Shaping hemophilia care: lessons and legacy of the SIPPET trial after 10 years.

The advent of nonreplacement therapies, such as emicizumab, has contributed to a marked reduction of the observed incidence of factor (F)VIII inhibitors in patients with severe hemophilia A. However, it should be clarified whether this decline reflects delayed FVIII exposure or a true reduction in immunogenicity. Thus, understanding the mechanisms driving anti-FVIII inhibitor formation, particularly during early exposure in previously untreated patients, remains a key objective in hemophilia care and is a still unmet need. Ten years ago, the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) trial marked a turning point by providing the first randomized evidence that plasma-derived FVIII products containing von Willebrand factor are associated with a lower inhibitor incidence than recombinant FVIII. These findings influenced international guidelines, prompted changes in clinical practice, and highlighted the importance of the choice of the product type during the early, immunologically vulnerable period of exposure to FVIII. Post-SIPPET studies expanded this evidence base, offering deeper insights into the immunogenicity of FVIII products and offering mechanistic insights into the influence on inhibitor development of gene mutations, nonneutralizing antibodies, immunoglobulin G subclass responses, epitope specificity, and epigenetic modulation. The legacy of SIPPET is not only in its immediate clinical impact but also in its catalyzing role for a broader, multidisciplinary effort to understand inhibitor occurrence in severe hemophilia A.