Influence of Antithrombin III on Coagulation and Inflammation in Porcine Septic Shock

Abstract

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 g ⅐ kg Ϫ1 ⅐ h Ϫ1 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 (nϭ10) or placebo (nϭ10). ATIII was administered as a 250-U/kg IV bolus infusion for 30 minutes (Ϫ60 to Ϫ30 minutes) followed by a single IV bolus of 125 U/kg (tϭ0) 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, 11.4Ϯ9.1 reciprocal titers, at 6 hours) was completely overcome by ATIII (PϽ0.05). ATIII significantly prevented the increase in thromboxane (TXB 2 ) levels, which were 809Ϯ287 pg/mL in the placebo and 420Ϯ174 pg/mL in the verum group after 6 hours (PϽ0.02). On the other hand, ATIII had no influence on TNF levels. In a lethal study with an increased dose of LPS (0.5 g ⅐ kg Ϫ1 ⅐ h Ϫ1 ). A significant reduction in mortality was observed in the ATIII group (0 of 7) compared with the placebo group (4 of 6) (PϽ0.05, 2 test) a significant reduction of pulmonary hypertension (placebo, 42.0Ϯ11.1 mm Hg; ATIII, 23.6Ϯ7.5 mm Hg, PϽ0.05), 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 Ⅲ disseminated intravascular coagulation Ⅲ pulmonary hypertension Ⅲ soluble fibrin monomers Ⅲ thromboxane S epsis as a severe complication of infection is characterized by systemic inflammation, activation of proteolytic cascades, coagulation abnormalities (DIC) and a gradually developing hypodynamic status with impaired organ perfusion, and finally death in a septic shock. Lung circulation in septic shock is characterized by hypertension and increased pulmonary resistance, resulting in low cardiac output, and, frequently, in lung failure. Mortality in septic shock is usually high, ie, in the range of 40% to 50%. 1 If associated with multi-organ dysfunction such as respiratory or renal failure, mortality might exceed 90%. 2 The initiating event for the development of sepsis is the activation of macrophages by lipopolysaccharide (LPS) liberated from Gram-negative bacteria via binding to its surface receptor CD14. 3 However, sepsis might be induced by other agents, such as Grampositive bacteria, fungi or viruses. The initial excessive secretion of cytokine mediators such as interleukin 1 (IL-1) and tumor necrosis factor (TNF-␣) is followed by the activation of biological cascades including the coagulation, the complement, the fibrinolytic and the...

Antithrombin III inhibits nuclear factor κB activation in human monocytes and vascular endothelial cells

“…27,28 Anticoagulant proteins, on the other hand, may have the ability to completely change the behavior of immune or vascular cells. 29,30 Among the natural anticoagulants, AT III has been proven to exert, in addition to its anticoagulant activities, potent anti-inflammatory effects in animal models and clinical studies [2][3][4][5][6] and to improve the clinical outcome of patients with severe sepsis when given in high doses. 7 These beneficial effects of AT III do not entirely result from inhibition of thrombin because selective inhibition of thrombin generation did not prove to have similar effectiveness.…”

“…1 Apart from its role in hemostasis, there is accumulating evidence that antithrombin III (AT III) exerts anti-inflammatory properties and improves survival in animalsepsis models and disseminated intravascular coagulation (DIC). [2][3][4] There are a number of compelling reasons why AT III may also be an effective therapeutic agent in patients with sepsis. [5][6][7] AT III was shown to reduce leukocyte-endothelial interaction, 8 to prevent microvascular leakage, 9 and to ameliorate ischemia/reperfusion injury.…”

Protective Effects of Recombinant Human Antithrombin III in Pig-to-Primate Renal Xenotransplantation

“…ATIII concentrate has been shown to prevent DIC in a porcine sepsis model (16), and recombinant human ATIII (rhATIII) attenuated both the coagulation and inflammatory responses in a baboon sepsis model (17). We therefore decided to test whether treatment with high doses of rhATIII would prevent coagulopathy and protect renal xenografts from early injury in the pig-to-baboon model.…”

Calf Intestinal Alkaline Phosphatase, a Novel Therapeutic Drug for Lipopolysaccharide (LPS)-Mediated Diseases, Attenuates LPS Toxicity in Mice and Piglets

“…One of the most life-threatening LPS-mediated diseases, Gram negative sepsis, is characterized by excessive production of the above-mentioned proinflammatory cytokines, activation of proteolytic cascades, coagulation abnormalities (Dickneite and Leithauser, 1999), and hemodynamic responses, resulting in hypotension, poor tissue perfusion, and multiorgan failure (Lin and Lowry, 1998;Howe, 2000).…”