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Blood, Vol. 95 No. 5 (March 1), 2000:
pp. 1729-1734
Lepirudin blunts endotoxin-induced coagulation activation
T. Pernerstorfer,
U. Hollenstein,
J.-B. Hansen,
P. Stohlawetz,
H.-G. Eichler,
S. Handler,
W. Speiser, and
B. Jilma
From the Department of Clinical Pharmacology-TARGET, Department of
Anesthesiology and General Intensive Care Medicine, Department of
Internal Medicine I, Division of Infectious Disease, Department of
Transfusion Medicine, and Clinical Institute of Medical and Chemical
Laboratory Diagnostics, University of Vienna, Vienna Medical School,
Vienna, Austria; and the Department of Medicine, University of Tromsø,
Tromsø, Norway.
During sepsis, lipopolysaccharide (LPS) triggers the development of
disseminated intravascular coagulation (DIC) via the tissue factor-dependent pathway of coagulation resulting in massive thrombin generation and fibrin polymerization. Recently, animal studies demonstrated that hirudin reduced fibrin deposition in liver and kidney
and decreased mortality in LPS-induced DIC. Accordingly, the effects of
recombinant hirudin (lepirudin) was compared with those caused by
placebo on LPS-induced coagulation in humans. Twenty-four healthy male
subjects participated in this randomized, double-blind,
placebo-controlled, parallel group study. Volunteers received 2 ng/kg
LPS intravenously, followed by a bolus-primed continuous infusion of
placebo or lepirudin (Refludan, bolus: 0.1 mg/kg, infusion: 0.1 mg/kg/h
for 5 hours) to achieve a 2-fold prolongation of the activated partial
thromboplastin time (aPTT). LPS infusion enhanced thrombin
activity as evidenced by a 20-fold increase of thrombin-antithrombin
complexes (TAT), a 6-fold increase of polymerized soluble fibrin,
termed thrombus precursor protein (TpP), and a 4-fold increase in
D-dimer. In the lepirudin group, TAT increased only 5-fold, TpP
increased by only 50%, and D-dimer only slightly exceeded baseline
values (P < .01 versus placebo). Concomitantly, lepirudin
also blunted thrombin generation evidenced by an attenuated rise in
prothrombin fragment levels (F1 + 2, P < .01 versus placebo) and blunted the expression of
tissue factor on circulating monocytes. This experimental model proved
the anticoagulatory potency of lepirudin in LPS-induced coagulation
activation. Results from this trial provide a rationale for a
randomized clinical trial on the efficacy of lepirudin in DIC.
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