Background and Objectives: Platelets play a vital role in haemostasis but if activated inappropriately can contribute to cardiovascular disease (CVD) and result in myocardial infarction (MI) and/or stroke. Platelet hyperreactivity is linked to several diseases that are risk factors for CVD, including diabetes. The underlying cause of platelet hyperreactivity in diabetes is still largely unknown. The aim of this study was therefore (i) to investigate the effects of hyperglycaemia and thrombopoietin (TPO) on platelet function and (ii) to determine whether the anti-diabetes treatments, metformin and rosiglitazone affect platelet function. Experimental design: The effect of 100 ng/mL TPO, 25 mM glucose, 40 μM metformin and 100 μM rosiglitazone on platelet function were investigated. The functional assays include CRP-XL, PAR1-AP or thrombin stimulated platelet aggregation, integrin activation, phosphatidylserine exposure, reactive oxygen species generation, mitochondrial membrane potential depolarisation and calcium signalling. Results: Glucose alone had no effect on platelet aggregation but enhanced mitochondrial membrane depolarisation and PS exposure. TPO significantly enhanced platelet aggregation, mitochondrial membrane depolarisation, ROS generation and PS exposure. Metformin had no significant effect on platelet aggregation, whereas Rosiglitazone significantly reduced platelet aggregation but also significantly increased PS exposure and ROS generation. Conclusion: Hyperglycaemia and TPO contribute to a pro-coagulant platelet phenotype via increased PS exposure, providing a potential explanation for the platelet hyperreactivity observed in patients with diabetes and other diseases associated with chronic hyperglycaemia and elevated serum levels of TPO. Rosiglitazone has both anti-platelet and pro-coagulant properties. The latter of which, with further research, could provide an explanation behind the increase risk of CVD observed in rosiglitazone treated patients.
|Date of Award||7 May 2019|
- The University of Bristol
|Supervisor||Ingeborg Hers (Supervisor) & Alastair W Poole (Supervisor)|