Alexander Brill and colleagues from Denisa Wagner's group demonstrated the pathogenetic role of DNA and histones in deep venous thrombosis (DVT) in vivo. This work is based on an observation less than a decade old that activated neutrophils can release Neutrophil Extracellular Traps (NETs), a mesh of fibers consisting of their nuclear material (DNA and histones) associated with enzymes such as myeloperoxidase and elastase. NETs were shown to entrap and kill microbes. In 2010, the Wagner lab reported that NETs also provide a scaffold and stimulus for thrombus formation. In vitro, NETs were shown to facilitate platelet adhesion and aggregation, and deoxyribonuclease (DNase), an enzyme that cleaves DNA, was shown to digest NETs breaking the clot (PNAS, 2010 Sep 7).
Now the Wagner team has found that neutrophils are not only incorporated in the thrombus in the experimental DVT in mice, but that they form NETs during thrombus development. Immunohistochemistry of thrombi revealed citrullination of histone 3 in the neutrophils, a specific modification that is typical of and required for NETs formation. Immunostaining also revealed frequent co-localization of the citrullinated histone with von Willebrand factor, suggesting that NETs cooperate with this classic platelet adhesion molecule implicated in thrombus formation in DVT. Overall, these findings led to the hypothesis that NETs can contribute to the pathogenesis of DVT. As proof of this, Brill and colleagues demonstrate that DVT can be exacerbated by infusion of purified histones, an integral part of NETs. Importantly, mice could be protected from DVT development by infusion of DNase 1.
The study shows that NETs constitute a previously overlooked important scaffold in venous thrombi, and also provide a new link between inflammation and thrombosis. The demonstrated anti-thrombotic effect of DNase 1 opens new approaches in prevention and treatment of DVT, a major health problem afflicting close to one million Americans and responsible for quarter of a million deaths every year.
Brill A, Fuchs TA, Savchenko A, Thomas GM, Martinod K, De Meyer SF, Bhandari AA, Wagner DD. Neutrophil Extracellular Traps Promote Deep Vein Thrombosis in Mice. J Thromb Haemost. 2011 Nov 1;10(1):136-44.
