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Abacavir (ABC) - antiretroviral drug used in HIV-therapy and associated with myocardial infarction - promotes thrombosis through purinergic P2X7R. The role of platelets as pro-thrombotic cells is acknowledged while that of neutrophils - due to their secretory capacity - is gaining recognition. This study analyses the role of neutrophils - specifically the secretome of ABC-treated neutrophils (SNThe effects of ABC or SNABC induced platelet-leukocyte interactions, a consequence not of a direct effect of ABC on platelets, but rather the activation of neutrophils, which triggered an interplay between platelet P-selectin and neutrophil PSGL-1. SNNeutrophils are target cells in ABC-induced thrombosis. ABC acts on neutrophil P2X7R, inducing the release of sLOX-1, which in turn activates platelets. Hence, sLOX-1 could be the missing link in the cardiovascular risk associated with ABC.

Cardiovascular diseases are a leading cause of death. Blood–cell interactions and endothelial dysfunction are fundamental in thrombus formation, and so further knowledge of the pathways involved in such cellular crosstalk could lead to new therapeutical approaches. Neutrophils are secretory cells that release well-known soluble inflammatory signaling mediators and other complex cellular structures whose role is not fully understood. Studies have reported that neutrophil extracellular vesicles (EVs) and neutrophil extracellular traps (NETs) contribute to thrombosis. The objective of this review is to study the role of EVs and NETs as key factors in the transition from inflammation to thrombosis. The neutrophil secretome can promote thrombosis due to the presence of different factors in the EVs bilayer that can trigger blood clotting, and to the release of soluble mediators that induce platelet activation or aggregation. On the other hand, one of the main pathways by which NETs induce thrombosis is through the creation of a scaffold to which platelets and other blood cells adhere. In this context, platelet activation has been associated with the induction of NETs release. Hence, the structure and composition of EVs and NETs, as well as the feedback mechanism between the two processes that causes pathological thrombus formation, require exhaustive analysis to clarify their role in thrombosis.

The coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has resulted in a pandemic with over 270 million confirmed cases and 5.3 million deaths worldwide. In some cases, the infection leads to acute respiratory distress syndrome (ARDS), which is triggered by a cytokine storm and multiple organ failure. Clinical hematological, biochemical, coagulation, and inflammatory markers, such as interleukins, are associated with COVID-19 disease progression. In this regard, neutrophilia, neutrophil-to-lymphocyte ratio (NLR), and neutrophil-to-albumin ratio (NAR), have emerged as promising biomarkers of disease severity and progression. In the pathophysiology of ARDS, the inflammatory environment induces neutrophil influx and activation in the lungs, promoting the release of cytokines, proteases, reactive oxygen species (ROS), and, eventually, neutrophil extracellular traps (NETs). NETs components, such as DNA, histones, myeloperoxidase, and elastase, may exert cytotoxic activity and alveolar damage. Thus, NETs have also been described as potential biomarkers of COVID-19 prognosis. Several studies have demonstrated that NETs are induced in COVID-19 patients, and that the highest levels of NETs are found in critical ones, therefore highlighting a correlation between NETs and severity of the disease. Knowledge of NETs signaling pathways, and the targeting of points of NETs release, could help to develop an effective treatment for COVID-19, and specifically for severe cases, which would help to manage the pandemic.

The P2X7 receptor (P2X7R) possesses a unique structure associated to an as yet not fully understood mechanism of action that facilitates cell permeability to large ionic molecules through the receptor itself and/or nearby membrane proteins. High extracellular adenosine triphosphate (ATP) levels—inexistent in physiological conditions—are required for the receptor to be triggered and contribute to its role in cell damage signaling. The inconsistent data on its activation pathways and the few studies performed in natively expressed human P2X7R have led us to review the structure, activation pathways, and specific cellular location of P2X7R in order to analyze its biological relevance. The ATP-gated P2X7R is a homo-trimeric receptor channel that is occasionally hetero-trimeric and highly polymorphic, with at least nine human splice variants. It is localized predominantly in the cellular membrane and has a characteristic plasticity due to an extended C-termini, which confers it the capacity of interacting with membrane structural compounds and/or intracellular signaling messengers to mediate flexible transduction pathways. Diverse drugs and a few endogenous molecules have been highlighted as extracellular allosteric modulators of P2X7R. Therefore, studies in human cells that constitutively express P2X7R need to investigate the precise endogenous mediator located nearby the activation/modulation domains of the receptor. Such research could help us understand the possible physiological ATP-mediated P2X7R homeostasis signaling.