Inhibition of coagulation and inflammation by activated protein C or antithrombin reduces intestinal ischemia/reperfusion injury in rats.

OBJECTIVE: To examine whether administration of activated protein C or antithrombin reduces local splanchnic derangement of coagulation and inflammation and attenuates intestinal dysfunction and injury following intestinal ischemia/reperfusion. DESIGN: Randomized prospective animal study. SETTING: University research institute. SUBJECTS: Adult male Wistar rats, weighing 300-325 g (n = 72). INTERVENTIONS: Rats were subjected to superior mesenteric artery occlusion consisting of 20 or 40 mins of ischemia and 3 hrs of reperfusion. A randomized intravenous administration of vehicle (0.9% NaCl), heparin, antithrombin, or activated protein C was performed during ischemia, 15 mins before reperfusion. Coagulation and fibrinolysis variables obtained from portal blood were correlated with mucosal fibrin deposition (determined by anti-rat fibrin antibody staining), intestinal function (glucose/water clearance), and intestinal injury (histologic evaluation by Park/Chiu score). MEASUREMENTS AND MAIN RESULTS: Activated protein C- or antithrombin-treated animals demonstrated less ischemia/reperfusion-induced intestinal dysfunction and histologic changes compared with control animals, whereas intravenous administration of heparin only showed less histologic derangement. Activated protein C- or antithrombin-treated animals showed less thrombin generation, fibrin degradation products, and fibrin deposition compared with control animals, as confirmed by histologic examination, whereas heparin administration showed only a limited reduction of portal fibrin degradation product concentrations. Furthermore, activated protein C or antithrombin administration markedly inhibited the inflammatory response, as reflected by reduced interleukin-6 plasma concentrations to baseline values, whereas heparin had no effect. CONCLUSIONS: Administration of activated protein C or antithrombin inhibited local and systemic derangement of coagulation and inflammation following intestinal ischemia/reperfusion, diminished mucosal fibrin deposition, and attenuated ischemia/reperfusion-induced intestinal injury. These observations suggest that activated protein C or antithrombin reduces ischemia/reperfusion-induced intestinal injury, both through their anticoagulant and anti-inflammatory effects.

Local intravascular coagulation and fibrin deposition on intestinal ischemia-reperfusion in rats.

BACKGROUND: This study investigates intravascular coagulation and thrombotic obstruction in the splanchnic vasculature after intestinal ischemia in relation to epithelial integrity and function. METHODS: Intestinal ischemia was induced in rats by superior mesenteric artery occlusion for 20 or 40 minutes. Intestinal injury was assessed by histologic analysis, biochemical markers, and functional studies. During reperfusion, portal and systemic blood samples were collected to analyze activation of coagulation and fibrinolysis. RESULTS: Superior mesenteric artery occlusion resulted in mild to moderate intestinal injury. Twenty and 40 minutes of ischemia and 3 hours of reperfusion resulted in local intestinal thrombin generation and conversion of fibrinogen to fibrin, reflected by 3- and 4-fold increases in thrombin-antithrombin complex levels and a 3-fold elevation of fibrin degradation products (D-dimer), respectively. During reperfusion, after a short-lasting initial activation of local fibrinolysis, plasminogen activator activity was suppressed, as indicated by an approximately 4-fold increase in portal plasma levels of the plasminogen activator inhibitor. D-dimer levels showed that activation of coagulation and depression of fibrinolysis resulted in fibrin formation, which was confirmed to be intravascular fibrin deposition by histologic examination. CONCLUSIONS: Intestinal ischemia-reperfusion results in local intravascular coagulation and fibrin deposition.