Anti-factor VIII antibodies in brothers with haemophilia A share similar characteristics

Research output: Contribution to journalArticle

Abstract

Introduction: The development of neutralizing antibodies (inhibitors) against coagulation factor VIII (FVIII) is currently the most serious complication for patients with haemophilia A undergoing FVIII replacement therapy. Several genetic factors have been acknowledged as risk factors for inhibitor development. Aim: To analyze the influence of genetic factors on the nature of the humoral immune response to FVIII in eight brother pairs with inhibitors. Methods: The domain specificity of FVIII-specific IgG was analysed by antibody binding to FVIII fragments and homologue-scanning mutagenesis (HSM). The FVIII-specific IgG subclasses were measured by direct ELISA. Results: Of the 16 patient analysed with both methods, 12 had A2- and 13 had C2-specific IgG. The presence of A1-, A3- or C1-specific IgG was identified in nine of 14 patients analysed by HSM. IgG1, IgG2 and IgG4 subclasses contributed to the anti-FVIII IgG response, and the amount of FVIII-specific IgG1 (r = 0.66) and IgG4 (r = 0.69) correlated significantly with inhibitor titres. Patients with high concentrations of total anti-FVIII IgG (r = 0.69) or high inhibitor titres (r = 0.52) had a high proportion of FVIII-specific IgG4. Statistical analysis revealed trends/evidence that the subclass distribution (P = 0.0847) and domain specificity to HC/LC (P = 0.0883) and A2/C2 (P = 0.0011) of anti-FVIII IgG were more similar in brothers compared to unrelated subjects. Conclusion: Overall, our data provide a first hint that anti-FVIII IgG characteristics are comparable among haemophilic brothers with inhibitors. Whether genetic factors also influence the nature of patients' antibodies needs to be confirmed in a larger study population.

Details

Authors
  • J. Kahle
  • A. Orlowski
  • D. Stichel
  • J. F. Healey
  • E. T. Parker
  • S. M. Donfield
  • J. Astermark
  • E. Berntorp
  • P. Lollar
  • D. Schwabe
  • C. Königs
Organisations
External organisations
  • University Hospital Frankfurt
  • Children's Healthcare of Atlanta
  • Rho, Inc.
  • Skåne University Hospital
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Hematology

Keywords

  • Anti-factor VIII antibodies, Epitope mapping, Factor VIII inhibitors, Haemophilia A, IgG subclasses
Original languageEnglish
Pages (from-to)292-299
JournalHaemophilia
Volume23
Issue number2
Publication statusPublished - 2017
Publication categoryResearch
Peer-reviewedYes