Coagulation factor XII haploinsufficiency is protective against venous thromboembolism in a population-scale multidimensional analysis
Year: 2025
Type: article
Study design: Observational Study
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.
Source: Nature Communications
Authors: 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, Pavan K. Bendapudi
Institutions: Broad Institute, Harvard University, Massachusetts General Hospital, University of North Carolina at Chapel Hill, Amsterdam University Medical Centers, University of Amsterdam, Yale University, Beth Israel Deaconess Medical Center, University of Helsinki, Institute for Molecular Medicine Finland, HiLIFE – Elämäntieteiden Instituutti
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: U.S. Department of Health and Human Services, American Cancer Society, National Aeronautics and Space Administration, Paul G. Allen Family Foundation, American Heart Association, Cancer Prevention and Research Institute of Texas, Massachusetts General Hospital, Holsworth Wildlife Research Endowment, Baden-Württemberg Stiftung, CSL Behring, Universiti Brunei Darussalam, Krishi Gobeshona Foundation, Amsterdam University Medical Centers, Chattogram Veterinary and Animal Sciences University, Abiomed, Cancer Research UK, Academy of Medical Sciences, European Commission, Rosetrees Trust, Commonwealth Scholarship Commission, Protein Research Foundation, Council of Scientific and Industrial Research, India, Deutsche Forschungsgemeinschaft, Fondation Leducq, Ministry of Education, Culture, Sports, Science and Technology, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, James Cook University, National Natural Science Foundation of China, Ministerstvo Školství, Mládeže a Tělovýchovy, King Saud University, China Postdoctoral Science Foundation, Ministero della Salute, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Kyushu University, Ligue Contre le Cancer, Princess Nourah Bint Abdulrahman University, Narodowe Centrum Nauki, Ministerio de Ciencia e Innovación, Gates Cambridge Trust, Universitas Indonesia, Wenzhou Municipal Science and Technology Bureau, Chinese Society of Clinical Oncology, Ernest Oppenheimer Memorial Trust, Guangzhou Municipal Health and Family Planning Commission, Youth Innovation Team Project for Talent Introduction and Cultivation in Universities of Shandong Province, King Salman Center for Disability Research, Guangzhou Municipal Science and Technology Bureau, Agencia Nacional de Investigación y Desarrollo, Université de Paris, National Institutes of Health, Horizon 2020 Framework Programme, Biotechnology and Biological Sciences Research Council, Japan Society for the Promotion of Science, Fundação para a Ciência e a Tecnologia, Japan Science and Technology Agency, European Regional Development Fund, Key Research and Development Projects of Shaanxi Province, Science and Technology Program of Guizhou Province, Birkbeck, University of London, Basic and Applied Basic Research Foundation of Guangdong Province, National Heart, Lung, and Blood Institute, National Center for Injury Prevention and Control, Yale Liver Center, Queensland Parks and Wildlife Service, H2020 European Research Council, HORIZON EUROPE European Research Council, Natural Science Foundation of Zhejiang Province
Awards: G2208403735, G2896215519, G3897532131, G4077987447, Advancing Atrial Fibrillation Precision Medicine, Machine Learning Artificial Intelligence Early Detection Stroke Atrial Fibrillation, Deciphering the Genomic Topology of Atrial Fibrillation, G8767518440, Regulation of coagulation and thrombosis by C1 inhibitor, Research Training in Hematology at UNC Chapel Hill, Small GTPases in the biology of platelets and megakaryocytes, IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVAL, Using Electrocardiogram Genetics to Inform Arrhythmia Risk, Coagulation Factor XII Recruitment and Activation During Thrombus Formation, Genomics of Cardiac Arrhythmias, Mechanisms of Coagulation Factor XII Recruitment and Activation at the Platelet Surface
OpenAlex ID: W4413891926