Anti-factor VIII inhibitors in haemophiliacs

Anti-factor VIII (F VIII) antibodies are detected in 15 to 30% of severe haemophilia patients, in general at a young age, before the first 50 days of exposure to the concentrates of F VIII whose they compromise the effectiveness. The risk is approximately four times weaker in patients with moderate or minor haemophilia. These antibodies are directed against several sites of the molecule of F VIII, located on the heavy chain (especially the A2 domain) or the light chain (C2 domain mainly or A3 or C1 domains). The anti-C2 inhibitors have probably a particular importance since this domain also contains binding sites to von Willebrand factor and to phospholipids. Among the factors of genetic risk to take into account appear the type of gene F VIII mutation (especially inversion of intron 22 in severe haemophilia, missense mutations in case of moderate or minor haemophilia), the ethnic factors and the antigens of class II of the major histocompatibility system. The type of concentrates of F VIII administered to patients can also exert a certain influence the more so as the products differ between each others by certain characteristics such as concentration of vWF, affinity to phospholipids, F Xa generation. Modifications of structure induced by certain processes of viral inactivation applied to two brands of plasmatic F VIII concentrates induced an abrupt increase in the number of the inhibitors in patients already largely exposed to anti-haemophilic fractions (Belgium, Holland, Germany). Apart from this particular situation, if the incidence of anti-F VIII inhibitors in the severe haemophiliacs only treated with by recombinant products is about 30%, lower values of incidence seem to have been obtained with some plasmatic products. The current data do not make it possible however to solve the question definitively. Other factors like the successive use of several types of concentrates (switch), their sequence or their mode of administration must also be examined.