NGAL deficiency elicits Hemophilia-like bleeding and clotting disorder

Coagulation is related to inflammation, but the key pathways, especially innate immunity inflammatory response-coagulation, hemostasis, and thrombosis regulation is poorly understood and need to be further explored. In the current study, we showed that innate immunity inflammatory mediator neutrophil gelatinase-associated apolipoprotein (NGAL) which was upregulated in plasma of deep vein thrombosis patients interacted with and potentiated thrombin, kallikrein, FXIa, and FVIIa and suppressed antithrombin to induce coagulation, hemostasis, and thrombosis. Furthermore, NGAL can augment thrombin-induced platelet aggregation. In multiple mice hemostasis and thrombosis models, NGAL overexpression or intravenous administration promoted coagulation and hemostasis and aggravated thrombus, whereas NGAL knockout or treatment with anti-NGAL monoclonal antibody significantly prolonged bleeding time and alleviated thrombus formation. Notably, NGAL knockout prolonged both mice tail bleeding time and artery occlusion time to over 40 min, resembling uncontrollable bleeding and clotting disorder seen in Hemophilia mice. Furthermore, anti-NGAL monoclonal antibody treatment markedly reduced the formation of blood clots in a mouse-tail thrombosis model induced by carrageenan, which is linked to inflammation. Collectively, these findings suggest NGAL is a crucial coagulation regulator and mediates the crosstalk between innate immunity inflammation and coagulation, hemostasis, and thrombus, and provide new target and strategy for the development of innovative antithrombotic drugs. ### Competing Interest Statement The authors have declared no competing interest.