eprintid: 10204794
rev_number: 13
eprint_status: archive
userid: 699
dir: disk0/10/20/47/94
datestamp: 2025-03-13 10:16:28
lastmod: 2025-03-13 10:16:28
status_changed: 2025-03-13 10:16:28
type: thesis
metadata_visibility: show
sword_depositor: 699
creators_name: Vendramin, Chiara
title: Pathophysiology of Thrombotic Thrombocytopenic Purpura: Interplay Between ADAMTS13 and VWF
ispublished: unpub
divisions: UCL
divisions: B02
divisions: C10
divisions: D19
note: Copyright © The Author 2025. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
abstract: Thrombotic Thrombocytopenic Purpura (TTP) is defined clinically by microangiopathic haemolytic anemia (MAHA) with thrombocytopenia. Acute TTP is characterised by widespread multi-organ thromboses. In TTP, deficiency of ADAMTS13 means the abnormal existence of circulating ultra-large VWF multimers. A variety of assays are available for ADAMTS13 quantification, but these all operate under static conditions. In normal physiology, the presence of shear flow is crucial to the process. 
A panel of assays is recommended to characterise the pathophysiology of TTP; the anti-ADAMTS13 IgG ELISA may be used as first line assay. In this thesis, firstly the inhibitory anti-ADAMTS13 antibody assay was developed using a Bethesda based assay and an in-house developed assay to detect human anti-chimeric antibodies to rituximab was established to investigate immune-mediated TTP patients with rituximab-induced serum sickness. 
Secondly, immune-mediated TTP cases were studied to understand the effect of reduced ADAMTS13 levels on thrombus formation and to assess impact of elective therapy, but also treatment response in acute iTTP patients at presentation with a flow-based assay with HUVECs. Both the shear flow assays showed increased microvascular thrombosis in iTTP patients with low ADAMTS13 activity levels. 
Lastly, the prothrombotic state in patients with TTP was assessed using a dynamic flow-based assay with anti-VWF A3 antibody, and the impact of VWF genetics in congenital TTP and the role of potential mutations in the regions encoding VWF functional domains were explored. The flow-based assay with anti-VWF A3 antibody might represent a new tool to monitor TTP patients at follow up and at high risk of relapse. Also, the incidence of VWF polymorphisms in patients affected by cTTP was higher than expected and it seemed that these variants might affect the prothrombotic risk of cTTP patients. 
Overall, this work has shown that all these assays together may provide advance understanding into the pathophysiology of TTP.
date: 2025-02-28
date_type: published
oa_status: green
full_text_type: other
thesis_class: doctoral_open
thesis_award: Ph.D
language: eng
primo: open
primo_central: open_green
verified: verified_manual
elements_id: 2360552
lyricists_name: Vendramin, Chiara
lyricists_id: CVEND56
actors_name: Vendramin, Chiara
actors_id: CVEND56
actors_role: owner
full_text_status: public
pages: 220
institution: UCL (University College London)
department: UCL Cancer Institute
thesis_type: Doctoral
citation:        Vendramin, Chiara;      (2025)    Pathophysiology of Thrombotic Thrombocytopenic Purpura: Interplay Between ADAMTS13 and VWF.                   Doctoral thesis  (Ph.D), UCL (University College London).     Green open access   
 
document_url: https://discovery.ucl.ac.uk/id/eprint/10204794/1/Vendramin_10204794_thesis.pdf