title: Extracellular histone release in response to traumatic injury: implications for a compensatory role of activated protein C.
abstract: BACKGROUND
  Tissue injury leads to the release of DAMPs (damage-associated molecular patterns) that may drive a sterile inflammatory response; however, the role of extracellular histone levels after traumatic injury remains unexplored. We hypothesized that extracellular histone levels would be increased and associated with poor outcomes after traumatic injury.
  
  
  METHODS
  In this prognostic study, plasma was prospectively collected from 132 critically injured trauma patients on arrival and 6 hours after admission to an urban Level I trauma intensive care unit. Circulating extracellular histone levels and plasma clotting factors were assayed and linked to resuscitation and outcome data.
  
  
  RESULTS
  Of 132 patients, histone levels were elevated to a median of 14.0 absorbance units (AU) on arrival, declining to 6.4 AU by 6 hours. Patients with elevated admission histone levels had higher ISS (Injury Severity Score), lower admission GCS (Glasgow Coma Scale) score, more days of mechanical ventilation, and higher incidences of multiorgan failure, acute lung injury, and mortality (all p ≤ 0.05). Histone levels correlated with prolonged international normalized ratio and partial thromboplastin time, fibrinolytic markers D-dimer and tissue-type plasminogen activator, and anticoagulants tissue factor pathway inhibitor and activated protein C (aPC; all p < 0.03). Increasing histone level from admission to 6 hours was a multivariate predictor of mortality (hazard ratio, 1.005; p = 0.013). When aPC level trends were included, the impact of histone level increase on mortality was abrogated (p = 0.206) by a protective effect of increasing aPC levels (hazard ratio, 0.900; p = 0.020).
  
  
  CONCLUSIONS
  Extracellular histone levels are elevated in response to traumatic injury and correlate with fibrinolysis and activation of anticoagulants. An increase in histone levels from admission to 6 hours is predictive of mortality, representing evidence of ongoing release of intracellular antigens similar to that seen in sepsis. Concomitant elevation of aPC abrogates this effect, suggesting a possible role for aPC in mitigating the sterile inflammatory response after trauma through the proteolysis of circulating histones.
  
  
  METHODS
  Prognostic study, level III.
authors.affiliation: Department of Surgery at San Francisco General Hospital, University of California, San Francisco, San Francisco, California, USA. matthew.kutcher@ucsfmedctr.org
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Kutcher
authors.forename: Jun
authors.initials: J
authors.lastname: Xu
authors.forename: Ryan F
authors.initials: RF
authors.lastname: Vilardi
authors.forename: Coral
authors.initials: C
authors.lastname: Ho
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.forename: Mitchell Jay
authors.initials: MJ
authors.lastname: Cohen
mesh_terms: D055371:Acute Lung Injury / Q000097:blood; D000328:Adult; D015415:Biomarkers / Q000097:blood; D006657:Histones / Q000097:blood* / Q000502:physiology; D006801:Humans; D015601:Injury Severity Score; D019934:International Normalized Ratio; D009102:Multiple Organ Failure / Q000097:blood; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D011486:Protein C / Q000502:physiology*; D013997:Time Factors; D014193:Trauma Centers; D014947:Wounds and Injuries / Q000097:blood* / Q000175:diagnosis / Q000401:mortality / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D006657:Histones; D011486:Protein C