title: Domain specificity of factor VIII inhibitors during immune tolerance induction in patients with haemophilia A.
abstract: BACKGROUND
  Frequent administration of high dosages factor VIII (FVIII), so-called immune tolerance induction (ITI), provides an efficient strategy to eradicate inhibitory antibodies in patients with haemophilia A. At present, our knowledge on the characteristics of inhibitory antibodies in patients undergoing ITI is limited.
  
  
  OBJECTIVE
  In this study we characterized the domain specificity of FVIII inhibitors in 11 haemophilia A patients during ITI.
  
  
  RESULTS
  In three of six patients who were successfully tolerized, inhibitory antibodies were directed predominantly against the FVIII light chain. In two other patients within this group, a significant contribution of A2 antibodies was observed which did not change during treatment. In the sixth patient the relative contribution of A2 inhibitors declined which coincided with an increase in antilight chain antibodies. In four of five patients who failed ITI, A2 inhibitors were observed. In two patients the contribution of A2 inhibitors increased during treatment, while in two other patients the contribution of A2 inhibitor remained constant. The fifth patient had inhibitory antibodies predominantly directed against the FVIII light chain.
  
  
  CONCLUSIONS
  Overall, our findings revealed changes in domain specificity of FVIII antibodies in five of 11 patients analysed. Remarkably, antibodies exclusively directed towards the light chain of FVIII were predominantly observed in patients who were successfully tolerized.
authors.affiliation: Department of Plasma Proteins, Van Creveld Laboratorium at Sanquin Research, Amsterdam, The Netherlands.
authors.forename: P M W
authors.initials: PM
authors.lastname: van Helden
authors.forename: P H P
authors.initials: PH
authors.lastname: Kaijen
authors.forename: E P
authors.initials: EP
authors.lastname: Mauser-Bunschoten
authors.forename: K
authors.initials: K
authors.lastname: Fischer
authors.forename: H M
authors.initials: HM
authors.lastname: van den Berg
authors.forename: J
authors.initials: J
authors.lastname: Voorberg
mesh_terms: D000918:Antibody Specificity; D019774:Blood Coagulation Factor Inhibitors / Q000276:immunology*; D015331:Cohort Studies; D005169:Factor VIII / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology*; D006467:Hemophilia A / Q000150:complications / Q000188:drug therapy / Q000276:immunology*; D006801:Humans; D007108:Immune Tolerance; D009154:Mutation
chemical_list: D019774:Blood Coagulation Factor Inhibitors; D005169:Factor VIII