Basic—Alimentary TractRole of the Protein C Pathway in the Extraintestinal Thrombosis Associated With Murine Colitis
Section snippets
Mice
Male C57BL/6 (WT control strain) mice (Jackson Laboratories, Bar Harbor, ME) or EPCR-TgN mice (Oklahoma Medical Research Foundation, Oklahoma City, OK) were used. The EPCR-TgN mice were backcrossed into C57BL/6 mice and exhibit normal size, weight, viability, fertility, blood cell count, and chemistries.11 EPCR protein levels in all organs of the transgenic mice are at least 8-fold higher than in their WT counterparts. There was no evidence of thrombotic or hemorrhagic complications or
Results
Exposure of the cremaster to epiillumination for 30 minutes in the absence of FITC-dextran did not induce any signs of platelet aggregation and thrombus formation in either venules or arterioles nor did it alter microvessel red blood cell velocities or shear rate. Table 1 summarizes the values for wall shear rate that were determined in arterioles and venules of all experimental groups immediately prior to the induction of light/dye injury. No significant differences in wall shear rate were
Discussion
Although IBD are associated with an increased risk for thrombosis,1, 2 the mechanisms that underlie the thrombus formation in extraintestinal tissues during chronic gut inflammation remain poorly understood. However, there is some evidence indicating that alterations in the protein C pathway, an anticoagulant system that limits the generation of thrombin, may contribute to the coagulation abnormalities that accompany IBD. For example, the results of a recent report indicate that the 2 major
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Cited by (20)
Interleukin-6 mediates the platelet abnormalities and thrombogenesis associated with experimental colitis
2013, American Journal of PathologyCitation Excerpt :All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee of Louisiana State University Health Sciences Center and were performed according to the criteria outlined by the National Institutes of Health. Acute colitis was induced with 3% dextran sodium sulfate (DSS; 40,000 molecular weight; MP Biomedicals, Solon, OH) dissolved in filter-purified drinking water for 7 days, as previously described.14,21 Control mice received regular drinking water without DSS.
Mechanisms of enhanced thrombus formation in cerebral microvessels of mice expressing hemoglobin-S
2011, BloodCitation Excerpt :ANS did not alter the number of circulating lymphocytes, monocytes, or platelets. Whereas coagulation parameters were not measured in ANS-treated mice, previous reports on other models (sepsis) have shown no dependence of the thrombosis response on neutrophils.24 Red blood cells were collected in microhematocrit tubes (StatSpin Technologies) and spun in a microhematocrit centrifuge (StatSpin Technologies) for 30 seconds.
Microvascular thrombosis and CD40/CD40L signaling
2011, Journal of Thrombosis and HaemostasisInterleukin-1β mediates the extra-intestinal thrombosis associated with experimental colitis
2010, American Journal of PathologyCitation Excerpt :Although no differences were noted in either the time of onset or time to flow cessation between venules of control and colitic mice, both variables were significantly reduced (consistent with accelerated thrombosis) in cremaster arterioles of colitic mice. The accelerated thrombus formation in arterioles of DSS colitic mice is consistent with previous reports.3,6 The figure also illustrates that a similar pattern of enhanced thrombosis in cremaster arterioles is evidenced in an immune model of colitis that results from the transfer of CD4+ T-cells from IL-10−/− mice into immunodeficient RAG-1−/− mice.
The protein C pathway in tissue inflammation and injury: Pathogenic role and therapeutic implications
2010, BloodCitation Excerpt :Besides its pathogenic role in intestinal inflammation, the association between the PC pathway and the risk for thromboembolism in IBD has been investigated. An investigation was undertaken aimed at determining whether the PC pathway contributes to the enhanced extraintestinal thrombosis that is observed in mice with dextran sodium sulfate–induced colitis.64 The thrombotic response was greatly attenuated in transgenic mice that overexpressed EPCR or by treatment of WT colitic mice with aPC, thus revealing that the PC pathway is a novel mediator of extraintestinal thrombosis.
Supported by grants from the National Institutes of Diabetes, Digestive and Kidney Diseases (P01 DK43785) and Leducq International Network Against Thrombosis (LINAT) awarded by the Leducq Foundation, Paris.
Conflicts of interest and financial disclosures: C. T. Esmon has patents and licenses on protein C production and the use of activated protein C in the treatment of sepsis, has a patent on endothelial protein C receptor, and is an investigator of the Howard Hughes Medical Institute. No conflicts of interest exist.