Role of the protein C pathway in the extra‐intestinal thrombosis associated with inflammatory bowel disease

Abstract

Inflammatory bowel diseases (IBD) are associated with an increased risk for thromboembolism. While thrombosis is known to contribute to the morbidity and mortality of patients with IBD, the underlying mechanisms that contribute to the genesis of a hypercoagulable state during intestinal inflammation remain poorly defined. The objective of this study was to determine whether the protein C pathway contributes to the enhanced extra‐intestinal thrombosis that is associated with dextran sodium sulfate (DSS)‐induced colitis in mice. Intravital microscopy was used to monitor thrombus formation in arterioles and venules of the cremaster muscle in colitic wild type (WT) and mutant mice that overexpress the endothelial cell protein C receptor (EPCR). Thrombus formation was induced using the light/dye endothelial injury model and quantified using the time of onset of the thrombus and time to blood flow cessation. Some WT mice were treated with either activated protein C (APC) or an APC neutralizing antibody (APC‐Ab). The DSS‐enhanced thrombosis response was greatly attenuated in the EPCR transgenic mice and in WT mice treated with APC immediately prior to photoactivation. Treatment with the APC‐Ab further promoted the DSS‐enhanced thrombosis response. These findings indicate that an altered protein C pathway contributes to the extra‐intestinal thrombosis that accompanies colonic inflammation. (P01 DK43785)