Lysophosphatidic acid promotes thrombus stability by inducing rapid formation of neutrophil extracellular traps：A new mechanism of thrombosis

BACKGROUND: Lysophosphatidic 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. OBJECTIVES: To investigate whether LPA could activate neutrophils to release NETs, predisposing to thrombosis and promoting thrombus stability. METHODS: Levels 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. RESULTS: Patients 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 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. CONCLUSION: This is the first study to implicate LPA in regulating the stability of thrombus 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 LPA-NETs signaling pathway.