Extracellular histones trigger disseminated intravascular coagulation by lytic cell death

Wu, Congqing; Zhang, Yan; Li, Lan; Pandeya, Ankit; Zhang, Guoying; Cui, Jian; Kirchhofer, Daniel; Wood, Jeremy P.; Smyth, Susan S.; Wei, Yinan; Li, Zhenyu

Histones are cationic nuclear proteins that are essential for the structure and functions of eukaryotic chromatin. However, extracellular histones trigger inflammatory responses and contribute to death in sepsis by unknown mechanisms. We recently reported that inflammasome activation and pyroptosis trigger coagulation activation through a tissue factor (TF)-dependent mechanism. Here, we show that histones trigger coagulation activation in vivo as evidenced by coagulation parameters and fibrin deposition in tissues. However, histone-induced coagulopathy was neither dependent on caspase 1/11 and gasdermin D (GSDMD), nor on TLR2 and TLR4, as deficiency of these genes in mice did not protect against histone-induced coagulopathy. Incubation of histones with macrophages induced lytic cell death and phosphatidylserine (PS) exposure, which is required for TF activity, a key initiator of coagulation. Neutralization of TF diminished histone-induced coagulation. Our findings reveal lytic cell death as a novel mechanism of histone-induce coagulation activation and thrombosis. Key Points Histones trigger DIC in a tissue factor dependent mechanism Histones induce tissue factor activation through lytic cell death