Potential pathogenic roles of NS1 and its antibodies in DENV infection. During DENV infection, NS1 can exist in monomeric, dimeric, or hexameric form. In the left panel, (1) NS1 is involved in DENV replication within cells [13, 23, 24]. The NS1 dimer can be anchored at the cell membrane, which may be involved in signaling transduction . (2) NS1 can bind to C4 protein and promotes its degradation . (3) NS1 can also bind to prothrombin and inhibit its activation . (4) The binding of NS1 to cells may enhance endocytosis and cytokine production, which may enhance DENV infection and increase vascular permeability . In the right panel, (5) anti-NS1 antibodies that cross-react with endothelial cells may induce endothelial damage . (6) Anti-platelet antibodies elicited by NS1 may inhibit platelet aggregation and cause thrombocytopenia . It is the integrated effects of NS1 and its antibodies, and the immunocomplexes they formed that may contribute to the development of thrombocytopenia, vascular leakage, and coagulopathy during the critical phase of DHF/DSS.