Inhibitors in hemophilia A: Mechanisms of inhibition, management and perspectives

Natalya M. Ananyeva*, Sebastien Lacroix-Desmazes, Charlotte Hauser, Midori Shima, Mikhail V. Ovanesov, Alexey V. Khrenov, Evgueni L. Saenko

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

75 Scopus citations


Factor VIII (FVIII) replacement therapy remains the mainstay in hemophilia A care. The major complication of replacement therapy is formation of antibodies, which inhibit FVIII activity, thus dramatically reducing treatment efficiency. The present review summarizes the accumulated knowledge on epitopes of FVIII inhibitors and mechanisms of their inhibitory effects. FVIII inhibitors most frequently target the A2, C2 and A3 domains of FVIII and interfere with important interactions of FVIII at various stages of its functional pathway; a class of FVIII inhibitors inactivates FVIII by proteolysis. We discuss therapeutic approaches currently used for treatment of hemophilia A patients with inhibitors and analyze the factors that influence the outcome. The choice between options should depend on the level of inhibitors and consideration of efficacy, safety, and availability of particular regimens. Advances of basic science open avenues for alternative targeted, specific and long-lasting treatments, such as the use of peptide decoys for blocking FVIII inhibitors, bypassing them with human/porcine FVIII hybrids, neutralizing FVIII-reactive CD4+ T cells with anti-clonotypic antibodies, or inducing immune tolerance to FVIII with the use of universal CD4+ epitopes or by genetic approaches.

Original languageEnglish (US)
Pages (from-to)109-124
Number of pages16
JournalBlood Coagulation and Fibrinolysis
Issue number2
StatePublished - Mar 1 2004


  • Anti-idiotypic antibodies
  • Epitope
  • Factor VIII
  • Hemophilia A
  • Immune response
  • Inhibitory antibody
  • Inhibitory mechanism
  • Peptide decoy
  • T cell
  • T-cell co-stimulatory interactions
  • Universal CD4 epitope
  • Xase complex

ASJC Scopus subject areas

  • Hematology


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