CUP Undergraduate Research


Pathways of Anticoagulation in a Mouse Model of Heart Failure

Date of Award

Spring 4-1-2015

Document Type

Restricted Access Thesis


College of Theology, Arts, & Sciences


Math & Science

Degree Name

Biology, BA

First Advisor

Dr. Rici Hallstrand


Blood clots can form in response to an injury to stop potentially dangerous bleeding. However, a number of conditions can cause the development of blood clots in critical locations, such as the heart. The protein C (PrC) anticoagulation pathway serves as a major system in the control of excessive thrombus/clot formation. PrC binds to endothelial protein C receptor (EPCR) and is presented to a thrombomodulin-thrombin complex which catalytically generates activated PrC (APC). Once PrC is activated and dissociated, it forms a complex with its cofactor protein, protein S (PrS), which enables it to provide effective feedback inhibition of Tissue Factor-initiated coagulation at FVIIIa and FVa. By irreversibly inhibiting these factors, APC effectively downregulates thrombin generation, thereby inhibiting the coagulation cascade and the formation of a blood clot. Thrombomodulin (TM), endothelial cell protein C receptor (EPCR), and protein S (PrS) are essential for APC generation and function. Thromboembolic complications are the most common complication for patients with heart failure. In this study we investigate the cardiac anticoagulation pathway in a mouse model of heart failure (HF), focusing on the ventricular endocardial surface that is prone to developing thrombi. In our HF model we found significantly lowered protein levels of EPCR, TM, and PrS on the endocardial surface; messenger RNA levels for these proteins were also shown to be lower in our HF model. Lowered levels of anticoagulation pathway components within endocardial endothelial cells may lead to an increased risk for thrombus formation in the heart. This study provides new insights into the pathogenesis of thrombus formation in failing heart ventricles.

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