Dengue virus modulates the fibrinolytic system to drive vascular leakage and serves as a therapeutic target for tranexamic acid.

Vascular leakage is the defining pathological hallmark of severe dengue, including dengue hemorrhagic fever and dengue shock syndrome. Despite its clinical importance, the mechanisms linking dengue virus infection to endothelial dysfunction remain incompletely understood, and no medicine is currently available. Emerging evidence implicates dysregulation of the host fibrinolytic system in dengue-induced vascular leakage, but its mechanistic role has not been evaluated. Here, we show that dengue virus infection activates endothelial fibrinolytic pathways to drive plasmin-mediated vascular leakage and viral propagation. This fibrinolytic pathway can be targeted with tranexamic acid (TXA). We integrated patient cohort analyses with endothelial cell and mouse models. Serum from dengue patients were profiled for fibrinolytic markers, and human microvascular endothelial cells were used to assess the impact of dengue virus and NS1 on tissue-type and urokinase-type plasminogen activators (tPA, uPA) and plasmin activity. Serum tPA and uPA levels were markedly elevated and correlated with dengue severity. In endothelial cells, dengue virus infection and NS1 exposure induced a pro-fibrinolytic state with increased tPA/uPA expression and plasminogen activation. Plasmin acted as a pathogenic amplifier, promoting viral replication and disrupting endothelial barrier function. Pharmacological blockade of fibrinolysis with the approved antifibrinolytic drug TXA reduced dengue virus replication, preserved endothelial integrity, and mitigated thrombocytopenia, liver injury, and vascular leakage in infected mice. These findings identify a previously unrecognized NS1-fibrinolysis-plasmin axis as a critical driver of dengue vascular pathology and support TXA as a promising adjunctive strategy to reduce hemorrhagic complications in severe dengue.