Heritability of elevated factor VIII antigen levels in factor V Leiden families with thrombophilia

Factor VIII activity (factor VIII:C) and factor VIII antigen (factor VIII:A g) levels above 150 IU/dl are associated with a five- to sixfold increased risk of venous thrombosis compared with levels < 100 IU/dl. These high leve ls are present in 25% of patients with a first episode of deep-vein thrombo sis and in 11% of healthy controls. von Willebrand factor (VWF) and blued g roup are important determinants of the factor VIII level in plasma and ther efore contribute to thrombotic risk, while factor VIII appears to be the fi nal effector Previously, we found Familial clustering of Factor VIII:C leve ls in women, which remained after adjustment for VWF and blood group. In th e present study, we analysed the familial influence on factor VIII:Ag level s exceeding 150 IU/dl in 17 large families with thrombophilia in which high Factor VIII:Ag levels contribute to thrombotic risk, As expected, blood gr oup was a main determinant of the plasma factor VIII level: 58 relatives (3 2%) had factor VIII levels above 150 IU/dl and 50 (86%) of these had blood group non-O. After adjustment for blood group and age, we found an associat ion between factor VIII:Ag levels in sister pairs (0.35, P = 0.003), brothe r pairs (0.35, P = 0.003), brother-sister pairs (0.35, P < 0.001) and in mo ther-son pairs (0.45, P = 0.02), but not in father-daughter or father-son p airs. The familial aggregation test was strongly positive for factor VIII:A g levels (P < 0.001) and remained so after adjustment for the influence of blood group. We conclude that high factor VIII:Ag levels are a highly preva lent risk factor for venous thrombosis and contribute to risk in families w ith thrombophilia, and that these high levels are likely to be genetically determined by factors other than just blood group.