title: Dual inhibition of thrombin and activated factor X attenuates disseminated intravascular coagulation and protects organ function in a baboon model of severe Gram-negative sepsis.
abstract: BACKGROUND
  Inhibition of procoagulant pathways may improve outcome in sepsis. We examined whether a dual short-acting thrombin (factor II) and factor X (FX)a inhibitor (SATI) ameliorates sepsis-induced disseminated intravascular coagulation (DIC) and is organ-protective.
  
  
  METHODS
  Escherichia coli were infused for 2 h in 22 anesthetized baboons. The control (CO) group (n = 8) received sterile isotonic solution only. In the treatment groups, SATI was administered starting 15 minutes after the end of the bacterial exposure. In the low-dose group (LD-SATI, n = 8), SATI was infused with 75 μg/kg/h for the first hour, followed by 23 μg/kg/h until the end of the study. In the high-dose SATI group (HD-SATI, n = 6), 225 μg/kg/h was administered for the first hour followed by continuous infusion of 69 μg/kg/h until termination of the study.
  
  
  RESULTS
  Sepsis-induced DIC was attenuated, as reflected by lower peak thrombin-antithrombin complexes (threefold) and D-dimer levels (twofold) in both SATI groups compared to the CO. This coincided with strongly improved cell/organ protection assessed by decreased levels of lactate dehydrogenase (threefold), creatinine (twofold), aspartate aminotransferase (threefold), and amylase (twofold) compared to the CO group. Anuria, which started at 8 h in the CO group, was prevented in both SATI groups. Peak interleukin-6 release at 12 h was prevented in the treatment groups. In both SATI groups, fewer catecholamines were necessary and no bleeding complications were observed.
  
  
  CONCLUSIONS
  Dual inhibition of thrombin and FXa preserved activation of coagulation, protected organ function and ameliorated inflammation in severe Gram-negative sepsis in baboons. SATI could be a novel therapeutic agent against sepsis-induced DIC.
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Centre, Vienna, Austria. herbert.schoechl@auva.at.|Department of Anesthesiology and Intensive Care Medicine, AUVA Trauma Centre Salzburg, Academic Teaching Hospital of the Paracelsus Medical University, Dr. Franz Rehrl Platz 5, 5020, Salzburg, Austria. herbert.schoechl@auva.at.
authors.forename: Herbert
authors.identifier: http://orcid.org/0000-0001-6028-1551
authors.initials: H
authors.lastname: Schöchl
authors.affiliation: Department of Experimental Trauma Surgery, Trauma Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Martijn
authors.initials: M
authors.lastname: van Griensven
authors.affiliation: Bayer Pharma AG, Acute Care Research, Wuppertal, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Heitmeier
authors.affiliation: Bayer Pharma AG, Acute Care Research, Wuppertal, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Laux
authors.affiliation: UT SPSS Statistics, Salzburg, Austria.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kipman
authors.affiliation: Department of Haematology and Cell Biology, Faculty of Health Sciences, University of the Free State, Bloemfontein, Free State, South Africa.
authors.forename: Jan
authors.initials: J
authors.lastname: Roodt
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Centre, Vienna, Austria.
authors.forename: Soheyl
authors.initials: S
authors.lastname: Bahrami
authors.affiliation: Ludwig Boltzmann Institute for Experimental and Clinical Traumatology, AUVA Research Centre, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Redl
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000991:Antithrombins / Q000494:pharmacology* / Q000627:therapeutic use; D001777:Blood Coagulation / Q000502:physiology; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy*; D004926:Escherichia coli / Q000378:metabolism / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000150:complications / Q000188:drug therapy; D015951:Factor Xa / Q000009:adverse effects / Q000819:agonists; D065427:Factor Xa Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D010215:Papio / Q000378:metabolism / Q000382:microbiology; D018805:Sepsis / Q000150:complications / Q000188:drug therapy; D013019:South Africa; D013917:Thrombin / Q000009:adverse effects / Q000037:antagonists & inhibitors
chemical_list: D000991:Antithrombins; D065427:Factor Xa Inhibitors; D013917:Thrombin; D015951:Factor Xa
keywords: DIC; Inflammation; MOF; SATI; Short-acting coagulation factor II/Xa inhibitor