title: Nuclear factor kappaB mediates a procoagulant response in monocytes during extracorporeal circulation.
abstract: OBJECTIVE
  The objective of this study was to examine the mechanism of procoagulant activity and inhibition in whole blood during extracorporeal circulation.
  
  
  METHODS
  In this study we examine the development of procoagulant activity and monocyte activation in heparinized whole blood passing through a closed circuit consisting of a pump and silicone envelope membrane oxygenator for 6 hours.
  
  
  RESULTS
  Anaphylatoxins, C3a and C5a, determined by means of enzyme-linked immunosorbant assay, appeared in the blood within 30 minutes of circulation. Circulated blood developed a marked potential for coagulation demonstrated in a 1-step clotting assay that reached maximal activity by 4 hours of circulation. This procoagulant activity was neutralized by anti-tissue factor antibody, suggesting a prominent role for the extrinsic pathway in pump-induced intravascular coagulation. Isolation of monocytes from circulated blood revealed that tissue factor expression is upregulated on the cell surface. Furthermore, we observed nuclear factor kappaB nuclear translocation in monocytes from blood passing through the circuit, suggesting that tissue factor expression was due to monocyte stimulation and transcriptional activation of the tissue factor gene. Tissue factor expression resulted in an approximately 30-fold increase in thrombin generation. Monocyte nuclear factor kappaB activation, monocyte tissue factor expression, thrombin generation, and the procoagulant activity of blood in extracorporeal circulation were all blocked by the proteasome inhibitor MG132.
  
  
  CONCLUSIONS
  We conclude that intravascular tissue factor expression during extracorporeal circulation of blood is due to nuclear factor kappaB-mediated activation of monocytes (possibly by complement), which can be controlled pharmacologically.
authors.affiliation: Department of Surgery, Division of Cardiothoracic Surgery, University of Washington School of Medicine, Seattle, Wash. 98104, USA.
authors.forename: Elizabeth N
authors.initials: EN
authors.lastname: Morgan
authors.forename: Timothy H
authors.initials: TH
authors.lastname: Pohlman
authors.forename: Craig
authors.initials: C
authors.lastname: Vocelka
authors.forename: Angela
authors.initials: A
authors.lastname: Farr
authors.forename: Gina
authors.initials: G
authors.lastname: Lindley
authors.forename: Wayne
authors.initials: W
authors.lastname: Chandler
authors.forename: Jeanette M
authors.initials: JM
authors.lastname: Griscavage-Ennis
authors.forename: Edward D
authors.initials: ED
authors.lastname: Verrier
mesh_terms: D001777:Blood Coagulation / Q000502:physiology*; D003167:Complement Activation; D005112:Extracorporeal Circulation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000502:physiology*; D016328:NF-kappa B / Q000502:physiology*; D010107:Oxygenators, Membrane; D013925:Thromboplastin / Q000378:metabolism
chemical_list: D016328:NF-kappa B; D013925:Thromboplastin