ACTIVATED PROTEIN-C RESISTANCE - FROM PHENOTYPE TO GENOTYPE AND CLINICAL-PRACTICE

The anticoagulant protein C system is an important regulator of the bl ood coagulation process. Its targets are the procoagulant cofactors fa ctor Va and factor VIIIa, which are cleaved and inactivated by activat ed protein C, protein S and intact factor V working as cofactors. Gene tic defects of protein C or protein S were, together with antithrombin III deficiency, the previously established major causes of familial v enous thromboembolism. However, these abnormalities are found in less than 5-10% of patients with thrombosis. Inherited resistance to activa ted protein C was recently identified as a major risk factor for venou s thromboembolism. The activated protein C-resistance phenotype is fou nd in 20-60% of the patients with venous thrombosis, depending on sele ction criteria and on the prevalence of activated protein C-resistance in the population. The frequency of activated protein C-resistance is 2-10% in the normal populations studied so far. In more than 90% of c ases, the molecular background for the activated protein C-resistance is a single point mutation in the factor V gene, which predicts substi tution of an arginine at position 506 by a glutamine. Mutated factor V is activated by thrombin or factor Xa in the normal way, but impaired inactivation of mutated factor Va by activated protein C results in a life-long hypercoagulability. Owing to the high prevalence of activat ed protein C-resistance in the population, it occasionally occurs in p atients with deficiency of protein S, protein C or antithrombin III. I ndividuals with combined defects suffer more severely from thrombosis, and often at a younger age, than those with Single defects, suggestin g thrombophilia to be a multigenetic disease.