Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Jilma, B; Marsik, C; Mayr, F; Graninger, MT; Taylor, FB; Ribel, MC; Erhardtsen, E; Handler, S; Eichler, HG.
Pharmacodynamics of active site-inhibited factor VIIa in endotoxin-induced coagulation in humans.
Clin Pharmacol Ther. 2002; 72(4):403-410
Doi: 10.1067/mcp.2002.127740
Web of Science
PubMed
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- Co-Autor*innen der Med Uni Graz
- Graninger Monika
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- Abstract:
- 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. 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. 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. 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Adult -
- Analysis of Variance -
- Binding Sites - drug effects
- Binding Sites - physiology
- Blood Coagulation - drug effects
- Blood Coagulation - physiology
- Double-Blind Method -
- E-Selectin - blood
- Endotoxins - pharmacology
- Factor VIIa - administration & dosage
- Factor VIIa - adverse effects
- Factor VIIa - antagonists & inhibitors
- Fever - chemically induced
- Fibrinolysin - antagonists & inhibitors
- Fibrinolysin - metabolism
- Humans -
- Interleukin-6 - blood
- Male -
- P-Selectin - blood
- Pancreatic Elastase - blood
- Recombinant Proteins - administration & dosage
- Recombinant Proteins - adverse effects
- Recombinant Proteins - antagonists & inhibitors
- Statistics, Nonparametric -
- Thrombin - antagonists & inhibitors
- Thrombin - metabolism
- Thrombomodulin - blood
- Tissue Plasminogen Activator - blood
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- alpha-2-Antiplasmin - metabolism