Tobias A. Fuchs1,2,3, Alexander Brill1,4,3, Daniel Duerschmied1,4,3, Daphne Schatzberg5,4,3, Marc Monestier6, Daniel D. Myers7,8, Shirley K. Wrobleski9,7, Thomas W. Wakefield10,7, John H. Hartwig5,11, Denisa D. Wagner1,4,3
1Department of Pathology, Harvard Medical School, Boston, MA 02115
2Immune Disease Institute, Boston, MA 02115, USA
3Program in Cellular and Molecular Medicine, Children’s Hospital Boston, Boston, MA 02115;
4Immune Disease Institute, Boston, MA 02115;
5Harvard University
6Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140;
7Section of Vascular Surgery and
8Unit for Laboratory Animal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109; and
9UNIVERSITY OF MICHIGAN
10Samuel and Jean Frankel Cardiovascular Center
11Translational Medicine Division, Brigham and Women’s Hospital, Boston, MA 02115
Tóm tắt
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.
