Coagulation and Inflammatory Response Mechanisms in Sepsis

Sepsis arises from a dysregulated host response to infection in which innate immune activation and coagulation pathways become tightly interwoven. Recognition of microbial components by pattern‐recognition receptors triggers a cascade of pro-inflammatory cytokines, complement activation and endothelial dysfunction. Concurrently, monocytes and endothelial cells upregulate tissue factor, initiating thrombin generation and microvascular thrombosis. Inflammasome complexes in myeloid cells further amplify this interplay by promoting pyroptosis and the release of coagulation initiators. Neutrophils and platelets contribute through the release of extracellular vesicles and neutrophil extracellular traps, altering vascular integrity and propagating disseminated intravascular coagulation. Together, these processes can drive widespread microthrombi formation, organ hypoperfusion and ultimately multi-organ failure. Recent advances have begun to dissect the molecular links between inflammatory sensors and coagulation triggers, revealing novel targets for therapeutic modulation and biomarkers for early detection of coagulopathy in septic patients.

Research from Nature Portfolio

Recent studies have characterised small-molecule inhibitors that disrupt the macrophage type I interferon–tissue factor axis. Two electrophilic compounds, dimethyl fumarate and 4-octyl itaconate, were shown to suppress interferon-stimulated induction of tissue factor, block caspase-11-mediated pyroptosis and reduce thrombin generation in models of bacterial and viral sepsis. Treatment with these agents attenuated pulmonary thromboinflammation and improved survival, indicating a direct link between innate immune signalling and coagulopathy.

Investigations in a murine lipopolysaccharide model have revealed that circulating neutrophils release extracellular vesicles enriched in mitochondrial superoxide dismutase 2. These vesicles protect the endothelium by scavenging reactive oxygen species, preserving barrier function and preventing disseminated intravascular coagulation. Supplementation with antioxidant strategies targeting endothelial oxidative stress markedly ameliorated coagulopathic complications and improved outcomes in septic mice.

Coagulation and Inflammatory Response Mechanisms in Sepsis publication trend

The graph below shows the total number of articles in coagulation and inflammatory response mechanisms in sepsis across all publications each year (not limited to Nature Index journals).

Technical terms

Tissue Factor (TF): A membrane-associated glycoprotein that initiates the extrinsic coagulation cascade by binding factor VII/VIIa.

Inflammasome: A cytosolic multiprotein complex that activates caspase-1 or caspase-11, leading to maturation of interleukin-1β and pyroptosis.

Pyroptosis: A lytic form of programmed cell death driven by gasdermin pores, releasing pro-inflammatory cellular contents.

Extracellular Vesicles (EVs): Membrane-bound particles released by cells that carry proteins, lipids and nucleic acids to mediate intercellular communication.

Disseminated Intravascular Coagulation (DIC): A systemic condition characterised by widespread microvascular thrombosis and simultaneous consumption of clotting factors, leading to bleeding and organ dysfunction.

References

1. Dimethyl fumarate and 4-octyl itaconate are anticoagulants that suppress Tissue Factor in macrophages via inhibition of Type I Interferon. Nature Communications (2023).
2. The pathogenesis and potential therapeutic targets in sepsis. MedComm (2023).
3. Inflammasome-Dependent Coagulation Activation in Sepsis. Frontiers in Immunology (2021).
4. Phospho-Tyr705 of STAT3 is a therapeutic target for sepsis through regulating inflammation and coagulation. Cell Communication and Signaling (2020).
5. Neutrophils restrain sepsis associated coagulopathy via extracellular vesicles carrying superoxide dismutase 2 in a murine model of lipopolysaccharide induced sepsis. Nature Communications (2022).