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. They are released during inflammation by activated leukocytes, primarily neutrophils, as part of neutrophil extracellular traps (NETs). Although NETs play an important role in innate immunity, components within NETs, namely histones, are linked to platelet activation and the development of thrombi. Indeed, mice that are unable to produce NETs have decreased thrombus formation. 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. The vascular endothelium plays an integral role in the regulation of blood flow, permeability, and prevention of thrombus formation. When the vascular endothelium becomes activated or damaged, it can result in a hypercoagulable state, mediated in part through the release of ultra-large (UL) von Willebrand factor (VWF) which leads to the capture and activation of platelets and formation of thrombi. Increased plasma VWF and ULVWF has been described in experimental and clinical sepsis, and is suggested to contribute to thrombosis in this condition. Although there are several known stimuli for the release of VWF, one novel stimulus may be through the release of histones from activated neutrophils. We had previously reported a dose-dependent effect of histones on platelet aggregation.However, the role of histones on endothelium, specifically VWF release, is unclear. In this report, we describe the effect of histones on VWF release from endothelial cells in vitro and in vivo. We evaluated whether histones induced ULVWF