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This study used established biomarkers of death from ischemic stroke (IS) versus stroke survival to perform network, enrichment, and annotation analyses. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of  IL6 ,  ALB ,  TNF ,  SERPINE1 ,  VWF ,  VCAM1 ,  TGFB1 , and  SELE . Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches  ALB  and  VWF . Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with  TLR2/4 ,  TNF ,  JAK-STAT ,  NOD ,  IL10 ,  IL13 ,  IL4 , and  TGF-β1/SMAD  pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due to IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell-surface interactions, and the proteoglycan-integrin extracellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: (a) that  NFKB1 ,  RELA  and  SP1  were the major regulating actors of the PPI network; and (b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, the proteoglycan-integrin-ECM complex, TGF-β1/SMAD, NF-κB/RELA and SP1.

New Drug Targets to Prevent Death Due to Stroke: A Review Based on Results of Protein-Protein Interaction Network, Enrichment, and Annotation Analyses