Premium
Variation in baseline factor VIII concentration in a retrospective cohort of mild/moderate hemophilia A patients carrying identical F8 mutations
Author(s) -
Loomans J. I.,
Velzen A. S.,
Eckhardt C. L.,
Peters M.,
Mäkipernaa A.,
Holmstrom M.,
Brons P. P.,
Dors N.,
Haya S.,
Voorberg J.,
Bom J. G.,
Fijnvandraat K.
Publication year - 2017
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13581
Subject(s) - medicine , von willebrand factor , missense mutation , cohort , genotype , clotting factor , abo blood group system , mutation , gastroenterology , platelet , genetics , biology , gene
Essentials Factor VIII levels vary in mild and moderate hemophilia A (MHA) patients with the same mutation. We aimed to estimate the variation and determinants of factor VIII levels among MHA patients. Age and genotype explain 59% of the observed inter‐individual variation in factor VIII levels. Intra‐individual variation accounted for 45% of the variation in the three largest mutation groups.Summary Background The bleeding phenotype in patients with mild/moderate hemophilia A ( MHA ) is inversely associated with the residual plasma concentration of factor VIII ( FVIII :C). Within a group of patients with the same F8 missense mutation, baseline FVIII :C may vary, because, in healthy individuals, von Willebrand factor ( VWF ) levels, ABO blood group and age are also known to influence baseline FVIII :C. Our understanding of the pathophysiologic process of the causative genetic event leading to reduced baseline FVIII :C in MHA patients is still limited. Objectives To estimate the variation and determinants of baseline FVIII :C among MHA patients with the same F8 missense mutation. Methods Three hundred and forty‐six patients carrying mutations that were present in at least 10 patients in the cohort were selected from the INSIGHT and the RISE studies, which are cohort studies including data of 3534 MHA patients from Europe, Canada, and Australia. Baseline FVIII :C was measured with a one‐stage clotting assay. We used Levene's test, univariate and multivariate linear regression, and mixed‐model analyses. Results For 59% of patients, the observed variation in baseline FVIII :C was explained by age and genotype. Compared to FVIII:C in patients with Arg612Cys, FVIII:C was significantly different in patients with eight other F8 missense mutations. Intra‐individual variation explained 45% of the observed variance in baseline FVIII :C among patients with the same mutation. Conclusion Our results indicate that baseline FVIII :C levels are not exclusively determined by F8 genotype in MHA patients. Insights into other factors may provide potential novel targets for the treatment of MHA .