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(Circulation. 1999;100:2485.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Heparin Blunts Endotoxin-Induced Coagulation Activation

T. Pernerstorfer, MD; U. Hollenstein, MD; J.-B. Hansen, MD; M. Knechtelsdorfer, MD; P. Stohlawetz, MD; W. Graninger, MD, PhD; H.-G. Eichler, MD, MSc; W. Speiser, MD; B. Jilma, MD

From the Department of Clinical Pharmacology–The Adhesion Research Group Elaborating Therapeutics (TARGET) (T.P., U.H., M.K., H.-G.E., B.J.), the Department of Anesthesiology & General Intensive Care Medicine (T.P.), the Department of Internal Medicine I, Division of Infectious Disease (W.G.), Department of Transfusion Medicine (P.S.), and the Clinical Institute of Medical and Chemical Laboratory Diagnostics (W.S.), University of Vienna, Austria, and the Department of Medicine, University of Tromsø (J.-B.H.), Tromsø, Norway.

Correspondence to Dr Thomas Pernerstorfer, Department of Clinical Pharmacology for TARGET, University of Vienna, Waehringer Guertel 18-20, A-1090 Wien, Austria. E-mail thomas.pernerstorfer{at}univie.ac.at

Background—Lipopolysaccharide (LPS) is a major trigger of sepsis-induced disseminated intravascular coagulation (DIC) via the tissue factor (TF)/factor VIIa–dependent pathway of coagulation. Experimental endotoxemia has been used repeatedly to explore this complex pathophysiology, but little is known about the effects of clinically used anticoagulants in this setting. Therefore, we compared with placebo the effects of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) on LPS-induced coagulation.

Methods and Results—In a randomized, double-blind, placebo-controlled trial, 30 healthy male volunteers received LPS 2 ng/kg IV followed by a bolus-primed continuous infusion of UFH, LMWH, or placebo. In the placebo group, activation of coagulation caused marked increases in plasma levels of prothrombin fragment F₁₊₂ (P<0.01) and polymerized soluble fibrin, termed thrombus precursor protein (TpP; P<0.01); TF-positive monocytes doubled in response to LPS, whereas levels of activated factor VII slightly decreased and levels of TF pathway inhibitor remained unchanged. UFH and LMWH markedly decreased activation of coagulation caused by LPS, as F₁₊₂ and TpP levels only slightly increased; TF expression on monocytes was also markedly reduced by UFH. TF pathway inhibitor values increased after either heparin infusion (P<0.01). Concomitantly, factor VIIa levels dropped by >50% at 50 minutes after initiation of either heparin infusion (P<0.01).

Conclusions—This experimental model proved the anticoagulatory potency of UFH and LMWH in the initial phase of experimental LPS-induced coagulation. Successful inhibition of thrombin generation also translates into blunted activation of coagulation factors upstream and downstream of thrombin.

Key Words: heparin • endotoxin • coagulation • anticoagulants • fibrin

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