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This review aims to address this gap by systematically analyzing the diagnostic and prognostic potential of these neglected biomarkers, with particular emphasis on their mechanistic connections to COVID-19 pathophysiology. Reduced levels of adiponectin and prostacyclin (PGI2) and elevated level of endothelin are associated with endothelial dysfunction, whereas elevated levels of endocan and endoglin are indicative of elevated vascular inflammation. Increased concentrations of markers such as angiopoietin, E-selectin, P-selectin, ICAM-1, and VCAM-1 suggest endothelial activation, while higher levels of fractalkine, galectin, HMGB1, and osteopontin reflect an ongoing inflammatory state. Immunological markers, including HMGB1, neopterin, and serum amyloid A, are significantly elevated, underscoring prolonged immune activation associated with severe COVID-19. Elevated levels of matrix metalloproteinases (MMPs) and soluble urokinase plasminogen activator receptor (SuPAR) highlight tissue remodeling and fibrinolytic imbalance related to vascular injury. Additionally, increases in soluble fms-like tyrosine kinase-1 (sFlt-1) and pentraxin reflect inflammatory pathways that exacerbate endothelial dysfunction. Elevated levels of syndecan-1 reflect endothelial glycocalyx degradation and impaired endothelial barrier integrity. Increased von Willebrand factor (vWF) indicates endothelial activation and injury with a prothrombotic shift. Elevated surfactant protein D (SP-D) is a marker of pulmonary epithelial injury and disruption of the alveolar\u2013capillary interface. Other biomarkers, such as the receptor for advanced glycation end products (RAGE) and MR-proADM, signal oxidative stress and endothelial damage. Collectively, these biomarkers emphasize the extensive vascular and endothelial impairment in COVID-19, suggesting their utility as diagnostic tools and potential targets for therapeutic intervention against the systemic effects of the disease. This review advocates for the integration of these biomarkers into standard monitoring and treatment protocols for COVID-19, thereby enhancing personalized care. 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