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

Corien L. Eckhardt, Alice S. van Velzen, Marjolein Peters, Jan Astermark, Paul P. Brons, Giancarlo Castaman, Marjon H. Cnossen, Natasja Dors, Carmen Escuriola-Ettingshausen, Karly Hamulyak, Daniel P. Hart, Charles R. M. Hay, Saturnino Haya, Waander L. van Heerde, Cedric Hermans, Margareta Holmstrom, Victor Jimenez-Yuste, Russell D. Keenan, Robert Klamroth, Britta A. P. Laros-van GorkomFrank W. G. Leebeek, Ri Liesner, Anne Makipernaa, Christoph Male, Evelien Mauser-Bunschoten, Maria G. Mazzucconi, Simon Mcrae, Karina Meijer, Michael Mitchell, Massimo Morfini, Marten Nijziel, Johannes Oldenburg, Kathelijne Peerlinck, Pia Petrini, Helena Platokouki, Sylvia E. Reitter-Pfoertner, Elena Santagostino, Piercarla Schinco, Frans J. Smiers, Berthold Siegmund, Annarita Tagliaferri, Thynn T. Yee, Pieter Willem Kamphuisen, Johanna G. van der Bom, Karin Fijnvandraat*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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.
Original languageEnglish
Pages (from-to)1954-1962
Issue number11
Publication statusPublished - 12 Sept 2013


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