Factor VIII inhibitor in a patient with mild haemophilia A and an Asn618-->Ser mutation responsive to immune tolerance induction and cyclophosphamide

Br J Haematol. 2002 Apr;117(1):136-40. doi: 10.1046/j.1365-2141.2002.03383.x.


We describe a patient with mild haemophilia A (original value of factor VIII activity 0.30 U/ml) who developed an inhibitor (36.1 Bethesda U/ml) which cross-reacted with his endogenous factor VIII. This caused a decline in basal factor VIII level (< 0.01 U/ml) and severe haemorrhagic events. Treatment to induce immune tolerance was started with factor VIII/von Willebrand factor (VWF) concentrates, but inhibitor levels increased progressively and the patient suffered serious bleeding. Cyclophosphamide was administered and, after 8 months treatment, factor VIII levels increased to 0.20 U/ml and the inhibitor could no longer be detected. Screening of his factor VIII gene revealed a missense mutation in exon 13 that predicts substitution of Asn618-->Ser in the A2 domain of factor VIII. Immunoprecipitation analysis showed that the antibodies present in the patient's plasma reacted with metabolically labelled A2 domain and, to a lesser extent, with factor VIII light chain. Inhibitory antibodies were completely neutralized by recombinant A2 domain, whereas no neutralization was observed after the addition of factor VIII light chain (A3-C1-C2) and C2 domain. More detailed analysis showed that the majority of inhibitory antibodies were directed against residues Arg484-Ile508, a previously identified binding site for factor VIII inhibitors. Our findings suggest that immune tolerance therapy and cyclophosphamide were successful in eradicating inhibitory antibodies against a common epitope on factor VIII.

Publication types

  • Case Reports

MeSH terms

  • Aged
  • Autoantibodies / analysis*
  • Cyclophosphamide / therapeutic use
  • Epitope Mapping
  • Factor VIII / administration & dosage
  • Factor VIII / genetics
  • Factor VIII / immunology*
  • Hemophilia A / blood*
  • Hemophilia A / therapy
  • Humans
  • Immunosuppressive Agents / therapeutic use
  • Male
  • Mutation, Missense
  • Precipitin Tests


  • Autoantibodies
  • Immunosuppressive Agents
  • Cyclophosphamide
  • Factor VIII