Haemophilia A is a rare congenital bleeding disorder caused by a deficiency of blood coagulation protein factor VIII (fVIII). Prophylactic fVIII infusions are the standard of care for the prevention of bleeds and their sequela. 1 However, 30% of individuals with severe deficiency will develop neutralizing antibodies, called inhibitors, against fVIII. 2 Most patients who develop inhibitors, particularly individuals with high titre inhibitors (titres ≥ 5 Bethesda units (BU) per mL), require immune tolerance induction (ITI) consisting of frequent and often high dose fVIII to induce peripheral tolerance. ITI is the standard of care for eradicating inhibitors with reported success Abstract Introduction: The formation of neutralizing antifactor VIII (fVIII) antibodies, called inhibitors, is the most common complication in modern haemophilia A care. Novel non-factor replacement therapies, such as emicizumab, have sought to address the limitations of bypassing agents for bleeding management in patients with inhibitors.However, immune tolerance induction (ITI) remains the primary method for eradicating inhibitors and restoring the hemostatic response to fVIII. Aim:The aim of this study was to review a case series of paediatric patients with haemophilia A and inhibitors who have received ITI for inhibitor eradication concomitantly with emicizumab prophylaxis for bleeding prevention.Methods: Single institution retrospective chart review of paediatric patients with severe haemophilia A receiving ITI and emicizumab.Results: Seven patients were included in this cohort. Six patients used three different recombinant fVIII products at 100 IU/kg three times per week, and one patient used a plasma-derived fVIII product at an initial dose of 50 IU/kg three times per week.

Background Elucidating the molecular pathogenesis underlying East Texas bleeding disorder (ET) led to the discovery of alternatively spliced F5 transcripts harboring large deletions within exon 13. These alternatively spliced transcripts produce a shortened form of coagulation factor V (FV) in which a large portion of its B‐domain is deleted. These FV isoforms bind tissue factor pathway inhibitor alpha (TFPIα) with high affinity, prolonging its circulatory half‐life and enhancing its anticoagulant effects. While two missense pathogenic variants highlighted this alternative splicing event, similar internally deleted FV proteins are found in healthy controls. Objective We identified a novel heterozygous 832 base pair deletion within F5 exon 13, termed F5‐Atlanta (F5‐ATL), in a patient with severe bleeding. Our objective is to investigate the effect of this deletion on F5 and FV expression. Methods & Results Assessment of patient plasma revealed markedly elevated levels of total and free TFPI and a FV isoform similar in size to the FV‐short described in ET. Sequencing analyses of cDNA revealed the presence of a transcript alternatively spliced using the ET splice sites, thereby removing the F5‐ATL deletion. This alternative splicing pattern was recapitulated by heterologous expression in mammalian cells. Conclusions These findings support a mechanistic model consisting of cis‐acting regulatory sequences encoded within F5 exon 13 that control alternative splicing at the ET splice sites and thereby regulate circulating FV‐short and TFPIα levels.