rs1057516616 — F11 c.25_28del (p.His9fs)

Factor XI Deficiency — The Coagulation Gene That Protects Against Clots

Coagulation factor XI (FXI) sits at a strategic crossroads in the clotting cascade. It amplifies thrombin generation inside growing clots, keeping fibrin networks stable and protecting them from the body's own clot-dissolving machinery. When the F11 gene is disrupted by a deletion like rs1057516616 (c.25_28del), the reading frame shifts at position 9 and protein synthesis terminates prematurely — a complete null allele that produces no functional FXI at all.

The result is one of the most paradoxical syndromes in hematology: people with severe FXI deficiency rarely bleed spontaneously, yet struggle to stop bleeding after surgery or injury — especially in the mouth, nose, and urinary tract where local fibrinolytic enzymes work hardest. At the same time, their missing FXI provides unexpected cardiovascular protection¹¹ unexpected cardiovascular protection
Epidemiological studies consistently show reduced ischemic stroke and DVT in severe FXI deficiency; FXI is now an active pharmaceutical target for "hemostasis-sparing" anticoagulation against stroke and venous thromboembolism — the biological rationale behind a new generation of FXIa-inhibitor drugs.

The Mechanism

FXI is activated during coagulation by two routes: contact with foreign surfaces (via Factor XIIa in the intrinsic pathway), and by thrombin feedback inside an established clot. The thrombin-feedback loop is the critical one: once a clot begins forming, thrombin activates more FXI, which amplifies further thrombin generation in a self-reinforcing cycle. FXI also activates the antifibrinolytic thrombin-activatable fibrinolysis inhibitor (TAFI), shielding the clot from plasmin-mediated dissolution.

The c.25_28del deletion removes four bases in exon 1 (CATT), disrupting the reading frame at His9²² His9
Histidine at position 9 of the mature FXI protein, early in the signal peptide region; frameshift here predicts no functional protein whatsoever. Heterozygous carriers produce FXI from the intact chromosome, but at roughly half normal levels (partial deficiency: 20–70 U/dL). Homozygous or compound heterozygous individuals produce essentially no FXI, with activity typically below 15 U/dL — the definition of severe FXI deficiency (hemophilia C).

Because FXI is needed for thrombus stabilization and propagation but plays a subsidiary role in the initial hemostatic response³³ subsidiary role in the initial hemostatic response
The initial plug that forms at an injury site relies primarily on platelets and tissue-factor-driven thrombin generation (the extrinsic pathway), which is FXI-independent to vessel injury, complete FXI deficiency disrupts the amplification loop without eliminating the primary clotting response. This explains the mild-to-moderate phenotype in most affected individuals.

The Evidence

The cardiovascular paradox of FXI deficiency is well documented. In a landmark Israeli study of 115 patients aged 45 or older with severe FXI deficiency⁴⁴ 115 patients aged 45 or older with severe FXI deficiency
Salomon et al., Blood 2008; patients compared to the expected stroke incidence derived from a national stroke survey of 1,528 patients with adjustment for four major cardiovascular risk factors, only one ischemic stroke was observed against an expected 8.56 (P=.003) — a roughly eight-fold reduction in stroke incidence. A companion study by the same group of 219 severe FXI-deficient patients⁵⁵ 219 severe FXI-deficient patients
Salomon et al., Thromb Haemost 2011; zero DVT cases compared to 4.68 expected from population-based studies found zero deep-vein thrombosis events versus 4.68 expected.

Bleeding risk in FXI-deficient patients, including this frameshift variant, is highly variable and not reliably predicted by FXI plasma levels⁶⁶ variable and not reliably predicted by FXI plasma levels
Barg et al., Blood 2024 — systematic review of management; standard lab values have "limited success" predicting perioperative bleeding risk. In a retrospective study of 198 FXI-deficient patients undergoing 252 surgical and obstetric procedures⁷⁷ 252 surgical and obstetric procedures
Weiss et al. 2023; Mount Sinai Health System 2011–2021; 13% of procedures had bleeding events; postpartum hemorrhage rate 11% vs ~5% in general population, the single strongest predictor of bleeding was personal history of prior bleeding (OR 5.92, P=.001) — not FXI activity level.

FXI deficiency is enriched in populations with Ashkenazi Jewish ancestry, where two ancient founder mutations (Glu117Stop and Phe283Leu, known as Type II and Type III) account for over 90% of abnormal alleles⁸⁸ over 90% of abnormal alleles
Payne et al. 2024; 403 documented F11 variants globally; Glu135Stop and Phe301Leu per updated nomenclature account for most Ashkenazi cases. The rs1057516616 frameshift (c.25_28del) is a distinct rare allele classified as Likely Pathogenic by ClinVar, with no ancestral enrichment data available — it was submitted by Counsyl in 2016 as a carrier screening finding.

Practical Actions

The critical moment for FXI-deficient individuals is before a procedure, not after a bleed. The oral cavity, pharynx, and urogenital tract — areas where the body dissolves clots aggressively via local fibrinolysis — are the highest-risk sites. Dental extractions, tonsillectomy, prostate surgery, and urinary procedures trigger bleeding in a substantial minority of affected patients.

First-line management for procedures in high-fibrinolytic sites includes antifibrinolytic agents such as tranexamic acid (mouthwash for dental work, systemic for larger procedures). For major surgery, fresh frozen plasma or FXI concentrate can raise plasma FXI to the 30–45 U/dL target range. A key limit: FXI replacement above 70 U/dL carries thrombotic risk — paradoxically, over-correcting a deficiency associated with stroke protection can become pro-thrombotic.

Neuraxial anesthesia (epidural, spinal) is a common concern in obstetric patients. A retrospective series of 174 neuraxial anesthesia procedures in FXI-deficient women found zero cases of epidural or spinal hematoma — supporting cautious use with individualized risk assessment.

Interactions

The rs1057516616 frameshift creates a complete null allele. When paired with a second null allele (homozygosity or compound heterozygosity with other F11 mutations such as the Ashkenazi founder mutations rs121908456 or rs121908453), the result is severe hemophilia C requiring active management of all invasive procedures.

The FXI pathway intersects with the Factor V and prothrombin pathways for net thrombotic risk. The paradox of FXI deficiency is dramatically reversed in individuals who also carry prothrombotic variants — a person with rs6025 (Factor V Leiden) and severe FXI deficiency may face a complex, uncertain net coagulation balance that warrants specialist hematology assessment rather than assuming either variant dominates.