Endotoxin-induced activation of the coagulation cascade in humans - Effectof acetylsalicylic acid and acetaminophen

During Gram-negative septic shock, lipopolysaccharide (LPS, endotoxin) indu ces tissue factor (TF) expression. TF expression is mediated by nuclear fac tor kappa B and amplified by activated platelets. TF forms a highly procoag ulant complex with activated coagulation factor VII (FVIIa). Hence, we hypo thesized that aspirin, which inhibits LPS-induced, nuclear factor kappa B-d ependent TF expression in vitro and platelet activation in vivo, may suppre ss LPS-induced coagulation in humans. Therefore, we studied the effects of aspirin on systemic coagulation activation in the established and controlle d 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 potentia l effects of antipyresis. Neither aspirin nor acetaminophen inhibited LPS-i nduced coagulation. However, LPS increased the percentage of circulating TF + monocytes by 2-fold. This increase was associated with a decrease in FVII a levels, which reached a minimum of 50% 24 hours after LPS infusion. Furth ermore, LPS-induced thrombin generation increased plasma levels of circulat ing polymerized, but not cross-linked, fibrin tie, thrombus precursor prote in), 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, su bstantially decreases FVIIa levels, and enhances plasma levels of thrombus precursor protein, which may be a useful marker of fibrin formation in huma ns.