Coagulation factor XII haploinsufficiency is protective against venous thromboembolism in a population-scale multidimensional analysis

Coagulation factor XII has been identified as a potential drug target that could prevent thrombosis without increasing the risk of bleeding. However, human data to support the development of factor XII-directed therapeutics are lacking. To assess the role of factor XII in venous thromboembolism, we examine genetic variation in the coding region of the F12 locus across 703,745 participants in the UK Biobank and NIH All of Us biorepositories. We find that heterozygous carriers of nonsense, frameshift, and essential splice site variants in F12 are protected against venous thromboembolism without an increased risk of bleeding or infection. We also show that F12 variant carriers generally experience a quantitative (type I) defect in circulating factor XII levels, though a subset of participants was also identified with possible qualitative (type II) deficiency. In vitro plasma-based thrombin generation is reduced at factor XII concentrations reflective of those seen in F12 variant carriers. We also show that F12 heterozygous mice are protected against venous thromboembolism and display an intermediate phenotype between wild-type and F12-null animals. We conclude that heterozygous loss of F12 represents a haploinsufficient state characterized by protection against venous thromboembolism and that therapeutically inhibiting factor XII is likely to be safe and effective.

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Journal
Nature Communications
Published
2025-09-01
DOI
https://doi.org/10.1038/s41467-025-62789-5
Citations
2
Primary Topic
Coagulation, Bradykinin, Polyphosphates, and Angioedema
Type
article
Field-Weighted Citation Impact
3.25

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article

Coagulation factor XII haploinsufficiency is protective against venous thromboembolism in a population-scale multidimensional analysis

Louis M. Feingold, Steven P. Grover, Satoshi Koyama, David S. Paul et al.
2 citations
Nature Communications
Coagulation, Bradykinin, Polyphosphates, and Angioedema
3.25
article

Coagulation factor XII haploinsufficiency is protective against venous thromboembolism in a population-scale multidimensional analysis

Louis M. Feingold, Steven P. Grover, Satoshi Koyama, David S. Paul, Kristen Lagasse Burke, Harish Eswaran, Joel Rämö, Amelia K. Haj, Justine Ryu, Alex B. Burgin, Wolfgang Bergmeier, Nigel Mackman, Sean J. Jurgens, Pavan K. Bendapudi, Patrick T. Ellinor, Lu-Chen Weng, Seung Hoan Choi, Joyce Francis, Sharjeel A. Chaudhry, Xin Wang, Alfonso Rodriguez Espada
article en
2 citations

Abstract

Coagulation factor XII has been identified as a potential drug target that could prevent thrombosis without increasing the risk of bleeding. However, human data to support the development of factor XII-directed therapeutics are lacking. To assess the role of factor XII in venous thromboembolism, we examine genetic variation in the coding region of the F12 locus across 703,745 participants in the UK Biobank and NIH All of Us biorepositories. We find that heterozygous carriers of nonsense, frameshift, and essential splice site variants in F12 are protected against venous thromboembolism without an increased risk of bleeding or infection. We also show that F12 variant carriers generally experience a quantitative (type I) defect in circulating factor XII levels, though a subset of participants was also identified with possible qualitative (type II) deficiency. In vitro plasma-based thrombin generation is reduced at factor XII concentrations reflective of those seen in F12 variant carriers. We also show that F12 heterozygous mice are protected against venous thromboembolism and display an intermediate phenotype between wild-type and F12-null animals. We conclude that heterozygous loss of F12 represents a haploinsufficient state characterized by protection against venous thromboembolism and that therapeutically inhibiting factor XII is likely to be safe and effective.

Nature CommunicationsVol. 16(1)
Broad Institute (US), University of North Carolina at Chapel Hill (US), Beth Israel Deaconess Medical Center (US), University of North Carolina Health Care (US), University of Helsinki (FI), Harvard University (US), Yale University (US), Massachusetts General Hospital (US), Institute for Molecular Medicine Finland (FI), Amsterdam University Medical Centers (NL), University of Amsterdam (NL)
American Heart Association, Massachusetts General Hospital, CSL Behring, Amsterdam University Medical Centers, European Commission, Fondation Leducq, National Institutes of Health, National Heart, Lung, and Blood Institute
Openalex Percentile: Top 7%
Coagulation, Bradykinin, Polyphosphates, and Angioedema
3.25
DOIOpen Access PDFOpenAlex
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