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Title: The effect of antiplatelet therapies on neutrophil migration
Author: Alsharif, Khalaf
ISNI:       0000 0004 5358 242X
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2015
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The platelet P2Y12 receptor antagonists such as clopidogrel and ticagrelor form an essential strategy for prevention of thrombotic events after acute coronary syndromes (ACS). In the PLATO study, ticagrelor reduced mortality in ACS patients compared to clopidogrel and the mechanisms underlying this mortality reduction are unclear. A post hoc analysis of PLATO suggests that ticagrelor may reduce susceptibility to pulmonary infection compared to clopidogrel, raising the possibility of differential effects of the drugs on host defence. This thesis investigates the effect of the P2Y12 inhibitors clopidogrel and ticagrelor on neutrophil function, specifically migration, and examines the effects of adenosine uptake inhibition by ticagrelor on neutrophil migration. Chemotaxis assay was used to investigate the effects of clopidogrel and ticagrelor on neutrophil migration in vitro. Isolated human and mice neutrophils were treated with various compounds and placed on the filter of transwell chemotaxis chambers with chemoattractant (keratinocytes-derived chemokine or interleukin-8) in the lower wells. The number of treated neutrophils that migrated to chemoattractant was counted and compared to their control. A thioglycollate induced-peritonitis model was use to study the effect of P2Y12 inhibitors on neutrophil recruitment in vivo. Mice were administered different agents and then thioglycollate was injected. The number and the percentage of neutrophils present in the lavage fluid was counted and calculated. The results of this thesis demonstrated that the P2Y12 receptor did not play a significant role in neutrophil migration in vitro and in vivo. In addition, the thioglycollate induced-peritonitis model did not show a significant effect of ticagrelor on neutrophil recruitment. Consequently, the relationship between ticagrelor, erythrocytes and adenosine on modulating neutrophil migration was investigated. The results showed that adenosine 10 -8M significantly potentiated neutrophil chemotaxis and this effect of adenosine was attenuated in the presence of erythrocytes. Ticagrelor and another inhibitor of erythrocyte adenosine uptake, dipyridamole, were able to preserve the effect of adenosine on neutrophil chemotaxis in the presence of erythrocytes. In conclusion, clopidogrel does not play a significant role in modulating neutrophil migration. In addition, this thesis describes a novel role for ticagrelor, as an adenosine uptake inhibitor, in modulating neutrophil migration by potentiating the effect of adenosine on neutrophil chemotaxis in the presence of erythrocytes. This represents a potential mechanism by which ticagrelor could influence host defence against bacterial infection and further work is required to explore the clinical relevance of these observations.
Supervisor: Ridger, Victoria ; Judge, Heather ; Storey, Robert Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available