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

Eckhardt, Corien L.; van Velzen, Alice S.; Peters, Marjolein; Astermark, Jan LU ; Brons, Paul P.; Castaman, Giancarlo; Cnossen, Marjon H.; Dors, Natasja; Escuriola-Ettingshausen, Carmen and Hamulyak, Karly, et al. (2013) In Blood 122(11). p.1954-1962
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 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... (More)
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. (Less)
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Contribution to journal
publication status
published
subject
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Blood
volume
122
issue
11
pages
1954 - 1962
publisher
American Society of Hematology
external identifiers
  • wos:000324570900019
  • scopus:84887363261
ISSN
1528-0020
DOI
10.1182/blood-2013-02-483263
language
English
LU publication?
yes
id
5e409e1b-0df1-4da6-9238-fe05b1b9ec96 (old id 4098990)
date added to LUP
2013-11-07 14:22:26
date last changed
2019-07-02 01:21:52
@article{5e409e1b-0df1-4da6-9238-fe05b1b9ec96,
  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 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.},
  author       = {Eckhardt, Corien L. and van Velzen, Alice S. and Peters, Marjolein and Astermark, Jan and Brons, Paul P. and Castaman, Giancarlo and Cnossen, Marjon H. and Dors, Natasja and Escuriola-Ettingshausen, Carmen and Hamulyak, Karly and Hart, Daniel P. and Hay, Charles R. M. and Haya, Saturnino and van Heerde, Waander L. and Hermans, Cedric and Holmstrom, Margareta and Jimenez-Yuste, Victor and Keenan, Russell D. and Klamroth, Robert and Laros-van Gorkom, Britta A. P. and Leebeek, Frank W. G. and Liesner, Ri and Makipernaa, Anne and Male, Christoph and Mauser-Bunschoten, Evelien and Mazzucconi, Maria G. and Mcrae, Simon and Meijer, Karina and Mitchell, Michael and Morfini, Massimo and Nijziel, Marten and Oldenburg, Johannes and Peerlinck, Kathelijne and Petrini, Pia and Platokouki, Helena and Reitter-Pfoertner, Sylvia E. and Santagostino, Elena and Schinco, Piercarla and Smiers, Frans J. and Siegmund, Berthold and Tagliaferri, Annarita and Yee, Thynn T. and Kamphuisen, Pieter Willem and van der Bom, Johanna G. and Fijnvandraat, Karin},
  issn         = {1528-0020},
  language     = {eng},
  number       = {11},
  pages        = {1954--1962},
  publisher    = {American Society of Hematology},
  series       = {Blood},
  title        = {Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A},
  url          = {http://dx.doi.org/10.1182/blood-2013-02-483263},
  volume       = {122},
  year         = {2013},
}