Several lines of evidence suggest that coagulation may induce the release o
f thrombopoietin (TPO) into plasma and that TPO levels are higher in dissem
inated intravascular coagulation. Therefore we set out to illuminate the me
chanism of TPO release in the setting of experimental endotoxemia, which in
duces activation of coagulation and platelets, Endotoxin (lipopolysachharid
e (LPS), 2 ng/kg) was infused into a total of 54 healthy men in two subsequ
ent studies, Volunteers received infusions of unfractionated heparin, low-m
olecular-weight heparin, lepirudin, or placebo in a randomized, placebo-con
trolled fashion after bolus injection of LPS. TPO levels increased on avera
ge by 27% to 38% in all groups at 6 hours (P < .05 vs baseline), although a
ll active drugs effectively blocked coagulation. Platelet counts dropped by
about 15% at 1 hour after LPS infusion, recovered after 2 days, and exceed
ed baseline values by 8% to 18% after 7 days (P < .001 vs baseline for all
groups). Yet lepirudin blunted the LPS-induced increase in circulating P-se
lectin by one half (P < .005 vs placebo), whereas both heparins did not dim
inish the increase in this platelet or endothelial activation marker as com
pared with placebo. Endotoxemia enhances TPO plasma levels independent of t
he degree of coagulation induction, which eventually results in increased p
latelet numbers. Of potential clinical interest is the observation that the
direct thrombin inhibitor lepirudin, in contrast to heparins, mitigated LP
S-induced platelet activation.