Both authors contributed equally to this study.
Intensive peri-operative use of factor VIII and the Arg593Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A
Version of Record online: 26 MAR 2009
© 2009 International Society on Thrombosis and Haemostasis
Journal of Thrombosis and Haemostasis
Volume 7, Issue 6, pages 930–937, June 2009
How to Cite
ECKHARDT, C.L., MENKE, L.A., VAN OMMEN, C.H., VAN DER LEE, J.H., GESKUS, R.B., KAMPHUISEN, P.W., PETERS, M. and FIJNVANDRAAT, K. (2009), Intensive peri-operative use of factor VIII and the Arg593Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A. Journal of Thrombosis and Haemostasis, 7: 930–937. doi: 10.1111/j.1538-7836.2009.03357.x
- Issue online: 20 MAY 2009
- Version of Record online: 26 MAR 2009
- Received 9 January 2009, accepted 18 March 2009
- hemophilia A;
- intensive FVIII exposure;
Summary. Background: A severe and challenging complication in the treatment of hemophilia A is the development of inhibiting antibodies (inhibitors) directed towards factor VIII (FVIII). Inhibitors aggravate bleeding complications, disabilities and costs. The etiology of inhibitor development is incompletely understood. Objectives: In a large cohort study in patients with mild/moderate hemophilia A we evaluated the role of genotype and intensive FVIII exposure in inhibitor development. Patients/methods: Longitudinal clinical data from 138 mild/moderate hemophilia A patients were retrospectively collected from 1 January 1980 to 1 January 2008 and analyzed by multivariate analysis using Poisson regression. Results: Genotyping demonstrated the Arg593Cys missense mutation in 52 (38%) patients; the remaining 86 patients had 26 other missense mutations. Sixty-three (46%) patients received intensive FVIII concentrate administration, 41 of them for surgery. Ten patients (7%) developed inhibitors, eight of them carrying the Arg593Cys mutation. Compared with the other patients, those with the Arg593Cys mutation had a 10-fold increased risk of developing inhibitors (RR 10; 95% CI, 0.9–119).The other two inhibitor patients had the newly detected mutations Pro1761Gln and Glu2228Asp. In both these patients and in five patients with genotype Arg593Cys, inhibitors developed after intensive peri-operative use of FVIII concentrate (RR 186; 95% CI, 25–1403). In five of the 10 inhibitor patients FVIII was administered by continuous infusion during surgery (RR 13; 95% CI, 1.9–86). Conclusion: The Arg593Cys genotype and intensive peri-operative use of FVIII, especially when administered by continuous infusion, are associated with an increased risk for inhibitor development in mild/moderate hemophilia A.