Haemostasis is maintained by a dynamic balance between pro- and anti-thrombotic mediators. Its dysregulation can lead to bleeding or thrombosis, and is a major cause of morbidity and mortality. Thus, elucidation of the mechanisms involved in maintaining or disrupting this balance have important implications in health and disease. Investigative tools enable characterization of the haemostatic system, but are often associated with limitations. For instance, haemostasis in animal models is often investigated by assessing bleeding responses in one particular vessel or tissue without a complete understanding of how the results translate to the regulation of haemostasis in other vascular beds. As a second example, microparticles (MPs) are a heterogeneous population of submicron-sized vesicles that may be important in thrombosis. With the exception of a few subtypes, MPs cannot be reliably characterized using widely accessible techniques. Finally, the thrombin generation assay (TGA), which measures ex vivo activation and inhibition of thrombin, is a promising tool for clinical assessment of thrombosis and haemostasis. However, characterization of thrombin generation in the general population, and the development of point of care testing are in their infancies. As a result, the TGA remains largely a research tool. The works described in this thesis specifically seek to address these three limitations in thrombosis and haemostasis research. The first isolated murine arterial bleeding model is presented and its characterization with respect to bleeding in other vascular tissues is described. In addition, a solid-phase capture assay for evaluating procoagulant, P-selectin-binding MPs, which are postulated to be mediators of thrombosis, was developed in order to determine whether these MPs associate with risk of recurrent venous thromboembolism. Lastly, a 25 x 20 mm chip that performs four individual thrombin generation assays using ~10 µl of capillary blood was developed as a proof of concept for point of care thrombin generation testing. / Thesis / Doctor of Philosophy (PhD)
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/20643 |
| Date | January 2016 |
| Creators | Vaezzadeh, Nima |
| Contributors | Gross, Peter L, Medical Sciences |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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