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

Abstract

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 tissue plasminogen | 1953 LI et aL.

Immunothrombosis in COVID-19: Implications of Neutrophil Extracellular Traps

“…In a study by Jimenez et al histone levels were strongly associated with the degree of VTE and with mortality, as well as with C-reactive protein (CRP) and circulating leukocytes [ 147 ]. Similarly, in other studies on thrombotic diseases, a significant acceleration of intrapulmonary thrombus lysis by a combination of DNase and tPA has also been observed [ 146 ].…”

“…LPA is a bioactive phospholipid, released by activated platelets, that induces the release of NETs. These may, in turn, activate further platelets to release more LPA and perpetuate the LPA–NET–platelet positive feedback mechanism [ 145 , 146 ]. In a study by Jimenez et al histone levels were strongly associated with the degree of VTE and with mortality, as well as with C-reactive protein (CRP) and circulating leukocytes [ 147 ].…”

Neutrophil Extracellular Traps: Signaling Properties and Disease Relevance

“…The core proteins of NETs are H2A, H2B, H3, and H4, which account for about 70% of the total NET proteins, followed by NE, S100A8, lactotransferrin, azurocidin, and cathepsin G [16,17]. In addition, previous studies and our work also found that NETs also contain matrix metalloproteinase-9 (MMP-9), [18,19], tissue factor (TF) [20], von Willebrand factor (vWF), and fibrinogen [5,21].…”

Cardiac thrombotic stability determined by contrast-enhanced echocardiography: investigative protocol and preliminary results

“…Cardioembolic events account for up to 30% of all ischemic strokes [ 2 ]. Accurate gauging of thrombotic stability is critical, helping to guide therapy and procedural planning [ 19 ]. TTE is widely accepted as the primary screening tool in this setting, because it is noninvasive, convenient, and usually highly specific and sensitive [ 9 ].…”