Abstract Number: PB2368
Meeting: ISTH 2020 Congress
Background: Lysophosphatidic acid (LPA), a bioactive phospholipid, released by activated platelets, could further induce platelet shape change and aggregation, which plays an important role in thrombosis. However, the interaction of LPA with neutrophils in thrombosis has not been studied. Recently, neutrophil extracellular traps (NETs) have been demonstrated to bind plasma proteins and activate platelets, which promotes thrombosis.
Aims: To investigate whether LPA could activate neutrophils to release NETs, thereby predisposing to thrombosis and promoting thrombus stability.
Methods: Venous blood samples were obtained from 26 patients with acute pulmonary embolism (APE) and 30 control subjects. Immunofluorescence of NETs and autotaxin, the LPA-producing ectoenzyme, in human intrapulmonary thrombi were performed. The study was approved by medical ethics committee and informed consents were obtained. Induction of NETs and the signaling pathways were explored in vitro. Statistical significance was assessed by unpaired t test for normally distributed variables or Mann-Whitney test for skewed distributed variables.
Results: APE patients showed elevated levels of neutrophils, the markers of NETs (dsDNA, MPO-DNA, citrullinated histone H3, and nucleosomes), and LPA. NETs existed in human intrapulmonary thrombi and were surrounded by autotaxin(Figure 1). We showed that LPA induced rapid release of NETs from human neutrophils via a peptidylarginine deiminase 4-dependent pathway (Figure 2). 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 thrombus. Furthermore, LPA-induced NETs could activate platelets to release LPA.
Conclusions: We are the first to implicate LPA in regulating the stability of thrombus by inducing rapid release of NETs via a PAD4-dependent pathway in vitro and ex vivo which could be a new mechanism of thrombosis. These findings provide a new insight into the prevention and therapy of venous thromboembolic disease by targeting the LPA-NETs signaling pathway.
[Figure 1.The increased levels of neutrophils, NETs and LPA in APE patients(A-C). ATX and NETs were present in intrapulmonary thrombus(D-E).]
To cite this abstract in AMA style:Peng R, Li T, Wang F, Hua L, Liu S, Pei J, Han Z, Pei S, Zhao Z, Jiang X, Chen X. Lysophosphatidic Acid Promotes Thrombus Stability by Inducing Rapid Formation of Neutrophil Extracellular Traps via a Peptidylarginine Deiminase 4-Dependent Pathway: A New Mechanism of Thrombosis [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/lysophosphatidic-acid-promotes-thrombus-stability-by-inducing-rapid-formation-of-neutrophil-extracellular-traps-via-a-peptidylarginine-deiminase-4-dependent-pathway-a-new-mechanism-of-thrombosis/. Accessed November 26, 2021.
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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/lysophosphatidic-acid-promotes-thrombus-stability-by-inducing-rapid-formation-of-neutrophil-extracellular-traps-via-a-peptidylarginine-deiminase-4-dependent-pathway-a-new-mechanism-of-thrombosis/