Diagnosis and management of factor XI alloinhibitors in patients with congenital factor XI deficiency-A large single-centre experience.

INTRODUCTION: Factor (F) XI deficiency is an inherited bleeding disorder with increased prevalence in Ashkenazi Jews where it is mainly caused by two variants, p.Glu135* (type II, leading to a null allele) and p.Phe301Leu (type III, missense variant). Inhibitor development is rare, and only seen in severe FXI deficiency (<20 IU/dL) upon exposure to plasma-based products. We report our experience of a large cohort of patients with severe FXI deficiency, including seven patients who developed FXI alloinhibitors, their presentation, natural history and subsequent perioperative management. METHODS: A single-centre retrospective database review of patients with FXI deficiency, including those who have subsequently developed inhibitors, and extraction of clinical, laboratory and genotype data, including operative management records. RESULTS: A total of 682 patients were identified with FXI deficiency, of whom 113 had FXI < 20 IU/dL and 42 had FXI ≤ 1 IU/dL. Factor XI inhibitors were seen in seven patients, six of whom were homozygous for the type II variant (prevalence of inhibitor with this genotype of 30%, risk of inhibitor upon plasma exposure 50%). FXI inhibitors were not seen, despite similar exposures, in patients with other genotypes. No alteration in bleeding phenotype occurred after inhibitor development and subsequent surgery was managed on 13 occasions with recombinant factor VIIa (rFVIIa), including low doses (15-30 µg/kg), with good haemostasis. The inhibitor spontaneously disappeared in four of seven patients over 1-22 years. CONCLUSION: FXI inhibitors were only observed in severe FXI deficient patients homozygous for p.Glu135* (null allele) upon plasma or FXI concentrate exposure, with a 30% prevalence. The bleeding phenotype was not altered and inhibitors may disappear with time. Adequate haemostasis in the perioperative setting is achievable with low doses of rFVIIa.

Postmortem diagnosis of severe factor X deficiency in a fetus with intracranial hemorrhage resulting in intrauterine death.

In patients with severe congenital factor X deficiency, spontaneous intracranial hemorrhage (ICH) is particularly frequent in early childhood. We describe a case of fetal death at 26 weeks due to massive ICH. Gene panel analysis of postmortem samples revealed homozygosity for a pathologic F10 gene variant (c.1210T>C, p.Cys404Arg), which impedes correct folding of the catalytic serine protease domain and, therefore, causes a significant reduction in FX levels. The parents, not consanguineous but of the same ethnic community, were found to be heterozygous for this variant and did not have any personal or family history of abnormal bleeding. To the best of our knowledge, this is the first reported case of severe FX deficiency resulting in ICH diagnosed through postmortem genetic analysis. It illustrates the importance of exploring the etiology of fetal or neonatal ICH, which may impact future pregnancies, and the treatment of a potential coagulopathy in the child.