Factor VIII Inhibitors in Haemophilia A Patients after Continuous Infusion of Factor VIII Concentrates.

Continuous infusion (CI) of coagulation factor concentrates has been used in haemophilia treatment since the early 1990s. Recent reports of the occurrence of an inhibitor (inh.) after CI have raised concerns about this method of treatment. We conduct a retrospective study to investigate the development of inh. After CI of factor VIII (FVIII) concentrates in Germany and report on further study results. A questionnaire was sent to 100 haemophilia treating colleagues in Germany. So far 42 colleagues have answered, in 19 haemophilia treatment centers CI was used as treatment modality, 5 of them still use it today. Altogether 200 CI were conducted in 128 patients (pat.). In 14 pat. Inh. Development was detected. 5 of these pat. Were suffering from severe, 1 from moderate and 8 from mild haemophilia, their median age was 27 years. Indications for treatment before inh. Detection were major bleeds and surgical procedures. Plasmaderived (9) and recombinant (4) factor concentrates were given in various infusion sets. Data concerning gene mutation, exposure days, inhibitor characteristic, former change of product, concomitant medication, vaccination and blood transfusion were collected. Regarding the genotype, we found 4 missense mutations, 2 intron-22-inversions, 1 small deletion, 1 splice site mutation, 6 were unknown. In our study strikingly the inh. Developed very often in pat. With mild or moderate haemophilia and genotypes that exhibit an inh. Prevalence of < 10 %. Our further data confirm the assumption that pat. With mild haemophilia might exhibit a much higher prevalence of inh. Development when treated with an “intensive FVIII - treatment” such as CI. On the other hand there might be an uncommon inh. pathomechanism in connection with CI, resulting in a peculiar group of pat. developing the inh. after this way of application. A prospective multicenter study to investigate the inhibitor development after CI should be conducted.