Effects of anticoagulation on thrombopoietin release during endotoxemia.
Several lines of evidence suggest that coagulation may induce the release of thrombopoietin (TPO) into plasma and that TPO levels are higher in disseminated intravascular coagulation. Therefore we set out to illuminate the mechanism of TPO release in the setting of experimental endotoxemia, which induces activation of coagulation and platelets. Endotoxin (lipopolysachharide [LPS], 2 ng/kg) was infused into a total of 54 healthy men in two subsequent studies. Volunteers received infusions of unfractionated heparin, low-molecular-weight heparin, lepirudin, or placebo in a randomized, placebo-controlled fashion after bolus injection of LPS. TPO levels increased on average by 27% to 38% in all groups at 6 hours (P <.05 vs baseline), although all active drugs effectively blocked coagulation. Platelet counts dropped by about 15% at 1 hour after LPS infusion, recovered after 2 days, and exceeded 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-selectin by one half (P <.005 vs placebo), whereas both heparins did not diminish the increase in this platelet or endothelial activation marker as compared with placebo. Endotoxemia enhances TPO plasma levels independent of the degree of coagulation induction, which eventually results in increased platelet numbers. Of potential clinical interest is the observation that the direct thrombin inhibitor lepirudin, in contrast to heparins, mitigated LPS-induced platelet activation.
Jilma-Stohlawetz
P
P
Department of Clinical Pharmacology, The Adhesion Research Group Elaborating Therapeutics, Vienna University School of Medicine, Austria.
Folman
C C
CC
von dem Borne
A E
AE
Pernerstorfer
T
T
Hollenstein
U
U
Knechtelsdorfer
M
M
Eichler
H G
HG
Jilma
B
B
D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage*; D000991:Antithrombins / Q000008:administration & dosage; D002097:C-Reactive Protein / Q000378:metabolism; D004311:Double-Blind Method; D019446:Endotoxemia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism*; D006493:Heparin / Q000008:administration & dosage*; D006629:Hirudins / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D008070:Lipopolysaccharides / Q000009:adverse effects; D008297:Male; D019007:P-Selectin / Q000097:blood; D010446:Peptide Fragments / Q000097:blood; D015539:Platelet Activation / Q000187:drug effects*; D010976:Platelet Count; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D011498:Protein Precursors / Q000097:blood; D011516:Prothrombin; D011994:Recombinant Proteins / Q000008:administration & dosage; D012995:Solubility; D013926:Thrombopoietin / Q000378:metabolism*
D000925:Anticoagulants; D000991:Antithrombins; D006629:Hirudins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D019007:P-Selectin; D010446:Peptide Fragments; D019038:Platelet Glycoprotein GPIb-IX Complex; D011498:Protein Precursors; D011994:Recombinant Proteins; C023592:glycocalicin; C029733:prothrombin fragment 1; C044183:prothrombin fragment 2; D011516:Prothrombin; D006493:Heparin; D002097:C-Reactive Protein; D013926:Thrombopoietin; C083544:lepirudin