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Investigation of the Role of Platelet Turnover on Platelet Inhibition and Thrombus Formation with Regard to Antiplatelet Therapy

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Investigation of the Role of Platelet Turnover on Platelet Inhibition and Thrombus Formation with Regard to Antiplatelet Therapy Investigation of the role of platelet turnover on platelet inhibition and thrombus formation with regard to antiplatelet therapy A thesis submitted for the degree of Doctor of Philosophy at the University of London by Thomas Höfer William Harvey Research Institute Barts and the London School of Medicine and Dentistry Queen Mary University of London Charterhouse Square London EC1M 6BQ United Kingdom ABSTRACT Aspirin is often prescribed in patients with acute coronary syndromes together with an ADP-P2Y12 inhibitor such as clopidogrel or prasugrel, an established treatment protocol called dual antiplatelet therapy. Although short lived, these drugs act irreversibly upon their targets and so are used as once-a-day treatments. The daily platelet turnover in healthy humans is approximately ten to fifteen per cent but can be considerably increased in disease conditions such as diabetes or chronic kidney disease. This leads to the daily emergence of an uninhibited subpopulation among the larger population of inhibited platelets. The aim of this thesis was the investigation of the role and contribution of this minority of uninhibited platelets in platelet aggregation and thrombus formation. Investigations found a nonlinear increase in arachidonic acid (AA)-induced aggregation in PRP containing rising proportions of uninhibited platelets mixed with aspirin-treated platelets. In contrast, stimulation of PRP containing mixed proportions of prasugrel active metabolite (PAM)-treated and uninhibited platelets by ADP showed a linear relationship between aggregatory responses and proportions of uninhibited platelets. This indicated that only uninhibited platelets would contribute to aggregate formation. However, confocal images of prelabelled platelets allowing the differentiation between inhibited and uninhibited platelets, revealed clustering of uninhibited platelets in the centre of aggregates surrounded by PAM-inhibited platelets. In contrast confocal images of uninhibited platelets combined with aspirin-treated platelets showed random, intermingled platelet distribution when stimulated by AA. Further in depth analyses by confocal microscopy and flow cytometry found the recruitment of PAM-inhibited platelets to be an active αIIbβ3-mediated process, independent of thromboxane A2 release. Whereas clustering of uninhibited platelets was not detected under flow conditions, an increase of platelet deposition with rising proportions of aspirin and/or PAM-free platelets was observed. These experiments clearly demonstrate that a general population of platelets can contain subpopulations that respond differently to overall stimulation of the population. 2 PUBLICATIONS Papers Thomas Hoefer, Nicholas S Kirkby, Michaela Finsterbusch, Paul C Armstrong, Timothy D Warner. Drug-free platelets can act as seeds for aggregate formation during anti-platelet therapy. Manuscript in submission for Circulation Research Abstracts Hoefer T, Warner TD. During anti-platelet therapy platelet turnover may lead to the emergence of a minority of uninhibited platelets sufficient to initiate and drive platelet aggregate formation. Heart 2013;99:suppl 2 A126-A127 doi:10.1136/heartjnl-2013-304019.236 Hoefer T, Kirkby NS, Mitchell JA, Warner TD. Associations between the proportions of P2Y12 receptor blocked and/or aspirin-treated platelets and the size of aggregatory responses. Proceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol9Issue3abst055P.pdf Hoefer T, Kirkby NS, Warner TD. Relationship between proportions of P2Y12 inhibited platelets and aggregation in vitro. Heart 2011;97:20 e7 doi:10.1136/heartjnl-2011-300920b.12 3 DECLARATION I hereby declare that I have personally undertaken all the work described in this thesis. 4 ACKNOWLEDGEMENTS I would like to thank all those who supported me during my PhD-project scientifically as well as personally. First and foremost, I would like to thank my supervisor Professor Tim Warner for giving me the opportunity to conduct my PhD-project under his supervision and introducing me to the exciting field of antiplatelet therapy. His expertise, enthusiasm and guidance but also his calm personality ensured a relaxed, friendly, supportive and personal work environment and made my PhD a very enjoyable experience. I would like to thank the members of Tim’s group for all their support throughout my time in the group. Thanks to Ivana for taking care of my purchases. She baffled me many times by negotiating remarkable deals on compounds and negotiated without compromising to ensure that items were delivered promptly. I am grateful for all constructive criticism I received from my colleagues, all the advice I was given and all the helping hands I could count on when my time management got the better of me. In particular I would like to thank Nick, for his never ending patience explaining many different assays, looking over my data and troubleshooting my experiments and for sharing his endless knowledge and insights on pretty much everything there is. Thanks to Tim, Ivana, Nick, Phil, Nikki, Mel, Paul, Martina, Rebecca, Fra and Bennett – for making my time in this group in many ways an unforgettable experience, for many great trips including a winter daytrip to freezing Brussels, the conference in Galveston (including daytrips in a minivan to NASA, submarines in concrete, off-shore oilrig museum that does not mention deep- water horizon and the aquarium), and an exciting daytrip to Paris – heavy rain and wet trousers included ;) and for several evenings in more or less dodgy pubs including a Caribbean bar in Manchester and a pub that serves sparkling water (thanks Nick!). I would also like to take the opportunity to thank my family for their kind support for always having been at my side, always supporting and motivating me and believing in me. 5 My most sincere gratitude goes to Michi for all her support, both scientifically and personal, her love and patience, for being by my side when I needed her most, for her incredible ability to motivate me - ranging from positive little words of encouragement to a forceful kick in the backside. My gratitude goes to all the friends within the William Harvey Research Institute: Andrew, Chris, Emma and Suborno just to name a few. Thanks for all the fun we had at lunch breaks and legendary Friday nights. Most importantly, thanks for letting me be part of your lives and being such good friends. It really helped making a PhD away from home such a brilliant experience. Finally, I would like to thank the Medical Research Council for funding my studentship. 6 TABLE OF CONTENTS ABSTRACT ..................................................................................................... 2 PUBLICATIONS ................................................................................................. 3 DECLARATION .................................................................................................. 4 ACKNOWLEDGEMENTS .................................................................................. 5 TABLE OF CONTENTS ..................................................................................... 7 LIST OF FIGURES ........................................................................................... 11 ABBREVIATIONS ............................................................................................ 15 CHAPTER 1: INTRODUCTION ....................................................................... 17 1.1. The Cardiovascular System ....................................................................... 18 1.2. Haemostasis ............................................................................................... 19 1.3. The platelet ................................................................................................. 20 1.3.1. Platelet formation, maturation and clearance from blood .......................... 20 1.3.2. Platelet morphology ......................................................................................... 22 1.4. Platelet functions ........................................................................................ 23 1.4.1. Platelet functions other than haemostasis/thrombosis ............................... 23 1.4.2. Haemostasis ..................................................................................................... 27 1.5. Thrombosis ................................................................................................. 31 1.5.1. Venous thrombosis .......................................................................................... 31 1.5.2. Atrial fibrillation ................................................................................................. 32 1.5.3. Atherothrombosis ............................................................................................. 33 1.6. Platelet inhibitors ....................................................................................... 35 1.6.1. Aspirin ................................................................................................................ 35 1.6.2. P2Y12 inhibitors ................................................................................................. 39 1.6.3. αIIbβ3 inhibitors .................................................................................................. 44 1.6.4. Phosphodiesterase (PDE) inhibitors ............................................................. 49 1.6.5. Other inhibitors ................................................................................................
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