The Emerging Role of Neutrophil Extracellular Traps in Arterial, Venous and Cancer-Associated Thrombosis

Abstract

Neutrophils play a vital role in the formation of arterial, venous and cancer-related thrombosis. Recent studies have shown that in a process known as NETosis, neutrophils release proteins and enzymes complexed to DNA fibers, collectively called neutrophil extracellular traps (NETs). Although NETs were originally described as a way for the host to capture and kill bacteria, current knowledge indicates that NETs also play an important role in thrombosis. According to recent studies, the destruction of vascular microenvironmental homeostasis and excessive NET formation lead to pathological thrombosis. In vitro experiments have found that NETs provide skeletal support for platelets, red blood cells and procoagulant molecules to promote thrombosis. The protein components contained in NETs activate the endogenous coagulation pathway to promote thrombosis. Therefore, NETs play an important role in the formation of arterial thrombosis, venous thrombosis and cancer-related thrombosis. This review will systematically summarize and explain the study of NETs in thrombosis in animal models and in vivo experiments to provide new targets for thrombosis prevention and treatment.

Proteome reveals antiviral host response and NETosis during acute COVID-19 in high-risk patients

“…In summary, the proteomic response of C19 patients during the acute disease phase was characterized by the activation of classical inflammatory pathways, combined with markers indicating activation of the coagulation cascade and matrix remodeling when compared to Ctrl-noninfl individuals (Figures 4 & 5; Figures S3; Tables S7 & 8). The unique combination of these processes together with the presence of specific markers, i.e., ANXA3, CCL7, HSPA1A, LCN2, LGALS9, MMP8, PPIB, PRTN3, and RETN pointed towards neutrophil degranulation and neutrophil extracellular trap (NET) formation in the acute disease phases in C19 patients, in line with previous studies describing innate immune cell activation in severe COVID-19 including neutrophil degranulation, NETosis, as well as pro-inflammatory / HLA-DRlo monocyte expansion (Bardoel et al, 2014;Middleton et al, 2020;Nicolai et al, 2020;Zhou et al, 2021;Smet et al, 2021) (Figure 5). In addition, we detected a strong activation of interleukin signaling including activation of TNF signaling and a type-2 inflammation with the potential to counteract TNF-related signaling, especially in monocyte-related functions.…”

“…Protein regulation in the acute-early phase was uniquely characterized by the involvement of inflammatory processes including interleukin signaling (i.e., Interestingly, a large proportion of proteins associated with neutrophil activity and NET formation such as ANXA3, CCL7, HSPA1A, LCN2, LGALS9, MMP8, PPIB, PRTN3, and RETN (Wang et al, 2020;Brinkmann et al, 2004) were upregulated in both acute phases (acute-early: 58/78, acute-late: 54/78) compared to Ctrl-noninfl with 36 proteins similarly regulated across both acute disease phases, confirming previous reports of increased NETosis in C19 patients by unbiased proteome screening (Bardoel et al, 2014;Middleton et al, 2020;Nicolai et al, 2020;Zhou et al, 2021;Smet et al, 2021) (Figure 5A). Similarly, the differential regulation of TNF (acute-early: 15/31, acute-late: 11/31) and IL-1 (acute-early: 7/23, acute-late: 7/23) signaling pathway associated proteins were detected in the acute disease phases when compared to Ctrl-noninfl (Figure 5B & C).…”

“…On the one hand, we hereby show regulation of significant players in the immune host response confirming the role of inflammatory cell death and tissue damage (Karki et al, 2021). On the other hand, we were able to add to previous studies by showing the dynamic of NETosis and inflammasome regulation (Bardoel et al, 2014;Middleton et al, 2020;Nicolai et al, 2020;Zhou et al, 2021;Smet et al, 2021) in severely affected patients in contrast to a type-2 centered immune response involving interleukin 4, 10, 13, and TNF signaling in both disease groups or in less severe disease only (e.g., Interleukin-2 family and IN signaling). These changes were found to be accompanied by remodeling processes.…”

“…The strong upregulation of proteins related to NET formation (Wang et al , 2020; Brinkmann et al , 2004) was observed during both acute COVID phases ( acute-early : 58/78, acute-late : 54/78) with 36 proteins similarly regulated. Activation of NET formation in context with other indicators of inflammasome activation (Bardoel et al , 2014; Middleton et al , 2020; Nicolai et al , 2020; Zheng et al , 2020; Zhou et al , 2021; Smet et al , 2021) specifically characterized patients with severe disease (WHO >= 4). The regulated proteins included CD177, a prominent activation marker present on the surface of circulating neutrophils (Nicolai et al , 2020; Bai et al , 2017), MME (CD10) as an immaturity marker of neutrophils and previously associated with severe COVID-19 (Schulte-Schrepping et al , 2020; Kaiser et al , 2021), PDGFRA as a marker of platelet degranulation, and PADI4 as a key regulator of NETosis, whereas the classical NETosis/degranulation marker MPO was not found to be regulated in any of the comparisons.…”

Potential Role of Neutrophil Extracellular Traps in Cardio-Oncology

“…NETs contain complicated protein components, which can activate the endogenous coagulation pathway promoting thrombosis. Therefore, NETs appear critical to the formation of cancer-related arterial and venous thrombosis [ 58 , 59 ].…”