Role of Neutrophils and NETs in Animal Models of Thrombosis

Abstract

Thrombosis is one of the major causes of mortality worldwide. Notably, it is not only implicated in cardiovascular diseases, such as myocardial infarction (MI), stroke, and pulmonary embolism (PE), but also in cancers. Understanding the cellular and molecular mechanisms involved in platelet thrombus formation is a major challenge for scientists today. For this purpose, new imaging technologies (such as confocal intravital microscopy, electron microscopy, holotomography, etc.) coupled with animal models of thrombosis (mouse, rat, rabbit, etc.) allow a better overview of this complex physiopathological process. Each of the cellular components is known to participate, including the subendothelial matrix, the endothelium, platelets, circulating cells, and, notably, neutrophils. Initially known as immune cells, neutrophils have been considered to be part of the landscape of thrombosis for more than a decade. They participate in this biological process through their expression of tissue factor (TF) and protein disulfide isomerase (PDI). Moreover, highly activated neutrophils are described as being able to release their DNA and thus form chromatin networks known as “neutrophil extracellular traps” (NETs). Initially, described as “dead sacrifices for a good cause” that prevent the dissemination of bacteria in the body, NETs have also been studied in several human pathologies, such as cardiovascular and respiratory diseases. Many articles suggest that they are involved in platelet thrombus formation and the activation of the coagulation cascade. This review presents the models of thrombosis in which neutrophils and NETs are involved and describes their mechanisms of action. We have even highlighted the medical diagnostic advances related to this research.

Thrombosis and Anticoagulation Therapy in Systemic Lupus Erythematosus

“…Neutrophils that produce NET structures trigger an inflammatory response that leads to endothelial damage and induces dendritic cells to produce interferons, thus, amplifying the autoimmune response [ 45 ]. NETs play a crucial role in thrombosis by participating in platelet adhesion and fibrin generation [ 46 ]. Therefore, intervening NETs could be a potential target for anticoagulation therapy.…”

Elevated plasma D-dimer levels in patients with anti-N-methyl-D-aspartate receptor encephalitis

“…Studies reported that neutrophil extracellular vesicles and neutrophil extracellular traps (NETs) contribute to thrombosis ( 18 ). Kamba et al demonstrated that neutrophils release tissue factors through NETs, induce thrombin generation, and promote hypercoagulation in vasculitis ( 19 , 20 ). Recent observations have demonstrated that NETs were blocked by therapeutic-dose low-molecular-weight heparin in coronavirus disease 2019 ( 21 ).…”

Pathogenesis and Therapy of Coagulation Disorders in Severe Acute Pancreatitis

“…NETs are a meshwork of DNA fibers comprising histones, antimicrobial proteins, and high-mobility group box 1 (HMGB1), exhibiting antimicrobial functions by trapping and killing extracellular pathogens in infectious diseases. 66 During inflammation, neutrophils are recruited first after endothelial injury and activation; 67 , 68 subsequently, activated platelets induce neutrophil necroptosis and NET formation 69 ( Figure 2 ). NETs enhance thrombin generation, 68 promote granulocyte-platelet and platelet aggregation via a collaborative interaction between histone, platelets, and inorganic polyphosphate, 66 , 69 and further activate the platelets.…”