Factor XI deficiency

Factor XI deficiency is a bleeding disorder with a mild and highly variable clinical phenotype. Affected individuals typically present with mucocutaneous bleeding such as bruising, epistaxis, menorrhagia, haematuria, and obstetric bleeding, including postpartum haemorrhage; severe spontaneous bleeding is infrequent, and joint or muscle haemorrhage is atypical. The disorder is often unmasked by trauma or surgery, on routine pre-surgical laboratory evaluation, or through family-based testing after a proband is identified. Clinical presentation may occur at any age and frequently follows a haemostatic challenge rather than a baseline symptom pattern; some individuals remain asymptomatic until adulthood. The bleeding tendency correlates poorly with the plasma factor XI activity level, and the bleeding phenotype can vary significantly between individuals with comparable factor XI activity and within a single pedigree.

The estimated prevalence is 1:1,000,000 in the general population. Carrier frequencies are markedly higher in Ashkenazi Jewish populations owing to common founder variants in F11.

Factor XI deficiency is caused by germline pathogenic variants in the F11 gene, encoding coagulation factor XI, a zymogen of the intrinsic coagulation pathway. Pathogenic variants reduce factor XI activity quantitatively or qualitatively. The reported variant spectrum is dominated by missense changes, with smaller proportions of nonsense, frameshift, slice-site, and indel variants.

Factor XI deficiency is inherited in an autosomal recessive manner. For couples in which both partners carry a pathogenic F11 variant, the recurrence risk for each pregnancy is 25% for an affected child and 50% for an unaffected carrier. Prenatal molecular testing is technically possible once the familial pathogenic variants have been identified. 

Diagnosis rests on a one-stage clot-based assay of plasma factor XI activity. A factor XI activity (FXI:C) below 20 U/dL defines severe deficiency, and levels of 20 to 70 U/dL define partial deficiency. A prolonged activated partial thromboplastin time (aPTT) is the typical initial screening abnormality and usually appears at factor XI activity around 30 U/dL.

• Establishing the diagnosis: a molecular genetic finding provides the definitive basis for diagnosis and complements clinical and biochemical evaluation.
• Family member testing: once the familial pathogenic variants are known, targeted analysis can clarify variant status in at-risk relatives within the framework of genetic counselling.

• Liang C, Jin JY, Shi HH, Li HX, Chen LL, Zhang YH, et al. Case report: allelic and biallelic variants in coagulation factor XI cause factor XI deficiency. Front Cardiovasc Med. 2024;11:1461899. doi:10.3389/fcvm.2024.1461899. PMID: . PMCID: PMC11599221.
• Davidson S, Gomez K. Laboratory and molecular diagnosis of factor XI deficiency. Semin Thromb Hemost. 2025;51(2):145-154. doi:10.1055/s-0044-1792033. PMID: . PMCID: PMC11906224