Neutrophil extracellular traps promote deep vein thrombosis in mice

By Alexander Brill, T. Fuchs, A. Savchenko, G. M. Thomas, K. Martinod, S. F. Meyer, Ashish A. Bhandari, Denisa D. Wagner. Journal of Thrombosis and Haemostasis, 2012

886 citations recorded by the source corpus.

Summary.  Background: Upon activation, neutrophils can release nuclear material known as neutrophil extracellular traps (NETs), which were initially described as a part of antimicrobial defense. Extracellular chromatin was recently reported to be prothrombotic in vitro and to accumulate in plasma and thrombi of baboons with experimental deep vein thrombosis (DVT). Objective: To explore the source and role of extracellular chromatin in DVT. Methods: We used an established murine model of DVT induced by flow restriction (stenosis) in the inferior vena cava (IVC). Results: We demonstrate that the levels of extracellular DNA increase in plasma after 6 h IVC stenosis, compared with sham‐operated mice. Immunohistochemical staining revealed the presence of Gr‐1‐positive neutrophils in both red (RBC‐rich) and white (platelet‐rich) parts of thrombi. Citrullinated histone H3 (CitH3), an element of NETs’ structure, was present only in the red part of thrombi and was frequently associated with the Gr‐1 antigen. Immunofluorescent staining of thrombi showed proximity of extracellular CitH3 and von Willebrand factor (VWF), a platelet adhesion molecule crucial for thrombus development in this model. Infusion of Deoxyribonuclease 1 (DNase 1) protected mice from DVT after 6 h and also 48 h IVC stenosis. Infusion of an unfractionated mixture of calf thymus histones increased plasma VWF and promoted DVT early after stenosis application. Conclusions: Extracellular chromatin, likely originating from neutrophils, is a structural part of a venous thrombus and both the DNA scaffold and histones appear to contribute to the pathogenesis of DVT in mice. NETs may provide new targets for DVT drug development.

Subfields: Hematology, Immunology, Immunology and Allergy

View Paper: https://www.semanticscholar.org/paper/0ea032e83293b2a8dc7a6fff1132efa217ed895a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Hematology

1. M. Egeblad
2. D. Scadden

In Immunology

1. V. Brinkmann
2. Arturo Zychlinsky
3. A. Mócsai
4. K. Martinod
5. D. Wagner
6. C. Rosales
7. K. Futosi
8. Szabina Fodor

In Immunology and Allergy

1. A. Mócsai
2. M. Egeblad
3. Arturo Zychlinsky

Citations in the corpus

• Neutrophil extracellular traps: Is immunity the second function of chromatin? (2012, background): “Consequently, NETs can be detected in venous thrombi (Brill et al., 2012).”
• Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis (2012, background): “Recently, our group showed that NETs activate platelets and trigger thrombosis (15) and are implicated in the pathogenesis of deep vein thrombosis (DVT) in mice (16).”
• Neutrophil cell surface receptors and their intracellular signal transduction pathways (2013, background): “Neutrophils participate in the development of various autoimmune and inflammatory diseases, including rheumatoid arthritis, systemic lupus erythematosus, blistering skin diseases, autoimmune vasculitides, anaphylactic reactions, aswell asmetabolic-vascular diseases such as atherosclerosis, thrombosi”
• Blood-Contacting Biomaterials: In Vitro Evaluation of the Hemocompatibility (2018, background): “Besides the ability to trap bacteria, NETs ability to promote thrombosis was demonstrated in animal models (Brill et al., 2012).”
• Diverse novel functions of neutrophils in immunity, inflammation, and beyond (2013, background): “A significant amount of extracellular DNA trap formation inside the thrombus could be observed upon flow restriction–induced venous thrombosis in mice (Brill et al., 2012; von Brühl et al., 2012) and obstruction-induced venous thrombosis in baboons (Fuchs et al., 2010).”
• Neutrophil extracellular traps in COVID-19. (2020, background): “vascularly, occlude arteries (54), veins (55), and microscopic vessels (56).”
• COVID-19 update: Covid-19-associated coagulopathy (2020, background): “The process involves histone (H) citrullination (Cit) by peptidylarginine deiminase (PAD)4, chromatin unwinding, breakdown of nuclear membranes and cytolysis [34, 35].”
• Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? (2018, background): “NETs can also stimulate the activation of coagulation cascades (Brill et al., 2012) and not only platelet adhesion (Massberg et al., 2010), but also erythrocyte adhesion (Fuchs et al., 2010).”
• Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice (2018, background): “A growing body of evidence indicates a role for NETs, not just in infections but also in noninfectious inflammatory diseases (13), thrombosis (16, 17), and impaired wound healing in diabetes (18).”
• Thrombosis: tangled up in NETs. (2014, background): “Through their histones, NETs may further enhance endothelial activation as histone infusion in combination with IVC stenosis greatly accelerated thrombus formation.(54) Histone infusion leads to VWF release(54) and signs of microthrombosis in mice.”
• COVID-19 and multisystem inflammatory syndrome in children and adolescents (2020, positive): “Abnormal coagulopathy (eg, elevated D­dimer or fibrinogen) has also been observed in many cases of MIS­C. NETosis plays a crucial part in promoting thrombosis; 86–88 therefore, the role of NETs in MIS­C is highly plausible.”