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Platelet Receptor Glycoprotein VI in Ischaemic Stroke 10.17863/CAM.51374 Induruwa, Isuru Pasanna 0000000270208179 Warburton, Elizabeth Jung, Stephanie Platelet activation, thrombus growth and subsequent thromboembolism underpins the pathophysiology of ischaemic stroke. At sites of atherothrombotic plaque rupture, it is established that platelet surface receptor glycoprotein (GP) VI-dimer binds to exposed sub-endothelial collagen, initiating the signalling required to cause platelet activation. Then, separate platelet-fibrin interactions cause the thrombus to grow, culminating in distal tissue ischaemia; crucial in thrombotic diseases such as ischaemic stroke. The work in this thesis demonstrates that GPVI-dimer binds to fibrin also, causing platelet activation through a mechanism independent of collagen. In ischaemic stroke this is important as it not only implicates GPVI-dimer in the large-artery atherosclerotic stroke subtype, it suggests a key role in cardioembolic stroke, where fibrin, rather than collagen, is the key platelet ligand. We compared the platelet surface expression of GPVI-dimer in a control, pre-stroke atrial fibrillation (AF), and a stroke population admitted to hospital using flow cytometry. We also measured platelet activation by platelet P-selectin exposure in all the cohorts. The results demonstrate that both AF and stroke patients have more ‘active’ circulating platelets compared to the controls. Furthermore, both AF and stroke patients – irrespective of AF type or stroke aetiology, express more GPVI-dimer on their platelets compared to controls. In the stroke cohort, GPVI-dimer expression was significantly higher at day-90 post-stroke than at admission. The ability of GPVI to interact with the two main ligands that drive thrombosis, collagen and fibrin, cements its role as a key platelet receptor in human thromboembolic disease. These results intimate an important role for GPVI-dimer in driving thrombotic risk pre-stroke, as well as after having a stroke, suggesting that the direct inhibition of GPVI-dimer could be a promising future antithrombotic target. University of Cambridge 2020-05-26 Thesis Doctoral Doctor of Philosophy (PhD) en British Heart Foundation Addenbrooke's Charitable Trust Cambridge BRC https://www.repository.cam.ac.uk/handle/1810/304293 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/fbd5d926-ab4c-4eea-b5ba-11fd6cab1edc/download be737457cb0038d30bb6ba78f1831451 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/9f819827-d138-4e3d-8c35-be663a6d8c77/download 87eda9de84448d1f82354d60eee3eb5f https://www.rioxx.net/licenses/all-rights-reserved/ Platelets Antiplatelet Glycoprotein Atrial Fibrillation Stroke Bleed