Immune-endothelial-coagulation crosstalk as a driver of multi-organ dysfunction in severe viral pneumonia

Viral burden or pathogen identity alone cannot adequately explain the progression of severe viral pneumonia from a compartmentalized respiratory infection to acute respiratory distress syndrome, multi-organ failure, and death. Maladaptive immunity, endothelial damage, and coagulation dysregulation are all functionally integrated in a host-driven pathological mechanism that mediates disease escalation. Systemic microvascular damage and pulmonary inflammation are linked by immune-endothelial-coagulation interaction. This review investigates the ways in which immunothrombosis and microcirculatory dysfunction are propagated by defective antiviral immunity, alveolar-capillary barrier failure, damage-associated molecular pattern and neutrophil extracellular trap release, endothelial glycocalyx degradation, complement-platelet interactions, coagulation cascade activation, and impaired fibrinolysis. Lung-derived inflammatory signals cause endothelial activation and procoagulant reprogramming in distal organs following systemic dissemination, resulting in organ-specific phenotypes such as acute kidney injury, secondary myocardial injury, ARDS in the lung, neurovascular unit dysfunction, and barrier-disruption-associated inflammatory amplification along the liver-gut axis. This framework may provide a rationale for exploring stage-adapted and phenotype-guided approaches to severe viral pneumonia, including early antiviral therapy, immunomodulation during disease progression, endothelial-coagulation axis targeting, and host-directed strategies. Further longitudinal cohorts, multi-omics analyses, mechanism-based stratification studies, and mechanism-embedded clinical trials will be needed to determine whether immune-endothelial-coagulation coupling can be translated from a mechanistic model into a clinically actionable framework for precision intervention.