Nonneutralizing FVIII-specific antibody signatures in patients with hemophilia A and in healthy donors

Helmut Schweiger, Judit Rejtő, Christoph J Hofbauer, Verena Berg, Peter Allacher, Karl Zwiauer, Clemens Feistritzer, Gerhard Schuster, Cihan Ay, Birgit M Reipert, Ingrid Pabinger

Research output: Journal article (peer-reviewed)Journal article

2 Citations (Scopus)

Abstract

Previous studies identified nonneutralizing FVIII-specific antibodies in the circulation of severe and nonsevere hemophilia A (sHA and nsHA) patients without FVIII inhibitors and also in some healthy individuals. To gain a better understanding of the nature of these nonneutralizing antibody responses, we analyzed and compared anti-FVIII antibody signatures in 3 study cohorts: previously treated sHA as well as nsHA patients without FVIII inhibitors, and healthy donors. FVIII-binding IgM, IgG1-4, and IgA antibodies were differentiated, FVIII-specificity was assessed, and associated apparent affinity constants were determined. Our results indicate that the nonneutralizing FVIII-specific antibody response in all study cohorts is dominated by IgG1 and IgA. Prevalences, titers, and affinities of these nonneutralizing antibodies were higher in the hemophilia A cohorts than in healthy donors. Stratification for the anti-hepatitis C virus (HCV) antibody status demonstrated the presence of FVIII-specific IgA with elevated titers in sHA patients with an active or past HCV infection when compared with HCV antibody-positive nsHA patients or HCV antibody-negative patients and healthy donors. Increased titers and affinities of FVIII-specific IgG1 antibodies were observed in a considerable number of hemophilia A patients as opposed to healthy subjects independently of the patients' anti-HCV antibody status. Overall, our findings support the hypothesis that the generation of nonneutralizing anti-FVIII antibodies in healthy individuals and in noninhibitor hemophilia A patients might be based on similar immune mechanisms. However, differences in prevalences, titers, and affinities of these antibodies indicate distinct differences in the antibody evolution between healthy individuals and patients.

Original languageEnglish
Pages (from-to)946-958
Number of pages13
JournalBlood advances
Volume6
Issue number3
DOIs
Publication statusPublished - 8 Feb 2022

Keywords

  • Factor VIII
  • Hemophilia A
  • Hepatitis C
  • Humans
  • Immunoglobulin A
  • Immunoglobulin G

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