Immunothrombosis in Sepsis: Cellular Crosstalk, Molecular Triggers, and Therapeutic Opportunities-A Review

Abstract

Sepsis remains a critical global health challenge characterized by life-threatening organ dysfunction arising from a dysregulated host response to infection. Immunothrombosis refers to the intersection of immune activation and coagulation pathways, particularly relevant in the context of sepsis. A growing body of evidence identifies immunothrombosis, a tightly interwoven process between innate immunity and coagulation. While immunothrombosis serves as a host defense mechanism under physiological conditions, its aberrant activation in sepsis precipitates microvascular thrombosis, organ ischemia, and progression toward disseminated intravascular coagulation (DIC). This review provides a comprehensive overview of the cellular contributors to immunothrombosis, including neutrophils, monocytes, platelets, and endothelial cells, and elucidates the signaling cascades, such as nuclear factor kappa B (NF-κB), mitogen-activated protein kinase (MAPK), and inflammasome activation, that govern their interplay. We further highlight emerging molecular mediators, including extracellular traps, tissue factor expression, and cytokine amplification loops, that collectively promote pathological thromboinflammation. A deeper understanding of these interconnected pathways offers critical insights into the pathogenesis of sepsis and unveils potential targets for timely intervention. Ultimately, this review aims to bridge immunological and hematological perspectives to inform the development of novel therapeutic strategies against sepsis-induced coagulopathy.

Keywords: NETosis; cellular crosstalk; disseminated intravascular coagulation (DIC); immunothrombosis; sepsis; signaling cascades; therapeutic strategies.

Figure 1

Immunothrombosis and thromboinflammation in septic infection. Immunothrombosis is a physiological protective mechanism that traps pathogens and prevents their spread in circulation. The PAMPs expressed by pathogens will trigger the activation of coagulation factor XII (FXII). The activated FXII (FXIIa) further initiates the coagulation cascade, eventually leading to the formation of thrombin. Thrombin will then activate platelets and cleave fibrinogen into fibrin. Fibrin and activated platelets form the microthrombus to trap the pathogens. However, thromboinflammation occurs when immunothrombosis is uncontrolled. In this pathological condition, the excessively activated platelets will interact with monocytes and neutrophils. These interactions induce the secretion of proinflammatory cytokines and the formation of macrothrombi. These large blood clots may cause disseminated intravascular coagulation (DIC), eventually blocking the blood vessels of different organs and resulting in multi-organ failure (MOF). If the affected organs are vital to survival, such as the brain, liver, kidney, and heart, it will eventually cause death. PAMPs, pathogen-associated molecular patterns; FXII, coagulation factor XII; FXIIa, activated coagulation factor XII; FXI, coagulation factor XI; FXIa, activated coagulation factor XI; FIX, coagulation factor IX; FIXa, activated coagulation factor IX; FX, coagulation factor X; FXa, activated coagulation factor X; DIC, disseminated intravascular coagulation; MOF, multi-organ failure. (Created in BioRender. Huang, C. (2025) https://BioRender.com/3370ji3 accessed on 17 June 2025).

Figure 2

Activation of neutrophils and formation of NETs. When monocytes and platelets detect PAMPs and DAMPs via their TLRs, these cells are activated by the signals. They will then activate the neutrophils. Most of the activated neutrophils will form the neutrophil extracellular traps (NETosis), while a minority of activated neutrophils will undergo necrosis (as represented by the dotted line in the figure). Both NETosis and necrosis release inner cell contents, known as alarmins. Alarmins are molecules released from the cells and hence are one subtype of DAMPs. Therefore, alarmins not only can perform procoagulant activity to activate the coagulation cascade to produce thrombus, but also further activate more monocytes and platelets to amplify the process. PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; TLR, Toll-like receptor; NETs, neutrophil extracellular traps; dsDNA, double-stranded DNA; HMGB1, high-mobility group box 1; FXIIa, activated coagulation factor XII; FXa, activated coagulation factor X. (Created in BioRender. Huang, C. (2025) https://BioRender.com/3370ji3 accessed on 17 June 2025).

Figure 3

Platelet activation and its interactions with various immune cells and endothelial cells. Different signals, including cytokines, PAMPs and DAMPs, can activate platelets. Firstly, the activated platelets can bind to different cell types other than platelets through adhesion molecules, which is known as heterotypic aggregation. The heterotypic aggregates (HAGs) typically form through the interaction of platelets with dendritic cells, neutrophils, or monocytes, giving rise to PDA, PNA and PMA, respectively. Secondly, activated platelets can interact with endothelial cells to increase endothelium permeability and recruit more leukocytes. Thirdly, activated platelets will release α- or δ-granule contents to enhance the activities of B-cells and T-cells. PAMPs, pathogen-associated molecular patterns; DAMPs, damage-associated molecular patterns; HAGs; heterotypic aggregates; PDA, platelet-dendritic aggregation; PNA, platelet–neutrophil aggregation; PMA, platelet–monocyte aggregation; Ag, antigen. (Created in BioRender. Huang, C. (2025) https://BioRender.com/3370ji3 accessed on 17 June 2025).

Figure 4

Activation of endothelial cells with their respective interactions with immune cells, molecules and factors during sepsis. ECs can be activated by PAMPs and cytokines through TLR and cytokine receptors, respectively. This activates the transcription factor NF-kB for higher expression of proinflammatory cytokines. The activated ECs also express von Willebrand factor for platelet binding, together with ICAM-1, VCAM-1, E-selectin and P-selectin for leukocyte recruitment and binding. The recruited immune cells will secrete proteases and ROS to increase endothelial permeability and induce EC apoptosis. The apoptotic ECs will also secrete ROS, which can elevate procoagulant TF expression and diminish anticoagulant TM and TFPI expressions. Together with the activated platelets, the thrombus formation is facilitated. PAMPs, pathogen-associated molecular patterns; TLR, Toll-like receptor; NF-kB, nuclear factor kappa B; ICAM-1, intercellular adhesion molecule 1; VCAM-1, vascular cell adhesion molecule 1; EC, endothelial cell; ROS, reactive oxidative species; TF, tissue factor; TM, thrombomodulin; TFPI, tissue factor pathway inhibitor; vWF, von Willebrand factor. (Created in BioRender. Huang, C. (2025) https://BioRender.com/3370ji3 accessed on 17 June 2025).