Large FVIII gene deletion confers very high risk of inhibitor development in three related severe haemophiliacs

Haemophilia. 2002 Jan;8(1):17-21. doi: 10.1046/j.1365-2516.2002.00578.x.


Haemophilia A displays a broad heterogeneity of genetic defects and of clinical severity. Inhibitor development is the main complication of replacement therapy in severe cases and most patients with inhibitors have gross gene rearrangement or point mutations, which hamper the production of normal circulating factor VIII (FVIII). We have investigated three related severe haemophilia A patients, all of whom have high titre inhibitors. By using long-range polymerase chain reaction (PCR) for FVIII gene inversion, we observed an unusual pattern in these patients. We therefore decided to screen the whole FVIII gene by conformation-sensitive gel electrophoresis. A large FVIII gene deletion spanning exon 2 to exon 25 was identified and we were able to obtain a 18.5 kb PCR product, which is specific for this mutation and useful for determining the carrier state in this family. All three haemophiliacs carrying this very large gene deletion show similar clinical history and very high-titre inhibitors, supporting the observation that inhibitor development seems to be an inherited characteristic. On the basis of our observations we think that this subgroup of patients at very high risk of inhibitor development should be identified by mutation analysis whenever possible, before the beginning of replacement therapy.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Base Sequence
  • Child
  • DNA Mutational Analysis
  • Exons
  • Factor VIII / genetics*
  • Factor VIII / immunology
  • Family Health
  • Genetic Testing
  • Hemophilia A / genetics*
  • Hemophilia A / immunology
  • Humans
  • Isoantibodies / blood*
  • Male
  • Middle Aged
  • Pedigree
  • Risk Factors
  • Sequence Deletion / genetics*


  • Isoantibodies
  • Factor VIII