Blood Pro-thrombotic Analytes and Platelet Activation Predict Post-Acute Sequelae of COVID-19

Abstract Post-Acute Sequelae of COVID-19 (PASC), or “long COVID,” describes persistent symptoms following recovery from SARS-CoV-2 infection. Early identification of circulating biomarkers predictive of PASC is critical for prognosis and therapeutic development yet remains poorly defined. To address this gap, we conducted a longitudinal, multi-omics analysis of blood samples from COVID-19 patients (n=75), stratified by acute disease severity and PASC status. We integrated targeted multiplex assays, untargeted proteomics (LC-MS), and whole blood flow cytometry to define immune and vascular signatures associated with PASC. Individuals with PASC exhibited sustained elevations in endothelial and vascular injury markers, including P-selectin and Tissue Factor, as well as persistent damage-associated molecular patterns (DAMPs) such as HMGB1 and S100A8. Pathway enrichment analysis revealed ongoing neutrophil degranulation, platelet activation, and extracellular matrix remodeling—indicating unresolved inflammation and immunothrombosis. These signatures persisted beyond 77 days post-symptom onset. Unlike prior studies that focused on single biomarkers or limited timepoints, our study offers a comprehensive longitudinal analysis combining proteomic and cellular data to define a durable immune-vascular signature specific to PASC. This integrative approach reveals mechanistic insights into PASC pathogenesis and highlights candidate biomarkers with potential utility in early risk stratification. Our findings underscore the critical role of chronic immune and endothelial dysfunction in long COVID and point toward actionable targets for intervention. This study lays the foundation for precision diagnostics and therapeutic strategies aimed at improving long-term outcomes in COVID-19 survivors.