Networks that stop the flow: A fresh look at fibrin and neutrophil extracellular traps

Neutrophil extracellular traps (NETs) are DNA and histone-based networks enriched with granule-derived proteins cast out by neutrophils in response to various inflammatory stimuli. Another molecular network, fibrin is the primary protein scaffold that holds both physiological blood clots and pathological thrombi together. There is mounting evidence that NETs and fibrin form a composite network within thrombi: in the past 10 years, a variety of molecular pathways have been revealed that help elucidate the nature of the NET-fibrin interaction. Besides discussing the effects of various NET components on hemostasis, this review takes a closer look at the interaction of these individual effects, with novel perspectives on how the NET and fibrin networks stabilize each other. Similarities and molecular connections are also outlined between the processes responsible for the degradation (fibrinolysis and NET lysis) as well as elimination of these networks. In addition, the complex relationship of pathogens with the NET-fibrin network is discussed, with a particular focus on the role of peptidyl-arginyl deiminases (PADs) in NET formation as well as in pathogen intrusion, where PADs act as a virulence factor expressed by bacteria -an aspect that is currently left out from discussions in the field.