PHD / DOTTORATO

The thesis sought to gain a deeper understanding of inhibitor development, a major complication of factor VIII (FVIII) replacement therapy in severe hemophilia A. We carried out 3 studies on previously untreated patients (PUPs) with severe hemophilia A, aged under 6 years old and initially inhibitor-free. In chapters I and II, we studied the signatures of IgG subclasses along treatment with FVIII during the first 50 exposure days (EDs), before and after inhibitor development, to identify hallmarks of inhibitor development and inhibitor persistence. Results confirmed IgG4 as the most prominent subclass in patients with inhibitors and suggested that IgG2 is the only subclass that could be considered a hallmark of inhibitor persistence, detectable as early as 2-4 months after inhibitor development and associated with an 11 times higher likelihood of persistence. In chapter III, we carried out an epidemiological cohort study to measure the risk of inhibitor development in patients upon a change of treatment approach consisting in a switch from plasma-derived products (pdFVIII) to recombinant products (rFVIII), promoting the use of each class in its optimal moment. The results showed that a switch after 50 EDs is immunologically safe. All in all, the evidence obtained along this thesis allowed to make essentially 2 recommendations: 1) To consider IgG2 as a candidate predictor of bad prognosis, associated with inhibitor persistence; 2) To consider a treatment switch in PUPs after 50 EDs from pdFVIII to rFVIII, allowing to combine the features of both product classes, each at their respective beneficial time.