title: Intensive peri-operative use of factor VIII and the Arg593-->Cys mutation are risk factors for inhibitor development in mild/moderate hemophilia A.
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.
  
  
  OBJECTIVE
  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.
  
  
  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).
  
  
  CONCLUSIONS
  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.
authors: Department of Pediatric Hematology, Emma Children's Hospital Acadmic Medical Center, Amsterdam, The Netherlands.
authors: C L
authors: CL
authors: Eckhardt
authors: L A
authors: LA
authors: Menke
authors: C H
authors: CH
authors: van Ommen
authors: J H
authors: JH
authors: van der Lee
authors: R B
authors: RB
authors: Geskus
authors: P W
authors: PW
authors: Kamphuisen
authors: M
authors: M
authors: Peters
authors: K
authors: K
authors: Fijnvandraat
mesh_terms: D000293:Adolescent; D000328:Adult; D001120:Arginine / Q000235:genetics*; D001323:Autoantibodies / Q000276:immunology*; D003545:Cysteine / Q000235:genetics*; D005169:Factor VIII / Q000276:immunology / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008137:Longitudinal Studies; D008875:Middle Aged; D009154:Mutation; D019990:Perioperative Care; D012189:Retrospective Studies; D012307:Risk Factors; D012720:Severity of Illness Index; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D005169:Factor VIII; D001120:Arginine; D003545:Cysteine