1. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A
- Author
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Eckhardt, C.L., Velzen, A.S. van, Peters, M., Astermark, J., Brons, P.P., Castaman, G., Cnossen, M.H., Dors, N., Escuriola-Ettingshausen, C., Hamulyak, K., Hart, D.P., Hay, C.R.M., Haya, S., Heerde, W.L. van, Hermans, C., Holmstrom, M., Jimenez-Yuste, V., Keenan, R.D., Klamroth, R., Gorkom, B.A.P., Leebeek, F.W.G., Liesner, R., Makipernaa, A., Male, C., Mauser-Bunschoten, E., Mazzucconi, M.G., Mcrae, S., Meijer, K., Mitchell, M., Morfini, M., Nijziel, M., Oldenburg, J., Peerlinck, K., Petrini, P., Platokouki, H., Reitter-Pfoertner, S.E., Santagostino, E., Schinco, P., Smiers, F.J., Siegmund, B., Tagliaferri, A., Yee, T.T., Kamphuisen, P.W., Bom, J.G. van der, Fijnvandraat, K., INSIGHT Study Grp, UCL - SSS/IREC/CARD - Pôle de recherche cardiovasculaire, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Centre de malformations vasculaires congénitales, Cardiovascular Centre (CVC), Vascular Ageing Programme (VAP), RS: CARIM School for Cardiovascular Diseases, Biochemie, Interne Geneeskunde, Pediatrics, Hematology, Epidemiology, Other departments, Paediatric Infectious Diseases / Rheumatology / Immunology, ACS - Amsterdam Cardiovascular Sciences, and AII - Amsterdam institute for Infection and Immunity
- Subjects
Invasive mycoses and compromised host Translational research [N4i 2] ,Adult ,medicine.medical_specialty ,Age-related aspects of cancer [ONCOL 2] ,Time Factors ,Adolescent ,Genotype ,Immunology ,Mutation, Missense ,Kaplan-Meier Estimate ,Hemophilia A ,DIAGNOSIS ,Biochemistry ,Gastroenterology ,Young Adult ,Interquartile range ,Risk Factors ,Internal medicine ,medicine ,Missense mutation ,Humans ,Cumulative incidence ,Desmopressin ,Genotyping ,POLYMORPHISMS ,Retrospective Studies ,Hematology ,Factor VIII ,Cardiovascular diseases [NCEBP 14] ,business.industry ,Incidence (epidemiology) ,DESMOPRESSIN ,Cell Biology ,Middle Aged ,MILD ,Antibodies, Neutralizing ,Confidence interval ,Treatment Outcome ,business ,medicine.drug ,Follow-Up Studies - Abstract
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 non-severe 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. ( Blood . 2013; 122(11):1954-1962) © 2013 by The American Society of Hematology.
- Published
- 2013
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