Blood Coagulation in COVID-19: Systems-Biology Evidence, Clinical Implications, and Therapeutic Opportunities in an Evolving Pandemic

Background: SARS-CoV-2 continues to cause substantial morbidity, with COVID-19-associated coagulopathy driving complications across acute and postacute stages. Host-targeted therapies that address this systemic pathology are urgently needed. Objective: To delineate the network pharmacology of COVID-19 and prioritize drug targets and repurposing candidates using disease-associated transcriptomic signatures and clinical biomarkers. Methods: We implemented an integrative biochem-informatics workflow. Bioinformatics analysis of COVID-19 transcriptomics defined severity-specific gene signatures and dysregulated pathways. A binary scoring matrix prioritized high-confidence drug targets by integrating differential expression, pathway enrichment, biomarker validity, and druggability. Finally, cheminformatics analysis with chemical similarity searching identified potential therapeutic compounds against these top-ranked candidates. Results: Enrichment analysis highlighted blood coagulation as the most significantly dysregulated pathway (FDR = 1.89 × 10–16), with COVID-19-associated coagulopathy also highly enriched (FDR = 6.48 × 10–7). Target prioritization ranked von Willebrand factor (VWF) as the top candidate. Drug screening identified 35 known VWF-targeting compounds, including the small molecule SP-8008. A subsequent similarity search identified 17 structural analogs of SP-8008, including CID 16204324, which has been independently reported as a SARS-CoV-2 main protease (Mpro/3CLpro) inhibitor. Additional high-confidence host targets spanned the RAAS/ACE2, complement (C5a), chemokine signaling (CCL2), and fibrinolysis/coagulation (PAI-1, F2/F3, PLG) regulators, supported by clinical biomarker evidence. Conclusion: Our integrative informatics analysis computationally prioritized coagulation-related pathways as prominent severity-associated host-response signatures in COVID-19. These systems-level findings position coagulation as a transcriptomically supported, central disease program rather than solely a secondary complication. The prioritization of VWF and additional host targets provides a data-driven framework for repositioning therapeutics against the coagulopathic sequelae of SARS-CoV-2 infection.