Neutrophil Extracellular Traps: Villains and Targets in Arterial, Venous, and Cancer-Associated Thrombosis

Abstract

Recent studies have demonstrated a role of neutrophils in both venous and arterial thrombosis. A key prothrombotic feature of neutrophils is their ability to release web-like structures composed of DNA filaments coated with histones and granule proteins referred to as neutrophil extracellular traps (NETs). NETs were discovered over a decade ago as part of our first line of host defense against invading microorganisms. Although NETs have a protective role against pathogens, recent data suggest that an uncontrolled and excessive NET formation within the vasculature may contribute to pathological thrombotic disorders. In vitro studies suggest that NETs promote vessel occlusion by providing a scaffold for platelets, red blood cells, extracellular vesicles, and procoagulant molecules, such as von Willebrand factor and tissue factor. In addition, NET components enhance coagulation by both activating the intrinsic pathway and degrading an inhibitor of the extrinsic pathway (tissue factor pathway inhibitor). NET formation has, therefore, been proposed to contribute to thrombus formation and propagation in arterial, venous, and cancer-associated thrombosis. This review will describe animal and human studies suggesting a role of NETs in the pathogenesis of various thrombotic disorders. Targeting NETs may be a novel approach to reduce thrombosis without affecting hemostasis.

Keywords: extracellular traps; extracellular vesicles; histones; neutrophils; thrombosis.

Fig 1.. NET formation.

Scanning electron microscopy of neutrophil (yellow) casting a net (green) entrapping Helicobacter pylori bacteria (blue). Neutrophils were co-cultivated with Helicobacter pylori for 2 hours, no additional stimulation. Image kindly provided by Dr. Volker Brinkmann, Max Planck Institute for Infection Biology, Berlin, Germany.

Figure 2.. Role of neutrophils and neutrophil extracellular traps in thrombosis.

A. Rupture or erosion of atherosclerotic plaques triggers thrombosis. Neutrophil extracellular traps (NETs) are found in arterial thrombi. B. Venous thrombi form in valve pockets and contain NETs. EC, endothelial cell.