Effect of interleukin-6 blockade on tissue factor-induced coagulation in human endotoxemia.
OBJECTIVE
Clinical trials show that interleukin (IL)-6 represents a predictive marker in human sepsis. Furthermore, IL-6 has been proposed as a candidate mediator for endotoxin (lipopolysaccharide)-induced coagulation activation: In a primate model, an (alphaIL-6 antibody (alphaIL-6 Ab) almost abolished lipopolysaccharide-induced coagulation activation. Therefore, we wished to determine if an alphaIL-6 Ab (B-E8) may also attenuate lipopolysaccharide-induced activation of coagulation in humans.


METHODS
The study was a randomized, double blind, placebo-controlled parallel group trial (n = 12 per group).


METHODS
University medical center.


METHODS
Healthy volunteers.


METHODS
Healthy volunteers were randomized to receive either 80 mg of a monoclonal anti-IL-6 Ab (B-E8) or placebo intravenously before bolus infusion of 2 ng/kg lipopolysaccharide.


RESULTS
B-E8 effectively decreased IL-6 bioactivity as measured by a Bg-bioassay in vitro and concentrations of C reactive protein. However, B-E8 did not decrease lipopolysaccharide-induced tissue factor-messenger RNA transcription or plasma concentrations of downstream coagulation variables (prothrombin fragment 1 + 2, thrombin-antithrombin III complexes, and D-dimer concentrations). Similarly, tumor necrosis factor-alpha concentrations, fibrinolytic activity (plasmin-antiplasmin complexes), endothelial activation (soluble E-selectin), and IL-10 were unaffected.


CONCLUSIONS
IL-6 does not appear to mediate early-phase lipopolysaccharide-induced coagulation activation in humans.
Derhaschnig
Ulla
U
Department of Clinical Pharmacology, University of Vienna, Vienna, Austria.
Bergmair
Doris
D
Marsik
Claudia
C
Schlifke
Irene
I
Wijdenes
John
J
Jilma
Bernd
B
D000328:Adult; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D001778:Blood Coagulation Disorders / Q000378:metabolism / Q000382:microbiology / Q000517:prevention & control; D002097:C-Reactive Protein / Q000187:drug effects / Q000378:metabolism; D004306:Dose-Response Relationship, Immunologic; D004311:Double-Blind Method; D019040:E-Selectin / Q000097:blood / Q000187:drug effects; D019446:Endotoxemia / Q000150:complications* / Q000276:immunology / Q000378:metabolism; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000150:complications* / Q000276:immunology / Q000378:metabolism; D005338:Fibrin Fibrinogen Degradation Products / Q000187:drug effects / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007262:Infusions, Intravenous; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood / Q000276:immunology; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D016133:Polymerase Chain Reaction; D013925:Thromboplastin / Q000187:drug effects / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D000093242:Interleukin-6 Inhibitors
D000911:Antibodies, Monoclonal; D002097:C-Reactive Protein; D019040:E-Selectin; D005338:Fibrin Fibrinogen Degradation Products; D016753:Interleukin-10; D015850:Interleukin-6; D008070:Lipopolysaccharides; D013925:Thromboplastin; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors; C036309:fibrin fragment D