Factor 8 (F8) gene mutation profile of Turkish hemophilia A patients with inhibitors

Blood Coagul Fibrinolysis. 2008 Jul;19(5):383-8. doi: 10.1097/MBC.0b013e3282f9b193.


Factor VIII (FVIII) replacement therapy is ineffective in hemophilia A patients who develop alloantibodies (inhibitors) against FVIII. The type of factor 8 (F8) gene mutation, genes in the major histocompatibility complex loci, and also polymorphisms in IL-10 and tumor necrosis factor-alpha are the major predisposing factors for inhibitor formation. The present study was initiated to reveal the F8 gene mutation profile of 30 severely affected high-responder patients with inhibitor levels of more than 5 Bethesda U (BU)/ml and four low-responder patients with inhibitors less than 5 BU/ml. Southern blot and PCR analysis were performed to detect intron 22 and intron 1 inversions, respectively. Point mutations were screened by DNA sequence analysis of all coding regions, intron/exon boundaries, promoter and 3' UTR regions of the F8 gene. The prevalent mutation was the intron 22 inversion among the high-responder patients followed by large deletions, small deletions, and nonsense mutations. Only one missense and one splicing error mutation was seen. Among the low-responder patients, three single nucleotide deletions and one intron 22 inversion were found. All mutation types detected were in agreement with the severe hemophilia A phenotype, most likely leading to a deficiency of and predisposition to the development of alloantibodies against FVIII. It is seen that Turkish hemophilia A patients with major molecular defects have a higher possibility of developing inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions / genetics
  • Blood Coagulation Factor Inhibitors*
  • Factor VIII / analysis
  • Factor VIII / genetics*
  • Hemophilia A / blood
  • Hemophilia A / genetics*
  • Humans
  • Introns / genetics
  • Male
  • Mutation*
  • Polymorphism, Genetic
  • Turkey


  • 3' Untranslated Regions
  • Blood Coagulation Factor Inhibitors
  • F8 protein, human
  • Factor VIII