• Tiewei Li, Rui Peng, Fang Wang, Lu Hua, Sheng Liu, Zhiyan Han, Jianqiu Pei, Shengqiang Pei, Zhenwen Zhao, Xin Jiang, and Xi Chen.
• Diagnostic Laboratory Service, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China.
• J. Thromb. Haemost. 2020 Aug 1; 18 (8): 1952-1964.

BackgroundLysophosphatidic acid (LPA), a bioactive phospholipid released by activated platelets, can induce platelet shape changes and aggregation, which may play an important role in thrombosis. In contrast, the interaction of LPA with neutrophils in thrombosis has not been studied. Recently, neutrophil extracellular traps (NETs) have been shown to bind plasma proteins and activate platelets, which promotes thrombosis.ObjectivesTo investigate whether LPA could activate neutrophils to release NETs, predisposing to thrombosis and promoting thrombus stability.MethodsLevels of neutrophils, NETs, and LPA were detected in 56 participants. Immunofluorescence of NETs and autotaxin, the LPA-producing ectoenzyme, were performed. Induction of NETs and signaling pathways were explored in vitro.ResultsPatients with acute pulmonary embolism showed elevated levels of neutrophils, NETs (dsDNA, MPO-DNA, citrullinated histone H3, and nucleosomes), LPA18:1, and LPA20:4. NETs were present in human intrapulmonary thrombi and were surrounded by autotaxin. LPA18:1 induced rapid release of NETs from human neutrophils via a peptidylarginine deiminase 4-dependent pathway. LPA-induced NETs provided a scaffolding for plasma protein binding and generated a tissue plasminogen activator (tPA)-resistant blood clot. Addition of deoxyribonuclease I to tPA significantly accelerated the lysis of clots and human intrapulmonary thrombi. Furthermore, LPA-induced NETs could activate platelets to release LPA.ConclusionThis is the first study to implicate LPA in regulating the stability of thrombi by inducing rapid release of NETs in vitro and ex vivo, which could be a new mechanism of thrombosis. These findings provide new insight into the prevention and therapy of venous thromboembolic disease by targeting the LPA-NET signaling pathway.© 2020 International Society on Thrombosis and Haemostasis.

10 keywords...

hide…