title: Neutrophil extracellular traps promote deep vein thrombosis in  mice.
abstract: 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.
authors: Immune Disease Institute, Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA, USA.
authors: A
authors: A
authors: Brill
authors: T A
authors: TA
authors: Fuchs
authors: A S
authors: AS
authors: Savchenko
authors: G M
authors: GM
authors: Thomas
authors: K
authors: K
authors: Martinod
authors: S F
authors: SF
authors: De Meyer
authors: A A
authors: AA
authors: Bhandari
authors: Denisa D
authors: DD
authors: Wagner
mesh_terms: D000818:Animals; D002843:Chromatin; D004247:DNA; D006657:Histones; D051379:Mice; D009504:Neutrophils / Q000378:metabolism*; D014682:Vena Cava, Inferior / Q000473:pathology; D020246:Venous Thrombosis / Q000209:etiology* / Q000473:pathology; D014841:von Willebrand Factor
chemical_list: D002843:Chromatin; D006657:Histones; D014841:von Willebrand Factor; D004247:DNA