rs1057517151 — F11 c.291del (p.Tyr98fs)

Frameshift deletion in coagulation factor XI causing likely-pathogenic partial or severe FXI deficiency (hemophilia C); heterozygous carriers have partial deficiency with variable surgical bleeding risk, homozygotes face severe deficiency with ~60% bleeding rate at high-risk surgical sites

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Factor XI Deficiency — The Coagulation Paradox

Coagulation factor XI (FXI) sits at a pivotal junction in the clotting cascade: it amplifies clot formation in tissues with high fibrinolytic activity — the mouth, nose, and urinary tract — where clots dissolve rapidly and need reinforcement. The F11 gene on chromosome 4q35.2 encodes FXI, and the c.291del frameshift (rs1057517151) removes a single guanine from a GGG triplet run, shifting the reading frame from codon 98 and creating a truncated, non-functional protein. The ClinVar classification is likely pathogenic11 likely pathogenic
ClinVar VCV000371284.3, submitted by Counsyl clinical laboratory, 2016.

This variant exemplifies one of medicine's interesting genetic paradoxes: a loss-of-function mutation that simultaneously raises your bleeding risk and may lower your risk of stroke and venous thromboembolism — because factor XI sits at the intersection of hemostasis (necessary clotting after injury) and thrombosis (pathological clotting that causes heart attacks and strokes).

The Mechanism

FXI is activated by factor XIIa in the contact pathway and by thrombin in a positive-feedback loop. Once activated, FXIa cleaves and activates factor IX, which in turn activates the tenase complex and drives the clotting cascade toward fibrin clot formation22 fibrin clot formation
The c.291del frameshift at codon 98 introduces a premature stop, eliminating the protein's catalytic serine protease domain entirely; no functional FXIa is produced from the affected allele.

The reason FXI deficiency causes a peculiar, site-specific bleeding pattern — rather than global deficiency — is that clot initiation via the extrinsic (tissue factor) pathway proceeds normally. It is clot maintenance that suffers: in tissues rich in fibrinolytic activity (plasminogen activators), FXI-mediated amplification is needed to sustain the clot against dissolution. This is why bleeding in FXI deficiency clusters at fibrinolysis-rich sites33 clusters at fibrinolysis-rich sites
Antifibrinolytic drugs like tranexamic acid correct this mechanism and are the primary surgical prophylaxis; PMID 27216469 — dental extractions, tonsillectomies, urologic procedures — rather than causing the spontaneous joint bleeds characteristic of hemophilia A and B.

The Evidence

Bleeding risk. A 2022 retrospective study of 198 patients undergoing 252 surgical and obstetric procedures44 198 patients undergoing 252 surgical and obstetric procedures
Handa et al. Thromb Res. 2022; PMID 36521104 found that 13% of procedures resulted in clinically significant bleeding. Personal bleeding history was the strongest predictor (OR 5.92, p=0.001); FXI level itself was a weaker predictor, with a threshold of 40 U/dL showing only 47% sensitivity. A 2016 expert review55 2016 expert review
Wheeler & Gailani. Expert Rev Hematol. 2016; PMID 27216469 quantified the difference between genotype classes: heterozygous carriers face an odds ratio of 2.6 for excessive bleeding; homozygotes face OR 13.0. For high-risk procedures (tooth extraction, tonsillectomy, urologic surgery), approximately 60% of severely deficient patients bleed without prophylaxis66 60% of severely deficient patients bleed without prophylaxis
Wheeler & Gailani 2016 versus far fewer at low-fibrinolysis sites.

A 2025 Italian cohort study of 93 FXI-deficient patients77 93 FXI-deficient patients
Santacroce et al. Int J Mol Sci. 2025; PMID 41009375 found that 88% were heterozygotes with mean FXI levels of 39 IU/dL (range 18–79). Critically, 30.8% of heterozygotes experienced hemorrhagic events — consistent with the known principle that there is no reliable linear correlation between FXI level and bleeding severity (Pearson r = −0.18). A patient at 60 U/dL may bleed after tonsillectomy; another at 25 U/dL may not.

Stroke and VTE protection. The clinical paradox: Salomon et al. Blood 200888 Salomon et al. Blood 2008
115 patients with severe FXI deficiency (activity <15 U/dL) followed in Israel; PMID 18268095 found only 1 ischemic stroke observed vs. 8.56 expected — an approximately 8-fold reduction. A 2022 observational study of 7,578 tested patients99 2022 observational study of 7,578 tested patients
Moser et al. Thromb Haemost. 2022; PMID 34555861 showed FXI deficiency associated with aHR 0.55 for cardiovascular events and aHR 0.45 for VTE (both nonsignificant trends toward protection due to small event numbers, but directionally consistent with the Israeli data). This cardioprotective property of FXI deficiency has driven major pharmaceutical interest in FXI inhibitors as next-generation anticoagulants.

Population context. Severe FXI deficiency affects approximately 1 in 1,000,000 people globally1010 1 in 1,000,000 people globally
MedlinePlus Genetics 2024. In Ashkenazi Jewish populations1111 Ashkenazi Jewish populations
Founder effect — two mutations (Type II and Type III) account for ~96% of affected alleles; PMID 2052060 the disease frequency rises dramatically: 1 in 450 individuals, with a heterozygous carrier frequency of approximately 1 in 8. The c.291del variant (rs1057517151) is a distinct frameshift reported in ClinVar as likely pathogenic — not one of the classic Ashkenazi founder mutations, and population frequency data are not available in gnomAD, consistent with extreme rarity.

