25 (20–50) (n = 14) 25 (20–40) (n = 9) 28 (22–50) (n = 10) 22 (20–25) (n = 0) The characteristics of patients with inhibitors (n = 9) were examined according to whether the inhibitor was high titre or low titre (Table 6). No clinically meaningful differences were found

between groups in age (months) or body weight-related dose at the time of start of prophylaxis. The number of exposure days to FVIII replacement therapy until inhibitor development was considerably greater in patients with low-titre vs. high-titre inhibitors (32 vs 14 days). Although identification of danger signals for inhibitor formation was stated as a study objective, this proved difficult to achieve in practice due to the retrospective nature of the data collection. Three danger signals PI3K Inhibitor Library supplier in the high titre group (two patients with surgery, one patient with vaccination) and two danger signals in the low titre group (two patients with severe bleeds) may have contributed to inhibitor development. Maximal inhibitor titre was >200 BU (median 12 BU) in the high-titre group and 2.9 BU (median 1.8 BU) in the low-titre group. Immune tolerance induction therapy was performed in four of the five high-titre patients and was successful in all four patients, Rapamycin price although two patients initially failed first-line treatment. The remaining patient was not treated because of a low ‘high-titre’ inhibitor (6 BU) that disappeared with ongoing prophylaxis.

None of the patients with low titre inhibitors (n = 4) received ITI therapy and all inhibitors disappeared with continued-prophylaxis. Two of the four patients with successful ITI outcomes achieved inhibitor eradication using rFVIII products and both went on to receive either pdFVIII or pdFVIII/VWF. The remaining two patients with successful ITI outcomes failed to achieve inhibitor eradication after 6 months’ treatment with rFVIII products, but were tolerized following a switch to a VWF-containing rFVIII. The study has a number of limitations including methodological weaknesses inherent with a retrospective design. The patient group was small and data are preliminary as multivariate statistical analysis is pending. Identification of danger signals for inhibitor formation proved

difficult to achieve due to the retrospective evaluation approach (data collected medchemexpress from patients’ medical charts). The higher incidence of inhibitors observed in patients treated with once-weekly prophylaxis may relate to the non-identification of danger signals before the start of early prophylaxis. This is in line with the EPIC study which was terminated early because of the presence of more danger signals than expected [47]. Acceptance has been good of an early prophylaxis scheme for prevention of inhibitor formation in PUPs with severe haemophilia A among centres in the eastern German network for coagulation disorders. From a theoretical viewpoint, the concept of early prophylaxis is convincing and many participating centres have adopted this approach.