title: Surgery and inhibitor development in hemophilia A: a systematic review.
abstract: BACKGROUND
  Although the association between intensive treatment and the formation of inhibiting antibodies towards factor VIII (FVIII) in hemophilia A has been demonstrated, the contributing effect of surgery is presently unclear. The release of immunological danger signals resulting from tissue damage during surgery in the presence of a high FVIII antigen load may elicit the formation of FVIII antibodies. The aim of this systematic review was to investigate the role of surgery in the inhibitor risk associated with intensive treatment as compared with treatment for bleeding and prophylactic administration of FVIII.
  
  
  METHODS
  A comprehensive literature search was performed that identified four cohort studies and three case control studies, comprising 342 inhibitor patients among a total of 957 hemophilia A patients.
  
  
  RESULTS
  Intensive treatment increased the inhibitor risk, most pronounced with intensive treatment of ≥ 5 exposure days (EDs) compared with < 3 EDs (OR, 4.1; 95% confidence interval, 2.6-6.5). Pooled odds ratio for inhibitor development in severe hemophilia patients that received intensive treatment for surgery at first exposure was 4.1 (95% confidence interval, 2.0-8.4) compared with treatment for bleeding or prophylaxis. Information on continuous infusion, previously treated patients and non-severe hemophilia A was insufficient for valid meta-analyses.
  
  
  CONCLUSIONS
  Intensive FVIII treatment for surgery at first exposure leads to a higher inhibitor risk in hemophilia A patients compared with intensive treatment for bleeding.
authors.affiliation: Department of Pediatric Hematology, Emma Children's Hospital, Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: C L
authors.initials: CL
authors.lastname: Eckhardt
authors.forename: J G
authors.initials: JG
authors.lastname: van der Bom
authors.forename: M
authors.initials: M
authors.lastname: van der Naald
authors.forename: M
authors.initials: M
authors.lastname: Peters
authors.forename: P W
authors.initials: PW
authors.lastname: Kamphuisen
authors.forename: K
authors.initials: K
authors.lastname: Fijnvandraat
mesh_terms: D016063:Blood Loss, Surgical / Q000517:prevention & control; D005169:Factor VIII / Q000008:administration & dosage / Q000627:therapeutic use*; D006467:Hemophilia A / Q000188:drug therapy / Q000601:surgery*; D006801:Humans; D018570:Risk Assessment; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D015842:Serine Proteinase Inhibitors; D005169:Factor VIII