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

Amelia K. Haj, David S. Paul, Sean J. Jurgens, Harish Eswaran, Lu-Chen Weng, Justine Ryu, Alfonso Rodriguez Espada, Sharjeel Chaudhry, Louis M. Feingold, Kristen Burke, Satoshi Koyama, Xin Wang, Joyce Francis, Seung Hoan Choi, Nigel Mackman, Wolfgang Bergmeier, Alex Burgin, Joel T. Rämö, Patrick T. Ellinor, Steven P. Grover and Pavan K. Bendapudi ()
Additional contact information
Amelia K. Haj: Massachusetts General Hospital
David S. Paul: University of North Carolina at Chapel Hill
Sean J. Jurgens: The Broad Institute of MIT and Harvard
Harish Eswaran: University of North Carolina at Chapel Hill
Lu-Chen Weng: The Broad Institute of MIT and Harvard
Justine Ryu: The Broad Institute of MIT and Harvard
Alfonso Rodriguez Espada: The Broad Institute of MIT and Harvard
Sharjeel Chaudhry: The Broad Institute of MIT and Harvard
Louis M. Feingold: Beth Israel Deaconess Medical Center
Kristen Burke: Beth Israel Deaconess Medical Center
Satoshi Koyama: The Broad Institute of MIT and Harvard
Xin Wang: The Broad Institute of MIT and Harvard
Joyce Francis: Beth Israel Deaconess Medical Center
Seung Hoan Choi: The Broad Institute of MIT and Harvard
Nigel Mackman: University of North Carolina at Chapel Hill
Wolfgang Bergmeier: University of North Carolina at Chapel Hill
Alex Burgin: The Broad Institute of MIT and Harvard
Joel T. Rämö: The Broad Institute of MIT and Harvard
Patrick T. Ellinor: The Broad Institute of MIT and Harvard
Steven P. Grover: University of North Carolina at Chapel Hill
Pavan K. Bendapudi: The Broad Institute of MIT and Harvard

Nature Communications, 2025, vol. 16, issue 1, 1-12

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-62789-5

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