Administration of Human Recombinant Activated Protein C Is Not Associated with Pancreatic Parenchymal Haemorrhage in L-Arginine-Induced Experimental Acute Pancreatitis

Context Microvascular thrombosis is a critical event in severe acute pancreatitis. Human recombinant activated protein C(Xigris®, Eli Lilly, Indianapolis, IN, USA) modulates the interplay between pro-inflammatory and pro-coagulant pathwaysand maintains microvascular patency. However, the anticoagulant properties of Xigris® may precipitate bleeding from theinflamed pancreas. Objective This study tests the hypothesis that Xigris® can ameliorate experimental acute pancreatitiswithout causing pancreatic haemorrhage. Methods Sprague Dawley rats were allocated as follows: Group 1: control (n=7);Group 2: acute pancreatitis (n=6); Group 3: administration of Xigris® 500 μg/kg body weight before induction of acutepancreatitis (n=6); and Group 4: Administration of Xigris® 500 μg/kg body weight 30 minutes after induction of acutepancreatitis (n=6). Acute pancreatitis was induced by intraperitoneal administration of L-arginine 300 mg/100 g bodyweight. Animals were sacrificed at 48 hours and biochemical, haematological, and histological markers of pancreatichaemorrhage and inflammation assessed. Results Median lipase in animals with acute pancreatitis was 10 U/mL (range: 7-16 U/mL) compared to 5.5 (range: 3-8 U/mL) in controls (P=0.028). Lipase was also elevated in animals given Xigris® bothbefore (12 U/mL, range: 8-22 U/mL; P=0.031 vs. control group) and after (46 U/mL, range: 9-71 U/mL; P=0.015 vs. controlgroup) induction of acute pancreatitis). Haemoglobin levels were similar among all groups (P=0.323). There was nohistological evidence of pancreatic haemorrhage in animals treated with Xigris®. Pre-treatment with Xigris® was associatedwith a significant reduction in pancreatic injury. This effect was absent when Xigris® was administered after induction ofacute pancreatitis. Conclusion Xigris® did not lead to pancreatic haemorrhage in experimental acute pancreatitis.Administration of Xigris® prior to induction of acute pancreatitis was associated with amelioration of injury. This effect wasnot seen with administration of Xigris® after induction of acute pancreatitis.


Saurabh Jamdar, Benoy I Babu, Mahesh Nirmalan, Maria Jeziorska, Raymond FT McMahon, Ajith K Siriwardena

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