Background: Coagulation factor XI (FXI, F11) inhibitors are a novel antithrombotic strategy that may carry a lower risk of spontaneous bleeding than existing therapies. However, human data to support the long-term efficacy and safety of this approach remain limited. We leveraged the genomics and proteomics data from two population-scale biobanks to assess the lifelong clinical consequences of heterozygous germline loss of function in F11.

Methods: We analyzed paired whole genome sequencing and clinical data from the UK Biobank (UKB, N=460,365) and NIH All of Us (AoU, N=302,190) biorepositories. Each rare (minor allele frequency ≤0.1%) germline variant in F11 was assigned an AlphaMissense score (AMS) between 0.0 and 1.0, with higher scores reflecting greater likelihood of harm to protein function based on in silico predictions. AlphaMissense has designated AMS ≥0.564 as the cutoff for predicted deleterious variants, and the variants that are most likely to cause impaired protein function (nonsense, essential splice site, and frameshift mutations) were assigned an AMS of 1.0. We used Firth's penalized logistic regression modeling adjusting for age, sex, and ancestry followed by trans-cohort fixed-effect meta-analysis to quantify the association between F11 variant carrier status and risk of thrombosis and bleeding. Additionally, FXI plasma protein levels were measured in 43,135 UKB participants (Olink® Explore 3072).

Results: Individuals who carry a loss of function variant in F11 (N=3,537; 99.9% heterozygous; 288 unique coding variants), experienced significantly reduced risk of venous thromboembolism (VTE) at AMS ≥0.564 (OR=0.57, 95% CI: 0.46-0.71, P<0.0001) and AMS=1.0 (OR=0.51, 95% CI: 0.37-0.70, P<0.0001). The protective effect of deleterious F11 variants remained after adjusting for polygenic risk score for VTE and factor V Leiden and prothrombin gene mutation G20210A carrier status, suggesting that the protection conferred by F11 variant carrier status is independent of known common genetic factors influencing VTE risk. F11 variant carriers (AMS ≥0.564) also displayed a significantly decreased risk of myocardial infarction (MI, OR=0.79, 95% CI: 0.64-0.97, P=0.02). Variant carrier status did not appear to be protective against non-cardioembolic ischemic stroke (NCEIS) or peripheral arterial disease (PAD). We did not find an increased risk of bleeding among heterozygous F11 variant carriers (OR=1.03, 95% CI: 0.87-1.21, P=0.68). Among 43,135 UKB participants with plasma proteomics data, F11 variant carriers had significantly lower circulating FXI levels (P<0.0001) than wild-type individuals. Additionally, we assessed the clinical impacts of three F11 founder variants (Type 1, ESS; Type 2, E135*; Type 3, F301L) that were first described in the Ashkenazi Jewish population and are known to reduce VTE risk. Carriers of these three variants collectively had significantly decreased plasma FXI levels (57% of non-carriers, P<0.0001) and were significantly protected against VTE (OR=0.68, 95% CI: 0.50-0.91, P=0.012).

Conclusions: Genetically-defined FXI deficiency results in plasma levels that are approximately 50% of normal and is associated with lifelong protection against both VTE and MI without significantly increased bleeding risk. Although we were unable to evaluate the impact of severe FXI deficiency (activity ≤1% of normal) caused by biallelic loss of function in F11, our findings suggest that FXI inhibition could be a safe and effective antithrombotic strategy.

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2025
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