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

J Thromb Haemost. 2009 Jun;7(6):930-7. doi: 10.1111/j.1538-7836.2009.03357.x.


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.

MeSH terms

  • Adolescent
  • Adult
  • Arginine / genetics*
  • Autoantibodies / immunology*
  • Cysteine / genetics*
  • Factor VIII / immunology
  • Factor VIII / therapeutic use*
  • Hemophilia A / drug therapy*
  • Hemophilia A / genetics
  • Humans
  • Longitudinal Studies
  • Middle Aged
  • Mutation*
  • Perioperative Care
  • Retrospective Studies
  • Risk Factors
  • Severity of Illness Index
  • Young Adult


  • Autoantibodies
  • Factor VIII
  • Arginine
  • Cysteine