NETs-Induced Thrombosis Impacts on Cardiovascular and Chronic Kidney Disease

Abstract

Arterial and venous thrombosis constitute a major source of morbidity and mortality worldwide. Association between thrombotic complications and cardiovascular and other chronic inflammatory diseases are well described. Inflammation and subsequent initiation of thrombotic events, termed immunothrombosis, also receive growing attention but are still incompletely understood. Nevertheless, the clinical relevance of aberrant immunothrombosis, referred to as thromboinflammation, is evident by an increased risk of thrombosis and cardiovascular events in patients with inflammatory or infectious diseases. Proinflammatory mediators released from platelets, complement activation, and the formation of NETs (neutrophil extracellular traps) initiate and foster immunothrombosis. In this review, we highlight and discuss prominent and emerging interrelationships and functions between NETs and other mediators in immunothrombosis in cardiovascular disease. Also, with patients with chronic kidney disease suffering from increased cardiovascular and thrombotic risk, we summarize current knowledge on neutrophil phenotype, function, and NET formation in chronic kidney disease. In addition, we elaborate on therapeutic targeting of NETs-induced immunothrombosis. A better understanding of the functional relevance of antithrombotic mediators which do not increase bleeding risk may provide opportunities for successful therapeutic interventions to reduce thrombotic risk beyond current treatment options.

COVID-19 and the risk of acute cardiovascular diseases: A two-sample Mendelian randomization study

“…Hyperin ammation known as "cytokine storm", coagulation dysfunction, and immunothrombosis are the pathophysiological features of COVID-19 and have been shown to be associated with an increased risk of CVDs in COVID-19 patients [48]. Activation of platelets and formation of NETs initiate immunothrombosis [49]. During NETosis, autoantigens, proin ammatory mediators, proteases, and cytotoxic enzymes are exposed, leading to cytokine storm [50].…”

Role and Therapeutic Targeting Strategies of Neutrophil Extracellular Traps in Inflammation

“…NETs mediate platelet activation, coagulation, and thrombosis. 65 The complete NETs stent-platelet-thrombin axis is capable of promoting intravascular thrombin activation and microvascular thrombosis in sepsis. 66 In the plasma-induced NETs model of COVID-19, SARS-CoV-2 activates complement C3 to drive platelet/NETs and induce the formation of NETs enriched with tissue factor, which in turn activates endothelial cells to express tissue factor, thus increasing their procoagulant activity, and further activates platelets to aggravate the inflammatory cycle.…”

Semaglutide modulates prothrombotic and atherosclerotic mechanisms, associated with epicardial fat, neutrophils and endothelial cells network

“…These results might suggest the association between higher adiposity or metabolic disorder [ 32 , 33 ], represented by high plasma FABP4 levels, and CAD. This adipokine is involved on endothelial metabolism and angiogenesis [ 34 ] and adipocytes inflammation and IR [ 35 ].Their proinflammatory mediators, complement activation, and neutrophils activity might initiate an immunothrombosis pathway [ 36 ]. Although most of the GLP-1ra have demonstrated a reduction on MACE incidence, we aimed to test the role of semaglutide in this network on preclinical studies based on endocrine activity of human adipose tissue, neutrophils, and endothelial cells and plasma and cell markers modulation on treated patients for 6 months.…”