Haemophilia A is one of the most common X-linked hereditary coagulation disorders with a freguency of ≈ 1 in 5,000 male births in all ethnic groups. A large number of different molecular defects have been described in patients with haemophilia A. The most common mutation in patients with the severe form is a partial inversion of factor VIII mediated by a 9.5 Kb sequence, present in the large intron 22 of factor VIII and twice more about 400 Kb telomeric to it. Different types of the partial inversion account for 43% of the molecular defects in those patients. A higher frequency for inhibitors development seems to be associated with this type of defect.

The aim of the study was to analyse DNA from 28 severe haemophilia A patients (FVIII<lu/dl) by southern blotting technique and correlate the defect with the frequency of inhibitors development and its severity. Using Bcl I restriction enzyme, cloned factor VIII cDNA probe (0.9 kb EcoRI/SstI fragment prepared from plasmid p482.6) and genomic DNAs, the recombination between homologous sequences located in intron 22 and upstream of the factor VIII gene was identified in 12 patients (43%). This recombination leads to an inversion that disrupts the factor VIII gene. In our small series the incidence of inhibitors (titer > 1.0 BU) was 58% (7/12) versus 44% (7/16) in the group of patients without the above recombination. The inhibitor titer was high (90 BU) in a 4 year-old haemophiliac and (8.0 BU) in another one.