Neutrophil extracellular traps (NETs) have received significant attention in recent years for their role in both the immune response and the vascular damage associated with inflammation. Platelets have been described as critical components of NETs since the initial description of this physio-pathological response of neutrophils. Platelets have been shown to play a dual role as responders and also as stimulators of NETs. The direct interaction with DNA leads to the entrapment of platelets into NETs, a phenomenon that significantly contributes to the thrombotic complications of inflammation and neutrophil activation, while the direct and paracrine stimulation of neutrophils by platelets has been shown to initiate the process of NET formation. In this review, we provide a comprehensive description of our current understanding of the molecular mechanisms underlying the entrapping of platelets into NETs and, in parallel, the platelet-driven cellular responses promoting NET formation. We then illustrate established examples of the contribution of NETs to vascular pathologies, describe the important questions that remain to be answered regarding the contribution of platelets to NET formation and NET-dependent cardiovascular complication, and highlight the fundamental steps taken towards the application of our understanding of platelets’ contribution to NETs for the development of novel cardiovascular therapies.

Granule secretion is an essential platelet function that contributes not only to haemostasis but also to wound healing, inflammation, and atherosclerosis. Granule secretion from platelets is facilitated, at least in part, by Soluble N-ethylmaleimide-Sensitive Factor (NSF) Attachment Protein Receptor (SNARE) complex-mediated granule fusion. Although α-synuclein is a protein known to modulate the assembly of the SNARE complex in other cells, its role in platelet function remains poorly understood. In this study, we provide evidence that α-synuclein is critical for haemostasis using α-synuclein-deficient (^−/−) mice. The genetic deletion of α-synuclein resulted in impaired platelet aggregation, secretion, and adhesion in vitro. In vivo haemostasis models showed that α-synuclein^−/− mice had prolonged bleeding times and activated partial thromboplastin times (aPTTs). Mechanistically, platelet activation induced α-synuclein serine (ser) 129 phosphorylation and re-localisation to the platelet membrane, accompanied by an increased association with VAMP 8, syntaxin 4, and syntaxin 11. This phosphorylation was calcium (Ca²⁺)- and RhoA/ROCK-dependent and was inhibited by prostacyclin (PGI₂). Our data suggest that α-synuclein regulates platelet secretion by facilitating SNARE complex formation.