The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development

Research output: Contribution to journalArticle


Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products ("true PUPs") and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.


  • B M Reipert
  • B Gangadharan
  • C J Hofbauer
  • V Berg
  • H Schweiger
  • J Bowen
  • J Blatny
  • K Fijnvandraat
  • E S Mullins
  • C Male
  • C McGuinn
  • S L Meeks
  • V C Radulescu
  • M V Ragni
  • M Recht
  • A D Shapiro
  • J M Staber
  • H M Yaish
  • E Santagostino
  • D L Brown
External organisations
  • Masaryk University
  • Medical University of Vienna
  • University of Utah
  • Baxalta Innovations GmbH
  • University of Applied Sciences Krems
  • Indiana University
  • University of Amsterdam
  • University of Cincinnati
  • Weill Cornell Medicine
  • Emory University
  • University of Kentucky
  • University of Pittsburgh
  • University of Oregon
  • University of Iowa
  • University of Milan
  • University of Texas
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Hematology
Original languageEnglish
Pages (from-to)5785-5796
Number of pages12
JournalBlood Advances
Issue number22
Publication statusPublished - 2020 Nov 24
Publication categoryResearch

Bibliographic note

© 2020 by The American Society of Hematology. B.M.R. and B.G. contributed equally to this study.