中性粒细胞通过形成中性粒细胞外囊（NETs）参与血栓形成的发病机制。血栓形成是骨髓增生性肿瘤（MPNs）患者发病率和死亡率的主要原因。最近的研究表明，在JAK2V617F中性粒细胞的患者和小鼠模型中，NET形成（NETosis）增加，并报道了NETosis在小鼠血栓形成病理生理学中的参与。本研究调查了JAK2V617F中性粒细胞是否足以促进血栓形成，或者是否需要与其他血细胞类型合作。在表达JAK2V617F在所有造血系列中的PF4iCre;Jak2V617F/WT小鼠中以及仅在白细胞中表达JAK2V617F的MRP8Cre;Jak2V617F/WT小鼠中研究了NETosis。在PF4iCre;Jak2V617F/WT小鼠中观察到NETosis增加和自发性肺血栓形成，并且这些现象在DNA酶治疗后消失。在MRP8Cre;Jak2V617F/WT小鼠中没有观察到自发性的NETosis或肺血栓形成，暗示仅变异中性粒细胞是不足以引发血栓形成的。体外实验表明，JAK2V617F突变的血小板能够通过JAK2V617F突变的中性粒细胞触发NETosis。PF4iCre;Jak2V617F/WT小鼠中的阿司匹林治疗降低了NETosis和肺血栓形成。在接受阿司匹林治疗的无细胞减少治疗的MPN患者中，血浆NET标志物浓度低于未接受阿司匹林治疗的MPN患者。我们的研究表明，JAK2V617F中性粒细胞单独是不足以促进血栓形成的，相反，血小板与中性粒细胞合作通过体内的NETosis来促进血栓形成。在MPNs中发现了阿司匹林在预防血栓形成中的新作用。Copyright© 2023国际血栓与止血学会。出版由Elsevier Inc. 版权所有。

Neutrophils participate in the pathogenesis of thrombosis through the formation of neutrophil extracellular traps (NETs). Thrombosis is the main cause of morbidity and mortality in patients with myeloproliferative neoplasms (MPNs). Recent studies have shown an increase in NET formation (NETosis) both in patients with JAK2V617F neutrophils and in mouse models, and reported the participation of NETosis in the pathophysiology of thrombosis in mice.This study investigated whether JAK2V617F neutrophils are sufficient to promote thrombosis or whether their cooperation with other blood cell types is necessary.NETosis was studied in PF4iCre;Jak2V617F/WT mice expressing JAK2V617F in all hematopoietic lineages, as occurs in MPNs, and in MRP8Cre;Jak2V617F/WT mice in which JAK2V617F is expressed only in leukocytes.In PF4iCre;Jak2V617F/WT mice, an increase in NETosis and spontaneous lung thrombosis abrogated by DNAse administration were observed. The absence of spontaneous NETosis or lung thrombosis in MRP8Cre;Jak2V617F/WT mice suggested that mutated neutrophils alone are not sufficient to induce thrombosis. Ex vivo experiments demonstrated that JAK2V617F-mutated platelets trigger NETosis by JAK2V617F-mutated neutrophils. Aspirin treatment in PF4iCre;Jak2V617F/WT mice reduced NETosis and reduced lung thrombosis. In cytoreductive-therapy-free MPN patients treated with aspirin, plasma NET marker concentrations were lower than in aspirin-untreated MPN patients.Our study demonstrates that JAK2V617F neutrophils alone are not sufficient to promote thrombosis; rather, platelets cooperate with neutrophils to promote NETosis in vivo. A new role for aspirin in thrombosis prevention in MPNs was also identified.Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.