Intensive peri-operative use of factor VIII and the Arg593-->Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A

C L Eckhardt, L A Menke, C H van Ommen, J H van der Lee, R B Geskus, P W Kamphuisen, M Peters, K Fijnvandraat*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

92 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)930-937
Number of pages8
JournalJournal of Thrombosis and Haemostasis
Volume7
Issue number6
DOIs
Publication statusPublished - Jun 2009
Externally publishedYes

Bibliographical note

2009 International Society on Thrombosis and Haemostasis

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