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 Holmström, Victor Jimenez-Yuste, Russell D. Keenan, Robert Klamroth, Britta A P Laros-van GorkomFrank W G Leebeek, Ri Liesner, Anne Mäkipernaa, 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

Research output: Contribution to journalArticle

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)

Original languageEnglish
Pages (from-to)1954-1962
Number of pages9
JournalBlood
Volume122
Issue number11
DOIs
Publication statusPublished - Sep 12 2013

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Factor VIII
Hemophilia A
Genes
Mutation
Confidence Intervals
Neutralizing Antibodies
Blood
Incidence
Missense Mutation
Hemorrhage

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Eckhardt, C. L., Van Velzen, A. S., Peters, M., Astermark, J., Brons, P. P., Castaman, G., ... Fijnvandraat, K. (2013). Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia a. Blood, 122(11), 1954-1962. https://doi.org/10.1182/blood-2013-02-483263

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

In: Blood, Vol. 122, No. 11, 12.09.2013, p. 1954-1962.

Research output: Contribution to journalArticle

Eckhardt, CL, Van Velzen, AS, Peters, M, Astermark, J, Brons, PP, Castaman, G, Cnossen, MH, Dors, N, Escuriola-Ettingshausen, C, Hamulyak, K, Hart, DP, Hay, CRM, Haya, S, Van Heerde, WL, Hermans, C, Holmström, M, Jimenez-Yuste, V, Keenan, RD, Klamroth, R, Laros-van Gorkom, BAP, Leebeek, FWG, Liesner, R, Mäkipernaa, A, Male, C, Mauser-Bunschoten, E, Mazzucconi, MG, McRae, S, Meijer, K, Mitchell, M, Morfini, M, Nijziel, M, Oldenburg, J, Peerlinck, K, Petrini, P, Platokouki, H, Reitter-Pfoertner, SE, Santagostino, E, Schinco, P, Smiers, FJ, Siegmund, B, Tagliaferri, A, Yee, TT, Kamphuisen, PW, Van Der Bom, JG & Fijnvandraat, K 2013, 'Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia a', Blood, vol. 122, no. 11, pp. 1954-1962. https://doi.org/10.1182/blood-2013-02-483263
Eckhardt CL, Van Velzen AS, Peters M, Astermark J, Brons PP, Castaman G et al. Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia a. Blood. 2013 Sep 12;122(11):1954-1962. https://doi.org/10.1182/blood-2013-02-483263
Eckhardt, Corien L. ; Van Velzen, Alice S. ; Peters, Marjolein ; Astermark, Jan ; Brons, Paul P. ; Castaman, Giancarlo ; Cnossen, Marjon H. ; Dors, Natasja ; Escuriola-Ettingshausen, Carmen ; Hamulyak, Karly ; Hart, Daniel P. ; Hay, Charles R M ; Haya, Saturnino ; Van Heerde, Waander L. ; Hermans, Cedric ; Holmström, Margareta ; Jimenez-Yuste, Victor ; Keenan, Russell D. ; Klamroth, Robert ; Laros-van Gorkom, Britta A P ; Leebeek, Frank W G ; Liesner, Ri ; Mäkipernaa, Anne ; Male, Christoph ; Mauser-Bunschoten, Evelien ; Mazzucconi, Maria G. ; McRae, Simon ; Meijer, Karina ; Mitchell, Michael ; Morfini, Massimo ; Nijziel, Marten ; Oldenburg, Johannes ; Peerlinck, Kathelijne ; Petrini, Pia ; Platokouki, Helena ; Reitter-Pfoertner, Sylvia E. ; Santagostino, Elena ; Schinco, Piercarla ; Smiers, Frans J. ; Siegmund, Berthold ; Tagliaferri, Annarita ; Yee, Thynn T. ; Kamphuisen, Pieter Willem ; Van Der Bom, Johanna G. ; Fijnvandraat, Karin. / Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia a. In: Blood. 2013 ; Vol. 122, No. 11. pp. 1954-1962.
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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)",
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AU - Siegmund, Berthold

AU - Tagliaferri, Annarita

AU - Yee, Thynn T.

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