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J Thromb Haemost. 2012 Jan;10(1):136-44. doi: 10.1111/j.1538-7836.2011.04544.x.

Neutrophil extracellular traps promote deep vein thrombosis in mice.

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  • 1Immune Disease Institute, Program in Cellular and Molecular Medicine, Children's Hospital Boston, Boston, MA, USA.

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.

Comment in

  • The NET effect of clot formation. [J Thromb Haemost. 2012]
PMID:
22044575
[PubMed - indexed for MEDLINE]
PMCID:
PMC3319651
Free PMC Article
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