Histones stimulate von Willebrand factor release in vitro and in vivo

Histones, nuclear proteins that normally package DNA in cells, are increasingly recognized as important mediators of inflammation and thrombosis, and have recently been linked to death in sepsis.1 They are released during inflammation by activated leukocytes, primarily neutrophils, as part of neutrophil extracellular traps (NETs).2 Although NETs play an important role in innate immunity, components within NETs, namely histones, are linked to platelet activation3 and the development of thrombi.4 Indeed, mice that are unable to produce NETs have decreased thrombus formation.5 Although most descriptions of the prothrombotic effects of histones are based on activation of platelets and fibrin formation, less is known about their effects on endothelial cells.