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Title: Investigating Aspirin and Ticagrelor for the prevention of tumour cell-induced platelet aggregation
Author: Chauhan, Meera
ISNI:       0000 0004 8498 3568
Awarding Body: University of Leicester
Current Institution: University of Leicester
Date of Award: 2019
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Background: Tumour-cell induced platelet aggregation (TCIPA) increases the metastatic potential of cancer. Mechanisms include protection of tumour cells from immune destruction, interaction of platelet receptors with tumour ligands to facilitate adhesion, and enrichment of the tumour microenvironment, promoting extravasation and proliferation. Use of antiplatelet agents could reduce TCIPA, resulting in reduced metastatic progression and increased patient survival. Ticagrelor, a P2Y12 antagonist, is an antiplatelet medication used in cardiovascular disease. To date, this has not been investigated for the reduction of TCIPA in cancer patients. This study investigated the effects of Ticagrelor and aspirin as monotherapy and dual therapy in metastatic breast and colorectal cancer patients. Method: Blood was collected from healthy volunteers and patients with metastatic cancer. The initial study focused on assay development, and in vitro experiments investigating platelet activation. An interventional study investigated platelet activation in healthy donors and patients with metastatic breast or colorectal cancer. Participants were randomised to receive aspirin or Ticagrelor for 2 weeks, followed by a 2-week washout and crossover to the other monotherapy, before completing 2 weeks of dual therapy. Blood samples were taken at baseline and the end of each treatment. Light transmission aggregometry assessed platelet reactivity in terms of spontaneous aggregation and aggregation response to agonists. Flow cytometry measured the activation status of the platelets by the amount of P-selectin expression, fibrinogen binding and Annexin-V binding. Extracellular vesicles were quantified by flow cytometry, and cell-free DNA by qPCR; these were explored as potential biomarkers. Results: 17 healthy volunteers and 57 metastatic cancer patients provided blood samples for the initial study. Cancer patients had significantly higher amounts of spontaneous aggregation and levels of P-selectin expression compared to healthy volunteers. 20 healthy people, 10 breast and 6 colorectal cancer patients started the interventional study. Colorectal patients had higher spontaneous aggregation at baseline, which could be significantly reduced by Ticagrelor. Breast patients had higher amounts of fibrinogen binding at baseline, and this was significantly reduced by Ticagrelor. Conclusion: Platelets from cancer patients are hyperreactive, as evidenced by their ability to spontaneously aggregate, and the higher expression of platelet activation markers. These platelets have a high sensitivity to P2Y12 inhibition, and Ticagrelor reduced the activation of platelets with a low incidence of patient adverse outcomes. This warrants larger studies into Ticagrelor as an adjunct to anticancer treatment and potential prophylactic treatment for cancer-associated venous thromboembolism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: Thesis