Journal
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 10, Issue 1, Pages 136-144Publisher
WILEY
DOI: 10.1111/j.1538-7836.2011.04544.x
Keywords
citrullination; deep vein thrombosis; histones; neutrophil extracellular traps; von Willebrand factor
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Funding
- National Heart, Lung, and Blood Institute of the National Institutes of Health [R01 HL041002, R01 HL095091, R01 HL102101]
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. 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.
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