© 1999 American Heart Association, Inc.
Thrombosis |
Endotoxin-Induced Activation of the Coagulation Cascade in Humans
Effect of Acetylsalicylic Acid and Acetaminophen
From the Departments of Clinical Pharmacology (T.P., U.H., L.D., H.-G.E., B.J.), Anesthesiology and General Intensive Care Medicine (T.P.), and Transfusion Medicine (P.S.), and the Clinical Institute of Medical and Chemical Laboratory Diagnostics (S.K., W.S.), University of Vienna, Austria.
Correspondence to Dr Thomas Pernerstorfer, Department of Clinical Pharmacology, The Adhesion Group Elaborating Therapeutics (TARGET), University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail thomas.pernerstorfer{at}univie.ac.at
Abstract—During Gram-negative
septic shock, lipopolysaccharide (LPS, endotoxin) induces
tissue factor (TF) expression. TF expression is mediated by nuclear
factor 
B and amplified by activated platelets. TF forms
a highly procoagulant complex with activated coagulation factor
VII (FVIIa). Hence, we hypothesized that aspirin, which inhibits
LPS-induced, nuclear factor B–dependent TF expression in vitro and
platelet activation in vivo, may suppress LPS-induced coagulation
in humans. Therefore, we studied the effects of aspirin on systemic
coagulation activation in the established and controlled setting of the
human LPS model. Thirty healthy volunteers were challenged with LPS (4
ng/kg IV) after intake of either placebo or aspirin (1000 mg).
Acetaminophen (1000 mg) was given to a third group to
control for potential effects of antipyresis. Neither aspirin nor
acetaminophen inhibited LPS-induced coagulation. However,
LPS increased the percentage of circulating TF+ monocytes
by 2-fold. This increase was associated with a decrease in FVIIa
levels, which reached a minimum of 50% 24 hours after LPS infusion.
Furthermore, LPS-induced thrombin generation increased plasma levels of
circulating polymerized, but not cross-linked, fibrin (ie, thrombus
precursor protein), whereas levels of soluble fibrin were unaffected.
In summary, a single 1000-mg dose of aspirin did not decrease
LPS-induced coagulation. However, our study showed, for the first time,
that LPS increases TF+ monocytes, substantially decreases
FVIIa levels, and enhances plasma levels of thrombus precursor protein,
which may be a useful marker of fibrin formation in humans.
Key Words: acetylsalicylic acid • acetaminophen • lipopolysaccharide • tissue factor • factor VIIa • coagulation
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