Effect of factor X inhibition on coagulation activation and cytokine induction in human systemic inflammation.
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 (F(1+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 F(1+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.
Hollenstein
Ursula M
UM
Department of Clinical Pharmacology, Division of Infectious Diseases, Hanusch Krankenhaus, University of Tromso, Tromso, Norway.
Pernerstorfer
Thomas
T
Homoncik
Monika
M
Hansen
John B
JB
Finzen
Haike
H
Handler
Sylvia
S
Jilma
Bernd
B
D000328:Adult; D000925:Anticoagulants / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology*; D018932:Chemokine CCL2 / Q000097:blood; D002809:Chondroitin Sulfates / Q000494:pharmacology*; D016207:Cytokines / Q000235:genetics*; D003871:Dermatan Sulfate / Q000494:pharmacology*; D004338:Drug Combinations; D004731:Endotoxins / Q000276:immunology / Q000633:toxicity; D005170:Factor X / Q000037:antagonists & inhibitors*; D006497:Heparan Sulfate / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology*; D015850:Interleukin-6 / Q000097:blood; D007700:Kinetics; D008070:Lipopolysaccharides / Q000633:toxicity*; D010865:Pilot Projects; D012016:Reference Values; D000979:alpha-2-Antiplasmin / Q000378:metabolism
D000925:Anticoagulants; D018932:Chemokine CCL2; D002809:Chondroitin Sulfates; D016207:Cytokines; D003871:Dermatan Sulfate; D004338:Drug Combinations; D004731:Endotoxins; D005170:Factor X; D006497:Heparan Sulfate; D015850:Interleukin-6; D008070:Lipopolysaccharides; D000979:alpha-2-Antiplasmin; C035838:danaparoid