title: Activation of the protein C pathway and endothelial glycocalyx shedding is associated with coagulopathy in an ovine model of trauma and hemorrhage.
abstract: Acute traumatic coagulopathy (ATC) is an endogenous coagulopathy that develops following tissue injury and shock. The pathogenesis of ATC remains poorly understood, with platelet dysfunction, activation of the protein C pathway, and endothelial glycocalyx shedding all hypothesized to contribute to onset. The primary aim of this study was to develop an ovine model of traumatic coagulopathy, with a secondary aim of assessing proposed pathophysiological mechanisms within this model.
  
  
  
  Twelve adult Samm-Border Leicester cross ewes were anesthetized, instrumented, and divided into three groups. The moderate trauma group (n = 4) underwent 20% blood volume hemorrhage, bilateral tibial fractures, and pulmonary contusions. The severe trauma group (n = 4) underwent the same injuries, an additional hamstring crush injury, and 30% blood volume hemorrhage. The remaining animals (n = 4) were uninjured controls. Blood samples were collected at baseline and regularly after injury for evaluation of routine hematology, arterial blood gases, coagulation and platelet function, and factor V, factor VIII, plasminogen activator inhibitor 1, syndecan 1, and hyaluranon levels.
  
  
  
  At 4 hours after injury, a mean increase in international normalized ratio of 20.50% ± 12.16% was evident in the severe trauma group and 22.50% ± 1.00% in the moderate trauma group. An increase in activated partial thromboplastin time was evident in both groups, with a mean of 34.25 ± 1.71 seconds evident at 2 hours in the severe trauma animals and 34.75 ± 2.50 seconds evident at 4 hours in the moderate trauma animals. This was accompanied by a reduction in ROTEM EXTEM A10 in the severe trauma group to 40.75 ± 8.42 mm at 3 hours after injury. Arterial lactate and indices of coagulation function were significantly correlated (R = -0.86, p < 0.0001). Coagulopathy was also correlated with activation of the protein C pathway and endothelial glycocalyx shedding. While a significant reduction in platelet count was evident in the severe trauma group at 30 minutes after injury (p = 0.018), there was no evidence of altered platelet function on induced aggregation testing. Significant fibrinolysis was not evident.
  
  
  
  Animals in the severe trauma group developed coagulation changes consistent with current definitions of ATC. The degree of coagulopathy was correlated with the degree of shock, quantified by arterial lactate. Activation of the protein C pathway and endothelial glycocalyx shedding were correlated with the development of coagulopathy; however, altered platelet function was not evident in this model.
authors.affiliation: From the Critical Care Research Group (N.v.Z., S.D., K.D., P.M., J.F.F.), The Prince Charles Hospital, Brisbane, Queensland, Australia; The University of Queensland School of Medicine (N.v.Z., E.M.M., A.S., M.C.R., J.F.F.), Herston, Queensland, Australia; Australian Defence Force (E.M.M., M.C.R.), Canberra, Australia; Darling Downs Vets (S.G.R.), Westbrook, Queensland, Australia; The Princess Alexandra Hospital (A.S.), Woolloongabba, Queensland, Australia; and Burns, Trauma and Critical Care Research Centre (M.C.R.), The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Natasha
authors.initials: N
authors.lastname: van Zyl
authors.forename: Elissa M
authors.initials: EM
authors.lastname: Milford
authors.forename: Sara
authors.initials: S
authors.lastname: Diab
authors.forename: Kimble
authors.initials: K
authors.lastname: Dunster
authors.forename: Peter
authors.initials: P
authors.lastname: McGiffin
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Rayner
authors.forename: Andrew
authors.initials: A
authors.lastname: Staib
authors.forename: Michael C
authors.initials: MC
authors.lastname: Reade
authors.forename: John F
authors.initials: JF
authors.lastname: Fraser
mesh_terms: D000818:Animals; D001778:Blood Coagulation Disorders / Q000378:metabolism*; D001780:Blood Coagulation Tests; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000166:cytology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D019276:Glycocalyx / Q000378:metabolism*; D006470:Hemorrhage / Q000378:metabolism*; D011486:Protein C / Q000378:metabolism*; D034561:Sheep, Domestic; D013997:Time Factors; D014947:Wounds and Injuries / Q000378:metabolism*
chemical_list: D011486:Protein C