Haemophilia A Genotype and Inhibitor Risk: Preliminary Results of a French Haemophilia Centre.

Caen Haemophilia centre monitored 343 haemophilia A patients, 62 of them with a severe defect. We report here the preliminary results of genotypes and factor VIII (FVIII) inhibitors response for the first 59 and particularly for 15 patients with FVIII inhibitors. For severe haemophilia A, the first step is a long PCR for intron 22 inversion, then PCR for intron 1 inversion. The second step is a direct sequencing of the FVIII gene in severe form without inversion and in moderate or mild disease. 41% (16 / 39) of the patients with severe haemophilia A have an intron 22 inversion, the remainder patients have single point mutations (17), principally on exon 14, large deletion (1), small deletion (3) or splice mutations (3). In the severe form, 10 of these patients have developed inhibitors: 6 with intron 22 inversion, 3 non sense mutations on exons 14 or 18, 1 large deletion on exon 14 and 1 splice mutation on intron 22. In the moderate or mild form, 20 patients have missense mutations, 5 of them have developed inhibitors. The genotype of three patients has been previously reported to be associated with a high incidence of inhibitors in moderate and mild form: Arg 593 Cys by loss of tolerance to exogenous and endogenous FVIII (1), Arg 2150 His by reducing the binding of FVIII to von willebrand factor (2). For the other two patients, we identified two missense mutations: Val 2017 Ala, Tyr 1786 Ser. We are processing genotypes for each haemophilia A patients to evaluate the genotype - phenotype relationship and the FVIII inhibitor risk related to genetic and environmental factors.