Eleftheriou, D; (2012) Endothelial injury and repair in childhood arterial ischaemic stroke. Doctoral thesis , UCL (University College London).

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Abstract

Abnormalities of the cervical or intracranial circulation, termed arteriopathies are the leading mechanism of both cause and recurrence of childhood arterial ischaemic stroke (AIS). Approximately 20% of children with AIS will have stroke recurrence but there are currently no robust biomarkers to identify this high risk group, and hence identification of patients who may be amenable to secondary preventative strategies has not been possible. This thesis attempts to address this unmet need by studying novel biomarkers to distinguish patients at risk of stroke recurrence. Indices of endothelial injury, repair and hypercoagulability were compared between patients with recurrent clinical disease course and children with a single event. Circulating endothelial cells (CECs) were higher in children with recurrent AIS, compared to those with no recurrence and controls. Further evidence of endothelial injury and cellular activation was derived by examining circulating microparticles (MP) profiles. Plasma from patients with AIS recurrence contained increased numbers of endothelial, platelet and neutrophil derived MP compared to those with no recurrence. These MPs were highly prothrombotic due to phosphatidylserine exposure providing a platform for the assembly and activation of coagulation factors; and also expression of tissue factor on some MP. An efficient in vitro assay to assess MP-related hypercoagulability by quantifying MP-mediated thrombin generation was established. Children with recurrent AIS were shown to have an enhanced MP-mediated thrombin generation. Lastly, a disturbance in endothelial progenitor cells (EPCs) in children with AIS recurrence was observed suggesting that there could be impairment of endothelial repair in these patients. In conclusion, despite the wide spectrum of clinical and radiological presentation of childhood AIS, the studies undertaken in this thesis suggest that there is an unfavourable imbalance between endothelial injury and repair, and excess hypecoagulability in children with recurrent AIS. These novel observations provide unique insights into the pathophysiology of paediatric AIS.

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