title: DAMP and DIC: The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC.
abstract: Disseminated intravascular coagulation (DIC) is a heterogeneous group of disorders, which manifest as a spectrum of haemorrhage and thrombosis complicating many primary conditions including sepsis, trauma and malignancies. The pathophysiology of this condition is complex. In the recent years there is growing evidence that damage associated molecular patterns (DAMPs) play a crucial role in the pathogenesis of DIC. Upon cell-death and/or cell activation of hematopoietic and parenchymal cells extracellular cell-free DNA as well as DNA binding proteins (e.g. histones and high mobility group box 1 protein [HMGB1]) are released into circulation. This release is a highly regulated process mediated among others by serine proteases, such as factor VII-activating protease (FSAP) and DNase1. Circulating cell-free DNA has been demonstrated to influence primary and secondary hemostasis by inducing platelet aggregation, promoting coagulation activation, inhibition of fibrinolysis and directly interfering with clot stability. In this respect cell-free DNA in tissue as well as released into the circulation after neutrophil activation in the form of neutrophil extracellular traps (NETs) has been shown to be cytotoxic and highly procoagulant. DNA-binding proteins such as histones and HMGB1 are also strongly procoagulant and are involved in the pathogenesis of DIC. The present review gives an overview on how extracellular DNA is released into circulation and the structure of circulating DNA. In addition it summarizes the effect of extracellular DNA and DNA-binding proteins on platelet activation, plasmatic coagulation as well as fibrinolysis.
authors.affiliation: Department of Medicine, Division of Hematology & Thromboembolism, David Braley Research Institute, Thrombosis & Atherosclerosis Research Institute (TaARI), Hamilton, Canada.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Liaw
authors.affiliation: Department of Emergency and Critical Care Medicine and Department of Systems Biology in Thromboregulation, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ito
authors.affiliation: Dept. of Emergency and Disaster Medicine, Juntendo University Graduate Sch. of Medicine, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Iba
authors.affiliation: Central Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom.
authors.forename: Jecko
authors.initials: J
authors.lastname: Thachil
authors.affiliation: Department of Hematology, Academic Medical Center and Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands. Electronic address: s.s.zeerleder@amc.uva.nl.
authors.forename: Sacha
authors.initials: S
authors.lastname: Zeerleder
mesh_terms: D001777:Blood Coagulation / Q000235:genetics*; D004268:DNA-Binding Proteins; D004211:Disseminated Intravascular Coagulation / Q000235:genetics*; D006801:Humans; D018375:Neutrophil Activation / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins
keywords: DAMP; DIC; Damage associated molecular pattern; Disseminated intravascular coagulation; Extracellular cell-free DNA; FSAP; Factor VII-activating protease; High mobility group box 1; Histones; NET; Neutrophil extracellular traps