Protective effect of antithrombin III in acute experimental pancreatitis in rats

Abstract

In the present study we investigated the therapeutic action of antithrombin III (AT III) in taurocholate-induced experimental pancreatitis with high lethality in rats. High-dose AT III treatment greatly improved the survival rate not only when given as pretreatment but also when given 2 hr after induction. No favorable effect on survival rate was observed on administration after 5 hr. Both intravascular and intraperitoneal AT III administration locally restored decreased AT III levels in the peritoneal cavity and increased plasma AT III to supranormal levels. The primary pancreatic insult seemed to be unaffected by the treatment, because neither the rise in plasma lipase nor the development of ascites or the extension of the pancreatic necrosis were diminished. Because heparin pretreatment of the rats was also effective, the mechanism of the beneficial action was probably mediated by inhibition of the proteases of the coagulation cascade, thereby preventing intravascular coagulation in the pancreas and distant organs and subsequent systemic complications. The high efficacy of AT III treatment in this experimental model may stimulate clinical studies evaluating the efficacy of AT III treatment in an early stage of acute pancreatitis.

Coagulation Abnormalities in Acute Pancreatitis

“…In taurocholate-induced experimental pancreatitis in rats, high dose AT treatment was shown to improve survival (Bleeker et al, 1992). In cerulein-induced AP, AT supplementation inhibited the release of high mobility group box 1 protein (HMGB1) as well as other proinflammatory cytokines in rats (Hagiwara et al, 2009).…”

High dose of intravenous antithrombin III without heparin in the treatment of disseminated intravascular coagulation and organ failure in four children

“…Several recent animal experiments, using 1&15 times the pretreatment high dose of antithrombin I11 alone (100-250 unitskg), have shown beneficial prophylactic effects on mortality and restoration of coagulation abnormalities resulting from DIC and/or MSOF [7,8]. The mechanisms of the beneficial effects on DIC are unknown.…”

“…The timing of onset of antithrombin I11 administration could be a pivotal factor; we started infusion as soon as the diagnosis of DIC was established, because high-dose antithrombin I11 treatment had shown only prophylactic effects in animal experiments [7,8]. The per-day dosages of antithrombin I11 concentrates were 3-6 times the usual, and were continued for 2 or 3 days.…”

Low-dose heparin for the prevention of post-ERCP pancreatitis: a randomized placebo-controlled trial

“…In the later study, a LMWH (Certoparin) was used but offered no benefit compared with placebo based on the frequency and severity of acute post-ERCP pancreatitis. The authors speculated that the discrepancy between the results of this clinical trial and the experimentally proven effects of heparin [20][21][22][23][24][25][26][27][28] might be explained by the drug chosen for the study. It is possible that the antiinflammatory capability of the heparin molecule is destroyed during the fragmentation process.…”

“…Heparin inhibits pancreatic proteases in both plasma and pancreatic tissue in animal models of acute pancreatitis, improves pancreatic microcirculation, and inhibits inflammatory cascade [20][21][22][23][24][25][26][27][28]. Salas et al [25] reported that heparin inhibits tumor necrosis factor (TNF)-induced interactions of leukocytes and endothelium, thereby reducing inflammation.…”