Treatment of porcine sepsis with high-dose antithrombin III reduces tissue edema and effusion but does not increase risk for bleeding

Abstract

We evaluated the effectiveness of antithrombin III (AT III) infusions designed to achieve supraphysiologic plasma levels of this serine protease inhibitor in preventing vascular permeability and disseminated intravascular coagulation in a pig model of sepsis. In addition, we determined whether high AT III doses were associated with increased bleeding risk. Sepsis was induced in 18 pigs by injection of lipopolysaccharide (LPS) (0.25 microg/kg per h for 3 h). At 90 min after the start of LPS infusion, pigs were randomized (n = 6 per group) to receive either human serum albumin as a placebo, AT III 120/5 (120 U/kg, 30-min bolus + 5 U/kg per h for 240 min), or AT III 250/10 (250 U/kg + 10 U/kg per h). Three additional animals served as negative controls (no LPS, no AT III). Treatment with AT III significantly reduced the amount of effluents in body cavities and fibrin monomers. AT III did not significantly increase bleeding risk as determined by organ hemorrhage. An additional assessment of AT III's bleeding risk [skin bleeding time (SBT)] was carried out in 35 nonseptic pigs treated with either AT III alone (120/5 or 250/10) or in the combination with heparin. Heparin administration alone produced a dose-dependent increase in SBT, but AT III alone did not. Addition of AT III 120/5 to heparin did not induce a further increase in bleeding time over heparin alone. These results indicate that administration of AT III in doses designed to achieve very high plasma concentrations significantly ameliorates symptoms of sepsis-induced vascular leakage and disseminated intravascular coagulation without increasing bleeding risk.

Porcine Models of Severe Sepsis: Emphasis on Porcine Peritonitis

“…Table 1 demonstrates endotoxin infusion amounts and time ranges in previous experimentation (7)(8)(9)(10)(11)(12). Murphey and Traber (13) and Vassilev et al (14) used a novel approach for endotoxin infusion titration, titrating it to mean pulmonary artery pressure.…”

Thrombin-induced endothelial barrier disruption in intact microvessels: role of RhoA/Rho kinase-myosin phosphatase axis

“…Initial data indicated that thrombin evokes pulmonary vascular leakage in awake sheep (23). Furthermore, it has been reported that a high dose of antithrombin III can reduce endotoxin-induced lung hyperpermeability and vascular leakage caused by ischemia-reperfusion injury in animals (11,29). Furthermore, it has been reported that a high dose of antithrombin III can reduce endotoxin-induced lung hyperpermeability and vascular leakage caused by ischemia-reperfusion injury in animals (11,29).…”

HS3ST1 genotype regulates antithrombin's inflammomodulatory tone and associates with atherosclerosis

“…AT treatment reduces morbidity and/or mortality in animal and non-human primate models of sepsis [9, 30, 38–40, 55]. Thus, the pro-inflammatory phenotype of Hs3st1 −/− mice suggests that HS AT+ mediates an anti-inflammatory activity of endogenous AT.…”

“…1), or pro-inflammatory effects (such as upregulating iNOS expression and stimulating leukocyte migration), depending on the experimental context [36, 37]. In vivo, AT’s anti-inflammatory effects predominate; AT therapy reduces morbidity and/or mortality in numerous animal and non-human primate models of sepsis [9, 38–40]. However, little is known of the mechanisms that regulate AT’s opposite inflammomodulatory activities.…”