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Approximately 25% of hemophilia A patients infused with factor VIII (fVIII) mount an immune response, which leads to its inactivation. Anti-fVIII autoantibodies are also seen rarely in individuals with normal fVIII. We have previously demonstrated that some anti-A2 and anti-C2 domain antibodies are fVIII inhibitors and that many patients have additional inhibitors with a fVIII light chain (LCh) epitope outside C2. Because the contribution of the different antibodies to the plasma inhibitor titer had been examined in a limited number of patients (14), we report in this study a more extensive analysis of 55 plasmas. The dominant inhibitors in 62% (13 of 21) of autoantibody plasmas were directed only against C2 or A2, but not both, whereas this pattern was found in only 15% (5 of 34) of hemophilic plasmas. In addition, anti-A2 inhibitors were present in 71% (24 of 34) of hemophilic plasmas, but only 33% (7 of 21) of autoantibody plasmas. These results demonstrated that the inhibitor response in hemophiliacs was more complex and the epitope specificity was somewhat different. A comparison of hemophiliacs treated only with plasma fVIII or recombinant fVIII showed no significant differences in the complexity of the inhibitor response, as = 2 different inhibitor antibodies were present in 78% (18 of 23) of the former and 82% (9 of 11) of the latter. In contrast, the major inhibitors in 35% (8 of 23) of hemophiliacs treated with plasma fVIII were directed against C2 and another LCh epitope within residues 1649-2137, but not A2, while none (0 of 11) treated with recombinant fVIII had this pattern.

Thirteen children up to 12 years of age and 14 patients being 65 or older were treated for prophylaxis, haemorrhages or peri-operatively. Obvious deviations were found in general condition, bleeding locations and types of surgeries for the elderly patients. Further, the data provide evidence of age group-related differences regarding reason for administration (see table 1) and dosages administered. The efficacy and tolerability of wilate®treatment in children and elderly was as high as in the total group.Young or old age seem to have an impact on clinical requirements of VWD. However, larger cohorts are required to confirm these first findings of the non-interventional study “Wilate SET”.Hegener: Octapharma AG: Employment. Feddern:Octapharma: Employment.

Previously treated patients (PTP), who have not developed an inhibitor (inh.) so far, are considered to be tolerant to factor VIII and at low risk for inh. development. Therefore inh. detection in a PTP should raise concerns about the concomitant variables such as product neo-antigenicity or way of application. To find out about the current situation regarding inh. development in PTP in Germany, we conduct a retrospective study. A questionnaire was sent to 87 haemophilia treating centers, so far 46 of them answered. 28 PTP-inh. developments during the last 5 years were reported. Age of the patient (median 35), severity of haemophilia A (18 severe, 2 moderate, 8 mild), exposuer days (median 30) and gene mutation (intron-22-inversions 31%, large deletions 13%, missense mutations 25%, stop mutation 6%, small deletion 13%) were recorded. 8 different factor VIII concentrates were given during inh. development (5 plasma derived, 3 recombinant). Way of application (16 times bolus infusion, 3 times continuous infusion, 5 times both), former change of product, infused amount until inh. development, inh. characteristic, concomitant diseases and medication were registered. In conclusion most of the patients were over 18 years old (17/28) when the inh. developed. Most of them had severe haemophilia A (18/28) and had at least one change of product before inh. detection. Our data are still too small to draw any conclusion concerning product neo-antigenicity or treatment modalities. Nevertheless it became obvious that inh. development in PTP is still a serious and underestimated problem in haemophilia treatment today. Secondly data showed that there is a variety of PTP definitions in Germany, referring to age of pat, number of exposure days and former change of product. An international definition for PTP would be helpful. A national haemophilia register would make it easier to evaluate data in the future and a prospective, not product related study should be conducted.

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.