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

Abstract

Summary. Factor VIII activity (factor VIII:C) and factor VIII antigen (factor VIII:Ag) levels above150 IU/dl are associated with a five-to sixfold increased risk of venous thrombosis compared with levels , 100 IU/dl. These high levels are present in 25% of patients with a first episode of deep-vein thrombosis and in 11% of healthy controls. von Willebrand factor (VWF) and blood group are important determinants of the factor VIII level in plasma and therefore contribute to thrombotic risk, while factor VIII appears to be the final effector. Previously, we found familial clustering of factor VIII:C levels in women, which remained after adjustment for VWF and blood group. In the present study, we analysed the familial influence on factor VIII:Ag levels exceeding 150 IU/dl in 12 large families with thrombophilia in which high factor VIII:Ag levels contribute to thrombotic risk. As expected, blood group was a main determinant of the plasma factor VIII level: 58 relatives (32%) 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 association between factor VIII:Ag levels in sister pairs (0´35, P 0´003), brother pairs (0´35, P 0´003), brother±sister pairs (0´35, P , 0´001) and in mother±son pairs (0´45, P 0´02), but not in father±daughter or father±son pairs. The familial aggregation test was strongly positive for factor VIII:Ag 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 prevalent risk factor for venous thrombosis and contribute to risk in families with thrombophilia, and that these high levels are likely to be genetically determined by factors other than just blood group.

Major Genetic Susceptibility for Venous Thromboembolism in Men: A Study of Danish Twins

“…Hemophilias are disorders with loss of protein function, whereas gain of function (high concentrations of factors VIII or IX) has been linked to thrombophilia. 31,32 High factor VIII levels aggregate in families, 33 pointing towards a genetic origin. However, this genetic disorder is apparently not sex linked and thus cannot explain the absence of detectable genetic effects among females in our study.…”

Elevated Factor VIII Levels and the Risk of Thrombosis

“…46 Analysis of familial aggregation of factor VIII levels Ն150 IU/dL in 12 large thrombophilic families 57 identified blood group as the main determinant: 86% of the subjects with factor VIII levels Ն150 IU/dL had blood group non-O. However, after adjustment for blood group and age, factor VIII levels Ն150 IU/dL still aggregated in these families.…”

Hypercoagulability: Too Many Tests, Too Much Conflicting Data

“…For high levels of factor VIII, it has been shown that there is familial clustering of high levels, even when the blood group effect has been taken into account. 79,80 Thrombosis as a Multicausal Disease Many risk factors for thrombosis known today are common in the general population, and therefore several will often be present in one individual. Acquired risk factors also have a high prevalence, and therefore a combination of several genetic and several acquired risk factors in one individual may not be infrequent.…”