T-cell responses in two unrelated hemophilia A inhibitor subjects include an epitope at the factor VIII R593C missense site

E. A. James, S. D. Van Haren, R. A. Ettinger, K. Fijnvandraat, J. A. Liberman, W. W. Kwok, J. Voorberg, K. P. Pratt*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

39 Scopus citations


Background:Development of neutralizing anti-factor (F)VIII antibodies ('inhibitors') is a serious clinical problem in hemophilia A. Increased inhibitor risk has been associated with certain FVIII missense substitutions, including R593C in the A2 domain. Objectives:The aim of the present study was to identify T-cell epitopes in FVIII and characterize T-cell responses in two unrelated hemophilia A subjects sharing F8-R593C and HLA-DRB1*1101 genotypes. We hypothesized that the hemophilic substitution site coincides with an important T-cell epitope. Patients/methods:The binding affinities of peptides for recombinant HLA-DR proteins were measured and compared with epitope prediction results. CD4+ T cells were stimulated using peptides and stained with fluorescent, peptide-loaded tetramers. Results:The inhibitor subjects, but not HLA-matched controls, had high-avidity HLA-DRB1*1101-restricted T-cell responses against FVIII589-608, which contains the hemophilic missense site. Antigen-specific T cells secreted Th1 and Th2 cytokines and proliferated in response to FVIII and FVIII592-603. FVIII589-608 bound with physiologically relevant (micromolar) IC50 values to recombinant DR0101, DR1101 and DR1501 proteins. Conclusions:Hemophilia A patients with R593C missense substitutions and these HLA haplotypes had an increased incidence of inhibitors in our cohorts, supporting a paradigm in which presentation of FVIII epitopes containing the wild-type R593 influences inhibitor risk in this hemophilia A sub-population.

Original languageEnglish
Pages (from-to)689-699
Number of pages11
JournalJournal of Thrombosis and Haemostasis
Issue number4
StatePublished - Apr 2011
Externally publishedYes


  • Factor VIII
  • HLA
  • Hemophilia A
  • Inhibitor
  • T-cell clones


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