Evidence map›Paper›PMID 40890099›Full record

ArticleNature communications2025

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 and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.

0numbers the graph read from it
0cells of the map it votes in
8citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

8 citing papers in PubMed.

  1. Article
  2. Review
  3. Trypsin is as procoagulant as factor XIIa.Bleeding, thrombosis and vascular biology · 2026
    Article
  4. Review
  5. Article
  6. Article
  7. Article
  8. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors.

Amelia K HajDepartment of Pathology, Massachusetts General Hospital, Boston, MA, USA.ORCID http://orcid.org/0000-0002-1453-341X
David S PaulDivision of Hematology, UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Sean J JurgensCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-1605-9782
Harish EswaranDivision of Hematology, UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0001-9604-1138
Lu-Chen WengCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Justine RyuCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Alfonso Rodriguez EspadaCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0009-0007-6743-5390
Sharjeel ChaudhryCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0001-8701-3979
Louis M FeingoldDivision of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Kristen BurkeDivision of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Satoshi KoyamaCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-9286-0360
Xin WangCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Joyce FrancisDivision of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center, Boston, MA, USA.
Seung Hoan ChoiCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Nigel MackmanDivision of Hematology, UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-9170-7700
Wolfgang BergmeierDivision of Hematology, UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.ORCID http://orcid.org/0000-0002-1211-8861
Alex BurginCenter for the Development of Therapeutics, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0009-0008-3880-5361
Joel T RämöCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID http://orcid.org/0000-0002-6429-5149
Patrick T EllinorCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Steven P GroverDivision of Hematology, UNC Blood Research Center, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Pavan K BendapudiCardiovascular Disease Initiative, The Broad Institute of MIT and Harvard, Cambridge, MA, USA. pbendapudi@mgb.org.ORCID http://orcid.org/0009-0007-0349-5714

Funding

IDENTIFICATION OF COMMON GENETIC VARIANTS FOR ATRIAL FIBRILLATION AND PR INTERVALR01HL092577 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI BENJAMIN, EMELIA J., ELLINOR, PATRICK THOMAS · 2009 to 2025
$20.6M
Research Training in Hematology at UNC Chapel HillT32HL007149 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Nigel S. Key · 1985 to 2026
$8.6M
Small GTPases in the biology of platelets and megakaryocytesR35HL144976 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI BERGMEIER, WOLFGANG · 2019 to 2025
$5.4M
Genomics of Cardiac ArrhythmiasR01HL139731 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI ELLINOR, PATRICK THOMAS · 2018 to 2022
$3.3M
Using Electrocardiogram Genetics to Inform Arrhythmia RiskR01HL157635 · NHLBI · MASSACHUSETTS GENERAL HOSPITAL · PI ELLINOR, PATRICK THOMAS, MIRSHAHI, TOORAJ · 2022 to 2025
$2.9M
Coagulation Factor XII Recruitment and Activation During Thrombus FormationR01HL166246 · NHLBI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI Pavan Bendapudi · 2023 to 2026
$2.8M
Regulation of coagulation and thrombosis by C1 inhibitorR01HL171042 · NHLBI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Steven P. Grover · 2024 to 2026
$2.2M
Mechanisms of Coagulation Factor XII Recruitment and Activation at the Platelet SurfaceR03HL162761 · NHLBI · BETH ISRAEL DEACONESS MEDICAL CENTER · PI BENDAPUDI, PAVAN · 2022 to 2023
$173k
NHLBI NIH HHS R01 HL092577NHLBI NIH HHS R01 HL139731NHLBI NIH HHS R01 HL157635NHLBI NIH HHS R01 HL166246NHLBI NIH HHS R01 HL171042NHLBI NIH HHS R03 HL162761NHLBI NIH HHS R35 HL144976NHLBI NIH HHS T32 HL007149U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI) 1R01HL166246
6 · The paper itself

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.

Indexed as

Factor XIIHaploinsufficiencyVenous ThromboembolismAdultAgedAnimalsFactor XII DeficiencyFemaleHeterozygoteHumansMaleMiceMice, Inbred C57BLMice, KnockoutMiddle AgedThrombinFactor XIIThrombin

Identifiers

PMID40890099
PMCPMC12402198

What OpenQuestion holds

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.