title: Interleukin-1 blockade attenuates mediator release and dysregulation of the hemostatic mechanism during human sepsis.
abstract: OBJECTIVE
  To define the influence of interleukin-1 activity on coagulation and fibrinolytic system activation and the release of proinflammatory mediators in the early human response to severe infection.
  
  
  METHODS
  All patients with severe sepsis syndrome who were enrolled from two surgical centers that were participating in a randomized, double-blind, placebo controlled, multicenter, multinational trial of recombinant human interleukin-1 receptor antagonist in the treatment of sepsis syndrome.
  
  
  METHODS
  Twenty-six patients with sepsis syndrome received an intravenous loading dose of recombinant human interleukin-1 receptor antagonist (100 mg) or placebo followed by a continuous 72-hour infusion of recombinant human interleukin-1 receptor antagonist (1.0 [n = 9] or 2.0 [n = 8] mg/kg per hour) or placebo (n = 9).
  
  
  METHODS
  Responses up to 72 hours after initiation of treatment.
  
  
  RESULTS
  Plasma levels of the anaphylatoxin C3a and thrombin-antithrombin III complexes were reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours (P < .05). Similarly, parameters of fibrinolysis, tissue-type plasminogen activator, and plasminogen activator inhibitor type 1 but not plasmin-alpha 2-antiplasmin complexes, were also significantly reduced (P < .05) after 72 hours of treatment with a high dose of recombinant human interleukin-1 receptor antagonist. Neutrophil elastase-alpha 1-antitrypsin complexes and phospholipase A2 levels were also significantly reduced in the high-dose recombinant human interleukin-1 receptor antagonist treatment group after 72 hours.
  
  
  CONCLUSIONS
  The results confirm that activation of the coagulation and fibrinolytic systems and release of soluble inflammatory mediators are consistently observed in patients with severe sepsis syndrome. Interleukin-1 activity contributes to activation of these processes as documented by the reduction in surrogate activation markers during recombinant human interleukin-1 receptor antagonist treatment.
authors.affiliation: Department of Surgery, Free University Hospital, Amsterdam.
authors.forename: M A
authors.initials: MA
authors.lastname: Boermeester
authors.forename: P A
authors.initials: PA
authors.lastname: van Leeuwen
authors.forename: S M
authors.initials: SM
authors.lastname: Coyle
authors.forename: G J
authors.initials: GJ
authors.lastname: Wolbink
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: S F
authors.initials: SF
authors.lastname: Lowry
mesh_terms: D000328:Adult; D001777:Blood Coagulation / Q000187:drug effects; D003167:Complement Activation / Q000187:drug effects; D004311:Double-Blind Method; D005342:Fibrinolysis / Q000187:drug effects; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D018375:Neutrophil Activation / Q000187:drug effects; D010741:Phospholipases A / Q000097:blood; D054467:Phospholipases A2; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors*; D018805:Sepsis / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D012795:Sialoglycoproteins / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D016209:Interleukin-8; D017472:Receptors, Interleukin-1; D012795:Sialoglycoproteins; D010741:Phospholipases A; D054467:Phospholipases A2