Effect of Factor X Inhibition on Coagulation Activation and Cytokine Induction in Human Systemic Inflammation

• Published in: The Journal of infectious diseases Vol. 186; no. 9; pp. 1270 - 1276
• Main Authors: Hollenstein, Ursula M., Pernerstorfer, Thomas, Homoncik, Monika, Hansen, John B., Finzen, Haike, Handler, Sylvia, Jilma, Bernd
• Format: Journal Article
• Language: English
• Published: Chicago, IL The University of Chicago Press 01.11.2002; University of Chicago Press; Oxford University Press
• Subjects: Adult; alpha-2-Antiplasmin - metabolism; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anticoagulants; Anticoagulants - pharmacology; Biological and medical sciences; Blood; Blood Coagulation - drug effects; Blood Coagulation - physiology; Chemokine CCL2 - blood; Chondroitin Sulfates - pharmacology; Coagulation; Cytokines; Cytokines - genetics; Dermatan Sulfate - pharmacology; Drug Combinations; Emergency and intensive care: infection, septic shock; Endotoxemia; Endotoxins; Endotoxins - immunology; Endotoxins - toxicity; Factor X - antagonists & inhibitors; Heparitin Sulfate - pharmacology; Human experimentation; Humans; Inflammation - chemically induced; Inflammation - immunology; Intensive care medicine; Interleukin-6 - blood; Kinetics; Lipopolysaccharides - toxicity; Major Articles; Medical sciences; Monocytes; Pilot Projects; Placebos; Reference Values; Sepsis; Human; Blood coagulation; Serine endopeptidases; Pathophysiology; Enzyme; Volunteer; Cytokine; Low molecular weight heparin; Thrombin; Inflammation; Systemic; Case control study; Endotoxin; Infection; Peptidases; Toxin; Factor X; Hydrolases; Inhibition; Coagulopathy; Danaparoid sodium
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/344646

Anticoagulants have gained increasing attention in the treatment of sepsis. This study used danaparoid to investigate the role of factor Xa in endotoxin-induced coagulation and inflammation and its effectiveness when coagulation activation has already occurred. Thirty healthy volunteers were enrolled in the randomized, placebo-controlled trial. Subjects received 2 ng/kg endotoxin and danaparoid 10 min or 3 h thereafter or placebo. Endotoxin increased prothrombin fragment 1+2 (F1+2) levels from 0.5 to 7.0 nmol/L at 5 h in the placebo group. Early danaparoid infusion inhibited endotoxin-induced thrombin formation: maximum F1+2 levels reached only 1.8 nmol/L (P<.01, vs. baseline or placebo). Delayed danaparoid infusion effectively blocked further thrombin formation. However, danaparoid did not alter endotoxin-induced changes in the fibrinolytic system, cytokine levels, activation of leukocytes, or tissue factor expression on monocytes. Danaparoid therefore selectively attenuates endotoxin-induced coagulopathy, even with delayed administration when coagulation activation is well under way