Damage-associated Molecular Patterns, Immunothrombosis, and Intravascular Inflammation in Sepsis: A Narrative...

Area of Science:

• Immunology
• Hematology
• Pathophysiology

Background:

• Sepsis is redefined as a dysregulated host response involving inflammation, coagulation, and endothelial injury, creating a thromboinflammatory network.
• This process, termed immunothrombosis, becomes pathogenic when excessive, moving beyond a simple inflammatory response.

Purpose of the Study:

• To review recent mechanistic advances linking damage-associated molecular patterns (DAMPs), endothelial dysfunction, and intravascular coagulation in sepsis.
• To explore how these factors contribute to the development of sepsis-induced coagulopathy and disseminated intravascular coagulation (DIC).

Main Methods:

• Integration of mechanistic studies on DAMPs (e.g., HMGB1, histones, mitochondrial DNA) and their receptors (TLRs, RAGE).
• Analysis of endothelial dysfunction, loss of anticoagulant molecules, and glycocalyx degradation.
• Examination of complement activation, protease-activated receptor signaling, platelet-leukocyte aggregates, and neutrophil extracellular traps (NETs) in promoting thrombosis.

Main Results:

• Endogenous alarmins propagate leukocyte activation, platelet aggregation, and endothelial disruption, leading to a procoagulant vascular endothelium.
• Microvascular thrombosis, capillary leakage, and organ ischemia result from this procoagulant state.
• Platelet-leukocyte aggregates and NETs facilitate fibrin deposition and DIC.

Conclusions:

• Targeted interventions like recombinant thrombomodulin, antithrombin, NET neutralization, and endothelial protection aim to restore vascular homeostasis.
• Multidomain biomarkers and machine learning may enable precision stratification of sepsis endotypes.
• Interrupting the axis of DAMP signaling, immune activation, and coagulation offers a promising path for personalized, mechanism-driven sepsis treatment.