Abstract
Sepsis is now considered a dysregulated host response in which inflammation, coagulation,
and endothelial injury converge to create a self-amplifying network of thromboinflammation.
This definition reflects maladaptive immunothrombosis—a defense mechanism that becomes
pathogenic when excessive, rather than an isolated inflammatory process. This review
integrates recent mechanistic advances linking damage-associated molecular patterns
(DAMPs), endothelial dysfunction, and intravascular coagulation. Endogenous alarmins,
such as high-mobility group box 1, histones, and mitochondrial DNA, engage in pattern
recognition (Toll-like receptors, receptor for advanced glycation end products) to
propagate leukocyte activation, platelet aggregation, and endothelial disruption.
The resulting loss of critical endothelial anticoagulant molecules (thrombomodulin,
endothelial cell protein C receptor, antithrombin) and glycocalyx degradation convert
the vascular endothelium into a procoagulant interface. Complement activation and
protease-activated receptor signaling reinforce this loop, producing microvascular
thrombosis, capillary leakage, and organ ischemia. Platelet–leukocyte aggregates and
neutrophil extracellular traps (NETs) serve as intravascular scaffolds for fibrin
deposition, thereby propagating disseminated intravascular coagulation (DIC). Targeted
interventions, including recombinant thrombomodulin, antithrombin supplementation,
neutralization of NETs and DAMPs, complement blockade, and endothelial-protective
strategies, seek to restore vascular homeostasis. A multidomain biomarker approach
integrating DAMPs, endothelial markers, and coagulation indices, combined with machine
learning–based phenotyping, may enable precision stratification of sepsis endotypes.
The convergence of DAMP signaling, immune activation, and coagulation underlies the
pathophysiologic continuum from sepsis-induced coagulopathy to DIC. Therapeutically
interrupting this axis represents the most promising avenue toward personalized, mechanism-driven
treatment in sepsis.
Keywords HMGB1 protein - histones - mitochondrial DNA - receptor for advanced glycation end
products - thromboinflammation
