title: Combination of antithrombin and recombinant thrombomodulin attenuates leukocyte-endothelial interaction and suppresses the increase of intrinsic damage-associated molecular patterns in endotoxemic rats.
abstract: BACKGROUND
  Both antithrombin (AT) and thrombomodulin are key players in physiological anticoagulant systems. Because the levels of both factors are known to decrease significantly during severe sepsis, we hypothesized that a combination therapy would be effective.
  
  
  METHODS
  A sepsis model was established using the intravenous infusion of lipopolysaccharide (LPS). A dose of 125 IU/kg of AT, 0.25 mg/kg of recombinant thrombomodulin, or a combination of both agents was injected immediately after LPS infusion (n = 7, each). Intravital observation of the mesenteric microcirculation was performed, and leukocyte adhesion and blood flow were calculated at 3 h after LPS infusion. Immediately after the observation, blood samples were obtained and coagulation markers, organ damage markers, the circulating levels of nucleosome and high-mobility group box 1 were measured.
  
  
  RESULTS
  Microscopic findings revealed the suppression of leukocyte adhesion and thrombus formation in the combination group. The number of adhesive leukocytes on the endothelium was significantly suppressed (P < 0.01), and the blood flow in venules was better maintained in the combination group compared with the placebo control (P < 0.01). The blood samples showed the suppressed activation in coagulation, no significant changes were observed in the organ damage markers in the treatment groups. The circulating levels of nucleosome and high-mobility group box 1 were both decreased significantly in the combination group compared with the placebo control (P < 0.01).
  
  
  CONCLUSIONS
  The coadministration of AT and recombinant thrombomodulin is effective for the suppression of leukocyte activation and cell death during sepsis.
authors.affiliation: Department of Emergency and Disaster Medicine, Juntendo University, Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan. Electronic address: toshiiba@juntendo.ac.jp.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Iba
authors.affiliation: Department of Emergency and Disaster Medicine, Juntendo University, Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Miki
authors.affiliation: Department of Emergency and Disaster Medicine, Juntendo University, Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Hashiguchi
authors.affiliation: Department of Emergency and Disaster Medicine, Juntendo University, Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamada
authors.affiliation: Department of Host Defense and Biochemical Research, Juntendo University, Graduate School of Medicine, Bunkyo-ku, Tokyo, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Nagaoka
mesh_terms: D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002450:Cell Communication / Q000187:drug effects*; D004359:Drug Therapy, Combination; D042783:Endothelial Cells / Q000166:cytology; D019446:Endotoxemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D024243:HMGB1 Protein / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D009504:Neutrophils / Q000166:cytology; D009707:Nucleosomes / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology*; D018805:Sepsis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D018180:Thrombomodulin / Q000008:administration & dosage*; D013927:Thrombosis / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D000991:Antithrombins; D024243:HMGB1 Protein; D008070:Lipopolysaccharides; D009707:Nucleosomes; D011994:Recombinant Proteins; D018180:Thrombomodulin
keywords: Antithrombin concentrate; High-mobility group box 1; Neutrophil extracellular traps; Nucleosome; Recombinant thrombomodulin