Practical Implications

The critical action for carriers of this variant is preoperative disclosure — especially before any procedure involving the mouth, throat, nose, or urinary tract. Antifibrinolytic therapy (tranexamic acid) is the mainstay of surgical prophylaxis for most procedures, targeting the fibrinolytic mechanism underlying site-specific bleeding. For severely deficient patients undergoing major surgery, FXI concentrate or fresh frozen plasma may be required.

Women with FXI deficiency warrant specific attention around childbirth: postpartum hemorrhage risk is elevated, and obstetric teams should be informed in advance. Neuraxial anesthesia appears safe — the Handa 2022 study found no epidural hematomas in 174 neuraxial procedures, including 5 patients with FXI <10 U/dL.

Because FXI deficiency appears protective against ischemic stroke and VTE, carriers should exercise caution before using anticoagulants, antiplatelet agents, or NSAIDs that compound bleeding risk without a clear clinical indication. Conversely, the FXI deficiency status should not prompt thromboprophylaxis — it is not a prothrombotic condition.

Interactions

Compound heterozygosity in F11 — carrying two different loss-of-function mutations on opposite chromosomes — produces a clinical picture equivalent to homozygosity: severe FXI deficiency with <15 U/dL activity. The c.291del variant could compound with any other pathogenic F11 allele (including the Ashkenazi Type II (rs121965063 / E117X) or Type III (rs121965064 / F283L) mutations) to produce severe deficiency in individuals who received one allele from each parent.

Acquired conditions that also impair hemostasis (thrombocytopenia, antiplatelet therapy, liver disease, von Willebrand disease) compound with FXI deficiency to increase bleeding risk beyond what either condition alone predicts. The reverse is also true: individuals with both FXI deficiency and a prothrombotic variant (Factor V Leiden rs6025, or prothrombin G20210A rs1799963) may have partially opposing effects — the FXI deficiency offering some bleeding tendency while the thrombophilic variant pushes toward clotting — producing unpredictable net clinical behavior that warrants specialist assessment.

Genotype Interpretations

What each possible genotype means for this variant.

II Non-carrier Normal

No F11 frameshift detected — normal factor XI production

You do not carry the rs1057517151 deletion in your F11 gene. Both copies of your coagulation factor XI gene are intact at this position, and this variant does not contribute to any bleeding tendency. The vast majority of people worldwide share this genotype — rs1057517151 is an extremely rare frameshift, not detected in major population databases. No action is needed for this variant.

DI Carrier Carrier

One copy of the F11 frameshift — partial factor XI deficiency with variable surgical bleeding risk

The c.291del frameshift removes a guanine from a GGG triplet at position 291 of the F11 coding sequence, shifting the reading frame at codon 98 (Tyr98). The resulting mRNA encodes a truncated protein lacking the catalytic serine protease domain and is likely rapidly degraded. Your intact copy produces sufficient FXI for baseline hemostasis, but reduced levels impair the amplification phase of clotting at fibrinolysis-rich sites.

Key clinical contexts:

  • Dental, ENT, and urologic surgery: These are the highest-risk procedures. Approximately 20–30% of heterozygotes bleed excessively without prophylaxis at these sites due to intense local fibrinolytic activity. Tranexamic acid 15 mg/kg (oral or IV) before such procedures significantly reduces this risk and is the standard preoperative intervention for most heterozygous carriers.

  • Obstetrics: Postpartum hemorrhage risk is elevated. FXI levels should be measured in the third trimester (FXI does not rise with pregnancy unlike fibrinogen or factor VIII). An obstetric bleeding management plan should be in place before delivery.

  • FXI level does not reliably predict bleeding: A personal history of bleeding with prior hemostatic challenges is the single strongest predictor of future surgical bleeding. A carrier who has undergone dental extraction without excessive bleeding may be at lower risk than one who has not been challenged.

  • Protective aspects: FXI deficiency is associated with reduced ischemic stroke risk and a trend toward lower VTE rates. This protective effect should be factored into any clinical decision about anticoagulation.

DD Homozygous Homozygous

Two copies of the F11 frameshift — severe factor XI deficiency with significant procedural and obstetric bleeding risk

Homozygous c.291del obliterates FXI production from both alleles. The resulting severe FXI deficiency (<15 U/dL) impairs the amplification and maintenance phase of clotting, particularly at sites of high fibrinolytic activity.

Key clinical characteristics: - Site-specific bleeding: Dental extractions, tonsillectomies, nasal surgery, and urologic procedures carry the highest risk — approximately 60% bleed without prophylaxis at these sites. - Normal hemostasis at most sites: Minor cuts, intramuscular injections, and most orthopedic procedures carry relatively low bleeding risk because the extrinsic (tissue factor) pathway proceeds normally. - Spontaneous bleeding is uncommon — unlike hemophilia A or B, spontaneous joint bleeds are rare. When they occur, it often indicates a very low FXI level or an additional hemostatic defect. - aPTT is prolonged: Routine pre-operative coagulation screens will flag an abnormal activated partial thromboplastin time — this is the usual route of diagnosis in unscreened individuals. - Paradoxical thrombotic protection: Severe FXI deficiency is associated with significantly reduced ischemic stroke incidence (~8-fold reduction in one Israeli cohort) and a trend toward lower VTE rates.

Treatment for procedures requires pre-planning: fresh frozen plasma (FFP) provides FXI but carries volume load risk; FXI concentrate (where available) enables targeted replacement without volume; tranexamic acid is the cornerstone for fibrinolysis-rich sites and can be used alongside FFP or FXI concentrate.