Jagroop-Dearing, I.A.; (2012) Effect of antithrombotic drugs on platelet function and receptors and an investigation into platelet cholesterol. Doctoral thesis , UCL (University College London).

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Abstract

The aim of this thesis was to assess several aspects of platelet function, especially in response to drugs. Peripheral arterial disease (PAD) is associated with hyperactive platelets that may be resistant to aspirin. Therefore, the effect of the administration of clopidogrel, aspirin or both anti-platelet agents was investigated in patients with PAD. Platelet function was assessed by different techniques including platelet shape change (PSC), an early phase of platelet activation that precedes aggregation. PSC was measured using a high-resolution channelyzer and expressed as median platelet volume (MPV). There was an increased inhibitory effect of clopidogrel plus aspirin on platelet activation. Clopidogrel was a more potent inhibitor of ADP-induced platelet activation than aspirin. The ADP receptors, P2Y1, P2Y12 and P2X1 influence platelet activation. The P2Y1 receptor antagonist MRS 2179 blocked ADP-and ADP plus serotonin-induced PSC in vitro. The P2Y12 receptor antagonist AR-C69931MX significantly inhibited ADP-induced PSC. We demonstrated for the first time that the IC50 of a P2Y1 receptor-blocker can be derived using PSC. Tirofiban is a glycoprotein IIb/IIIa receptor antagonist and therefore a powerful inhibitor of platelet aggregation. Tirofiban did not affect fibrinogen/agonist-induced PSC but inhibited platelet aggregation in vitro. A lack of inhibition of PSC may limit the use of tirofiban in clinical practice. Current methods to measure platelet cholesterol (PC) involve complex extraction processes. A faster and simpler technique to measure PC was developed. There was a significant correlation between PC and some circulating lipid levels. This method may be useful for multiple sampling. PC may represent ‘tissue’ cholesterol levels. Furthermore, because high PC is associated with increased platelet activity, statins may decrease both PC and risk of thrombosis. The findings in this thesis may provide a better understanding of platelet function and how to assess it. Furthermore, potential therapeutic targets are discussed.

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