Immunothrombosis: Molecular Drivers, Endothelial Gatekeeping, and the Failure of Resolution

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 across its cellular, 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 tissue-factor decryption, NET formation and clearance, complement amplification loops, and contact-pathway activation.