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Elucidating the Mechanisms of Thromboembolism and Structural Arterial Disease in Children with Inflammatory Bowel Disease

Bonner, JOE; (2017) Elucidating the Mechanisms of Thromboembolism and Structural Arterial Disease in Children with Inflammatory Bowel Disease. Doctoral thesis , UCL (University College London). Green open access

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Abstract

Inflammatory bowel disease (IBD) is a group of life-long relapsing and remitting inflammations of the gastrointestinal (GI) tract, with complex aetiology and no known cure. Incidence world-wide is increasing, especially among paediatric-onset cases. In addition to known primary morbidities, recent epidemiological evidence suggests an increased life-time risk of cardiovascular events in IBD patients, however the mechanism for this is unknown. This thesis attempts to investigate the hypothesis that chronic inflammation in IBD promotes vascular dysfunction, which leads to increased cardiovascular risk, and is detectable in paediatric IBD. Mechanisms of endothelial microparticle (MP) formation were investigated, and it was found cytokines associated with IBD stimulate MP release in a synergistic manner. Additionally, markers of endothelial injury, hypercoagulability and circulating microparticles (MPs) were assessed in paediatric IBD patients and compared to healthy controls. Circulating endothelial cells (CECs) were raised in paediatric IBD, with even inactive patients having significantly higher CECs. This was corroborated by increased circulating levels of MPs, particularly those derived from neutrophils, the endothelium and those expressing tissue factor (TF). Paradoxically, plasma from patients showed delayed thrombin generation, as well as MP-mediated thrombin generation, measured by an in vitro assay. Patients also showed increased plasma activity of TF and derangement of the TF/TFPI axis. Patients were assessed for structural arterial disease by assessment of carotid-femoral pulse wave velocity (PWV), but showed no difference to healthy controls. Finally, assessment of plasma cytokines and vascular injury markers by multi-plex electrochemiluminescent assay showed an increase in multiple pro-inflammatory cytokines in paediatric IBD. In summary, these novel findings suggest an increase in vascular injury in paediatric IBD along with promotion of a pro-thrombotic state. These findings provide a unique insight into the cardiovascular complications of IBD patients.

Type: Thesis (Doctoral)
Title: Elucidating the Mechanisms of Thromboembolism and Structural Arterial Disease in Children with Inflammatory Bowel Disease
Event: University College London
Open access status: An open access version is available from UCL Discovery
Language: English
Keywords: Inflammatory Bowel Disease, children, paediatric, thromboembolism, microparticle, endothelium, inflammation
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > UCL GOS Institute of Child Health > ICH Infect, Imm, Infla. and Physio Med
URI: http://discovery.ucl.ac.uk/id/eprint/1536130
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