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Maintaining Factor VIII Tolerance in Patients with Severe Hemophilia A on Emicizumab: A Four-Patient Case Series Emily E Mason, Amy Dunn. Nationwide Children's Hospital, Columbus, OH, USA

Abstract

Background The development of factor VIII (FVIII) inhibitors remains a major treatment-related complication in patients with severe Hemophilia A (SHA), occurring in approximately 30% of individuals within the first 50 exposure days to FVIII concentrates [1]. Even after successful immune tolerance induction (ITI), patients with a history of inhibitors remain at risk for inhibitor recurrence, which increases morbidity, treatment complexity, and cost. The introduction of emicizumab has transformed prophylaxis by reducing bleeding rates and minimizing factor exposure. However, non-factor therapies do not provide antigenic stimulation, raising concern that FVIII tolerance may wane over time. FVIII remains essential for managing breakthrough bleeding and perioperative hemostasis.  Current guidelines offer no consensus on whether or how to maintain FVIII exposure in tolerized patients who transition from FVIII to emicizumab prophylaxis, and available data are limited.   Objective To describe our institutional approach and outcomes in sustaining FVIII tolerance in patients with prior inhibitors who transitioned to emicizumab. Methods We reviewed all patients in our clinic with a history of a tolerized inhibitor based on International Society on Thrombosis and Haemostasis definitions. We identified four patients with SHA with a remove inhibitor history, all successfully tolerized through ITI. After initiating emicizumab prophylaxis, our center implemented monthly low-dose FVIII infusions (targeting 10-50 IU/kg) to maintain antigenic exposure. Clinical data were collected on inhibitor recurrence, breakthrough bleeding, infusion reactions, injection site reactions, and thrombotic events. Inhibitor titers were obtained at least annually and were initially reported by the CDC until the chromogenic Bethesda assay became widely available in 2021.  Results All patients were tolerized a median of 10.5 years prior to transitioning to emicizumab prophylaxis (range: 9-14 years). Over a median follow-up of 4.5 years (range: 2-7), no patient developed recurrent inhibitors. All patients tolerated FVIII infusions without allergic reactions or anamnestic responses. Breakthrough bleeding and surgical episodes were managed with FVIII without complications. No thrombotic events occurred. Conclusions Monthly FVIII infusions alongside emicizumab may help preserve tolerance in patients with prior inhibitors while reducing infusion frequency and improving quality of life. This strategy is not evidence-based and larger studies are needed to define optimal protocols and long-term outcomes, as current literature offers limited guidance on balancing inhibitor risk with reduced factor exposure in the era of non-factor prophylaxis. References Gouw, S.C., et al. Factor VIII products and inhibitor development in severe hemophilia A. N Engl J Med, 2013. 368(3): p. 231-9. Batsuli, G., et al., Emicizumab in tolerized patients with hemophilia A with inhibitors: A single-institution pediatric cohort assessing inhibitor status. Res Pract Thromb Haemost, 2021. 5(2): p, 342-348. Singh, P,. et al., Post-Immune Tolerance Induction Prophylactic FVIII Infusions May Not be Necessary for Tolerized Patients on Emicizumab. Blood, 2023. 142: p. 5476-5477.

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