Vendramin, Chiara;
(2025)
Pathophysiology of Thrombotic Thrombocytopenic Purpura: Interplay Between ADAMTS13 and VWF.
Doctoral thesis (Ph.D), UCL (University College London).
Preview |
Text
Vendramin_10204794_thesis.pdf Download (3MB) | Preview |
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.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | Pathophysiology of Thrombotic Thrombocytopenic Purpura: Interplay Between ADAMTS13 and VWF |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | 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. |
| UCL classification: | UCL 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 Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10204794 |
Archive Staff Only
 |
View Item |
