Effects of anticoagulation on thrombopoietin release during endotoxemia

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.