Galectin-9 drives thrombo-inflammatory circuits initiating venous thrombosis
- 1University of Birmingham
Abstract
Background: Venous thromboembolism is increasingly recognized as a thrombo-inflammatory disease, yet the pathways linking inflammation to venous thrombus initiation remain incompletely defined. Galectin-9 (Gal-9), a {beta}-galactoside-binding lectin elevated in inflammatory disorders, has no defined role in venous thrombosis. Methods: Using plasma from patients with deep vein thrombosis (DVT), Gal-9-deficient mice, an inferior vena cava stenosis model, intravital microscopy, microfluidics, and ex vivo platelet and neutrophil assays, we assessed the functional contribution of Gal-9 to venous thrombosis. Results: Plasma Gal-9 was elevated in DVT patients, correlated with D-dimer at presentation, and declined over 3-month follow-up. Gal-9 deletion did not alter hemostasis but markedly impaired thrombus initiation, with reduced platelet and neutrophil recruitment to the vessel wall and reduced intra-thrombus neutrophil extracellular trap (NET) formation. TNF-/IFN-{gamma}-stimulated endothelial cells upregulated Gal-9 and promoted platelet adhesion and fibrin(ogen) deposition, which Gal-9 neutralization partially reversed. Under venous shear, immobilized recombinant Gal-9 potentiated platelet activation and thrombus formation, particularly alongside collagen, whereas Gal-9 inhibition suppressed these responses. Gal-9-activated platelets promoted NETosis and shifted thrombus composition toward a NET-rich inflammatory phenotype. Conclusions: Gal-9 is a previously unrecognized driver of venous thrombo-inflammation, linking vascular inflammation to platelet activation, NET formation, and thrombosis. Genetic deletion attenuated these responses in vivo, and antibody-mediated Gal-9 neutralization suppressed platelet activation and thrombus formation in vitro, identifying the Gal-9 glycan-binding pathway as a therapeutic target that disrupts thrombosis without impairing hemostasis.
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BibTeX
@misc{konkoth2026galectin9,
title = {{Galectin-9 drives thrombo-inflammatory circuits initiating venous thrombosis}},
author = {A. A. Konkoth and A. Abo Mansour and K. Whitworth and I. Budnik and D. Steiner and C. Ay and D. Lezama and H. M. McGettrick and D. Kavanagh and F. Maione and J. El-Awaisi and G. E. Rainger and J. Rayes and A. Brill and A. J. Iqbal},
howpublished = {bioRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.05.757779},
url = {https://www.biorxiv.org/content/10.64898/2026.11.05.757779v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Galectin-9 drives thrombo-inflammatory circuits initiating venous thrombosis
AU - A. A. Konkoth
AU - A. Abo Mansour
AU - K. Whitworth
AU - I. Budnik
AU - D. Steiner
AU - C. Ay
AU - D. Lezama
AU - H. M. McGettrick
AU - D. Kavanagh
AU - F. Maione
AU - J. El-Awaisi
AU - G. E. Rainger
AU - J. Rayes
AU - A. Brill
AU - A. J. Iqbal
PY - 2026
DA - 2026/11/05
PB - bioRxiv
DO - 10.64898/2026.11.05.757779
UR - https://www.biorxiv.org/content/10.64898/2026.11.05.757779v1
AB - Background: Venous thromboembolism is increasingly recognized as a thrombo-inflammatory disease, yet the pathways linking inflammation to venous thrombus initiation remain incompletely defined. Galectin-9 (Gal-9), a {beta}-galactoside-binding lectin elevated in inflammatory disorders, has no defined role in venous thrombosis. Methods: Using plasma from patients with deep vein thrombosis (DVT), Gal-9-deficient mice, an inferior vena cava stenosis model, intravital microscopy, microfluidics, and ex vivo platelet and neutrophil assays, we assessed the functional contribution of Gal-9 to venous thrombosis. Results: Plasma Gal-9 was elevated in DVT patients, correlated with D-dimer at presentation, and declined over 3-month follow-up. Gal-9 deletion did not alter hemostasis but markedly impaired thrombus initiation, with reduced platelet and neutrophil recruitment to the vessel wall and reduced intra-thrombus neutrophil extracellular trap (NET) formation. TNF-/IFN-{gamma}-stimulated endothelial cells upregulated Gal-9 and promoted platelet adhesion and fibrin(ogen) deposition, which Gal-9 neutralization partially reversed. Under venous shear, immobilized recombinant Gal-9 potentiated platelet activation and thrombus formation, particularly alongside collagen, whereas Gal-9 inhibition suppressed these responses. Gal-9-activated platelets promoted NETosis and shifted thrombus composition toward a NET-rich inflammatory phenotype. Conclusions: Gal-9 is a previously unrecognized driver of venous thrombo-inflammation, linking vascular inflammation to platelet activation, NET formation, and thrombosis. Genetic deletion attenuated these responses in vivo, and antibody-mediated Gal-9 neutralization suppressed platelet activation and thrombus formation in vitro, identifying the Gal-9 glycan-binding pathway as a therapeutic target that disrupts thrombosis without impairing hemostasis.
ER -