Familial thrombophilia : Resistance to activated protein C and protein S deficiency

Sammanfattning: Inherited resistance to activated protein C (APC-resistance) and protein S deficiency are associated with functional impairment of the protein C anticoagulant system, resulting in lifelong hypercoagulability andincreased risk of thrombosis. APC-resistance is the most common genetic cause of thrombosis being present in 20% to 60% of thrombosis patients.A linkage study was performed in a large thrombophilic family with independent inheritance of APCresistance and protein S deficiency. APC-resistance was found to co-segregate with two neutral polymorphisms in the factor V gene. A point mutation changing Arg506 to a Gln in the factor V gene was the cause of APC-resistance in the family. The mutation (FV:Q506) is localised in one of the APC-cleavage sites of factor V, rendering mutated factor Va resistant to cleavage by activated protein C (APC). The factor V mutation was analysed in 308 members from 50 thrombosis-prone families with inherited APC-resistance.In 94% (47/50) of APC-resistant families the same factor V gene mutation was identified. The magnitude of thrombotic risk was dependent on the factor V genotype. We investigated 327 individuals in 18 thrombosis-prone families with inherited deficiency of free protein S. Deficiency of free protein S was caused by equimolar relationship between total protein S and B-chain containing isoforms of C4BP. Moreover, type I deficiency (low free and total protein S) and type IIIdeficiency (low free but normal total protein S) coexisted in 14 out of 18 families, demonstrating the twotypes to be phenotypic variants of the same genetic disease. Deficiency of free protein S was a strong riskfactor for thrombosis in these families. However, thrombophilia penetrance was highly variable. TheFV:Q506 mutation causing APC-resistance was identified as an additional genetic risk factor in 39% (7/18)of the families. Thus, familial thrombophilia isa multiple genetic disorder.Biochemically affected family members had higher levels of prothrombin fragment Fl +2 than their normalrelatives. The results demonstrate that individuals with APC-resistance or protein S deficiency have animbalance between pro- and anti-coagulant forces, resulting in increased thrombin generation andhypercoagulability.