Date

December 2010

Document Type

Dissertation

Degree Name

Ph.D.

Department

Dept. of Biomedical Engineering

Institution

Oregon Health & Science University

Abstract

In the event of vascular injury, careful orchestration of blood platelet recruitment and coagulation protein activation functions to stop blood loss. Elucidation of the molecular mechanisms that mediate hemostasis is essential to understanding the dysfunction of this process under pathological conditions. This dissertation centers on characterizing the role of the coagulation enzyme thrombin in hemostasis, utilizing biophysical techniques to reveal unique interactions of thrombin with platelets and thrombi. The platelet receptor GPIb has been shown to mediate platelet-thrombin interactions in solution. Functional results presented here extend these findings to demonstrate that GPIb supports platelet interactions with both wild-type thrombin and the thrombin mutant, WE, under shear flow. In addition to its capacity for thrombin binding, the platelet surface is key in thrombin formation, supporting activation of prothrombin (the precursor to thrombin) by factor Xa. Upon formation, however, the fate and distribution of thrombin remains unclear. Results described in this thesis confirm binding of factor Xa and prothrombin to platelets, and emphasize the role of fibrin(ogen) in thrombin distribution on thrombi. Elevated rates of thrombosis are observed in patients with cancer, which may correlate to the expression and release of procoagulant molecules by tumor cells. In order to evaluate the mechanisms of thrombus formation, a novel ex vivo model of occlusive thrombus formation was developed. Utilizing this model, tumor cells were shown to promote the formation of occlusive thrombi in a manner dependent upon tissue factor and the activity of thrombin. Collectively, this dissertation provides new insights into the function of thrombin in hemostasis and thrombosis.

Identifier

doi:10.6083/M4JQ0Z0M

School

School of Medicine

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