Extracellular DNA traps promote thrombosis

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

Priming of neutrophils toward NETosis promotes tumor growth

“…27 The NETting process could also have a predominant role in the generation of a beneficial extracellular matrix by delivering proteinases and could also favor the release of inflammatory and angiogenic factors. For example, NETs have been shown to contain and activate matrix metalloproteinases, 28 preserve the enzymatic activity of elastase 29 and recruit platelets, 30 important cells for angiogenesis. 31 Neutrophils were described to suppress the cytotoxic CD8 C antitumoral response, which is associated with the generation of ROS.…”

Biology, role and therapeutic potential of circulating histones in acute inflammatory disorders

“…The ability of NETs and histones to influence the coagulation cascade and actually initiate venous thrombosis8, 133, 134 is the most recent detail in the emerging field of NETosis research. Clinically, circulating nucleosomes are independent prognostic markers of disseminated intravascular coagulopathy (DIC)135 and some countries, notably Japan, are actively promoting the use of anticoagulants as histone detoxification agents in DIC 136.…”

“…More recently, controlled histone degradation has been described in neutrophils leading to chromatin decondensation and release of genomic DNA laced with granular proteins as neutrophil extracellular traps (NETs) 6, 7. These meshwork‐like structures promote intravascular thrombosis,8 limit spread of microorganisms, encourage cancer metastasis9 and cause direct injury to adjacent cells 10…”

Venous thromboembolism in systemic autoimmune diseases: A narrative review with emphasis on primary systemic vasculitides

“…31 In an ex-vivo study, NETs have been shown to stimulate platelet binding and aggregation and induce formation of red blood cell rich thrombus. 32 Recently, loss-of-function mutations in the CECR1 (cat eye syndrome chromosome region, candidate1) gene encoding adenosine deaminase 2 (ADA2) have been reported to be associated with inflammatory vasculopathy. 33,34 It is unclear whether this new subset of inflammatory vasculitis caused by genetic mutations is associated with venous thrombosis.…”