title: Plasma-derived human antithrombin attenuates ventilator-induced coagulopathy but not inflammation in a Streptococcus pneumoniae pneumonia model in rats.
abstract: BACKGROUND
  Mechanical ventilation exaggerates pneumonia-associated pulmonary coagulopathy and inflammation. We hypothesized that the administration of plasma-derived human antithrombin (AT), one of the natural inhibitors of coagulation, prevents ventilator-induced pulmonary coagulopathy, inflammation and bacterial outgrowth in a Streptococcus pneumoniae pneumonia model in rats.
  
  
  METHODS
  Forty-eight hours after induction of S. pneumoniae pneumonia rats were subjected to mechanical ventilation (tidal volume 12 mL kg(-1), positive end-expiratory pressure 0 cmH(2)O and inspired oxygen fraction 40%). Rats were randomized to systemic treatment with AT (250 IU administered intravenously (i.v.) before the start of mechanical ventilation) or placebo (saline). Non-ventilated, non-infected rats and non-ventilated rats with pneumonia served as controls. The primary endpoints were pulmonary coagulation and inflammation in bronchoalveolar lavage fluid (BALF).
  
  
  RESULTS
  Pneumonia was characterized by local activation of coagulation and inhibition of fibrinolysis, resulting in increased levels of fibrin degradation products and fibrin deposition in the lung. Mechanical ventilation exaggerated pulmonary coagulopathy and inflammation. Systemic administration of AT led to supra-normal BALF levels of AT and decreased ventilator-associated activation of coagulation. AT neither affected pulmonary inflammation nor bacterial outgrowth from the lungs or blood.
  
  
  CONCLUSIONS
  Plasma-derived human AT attenuates ventilator-induced coagulopathy, but not inflammation and bacterial outgrowth in a S. pneumoniae pneumonia model in rats.
authors.affiliation: Interdepartmental Division of Critical Care Medicine, University of Toronto, Keenan Research Center, Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, ON, Canada. h.aslami@amc.uva.nl
authors.forename: H
authors.initials: H
authors.lastname: Aslami
authors.forename: J J
authors.initials: JJ
authors.lastname: Haitsma
authors.forename: J J
authors.initials: JJ
authors.lastname: Hofstra
authors.forename: S
authors.initials: S
authors.lastname: Florquin
authors.forename: C
authors.initials: C
authors.lastname: Dos Santos
authors.forename: C
authors.initials: C
authors.lastname: Streutker
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: M
authors.initials: M
authors.lastname: Levi
authors.forename: A S
authors.initials: AS
authors.lastname: Slutsky
authors.forename: M J
authors.initials: MJ
authors.lastname: Schultz
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D058833:Antithrombin Proteins / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D001778:Blood Coagulation Disorders / Q000097:blood / Q000209:etiology / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008297:Male; D011018:Pneumonia, Pneumococcal / Q000150:complications / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects*; D013997:Time Factors; D055397:Ventilator-Induced Lung Injury / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology
chemical_list: D000925:Anticoagulants; D058833:Antithrombin Proteins; D005338:Fibrin Fibrinogen Degradation Products; D018836:Inflammation Mediators