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.
|Date of Award||1 Apr 2013|
|Supervisor||Neil McHugh (Supervisor)|