Neave, Emma Lucy Annabel;
(2025)
Thrombotic microangiopathies in
pregnancy: presentations, pathogenesis,
challenges.
Doctoral thesis (M.D(Res)), UCL (University College London).
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Abstract
Thrombotic thrombocytopenic purpura (TTP) and complement-mediated haemolytic uraemic syndrome (CM-HUS) are rare but serious thrombotic microangiopathies which can occur in pregnancy. Distinguishing between pregnancy-associated TTP and CM-HUS, and the commoner gestational hypertensive disorders preeclampsia and HELLP syndrome can be challenging, because of clinical overlap and lack of readily available diagnostic tests. This thesis aims to (i) examine clinical presentations of pregnancyassociated TTP and CM-HUS, (ii) investigate shared pathogenesis between TTP, CM-HUS and preeclampsia, and (iii) consider how to achieve accurate diagnosis quickly. To address these aims, firstly a detailed literature review was performed, and secondly a single centre observational study was designed and executed (with regional ethics approval). A ‘complicated pregnancies’ cohort, with features possibly consistent with CM-HUS or TTP, were recruited, in addition to normal pregnant controls. Clinical data were collected and blood samples obtained on a single occasion. ADAMTS13 activity, VWF activity and antigen, complement markers, and angiogenic markers sFlt-1 and PlGF were measured. A novel assay to measure ex-vivo complement deposition on cultured HMEC-1 cells by flow cytometry was devised and study samples assessed. Review of clinical and laboratory parameters in the complicated pregnancies cohort (n=108) did not reveal any ‘occult’ cases of TTP or CM-HUS, suggesting that these remain rare causes of obstetric pathology. Literature review and two described locally-managed cases illustrate significant potential for misdiagnosis however. Criteria for considering TTP or CM-HUS in pregnancy to improve diagnostic accuracy were proposed. Case control analysis of preeclampsia (n= 34) versus normal pregnant controls (n=48) revealed marked elevations in VWF, VWF antigen/ADAMST13 ratio, and terminal complement activation in preeclampsia, with reduced VWF activity/antigen ratio. Correlations with thrombocytopenia, fetal growth restriction and sFlt-1/PlGF were observed. These findings build on an existing evidence for a role for complement, VWF and ADAMTS13 in preeclampsia pathogenesis, with potential diagnostic/therapeutic utility.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | M.D(Res) |
| Title: | Thrombotic microangiopathies in pregnancy: presentations, pathogenesis, challenges |
| 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/10205890 |
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