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Assessment of platelet activation and function in ischaemic stroke, transient ischaemic attack and asymptomatic severe carotid stenosis

McCabe, Dominick John Henry; (2004) Assessment of platelet activation and function in ischaemic stroke, transient ischaemic attack and asymptomatic severe carotid stenosis. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

Platelets play a pivotal role in haemostasis and thromboembolism, and a better understanding of the cellular mechanisms involved in platelet activation should improve our understanding of the pathogenesis of ischaemic cerebrovascular disease (CVD). The purpose of this thesis was to perform a comprehensive assessment of platelet activation and function in patients with ischaemic stroke, TIA, and asymptomatic severe carotid stenosis. We hypothesised that patients with ischaemic CVD would have excessive platelet activation compared with controls without a history of stroke or TIA. We also hypothesised that we would find excessive platelet activation in patients with recently symptomatic compared with asymptomatic severe carotid stenosis. We examined the prevalence of 'aspirin resistance' in ischaemic CVD using a relatively novel platelet function analyser, called the PFA-100®, and investigated the ex vivo response to increasing doses of oral aspirin in the convalescent phase after ischaemic stroke or TIA. We found elevated levels of CD62P and monocyte-platelet complexes using whole blood flow cytometry, and elevated von Willebrand factor antigen levels using a latex agglutination assay, in the acute and convalescent phases after ischaemic stroke or TIA compared with controls. We did not find a significant increase in the percentage of reticulated platelets, or in the levels of soluble P-selectin or E-selectin in ischaemic CVD patients compared with controls. The mean platelet count and the percentage of leucocyte-platelet complexes were significantly higher in patients with recently symptomatic compared with asymptomatic severe carotid stenosis. Using the PFA-100®, 60% of patients in the acute phase and 43% of patients in the convalescent phase after ischaemic stroke or TIA were 'resistant' to the antiplatelet effects of aspirin ex vivo. Preliminary studies did not provide any convincing evidence that the ex vivo response to aspirin therapy was more pronounced as the dose was increased from 75 mg to 150 mg to 300 mg daily in the convalescent phase after ischaemic CVD. Preliminary platelet aggregometry studies in platelet rich plasma (PRP) revealed that two patients who were aspirin resistant on 75 mg daily using epinephrine-induced platelet aggregometry, were aspirin responsive on higher doses of the drug. The fact that sodium arachidonate- induced platelet aggregation was inhibited to a significant degree in all of our patients suggests that cyclooxygenase-independent mechanisms are important in mediating aspirin resistance using the PFA-100®. Our data suggest that elevated VWF levels in ischaemic CVD are likely to play an important role in mediating aspirin resistance using this device. There was poor concordance between the results obtained with the PFA-100® and platelet aggregometry. However, because the PFA-100 measures platelet function in whole blood at moderately high shear rates, it should more closely mimic in vivo platelet aggregation in patients with atherosclerosis in comparison with platelet aggregometry in PRP that is performed at very low shear rates. We have confirmed that excessive platelet activation occurs in patients with ischaemic stroke or TIA, and have shown that a large proportion of ischaemic CVD patients are 'resistant' to the antiplatelet effects of aspirin therapy ex vivo. Further studies are required to determine whether one can use assays of platelet activation and function to monitor and / or predict the response to antiplatelet therapy in this patient population.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: Assessment of platelet activation and function in ischaemic stroke, transient ischaemic attack and asymptomatic severe carotid stenosis
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Thesis digitised by ProQuest.
Keywords: Health and environmental sciences; Cerebrovascular disease
URI: https://discovery.ucl.ac.uk/id/eprint/10104508
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