© 1999 American Heart Association, Inc.
Thrombosis |
Influence of Antithrombin III on Coagulation and Inflammation in Porcine Septic Shock
From Centeon Pharma GmbH, 35002 Marburg (G.D.) and the Medical Clinic, Justus-Liebig-University, 35385 Gießen (B.L.), Germany.
Correspondence to PD Dr Gerhard Dickneite, Centeon Pharma GmbH, Preclinical Pharmacology, PO Box 1230, D-35002 Marburg/Germany, Emil von Behring-Straße 76, 35041 Marburg/Germany. E-mail Dicknei1{at}MSMBWMD.Hoechst.com
Abstract—The
physiological inhibitor of thrombin,
antithrombin III (ATIII, Kybernin P) was investigated for its
antiinflammatory and anticoagulant effects in a pig model of septic
shock. Pigs were infused with a dose of 0.25 µg ·
kg-1 · h-1 of
lipopolysaccharide (LPS) over a period of 3 hours. Animals
developed systemic inflammation, disseminated intravascular coagulation
(DIC), organ failure and cardiovascular abnormalities,
namely pulmonary hypertension and systemic hypotension. Twenty
septic pigs were allocated to 2 study groups, treated either with ATIII
(n=10) or placebo (n=10). ATIII was administered as a 250-U/kg IV bolus
infusion for 30 minutes (-60 to -30 minutes) followed by a single IV
bolus of 125 U/kg (t=0) and a second 30-minute infusion of 250 U/kg
(120 to 150 minutes). ATIII significantly prevented the development of
a DIC; the increase in fibrin monomers (placebo, 11.4±9.1 reciprocal
titers, at 6 hours) was completely overcome by ATIII
(P<0.05). ATIII significantly prevented the increase in
thromboxane (TXB2) levels, which were 809±287
pg/mL in the placebo and 420±174 pg/mL in the verum group after 6
hours (P<0.02). On the other hand, ATIII had no
influence on TNF levels. In a lethal study with an increased dose of
LPS (0.5 µg · kg-1 ·
h-1). A significant reduction in mortality was
observed in the ATIII group (0 of 7) compared with the placebo group (4
of 6) (P<0.05, 
2 test) a significant
reduction of pulmonary hypertension (placebo, 42.0±11.1
mm Hg; ATIII, 23.6±7.5 mm Hg, P<0.05), but no
effect on systemic hypotension, was noted in the ATIII group. It was
thus concluded that modulation of the procoagulatory state by
substitution of ATIII results in a late beneficial antiinflammatory
effect in this model of septic shock.
Key Words: lipopolysaccharide • disseminated intravascular coagulation • pulmonary hypertension • soluble fibrin monomers • thromboxane
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