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http://hdl.handle.net/11375/19898
Title: | Studies of the Endothelial Protein C Receptor |
Authors: | Pepler, Laura |
Advisor: | Liaw, Patricia |
Department: | Medical Sciences (Blood and Cardiovascular) |
Keywords: | protein C;thrombosis;inflammation;endothelial protein C receptor;fibrinolysis;hematopoiesis |
Publication Date: | 2016 |
Abstract: | The endothelial protein C receptor (EPCR) binds to protein C (PC) and increases the rate of activated protein C (APC) generation by the thrombin-thrombomodulin (TM) complex. APC exerts anticoagulant, anti-inflammatory, and cytoprotective effects, which are EPCR-dependent. The thrombin-TM complex is also a potent activator of thrombin activable fibrinolysis inhibitor (TAFI), leading to impaired clot lysis. Mutations and polymorphisms identified in the EPCR gene, which can affect the efficiency of PC activation, have been associated with an increased risk of thrombosis. In this thesis we investigate the impact of impaired PC binding to EPCR on coagulation, inflammation, and fibrinolysis using novel in vitro and in vivo models. Using a murine model that harbours a variant of EPCR that does not bind PC (R84A), we demonstrate that upon thrombotic challenge, there is an increase in thrombin generation and fibrin deposition in the lungs. Upon inflammatory challenge, impaired PC/EPCR interactions also result in increased thrombin generation and increased neutrophil infiltration into the lungs. Using cells that express TM and a human variant of EPCR that does not bind PC (R96C), we demonstrate that clot lysis is delayed in normal plasma independent of TAFI activation, suggesting PC and TAFI do not compete for activation by the thrombin-TM complex. In contrast, delayed clot lysis in plasma deficient of PC is a result of greater TAFI activation by the thrombin-TM complex. Taken together, impairment of the PC pathway contributes to thrombosis through pro-coagulant, pro-inflammatory and anti-fibrinolytic mechanisms. Interestingly, mice with EPCR variant R84A, develop bone marrow failure and splenomegaly, revealing a novel role for EPCR in the bone marrow. Taken together, PC/EPCR interactions regulate the coagulation, inflammation, and fibrinolytic pathways, which may have a significant impact on maintaining hematopoietic homeostasis. |
URI: | http://hdl.handle.net/11375/19898 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Pepler_Laura_P_201607_PhD.pdf | Thesis | 7.12 MB | Adobe PDF | View/Open |
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