Abstract 487: Extracellularhistonestrigger Disseminated Intravascular Coagulation By Lytic Cell Death

Abstract

Background: Histones are cationic nuclear proteins that are essential for the structure andfunctions of eukaryotic chromatin. However, extracellular histones trigger inflammatoryresponses and contribute to death in sepsis by unknown mechanisms. We recently reported thatinflammasome activation and pyroptosis trigger coagulation activation through a tissue factor(TF)-dependent mechanism. Objective and methods: We used a combination of various deficient mice to elucidate the molec-ular mechanism of histone-induced coagulation. Results: We show that histones trigger coagulation activation in vivo as evidenced bycoagulation parameters and fibrin deposition in tissues. However, histone-induced coagulopathywas neither dependent on intracelluar inflammasome pathwyas involving caspase 1/11 andgasdermin D (GSDMD), nor on cell surface TLR2 and TLR4 mediated host immune response, asdeficiency 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 TFdiminished histone-induced coagulation. Conclusion: Our findings reveal lytic cell death as a novel mechanism of histone-inducecoagulation activation and thrombosis.