Deficiency of neutrophil gelatinase-associated lipocalin elicits a hemophilia-like bleeding and clotting disorder in mice

作者：Min Xue, Shaoying Wang, Changjiang Li, Yuewei Wang, Ming Liu, Xiaoshan Huang, Wang Gan, Qikai Yin, Dandan Xiao, Shuo Yang, Musan Yan, Liyuan Niu, Muhammad Awais, Chuanbin Shen, Jianxun Wang, Ren Lai, Heyu Ni, Xiaopeng Tang · 发表于：Blood · 年份：2024 · DOI：10.1182/blood.2024026476 · 被引用次数：9 · 研究领域：Blood Coagulation and Thrombosis Mechanisms、Venous Thromboembolism Diagnosis and Management、Trauma, Hemostasis, Coagulopathy, Resuscitation

ABSTRACT: Coagulation is related to inflammation, but the key pathway, especially innate immune system and coagulation regulation, is not well understood and need to be further explored. Here, we demonstrated that neutrophil gelatinase-associated lipocalin (NGAL), an innate immune inflammatory mediator, is upregulated in patients with thrombosis. Furthermore, it contributes to the initiation and amplification of coagulation, hemostasis, and thrombosis. This occurs by enhancing tissue factor expression on the cell surface, potentiating various clotting factors such as thrombin, kallikrein, factor XIa (FXIa), and FVIIa, promoting thrombin-induced platelet aggregation, and inhibiting antithrombin. NGAL knockout led to strikingly prolonged clot reaction time and kinetic time in thromboelastography analysis, along with reduced thrombus generation angle and lower thrombus maximum amplitude, which were in line with remarkably prolonged activated partial thromboplastin time and prothrombin time. In several mouse hemostasis and thrombosis models, NGAL overexpression or IV administration promoted coagulation and hemostasis and aggravated thrombosis, whereas NGAL knockout or treatment with anti-NGAL monoclonal antibody significantly prolonged bleeding time and alleviated thrombus formation. Notably, NGAL knockout prolonged mouse tail bleeding time or artery occlusion time to over 40 or 60 minutes, respectively, resembling uncontrollable bleeding and clotting disorder seen in hemophilic ...