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The clinical course of COVID-19 ranges from mild symptoms to severe complications, and common laboratory markers such as D-dimer, ferritin, interleukin-6 (IL-6), and C-reactive protein (CRP) often do not accurately predict which patients will develop severe disease. In this study, we reviewed current literature and analyzed additional data to assess emerging biomarkers that may help identify high-risk cases earlier. These include circulating cell-free DNA (cfDNA) produced during neutrophil extracellular trap formation (NETosis), hyaluronic acid (HA), hypoxia-inducible factor (HIF) isoforms, and related long non-coding RNAs such as HAS2-AS1 and HIF1-AS1. Increased levels of cfDNA/NETs, HA, and elevated expression of HIF isoforms and their lncRNAs are closely associated with key features of severe COVID-19, including immune-related blood clotting, low oxygen levels, vascular damage, and chronic inflammation. These biomarkers show promise for use in risk assessment tools that could support earlier clinical decisions and improve outcomes in patients with COVID-19.