Risk stratification for thrombosis in type 2 diabetic patients

Daniels, Sarah (2019) Risk stratification for thrombosis in type 2 diabetic patients. Doctoral thesis (PhD), Manchester Metropolitan University in collaboration with Manchester University NHS Foundation Trust.

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Abstract

The leading cause of mortality in type 2 diabetes mellitus patients is cardiovascular disease, with patients exhibiting platelet hyperreactivity and prothrombotic propensity. The mechanisms that underpin these effects however are unclear. The aim of this study was to determine which of the biochemical features associated with type 2 diabetes are responsible for increased platelet reactivity. Whole blood from fasted healthy participants supplemented with increasing concentrations of glucose, exhibited a significant elevation in mean platelet volume (MPV) and basal IIb3 receptor activation. Platelet aggregation in response to ADP and collagen was not increased by acute hyperglycaemia in platelet rich plasma or whole blood, and there was no significant increase in –granule secretion or IIb3 activation following ADP stimulation. Furthermore, in type 2 diabetic patients, HbA1c and fasting blood glucose correlated with MPV, but not platelet activation or aggregation. This suggests that hyperglycaemia elevates MPV and increases IIb3 activation in circulating platelets, but does not increase platelet reactivity as previously reported. The key finding from this study was the strong positive correlation for low-density lipoprotein cholesterol (LDL-C) and both ADP and collagen-activated platelet aggregation, and this was independent of diabetes. More importantly, patients with LDL-C over 2.0 mmol/L had significantly increased platelet aggregation. Furthermore, LDL-C was associated with elevated platelet production, and participants with LDL-C over 3.0 mmol/L had significantly increased immature platelet fraction. This study demonstrates that LDL-C may act as a biomarker to identify type 2 diabetes patients who would benefit from antiplatelet prophylaxis. Additionally, lipid-lowering medication could indirectly provide antithrombotic benefit by reducing LDL-C levels. Moreover, enhanced platelet production mediated by elevated LDL-C is likely responsible for both enhanced platelet reactivity and reduced antiplatelet efficacy in type 2 diabetic patients.