title: Pharmacodynamics of active site-inhibited factor VIIa in endotoxin-induced coagulation in humans.
abstract: BACKGROUND
  Inhibition of the tissue factor-factor VIIa pathway attenuated the activation of coagulation and prevented death in a gram-negative bacteremia primate model of sepsis. This lethal animal model suggested that tissue factor also influences inflammatory cascades.
  
  
  METHODS
  This trial examined the pharmacodynamic effects of active site-inhibited factor VIIa (FFR-recombinant factor VIIa [rFVIIa]; ASIS) on endotoxin-induced procoagulant, fibrinolytic, and inflammatory responses in healthy humans. A double-blind, randomized, placebo-controlled, parallel-group study was conducted in 12 healthy male volunteers. Subjects received a bolus infusion of 2-ng/kg endotoxin, followed by a bolus infusion of ASIS (400 microg/kg) or placebo 10 minutes later.
  
  
  RESULTS
  Endotoxin injection induced inflammation, activation of coagulation, and activation and subsequent inhibition of fibrinolysis. ASIS infusion completely blocked thrombin and fibrin generation, as measured by plasma levels of prothrombin fragment (no increase in the ASIS group, as compared with a 13-fold increase in the placebo group at 4 hours; P <.01), soluble fibrin, and fibrin split product D-dimer. ASIS did not alter endotoxin-induced changes in the fibrinolytic system, cytokine levels, or markers of endothelial (E-selectin, thrombomodulin) or platelet (P-selectin) activation.
  
  
  CONCLUSIONS
  In summary, ASIS effectively and selectively attenuates tissue factor-induced thrombin generation. Because ASIS was well tolerated, this study provides seminal data to further characterize its anticoagulant and putative anti-inflammatory effects in critically ill patients.
authors.affiliation: Department of Clinical Pharmacology, Vienna University, Vienna, Austria. Bernd.Jilma@univie.ac.at
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
authors.forename: Claudia
authors.initials: C
authors.lastname: Marsik
authors.forename: Florian
authors.initials: F
authors.lastname: Mayr
authors.forename: Monika T
authors.initials: MT
authors.lastname: Graninger
authors.forename: Fletcher B
authors.initials: FB
authors.lastname: Taylor
authors.forename: Mette C
authors.initials: MC
authors.lastname: Ribel
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Erhardtsen
authors.forename: Sylvia
authors.initials: S
authors.lastname: Handler
authors.forename: Hans Georg
authors.initials: HG
authors.lastname: Eichler
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D001777:Blood Coagulation / Q000187:drug effects* / Q000502:physiology; D004311:Double-Blind Method; D019040:E-Selectin / Q000097:blood; D004731:Endotoxins / Q000494:pharmacology*; D015942:Factor VIIa / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors*; D005334:Fever / Q000139:chemically induced; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008297:Male; D019007:P-Selectin / Q000097:blood; D010196:Pancreatic Elastase / Q000097:blood; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000037:antagonists & inhibitors; D018709:Statistics, Nonparametric; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D018180:Thrombomodulin / Q000097:blood; D010959:Tissue Plasminogen Activator / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000979:alpha-2-Antiplasmin / Q000378:metabolism
chemical_list: D019040:E-Selectin; D004731:Endotoxins; D015850:Interleukin-6; D019007:P-Selectin; D011994:Recombinant Proteins; D018180:Thrombomodulin; D014409:Tumor Necrosis Factor-alpha; D000979:alpha-2-Antiplasmin; C427263:phenylalanyl-phenylalanyl-arginyl-recombinant FVIIa; D015942:Factor VIIa; D010196:Pancreatic Elastase; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin