G. Dickneite et B. Leithauser, Influence of antithrombin III on coagulation and inflammation in porcine septic shock, ART THROM V, 19(6), 1999, pp. 1566-1572
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 mu g . kg
(-1) . h(-1) of lipopolysaccharide (LPS) over a period of 3 hours. Animals
developed systemic inflammation, disseminated intravascular coagulation (DI
C), organ failure and cardiovascular abnormalities, namely pulmonary hypert
ension and systemic hypotension. Twenty septic pigs were allocated to 2 stu
dy groups, treated either with ATIII (n=10) or placebo (n=10). ATIII was ad
ministered as a 250-U/kg IV bolus infusion for 30 minutes (-60 to -30 minut
es) 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 th
e development of a DIG; 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, w
hich were 809+/-287 pg/mL in the placebo and 420+/-174 pg/mL in the verum g
roup after 6 hours (P<0.02). On the other hand, ATIII had no influence on T
NF levels. In a lethal study with an increased dose of LPS (0.5 mu g . 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, chi(2) te
st) 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 hypoten
sion, was noted in the ATIII group. It was thus concluded that modulation o
f the procoagulatory state by substitution of ATIII results in a late benef
icial antiinflammatory effect in this model of septic shock.