RESISTANCE TO ACTIVATED PROTEIN-C DUE TO MUTATED FACTOR-V AS A NOVEL CAUSE OF INHERITED THROMBOPHILIA

Inherited resistance to activated protein C (APC) was recently recogni zed as a novel cause underlying venous thrombophilia. In most cases AP C-resistance is due to a single point mutation in the factor V gene le ading to a replacement of Arg506 with Gin (factor V Leiden). Amino add substitution occurs at one of the APC cleavage sites of factor Va, re ndering it resistant to APC inactivation. Plasma anticoagulant respons e to exogenous APC as a simple diagnostic assay of APC resistance show s good sensitivity and specificity as compared to gene analysis, yet s tandardization of the results needs to be improved. The APC-resistance trait is present in 2%-6% of the general population and was found to be associated with venous thrombophilia in about 20% of patients with unexplained thrombosis. Clinical features are substantially similar to other congenital plasma abnormalities predisposing to thrombosis (ant ithrombin III, protein C, protein S deficiencies); yet the overall cli nical penetrance of the defect seems lower, at least for the heterozyg ous condition. Preliminary data suggest a higher risk of thrombosis in APC-resistant homozygous individuals or in patients exhibiting APC-re sistance together with other thrombophilic genetic defects. To date, g enetically determined APC-resistance does not seem to play a significa nt role in the development of arterial thrombotic disease.