{"id":{"repo_id":"cambridge","oai_identifier":"oai:www.repository.cam.ac.uk:1810/304293"},"canonical_url":"https://search.dev.ndltd.org/etd/cambridge/oai:www.repository.cam.ac.uk:1810/304293","repository":{"repo_id":"cambridge","name":"Cambridge University","base_url":"https://api.repository.cam.ac.uk/server/oai/request"},"display":{"title":"Platelet Receptor Glycoprotein VI in Ischaemic Stroke","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Induruwa, Isuru Pasanna"],"institution":"University of Cambridge","degree_name":"Doctor of Philosophy (PhD)","degree_level":"Doctoral","degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["Warburton, Elizabeth","Jung, Stephanie"],"committee_chairs":[],"committee_members":[],"year":2020,"date_issued":"2020-05-26","date_published":"2020-05-26","updated_at":"2026-07-22T22:24:16Z","subjects":["Platelets","Antiplatelet","Glycoprotein","Atrial Fibrillation","Stroke","Bleed"],"languages":["en"],"rights":[],"rights_urls":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/9f819827-d138-4e3d-8c35-be663a6d8c77/download","https://www.rioxx.net/licenses/all-rights-reserved/"],"identifier_entries":[{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000270208179"],"render_values":[{"text":"0000-0002-7020-8179","href":"https://orcid.org/0000-0002-7020-8179","code":true}]}]},"links":{"outbound_url":"https://doi.org/10.17863/CAM.51374","outbound_label":"DOI","outbound_source":"dc:identifier.doi"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Warburton, Elizabeth","Jung, Stephanie"]},{"key":"dc:contributor.sponsor","label":"Sponsor","values":["British Heart Foundation Addenbrooke's Charitable Trust Cambridge BRC"]},{"key":"dc:creator","label":"Author","values":["Induruwa, Isuru Pasanna"]},{"key":"dc:creator.authoridentifier","label":"Author Identifier","values":["0000000270208179"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.issued","label":"Date","values":["2020-05-26"]},{"key":"dc:publisher.institution","label":"Dc Publisher Institution","values":["University of Cambridge"]},{"key":"dc:relation.isreferencedby.uri","label":"Dc Relation Isreferencedby URI","values":["https://www.repository.cam.ac.uk/handle/1810/304293"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Doctoral"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["Doctor of Philosophy (PhD)"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Platelets","Antiplatelet","Glycoprotein","Atrial Fibrillation","Stroke","Bleed"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language","label":"Dc Language","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/9f819827-d138-4e3d-8c35-be663a6d8c77/download","https://www.rioxx.net/licenses/all-rights-reserved/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.doi","label":"DOI","values":["10.17863/CAM.51374"]},{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/fbd5d926-ab4c-4eea-b5ba-11fd6cab1edc/download"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["Platelet activation, thrombus growth and subsequent thromboembolism underpins the pathophysiology of ischaemic stroke. 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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."]},{"key":"dc:format.checksum.md5","label":"Dc Format Checksum Md5","values":["be737457cb0038d30bb6ba78f1831451","87eda9de84448d1f82354d60eee3eb5f"]},{"key":"dc:title","label":"Title","values":["Platelet Receptor Glycoprotein VI in Ischaemic Stroke"]}]}],"canonical_facts":{"dc:contributor.advisor":["Warburton, Elizabeth","Jung, Stephanie"],"dc:contributor.sponsor":["British Heart Foundation Addenbrooke's Charitable Trust Cambridge BRC"],"dc:creator":["Induruwa, Isuru Pasanna"],"dc:creator.authoridentifier":["0000000270208179"],"dc:date.issued":["2020-05-26"],"dc:description.abstract":["Platelet activation, thrombus growth and subsequent thromboembolism underpins the pathophysiology of ischaemic stroke. 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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. 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