than normal factor Va to APC-mediated inacti~ation?,‘~ APC resistance is highly prevalent in the general population (3% to S%), affected individuals being at increased risk of thrombosis throughout their It is a major factor in the development of venous thromboembolism, and is found in more than half of patients with inherited thr~mbophilia.’~ Here APC resistance will be considered in the context of other genetic defects known to cause thrombophilia and the molecular mechanisms involved in the protein C system will be briefly reviewed. Antithrombin 111-deficiency and other rare genetic defects causing thrombosis33’6”8 will not be discussed.