The coming of age of neutrophil extracellular traps in thrombosis: Where are we now and where are we headed?

Thrombosis remains a major problem in our society, manifesting across multiple demographic groups and with high associated morbidity and mortality. Thrombus development is the result of a complex mechanism in which multiple cell types and soluble factors play a crucial role. One cell that has gained the most attention in recent years is the neutrophil. This key member of the innate immune system can form neutrophil extracellular traps (NETs) in response to activating stimuli in circulation. NETs form a scaffold for thrombus formation, both initiating the process and stabilizing the final product. As the first responders of the host immune system, neutrophils have the flexibility to recognize a variety of molecules and can quickly interact with a range of different cell types. This trait makes them sensitive to exogenous stimuli. NET formation in response to pathogens is well established, leading to immune-mediated thrombus formation or immunothrombosis. NETs can also be formed during sterile inflammation through the activation of neutrophils by fellow immune cells including platelets, or activated endothelium. In chronic inflammatory settings, NETs can ultimately promote the development of tissue fibrosis, with organ failure as an end-stage outcome. In this review, we discuss the different pathways through which neutrophils can be activated toward NET formation and how these processes can result in a shared outcome: thrombus formation. Finally, we evaluate these different interactions and mechanisms for their potential as therapeutic targets, with neutrophil-targeted therapies providing a future approach to treating thrombosis. In contrast to current practices, such treatment could result in reduced pathogenic blood clot formation without increasing the risk of bleeding.