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Thesis Submitted for the Degree of Doctor of Philosophy University of Bath Department of Pharmacy and Pharmacology April 2013

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Thesis Submitted for the Degree of Doctor of Philosophy University of Bath Department of Pharmacy and Pharmacology April 2013 University of Bath PHD Evaluating digital vascular perfusion and platelet dysfunction in Raynaud’s phenomenon and systemic sclerosis Pauling, John Award date: 2013 Awarding institution: University of Bath Link to publication Alternative formats If you require this document in an alternative format, please contact: [email protected] General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Download date: 07. Oct. 2021 Evaluating digital vascular perfusion and platelet dysfunction in Raynaud’s phenomenon and systemic sclerosis submitted by John D Pauling A thesis submitted for the degree of Doctor of Philosophy University of Bath Department of Pharmacy and Pharmacology April 2013 COPYRIGHT Attention is drawn to the fact that copyright of this thesis rests with the author. A copy of this thesis has been supplied on condition that anyone who consults it is understood to recognise that its copyright rests with the author and that they must not copy it or use material from it except as permitted by law or with the consent of the author. This thesis may be made available for consultation within the University Library and may be photocopied or lent to other libraries for the purposes of consultation. Abstract Raynaud’s phenomenon (RP) describes excessive vasoconstriction of the digital microvasculature in response to cold exposure and emotional stress. RP is typically the earliest clinical manifestation of systemic sclerosis (SSc); a complex multisystem disease of unknown aetiology characterized by vasculopathy, inflammation and fibrosis. Vasculopathy is considered an essential pre-requisite to tissue remodeling, characterized by excessive collagen synthesis and tissue fibrosis, which occurs in the skin and other organs of patients with SSc. There is mounting evidence associating platelets with important biological functions beyond primary haemostasis. Upon activation, platelets release a large array of mediators implicated in vasoconstriction, inflammation and fibrosis, which has led me to consider the contribution of platelets to the pathogenesis of both RP and SSc. The principal aim of this thesis is to explore the impact of targeted anti-thrombotic therapy on digital microvascular function, platelet activation, oxidative stress and eicosanoid biosynthesis in RP and SSc. It is not possible to examine the impact of anti-platelet therapy on microvascular function, without first identifying sensitive methods for assessing digital microvascular function in humans. I shall report the findings of work examining established (infrared thermography) and novel (laser speckle contrast imaging) methods for the objective assessment of digital microvascular function in RP and SSc. I shall critically appraise the application of these methods alongside subjective patient self-report assessment of digital vascular function. I shall examine associations between digital vascular function, platelet activation, oxidative stress and eicosanoid biosynthesis between primary RP and SSc. I shall also report the findings of an investigator-led early phase clinical trial of targeted anti-thrombotic medication in RP and SSc. The major findings of this study were highlighting the strengths and limitations of established and novel methods for objective microvascular assessment in RP and SSc, and the poor agreement that exists between objective and subjective methods for assessing RP severity. I have identified similarities and differences in platelet activation and eicosanoid biosynthesis in primary RP and SSc. I shall present evidence of apparent efficacy of asasantin retard therapy on subjective, but not objective, assessments of digital microvascular function; the relevance of which shall be discussed in detail. i Declaration of work undertaken by myself and in conjunction with others All of the work reported in this thesis was designed and undertaken by myself unless otherwise stated. Urinary samples for eicosanoid analysis were went to the Eicosanoid Core Laboratory at Vanderbilt University Medical Center in Nashville, TN, USA. This laboratory has pioneered the identification and characterization of novel eicosanoids including the isoprostanes. The Gas-Chromatography Mass-Spectrometry studies used to quantify urinary eicosanoids