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Research Article

Extracellular DNA traps promote thrombosis

Tobias A. Fuchs, Alexander Brill, Daniel Duerschmied, Daphne Schatzberg, Marc Monestier, Daniel D. Myers Jr., Shirley K. Wrobleski, Thomas W. Wakefield, John H. Hartwig, and Denisa D. Wagner
PNAS September 7, 2010 107 (36) 15880-15885; https://doi.org/10.1073/pnas.1005743107
Tobias A. Fuchs
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Alexander Brill
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Daniel Duerschmied
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Daphne Schatzberg
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Marc Monestier
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Daniel D. Myers
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Shirley K. Wrobleski
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Thomas W. Wakefield
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John H. Hartwig
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Denisa D. Wagner
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  • For correspondence: wagner@idi.harvard.edu
  1. Edited by Barry S. Coller, The Rockefeller University, New York, NY, and approved July 2, 2010 (received for review April 28, 2010)

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Abstract

Neutrophil extracellular traps (NETs) are part of the innate immune response to infections. NETs are a meshwork of DNA fibers comprising histones and antimicrobial proteins. Microbes are immobilized in NETs and encounter a locally high and lethal concentration of effector proteins. Recent studies show that NETs are formed inside the vasculature in infections and noninfectious diseases. Here we report that NETs provide a heretofore unrecognized scaffold and stimulus for thrombus formation. NETs perfused with blood caused platelet adhesion, activation, and aggregation. DNase or the anticoagulant heparin dismantled the NET scaffold and prevented thrombus formation. Stimulation of platelets with purified histones was sufficient for aggregation. NETs recruited red blood cells, promoted fibrin deposition, and induced a red thrombus, such as that found in veins. Markers of extracellular DNA traps were detected in a thrombus and plasma of baboons subjected to deep vein thrombosis, an example of inflammation-enhanced thrombosis. Our observations indicate that NETs are a previously unrecognized link between inflammation and thrombosis and may further explain the epidemiological association of infection with thrombosis.

  • neutrophils
  • platelets
  • histones
  • red blood cells
  • chromatin

Footnotes

  • 1To whom correspondence should be addressed. E-mail: wagner{at}idi.harvard.edu.
  • Author contributions: T.A.F. and D.D.W. designed research; T.A.F., A.B., D.D., D.S., D.D.M., S.K.W., T.W.W., and J.H.H. performed research; M.M., D.D.M., S.K.W., and T.W.W. contributed new reagents/analytic tools; T.A.F. analyzed data; and T.A.F. and D.D.W. wrote the paper.

  • The authors declare no conflict of interest.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1005743107/-/DCSupplemental.

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    Extracellular DNA traps promote thrombosis
    Tobias A. Fuchs, Alexander Brill, Daniel Duerschmied, Daphne Schatzberg, Marc Monestier, Daniel D. Myers, Shirley K. Wrobleski, Thomas W. Wakefield, John H. Hartwig, Denisa D. Wagner
    Proceedings of the National Academy of Sciences Sep 2010, 107 (36) 15880-15885; DOI: 10.1073/pnas.1005743107

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    Extracellular DNA traps promote thrombosis
    Tobias A. Fuchs, Alexander Brill, Daniel Duerschmied, Daphne Schatzberg, Marc Monestier, Daniel D. Myers, Shirley K. Wrobleski, Thomas W. Wakefield, John H. Hartwig, Denisa D. Wagner
    Proceedings of the National Academy of Sciences Sep 2010, 107 (36) 15880-15885; DOI: 10.1073/pnas.1005743107
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