Moreover, the switching between FVIII product brands did not increase the inhibitor risk over the first 50 ED [27]. At variance with the comparison of the retrospective French cohorts that showed lower inhibitor risk in patients treated with a single FVIII plasma-derived vs. a recombinant product [28], the CANAL results were consistent with the findings of another recent English study that failed to detect significant BGB324 order differences in inhibitor

risk at multivariate analysis [29], and highlighted that clinically relevant inhibitors develop with substantially comparable figures irrespective of type of product. On the other hand, the prospective long-term rFVIII registration studies clearly showed that approximately one-third of detected inhibitors was transient and that only about half were high-titre (>10 BU/mL) inhibitors (Table 2) [11]. These discrepancies in inhibitor detection may be attributed to the different study designs (retrospective, multicenter and multinational involving many product brands and modality of treatment, different ED) and, particularly to the fact that low-titre

and transient inhibitors were probably not detected in the older plasma-derived FVIII studies, resulting in an under-estimation of the overall incidence of inhibitors. Thus, the protective role of VWF in reducing FVIII immunogenicity is supported more by the in vitro data and preclinical experiments in animal OTX015 manufacturer models rather than in the clinical setting (Table 1), where there is no conclusive evidence to support the lower risk of inhibitor development of VWF-containing plasma-derived products; indeed, the possible advantages seem confined to some but not 上海皓元医药股份有限公司 to all products and to

the development of low-titre inhibitors [27–29]. Moreover, epidemiological data on inhibitor development in the rFVIII PUPs studies [11] may be revisited based on the present knowledge that makes it possible to identify risk profiles for the study populations (Table 2). The most convincing predisposing or protective effects of factors affecting inhibitor development briefly discussed in these paragraphs are represented and summarized in Fig. 1. The increasing and evolving knowledge of cellular immune response to exogenous FVIII provided new insights into the understanding of inhibitor development in haemophilia A. The environmental conditions at first FVIII exposures interplay with the patient’s genetic background, which influences the recognition of non-self; together with the F8 mutation type, an important role for immune-regulatory genes is emerging, consistent with the up- or down-regulation of cellular response against the foreign antigen in the presence (or absence) of danger signals.