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Background Immune tolerance induction (ITI) is the treatment of choice for eradication of anti-factor VIII (FVIII) neutralizing alloantibodies (inhibitors) in people with inherited hemophilia A and high-responding inhibitor (PwHA-HRi). The association between ITI outcome and time elapsed between inhibitor detection and start of ITI ( increment t(inhi-ITI)) is debatable. Objective The aim of this study was to evaluate this association among a large cohort of severe PwHA-HRi. Methods Severe (factor VIII activity level 0.6-1.7 year), third (>1.7-9.2 years), and fourth quartile (>9.2-24.5 years). The overall success rate was 65.5% (93/142), with no difference among first, second, third, and fourth quartiles (62.9%, 69.4%, 58.3%, and 71.4%, respectively) even after adjusting the analyses for potential confounders. Conclusion In conclusion, delayed ITI start is not associated with failure of ITI in PwHA-HRi. Therefore, ITI should be offered for these patients, regardless of the time elapsed between the detection of inhibitor and the ITI start.

This illustrated review focuses on the development of inhibitors in patients with congenital hemophilia, which is the most serious treatment-related complication in these patients. Hemophilia A (HA) is an inherited X-linked bleeding disorder affecting 1:5000-10 000 newborn males worldwide. It results from the deficiency of coagulation factor VIII (FVIII), due to mutation(s) in its coding gene (F8). Treatment requires administration of FVIII-containing products either on demand or as prophylaxis, which can induce inhibitor development in 20%-35% of patients. Inhibitors are alloantibodies that neutralize the procoagulant activity of exogenous FVIII. During the initial administration of FVIII-containing products, patients with HA can develop a proinflammatory immune response with synthesis of anti-FVIII IgG1, which has no FVIII inhibitory activity. However, in patients with inhibitors, immune response shifts toward an anti-inflammatory/regulatory pattern favoring the synthesis of anti- FVIII IgG4 antibodies. Patients with inhibitors present with bleeding episodes that are difficult to control, and they have reduced response to FVIII replacement. Currently, immune tolerance induction is the available treatment for eradication of persistent high-titer inhibitors. Despite the clinical relevance, the immunological mechanisms for inhibitor development in patients with HA remains unexplained.