Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A

<p>Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.</p>

Le Paysan de Cochinchine... Hebdomadaire de soutien des intérêts agricoles ["puis" Hebdomadaire français]

22 février 19401940/02/22 (N246)-1940/02/22

Von Willebrand Factor antigen and age explain variation in baseline FVIII:C among nonsevere hemophilia A patients with the same F8 genotype (Arg593Cys and Asn618Ser)

Introduction and Objectives: Non-severe hemophilia A (baseline FVIII:C, 2-40 IU/dL) is caused by a mutation in the F8 gene. There is limited knowledge on the factors determining the variation in baseline FVIII:C. The aim is to identify the determinants of baseline FVIII:C in non-severe hemophilia A patients. Materials and Methods: We analyzed clinical data for non-severe hemophilia A patients, treated between 1980-2013, in European Haemophilia Treatment Centers (HTCs) participating in the INSIGHT/RISE project. We performed analyses on mutations that were present in ≥10 patients. Age (at FVIII:C measurement), F8 gene mutation, VWF:Ag, VWF:Act and HTC were analyzed as potential determinants by multivariate regression analyses. Results: We identified nine missense mutations present in ≥10 patients in 321 individuals, median age 23 years (IQR 7-47). From these individuals we had data on 667 FVIII:C measurements in 5 HTCs. Median baseline FVIII:C, VWF:Ag and VWF: Act were 17 IU/dL (IQR 11-22), 98 IU/dL (IQR 78-128) and 91 IU/dL (70-115) respectively. Baseline FVIII:C, VWF:Ag and VWF:Act all increased with age, both in the total population and within the two largest mutation groups (Asn618Ser, 113 patients; Arg593Cys, 107 patients). VWF:Ag, age and F8 mutation were significant predictors of baseline FVIII:C (p <0.0001-0.024). In mutations that were present in ≥10 patients the determinants age, F8 mutation, VWF:Ag and HTC together explained 61% of the variation in baseline FVIII:C. Within the specific mutation group Asn618Ser only 21% of the variance in baseline FVIII:C was explained by the combined potential determinants, with VWF:Ag and HTC as significant predictors (p = 0.008 and 0.013 respectively). Among individuals with the Arg593Cys F8 genotype the determinants age, VWF:Ag and HTC were significant predictors (p <0.0001 for age and VWF:Ag and p = 0.04 for HTC), together explaining 34% of the variance in baseline FVIII:C. Conclusion: In non-severe hemophilia A patients carrying the same F8 mutation the determinants age, VWF:Ag and HTC contribute to baseline FVIII:C to variable extends. With the studied determinants we can only explain 61% of the variance in baseline FVIII:C. This suggests that yet unknown factors influence FVIII:C in nonsevere hemophilia A