Molecular determinants of thrombosis recurrence risk across venous thromboembolism subtypes

Venous thromboembolism (VTE) is a frequent (annual incidence of 1-2 per 1000 individuals) and potentially life-threatening (case-fatality rate up to 10%) disease. VTE is associated with serious short-term and long-term complications, including a recurrence rate approaching 20% within 5 years. Anticoagulant therapy, the mainstay of VTE treatment, drastically reduces the risk of early VTE recurrence, but it exposes patients to a substantial risk of bleeding. We analyzed the genomic architecture of VTE recurrence using data from 6355 patients across 8 cohorts (including 1775 recurrences), enriched by subgroup analyses, according to sex and clinical manifestation of first VTE, which led to the identification of 28 molecular markers. Through genome-wide association studies, we identified 1 locus associated with VTE recurrence, GPR149/MME. Among all variants known to be associated with first VTE, KNG1, and FGG were associated with recurrence. Additionally, Mendelian randomization analyses identified 7 proteins as risk factors for recurrence: elevated plasma levels of coagulation factor XI, coagulation factor VIII, von Willebrand factor, histo-blood group ABO system transferase, and Golgi membrane protein 2; and decreased levels of proprotein convertase subtilisin/kexin 9 and pro-interleukin-16. Subgroup analyses revealed 18 molecular determinants associated with VTE recurrence, with notable differences between subgroups. For example, the exonic variant SLC4A1 p.Glu40Lys was significantly associated in patients who experienced pulmonary embolism but showed no effect in those with deep vein thrombosis. These findings emphasize the role of specific genetic loci and protein pathways in influencing VTE recurrence and provide valuable insights into potential therapeutic targets. Further research is needed to clarify the biological mechanisms driving these associations.

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Publication Details

Journal
Blood
Published
2025-08-14
DOI
https://doi.org/10.1182/blood.2024027879
Citations
6
Primary Topic
Venous Thromboembolism Diagnosis and Management
Type
article
Field-Weighted Citation Impact
11.22

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article

Molecular determinants of thrombosis recurrence risk across venous thromboembolism subtypes

Lénaïck Gourhant, Catherine A. Lemarié, Pierre Suchon, David M. Smadja et al.
6 citations
Blood
Venous Thromboembolism Diagnosis and Management
11.22
article

Molecular determinants of thrombosis recurrence risk across venous thromboembolism subtypes

Lénaïck Gourhant, Catherine A. Lemarié, Pierre Suchon, David M. Smadja, Ohanna Cavalcanti de Lima Bezerra, Ming‐Huei Chen, Laura B. Harrington, Robert Olaso, Hélène Jacqmin‐Gadda, Frits R. Rosendaal, Sven Danckwardt, Florian Thibord, Joseph Emmerich, Jean‐François Deleuze, Delphine Daian, Astrid van Hylckama Vlieg, Andrew D. Johnson, Louisa Goumidi, Céline Besse, Anne Boland, Jennifer A. Brody, David‐Alexandre Trégouët, Françis Couturaud, Kerri L. Wiggins, Pierre‐Emmanuel Morange, Stéphanie Debette, Marc Rodger, Noémie Saut, Ilana Caro, Floriane Samaria, France Gagnon, Gaëlle Munsch, Marine Germain, Nicholas L. Smith
article en
6 citations

Abstract

Venous thromboembolism (VTE) is a frequent (annual incidence of 1-2 per 1000 individuals) and potentially life-threatening (case-fatality rate up to 10%) disease. VTE is associated with serious short-term and long-term complications, including a recurrence rate approaching 20% within 5 years. Anticoagulant therapy, the mainstay of VTE treatment, drastically reduces the risk of early VTE recurrence, but it exposes patients to a substantial risk of bleeding. We analyzed the genomic architecture of VTE recurrence using data from 6355 patients across 8 cohorts (including 1775 recurrences), enriched by subgroup analyses, according to sex and clinical manifestation of first VTE, which led to the identification of 28 molecular markers. Through genome-wide association studies, we identified 1 locus associated with VTE recurrence, GPR149/MME. Among all variants known to be associated with first VTE, KNG1, and FGG were associated with recurrence. Additionally, Mendelian randomization analyses identified 7 proteins as risk factors for recurrence: elevated plasma levels of coagulation factor XI, coagulation factor VIII, von Willebrand factor, histo-blood group ABO system transferase, and Golgi membrane protein 2; and decreased levels of proprotein convertase subtilisin/kexin 9 and pro-interleukin-16. Subgroup analyses revealed 18 molecular determinants associated with VTE recurrence, with notable differences between subgroups. For example, the exonic variant SLC4A1 p.Glu40Lys was significantly associated in patients who experienced pulmonary embolism but showed no effect in those with deep vein thrombosis. These findings emphasize the role of specific genetic loci and protein pathways in influencing VTE recurrence and provide valuable insights into potential therapeutic targets. Further research is needed to clarify the biological mechanisms driving these associations.

BloodVol. 146(19)
Kaiser Permanente (US), Université de Bordeaux (FR), Inserm (FR), Université de Bretagne Occidentale (FR), University of Toronto (CA), Universität Ulm (DE), Johannes Gutenberg University Mainz (DE), University of Washington (US), Université Paris Cité (FR), Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR), Université Paris-Saclay (FR), Leiden University Medical Center (NL), CEA Paris-Saclay - Etablissement de Saclay (FR), VA Office of Research and Development (US), Institut des Maladies Neurodégénératives (FR), Assistance Publique Hôpitaux de Marseille (FR), Kaiser Permanente Washington Health Research Institute (US), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), Sorbonne Paris Cité (FR), University Medical Center of the Johannes Gutenberg University Mainz (DE), CEA Paris-Saclay - Etablissement de Fontenay-aux-roses (FR), Seattle Epidemiologic Information and Research Center (US), Bordeaux Population Health (FR), National Heart, Lung, and Blood Institute (US), Hôpital Européen (FR), Framingham Heart Study (US), Public Health Ontario (CA), CEA Paris-Saclay (FR), Paris Cardiovascular Research Center (FR), Centre Hospitalier Régional Universitaire de Brest (FR), University Hospital Ulm (DE), Hôpital de la Timone (FR), Centre de Recherche Épidémiologie et Statistique (FR), Naval Research Laboratory Information Technology Division, McGill University (CA)
School of Medicine, Boston University, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, University of Toronto, Université de Bordeaux, National Institutes of Health, Canadian Institutes of Health Research, National Heart, Lung, and Blood Institute
Good health and well-being
Openalex Percentile: Top 1%
Venous Thromboembolism Diagnosis and Management
11.22
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