title: Tissue factor/factor VIIa pathway mediates coagulation activation in induced-heat stroke in the baboon.
abstract: OBJECTIVE
  Excessive activation of coagulation, which can culminate in overt disseminated intravascular coagulation, is a prominent feature of heat stroke. However, neither the mechanism that initiates the coagulation activation nor its pathogenic role is known. We examined whether the tissue factor/factor VIIa complex initiates the coagulation activation in heat stroke and, if so, whether upstream inhibition of coagulation activation through its neutralization may minimize cellular injury and organ dysfunction. We also examined whether coagulation inhibition influences heat stroke-induced fibrinolytic and inflammatory responses.
  
  
  METHODS
  Randomized controlled study.
  
  
  METHODS
  Comparative Medicine Department, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  
  
  METHODS
  Baboons (Papio Hamadryas).
  
  
  METHODS
  Twelve anesthetized baboons assigned randomly to recombinant nematode anticoagulant protein c2, a powerful inhibitor of tissue factor/factor VIIa-dependent coagulation (n = 6), or a control group (n = 6) were heat-stressed in a prewarmed neonatal incubator at 44-47°C until systolic blood pressure fell <90 mm Hg, signaling the onset of severe heat stroke. Recombinant nematode anticoagulant protein c2 was administered as a single intravenous dose of 30 μg/kg body weight at onset of heat stroke. The control group received an equivalent volume of sterile saline intravenously.
  
  
  RESULTS
  Heat stroke was associated with coagulation activation and fibrin formation as evidenced by the increased plasma thrombin-antithrombin complexes, endogenous thrombin potential, and D-dimer levels. Recombinant nematode anticoagulant protein c2 induced significant inhibition of thrombin generation and fibrin formation. Inhibition of coagulation in recombinant nematode anticoagulant protein c2-treated animals did not influence either fibrinolysis (assessed by tissue plasminogen activator, plasmin-α2-antiplasmin complexes, and plasminogen activator inhibitor) or the release of pro- and anti-inflammatory cytokines. No difference in markers of cell injury and organ dysfunction was observed between recombinant nematode anticoagulant protein c2-treated and control groups.
  
  
  CONCLUSIONS
  Tissue factor/factor VIIa-dependent pathway initiates coagulation activation in induced-heat stroke in the baboon without an effect on fibrinolysis and inflammation. The findings suggest also that coagulation activation is not a prerequisite of cell injury and organ dysfunction.
authors.affiliation: King Abdullah International Medical Research Center, Riyadh, Saudi Arabia. bouchamaab@ngha.med.sa
authors.forename: Abderrezak
authors.initials: A
authors.lastname: Bouchama
authors.forename: Falah
authors.initials: F
authors.lastname: Al-Mohanna
authors.forename: Lina
authors.initials: L
authors.lastname: Assad
authors.forename: Engin
authors.initials: E
authors.lastname: Baturcam
authors.forename: Abdelmoneim
authors.initials: A
authors.lastname: Eldali
authors.forename: Tarek
authors.initials: T
authors.lastname: Owaidah
authors.forename: Mohammed
authors.initials: M
authors.lastname: Dehbi
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology*; D001784:Blood Gas Analysis; D015942:Factor VIIa / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*; D018883:Heat Stroke / Q000097:blood* / Q000150:complications / Q000503:physiopathology; D015801:Helminth Proteins / Q000494:pharmacology; D007249:Inflammation / Q000209:etiology / Q000503:physiopathology; D048529:Papio hamadryas; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011994:Recombinant Proteins / Q000494:pharmacology; D018180:Thrombomodulin / Q000097:blood; D013925:Thromboplastin / Q000032:analysis / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D015801:Helminth Proteins; D011994:Recombinant Proteins; D018180:Thrombomodulin; C400226:anti-coagulant protein C2, Ancylostoma caninum; D013925:Thromboplastin; D015942:Factor VIIa