Immunothrombosis: Molecular drivers, endothelial gatekeeping, and the failure of resolution
- 1Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center, Shreveport, LA, USA
- 2Corresponding author. Louisiana State University Health Sciences Center-Shreveport, Department of Pathology and Translational Pathobiology, BRI F7-26, Shreveport, LA, 71103, USA.
Abstract
Immunothrombosis describes the coordinated engagement of innate immunity and the coagulation system as a host-defense response. Microthrombi assembled at sites of pathogen exposure compartmentalize infection, restrict microbial dissemination, and support clearance without compromising the broader vasculature. When the spatial and temporal boundaries of this response fail, the same effector machinery propagates systemically and gives rise to the thromboinflammatory disorders that dominate modern critical care: sepsis-induced coagulopathy (SIC) and its progression to disseminated intravascular coagulation (DIC), the pulmonary microthrombosis of severe COVID-19, and the prothrombotic state of advanced malignancy. Here we synthesize the molecular drivers and regulatory checkpoints that govern the transition from protective to pathologic immunothrombosis. We first clarify the conceptual distinction between immunothrombosis and thromboinflammation and frame SIC and DIC as sequential stages of a single continuum. We then dissect the activation of tissue factor (TF) across its cellular, Nuclear Extracellular Trap (NET)-associated, and extracellular-vesicle compartments, with particular attention to pyroptotic decryption mediated by the caspase-11/caspase-4 axis. The endothelium is positioned as the principal gatekeeper, with phenotypic state transitions, Weibel–Palade body exocytosis, and glycocalyx kinetics determining whether activation remains compartmentalized. Amplification is examined through platelet–neutrophil crosstalk, NET heterogeneity, complement–coagulation interplay, and the inflammasome–pyroptosis axis. Resolution biology is treated in equal depth, with emphasis on DNase-mediated NET clearance, macrophage efferocytosis, and contact-system engagement on residual NET scaffolds. Finally, we map these mechanisms onto three disease modules (sepsis, COVID-19, and cancer-associated thrombosis), discuss the limits of conventional anticoagulation, and outline emerging therapeutic strategies aimed at TF decryption, NET formation and clearance, complement amplification loops, and contact-pathway activation.
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BibTeX
@article{shaaban2026immunothrombosis,
title = {{Immunothrombosis: Molecular drivers, endothelial gatekeeping, and the failure of resolution}},
author = {Nirvana Shaaban and Nirav Dhanesha},
journal = {Thrombosis Update},
year = {2026},
month = oct,
doi = {10.1016/j.tru.2026.100256},
url = {https://doi.org/10.1016/j.tru.2026.100256},
note = {CC BY},
}
RIS
TY - JOUR
TI - Immunothrombosis: Molecular drivers, endothelial gatekeeping, and the failure of resolution
AU - Nirvana Shaaban
AU - Nirav Dhanesha
PY - 2026
DA - 2026/10/30
JO - Thrombosis Update
DO - 10.1016/j.tru.2026.100256
UR - https://doi.org/10.1016/j.tru.2026.100256
AB - Immunothrombosis describes the coordinated engagement of innate immunity and the coagulation system as a host-defense response. Microthrombi assembled at sites of pathogen exposure compartmentalize infection, restrict microbial dissemination, and support clearance without compromising the broader vasculature. When the spatial and temporal boundaries of this response fail, the same effector machinery propagates systemically and gives rise to the thromboinflammatory disorders that dominate modern critical care: sepsis-induced coagulopathy (SIC) and its progression to disseminated intravascular coagulation (DIC), the pulmonary microthrombosis of severe COVID-19, and the prothrombotic state of advanced malignancy. Here we synthesize the molecular drivers and regulatory checkpoints that govern the transition from protective to pathologic immunothrombosis. We first clarify the conceptual distinction between immunothrombosis and thromboinflammation and frame SIC and DIC as sequential stages of a single continuum. We then dissect the activation of tissue factor (TF) across its cellular, Nuclear Extracellular Trap (NET)-associated, and extracellular-vesicle compartments, with particular attention to pyroptotic decryption mediated by the caspase-11/caspase-4 axis. The endothelium is positioned as the principal gatekeeper, with phenotypic state transitions, Weibel–Palade body exocytosis, and glycocalyx kinetics determining whether activation remains compartmentalized. Amplification is examined through platelet–neutrophil crosstalk, NET heterogeneity, complement–coagulation interplay, and the inflammasome–pyroptosis axis. Resolution biology is treated in equal depth, with emphasis on DNase-mediated NET clearance, macrophage efferocytosis, and contact-system engagement on residual NET scaffolds. Finally, we map these mechanisms onto three disease modules (sepsis, COVID-19, and cancer-associated thrombosis), discuss the limits of conventional anticoagulation, and outline emerging therapeutic strategies aimed at TF decryption, NET formation and clearance, complement amplification loops, and contact-pathway activation.
SN - 2666-5727
ER -