Bleeding Predictability in Patients with Factor XI Deficiency: The Experience of Reference Centers in Southern Italy

Background: Factor XI (FXI) deficiency, or hemophilia C, is a rare bleeding disorder resulting from reduced levels or dysfunctional FXI protein due to mutations in the F11 gene. Aim of the Study: This study investigated the correlation between FXI activity levels, F11 genotype and bleeding phenotypes Methods: Clinical and genetic characteristics of 93 individuals from southern Italy diagnosed with congenital FXI deficiency, including 39 index cases and their relatives were evaluated. FXI:C plasma levels were measured. Sanger sequencing of F11 was performed and pathogenicity of variants identified was assessed using in silico tools. Results: FXI activity levels ranged widely (1–69%), with most cases being heterozygous and showing moderate deficiency. Only 12 individuals had severe FXI deficiency, typically associated with homozygosity or compound heterozygosity. Bleeding symptoms varied from mild to severe and occurred in 31% of subjects, though only a minority of those with severe deficiency experienced spontaneous or surgery-related bleeding. Sanger sequencing revealed 24 distinct F11 gene variants, predominantly missense mutations, with three novel variants (p.Val89*, p.Leu306Pro, and p.Trp515Gly). Common mutations included p.Glu135* and p.Glu315Lys. Variants were distributed across the gene, with no domain-specific clustering. No clear genotype-phenotype correlation was observed). Conclusions: FXI levels alone did not reliably predict bleeding risk, highlighting the influence of additional factors such as age, gender, and clinical history. The study reinforces the allelic and clinical heterogeneity of FXI deficiency and the limited utility of FXI:C levels alone for predicting bleeding severity. Comprehensive risk assessment models integrating clinical and molecular data are necessary for optimal patient management. Further research is needed to clarify the complex genotype–phenotype relationships in FXI deficiency.