in this thesis were undertaken in collaboration with Professor Ginger L. Milne who is the Research Associate Professor of Medicine and Pharmacology within the Division of Clinical Pharmacology at Vanderbilt University. The ELISA kit for human soluble CD40 ligand required the use of an orbital microplate shaker. These assays were undertaken with the help of Jean-Phillippe Walhin within the Centre of Excellence for DisAbility Sport & Health at the University of Bath. I received support with the statistical analysis undertaken in Chapter 4 from Steve Raper within the Centre for Mathematical Biology at the University of Bath. I received support with the statistical analysis (reproducibility work) reported in Chapter 5 from Dr Anita McGrogan within the Department of Pharmacy and Pharmacology at the University of Bath. ii Acknowledgements First and foremost, I would like to thank Professor Neil McHugh for his encouragement, reassurance and support in undertaking this work. Without Neil’s support this work would not have been completed. I would like to thank Professor Steve Ward and Dr Malcolm Watson within the Department of Pharmacy and Pharmacology for their additional support and supervsion. I would like to extend that gratitude to all my colleagues at the Royal National Hospital for Rheumatic Diseases for their help in identifying potential patients and general support. I should like to extend particular thanks to Sue Brown for her support and Dr William Tillett who provided an ongoing source of advice, understanding, support and friendship. I wish to thank Dr Jacqueline Shipley, Dr Nigel Harris and Darren Hart within the clinical measurement department of the RNHRD for their help, support and kindness, particularly during times of need. I am hugely grateful to all my colleagues within the Bath Institute for Rheumatic Diseases for helping me undertake laboratory work. I would like to extend particular thanks to Juliet Dunphy for her support undertaking the ELISA studies. Thank you to Professors Valerie O’Donnell and Ginger Milne for their collaborative advice and support in undertaking the eicosanoid work. I am indebted to Mrs Anne Mawdsley and all the patrons of the Raynaud’s and Scleroderma Association, without whose support, this work could not have been undertaken. I owe a specific debt to the family of Mrs E Dando who bequeathed the funds necessary to undertake this work. I would like to thank all of the healthy volunteers and patients who generously gave up their time to make such a vital contribution to this research. Finally, I wish to thank all of my family, and in particular my wife Shaney, for their endless support and encouragement. I dedicate this thesis to them. iii Abbreviations AA Arachidonic acid ACA Anti-centromere autoantibody ADP Adenosine diphosphate ARA American Rheumatism Association AVA Arteriovenous anastamoses BHT 2,6-Di-tert-butyl-4-methylphenol -TG -thromboglobulin CTD connective tissue disease CTGF connective tissue growth factor COX cyclooxygenase CV coefficient of variation dcSSc diffuse cutaneous systemic sclerosis DDD distal dorsal difference DP digital pitting DU digital ulceration EC Endothelial cell ECM Extracellular matrix ELISA enzyme-linked immunosorbant assay EMS Electromagnetic spectrum EMR Electromagnetic radiation EMW Electromagnetic waves ERA Endothelin receptor antagonists FLPI full field laser perfusion imaging GI gastrointestinal Hep-2 Human Epithelial-2 cells 12-HETE 12-Hydroxyeicosatetraenoic acid (12-HETE) ILD Interstitial lung disease IR Infrared IRT infrared thermography Laser Light Amplification by Stimulated Emission of Radiation lcSSc limited cutaneous systemic sclerosis LDF laser Doppler flowmetry LDPI laser Doppler perfusion imaging LOX lipoxygenase iv LSCI laser speckle contrast imaging MCP metacarpophalangeal MCTD mixed connective tissue disease MTP metatarsophalangeal NC nailfold capillaroscopy OMERACT Outcome MEasures in Rheumatoid Arthritis Clinical Trials PAH pulmonary arterial hypertension PDGF platelet derived growth factor PF-4 platelet factor-4 PGE1 prostaglandin E1 PGI2 prostaglandin I2 PFP platelet free plasma PPP platelet poor plasma PRP platelet rich plasma RCS Raynaud’s condition score RCT Randomised controlled trial ROI Region of interest ROS reactive oxygen species RP Raynaud’s phenomenon rs Spearman’s Rho or Spearman’s rank correlation coefficient sCD40L soluble CD40 ligand SCTC Scleroderma Clinical Trials Consortium SLE systemic lupus erythematosis sP-selectin soluble P-selectin SRC scleroderma renal crisis SSc systemic sclerosis
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