Endotoxin-induced activation of the coagulation cascade in humans: effect of acetylsalicylic acid and acetaminophen.
During Gram-negative septic shock, lipopolysaccharide (LPS, endotoxin) induces tissue factor (TF) expression. TF expression is mediated by nuclear factor kappaB 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 kappaB-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.
Pernerstorfer
T
T
Department of Clinical Pharmacology, University of Vienna, Austria. thomas.pernerstorfer@univie.ac.at
Stohlawetz
P
P
Hollenstein
U
U
Dzirlo
L
L
Eichler
H G
HG
Kapiotis
S
S
Jilma
B
B
Speiser
W
W
D000082:Acetaminophen / Q000008:administration & dosage*; D000328:Adult; D018712:Analgesics, Non-Narcotic / Q000008:administration & dosage*; D000941:Antigens / Q000378:metabolism; D000990:Antithrombin III / Q000378:metabolism; D001241:Aspirin / Q000008:administration & dosage*; D001777:Blood Coagulation / Q000187:drug effects*; D019281:Dimerization; D004311:Double-Blind Method; D005167:Factor VII / Q000378:metabolism; D015942:Factor VIIa / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005340:Fibrinogen / Q000737:chemistry / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006801:Humans; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000008:administration & dosage*; D009000:Monocytes / Q000737:chemistry / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000737:chemistry / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D010976:Platelet Count; D011486:Protein C / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D011516:Prothrombin / Q000378:metabolism; D012995:Solubility; D013925:Thromboplastin / Q000032:analysis / Q000378:metabolism
D018712:Analgesics, Non-Narcotic; D000941:Antigens; D005343:Fibrinolytic Agents; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010446:Peptide Fragments; D011486:Protein C; D011498:Protein Precursors; C042580:factor VII clotting antigen; D000082:Acetaminophen; C029733:prothrombin fragment 1; C044183:prothrombin fragment 2; D000990:Antithrombin III; D005167:Factor VII; D011516:Prothrombin; D005337:Fibrin; D005340:Fibrinogen; D013925:Thromboplastin; D015942:Factor VIIa; D001241:Aspirin