Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.598024
Title: The regulation of platelet function in patients with peripheral arterial disease
Author: Dickinson, Karen Joanna
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2011
Availability of Full Text:
Access from EThOS:
Abstract:
Platelets play an important role in the pathogenesis of atherothrombosis and, as such, measuring platelet dysfunction in patients with peripheral arterial disease (PAD) may be a useful prognostic marker for future cardiovascular events. Detecting increased platelet activity but also reduced platelet inhibition is important in the management of these patients. Prediction of cardiovascular risk could allow tailored anti-platelet regimens in high risk groups. Dissection of platelet function in patients with PAD could allow cardiovascular risk stratification and the aim of this thesis was to develop methods to allow 'platelet profiling' in patients with PAD to determine an individual's platelet reactivity. Platelet fibrinogen binding and platelet-leukocyte interactions were determined using flow cytometry. The mechanism of platelet inhibition by nitric oxide (NO) was elucidated further using various inhibitors of the nitric oxide signalling pathway, measurement of cGMP levels and Western blotting for vasodilator stimulated phosphoprotein. In addition, the cytokine profile of these patients was determined, with particular reference to those chemokines important in platelet leukocyte interactions. , Patients with peripheral arterial disease exhibited largely unchanged basal platelet activity (as measured by platelet-leukocyte aggregates and platelet fibrinogen binding), but significantly increased response to the agonist, adenosine diphosphate (ADP). Platelet inhibition in response to NO was reduced in patients with critical limb ischaemia (CLI). In patients with CLI, further work using modulators of the NO pathway demonstrated that the reduced platelet inhibition by NO may be attributable to abnormal protein kinase G (PKG) function. In addition, a global reduction in plasma chemokine levels was seen with increasing disease severity in PAD, including RANTES, MCP-1α and IL-10. This suggests a potential humoral or platelet factor present in patients with PAD causing this change and questions the traditional Th/Th-type cytokine dichotomy in favour of a more integrated cytokine network system. If these observations correlate with clinical outcomes this profiling tool will have important clinical value. This could have therapeutic implications e.g. dual anti-platelet therapy for high risk patients with PAD. Furthermore it would be interesting to study the effect of c1opidogrel and cilostazol or dipyridamole in combined approach to reducing platelet activation (P2Y12 antagonism) and increasing platelet inhibition (phosphodiesterase, PDE inhibition). New therapeutic ideas could be tested, directed by a patients 'profile' in order to combat this platelet hyperactivity in an attempt to reduce the significant cardiovascular morbidity and mortality associated with PAD.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.598024  DOI: Not available
Share: