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Title: The VWF-ADAMTS13 axis and related haematological aspects of acute ischaemic brain injury
Author: Taylor, Alice
Awarding Body: UCL (University College London)
Current Institution: University College London (University of London)
Date of Award: 2020
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The main focus of this thesis is examination of the role of the VWF-ADAMTS13 axis in acute ischaemic brain injury. Acute ischaemic stroke and transient ischaemic attack (TIA) are associated with raised von Willebrand factor (VWF) and decreased ADAMTS13 activity but association with outcome has not been studied. We prospectively explored VWF antigen (VWF:Ag) and activity (VWF:Act) levels and ADAMTS13 in 308 adults with acute ischaemic stroke (n=103), TIA (n=80), haemorrhagic stroke (n=16) or controls (n=109), with serial samples taken from presentation until after 6 weeks (median follow up 188 days). Severity was assessed at presentation and at follow up using the National Institutes of Health Stroke Score (NIHSS) and modified Rankin scale (mRS). We demonstrate resolution of VWF:Ag-ADAMTS13Ac ratio in convalescence in ischaemic stroke (IS, 2.42 to 1.66; p=0.008; TIA, 1.89 to 0.65; p=<0.0001). A raised VWFAg/ ADAMTS13 ratio at presentation of acute IS or TIA was associated with increased mortality, including when adjusted for age. Thrombolysis resulted in prompt reduction of the VWF:Ag- ADAMTS13Ac ratio. Therapeutic targets to VWF and ADAMTS13 activity merit further investigation. In conjunction with this, we studied the pharmacokinetics of ADAMTS13 activity in plasma of 6 patients with congenital thrombotic thrombocytopenic purpura (TTP) receiving regular infusions. There was variability in ADAMTS13 half-life, suggesting analysis of inter-individual clearance is necessary for future optimisation of treatment, particularly in the era of recombinant ADAMTS13. Haematological laboratory investigations in patients under 60 years of age presenting to the hyperacute stroke unit (HASU) were retrospectively reviewed, examining 609 stroke and TIA patients over a 31-month period. We examined the haematocrit and platelet count, and potential for primary haematological cause such as myeloproliferative disease (MPD) or TTP. One quarter of the cohort merited further follow up. Thrombophilia testing has now altered so that triple antiphospholipid antibody testing is performed rather than heritable risk factors for venous thrombosis. The work overlaps between clinical haematology, stroke medicine and laboratory haemostasis; with promise for future investigation and therapy in diseases with pathogenesis common to all.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available