UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Modulation of endothelial organelle size as an antithrombotic strategy

Ferraro, F; Patella, F; Costa, JR; Ketteler, R; Kriston-Vizi, J; Cutler, DF; (2020) Modulation of endothelial organelle size as an antithrombotic strategy. Journal of Thrombosis and Haemostasis 10.1111/jth.15084. (In press). Green open access

[img]
Preview
Text
jth.15084.pdf - Accepted version

Download (15MB) | Preview

Abstract

BACKGROUND: It is long-established that Von Willebrand Factor (VWF) is central to haemostasis and thrombosis. Endothelial VWF is stored in cell-specific secretory granules, Weibel-Palade bodies (WPBs), organelles generated in a wide range of lengths (0.5 to 5.0 μm). WPB size responds to physiological cues and pharmacological treatment, and VWF secretion from shortened WPBs dramatically reduces platelet and plasma VWF adhesion to an endothelial surface. OBJECTIVE: We hypothesised that WPB-shortening represented a novel target for antithrombotic therapy. Our objective was to determine whether compounds exhibiting this activity do exist. METHODS: Using a microscopy approach coupled to automated image analysis, we measured the size of WPB bodies in primary human endothelial cells treated with licensed compounds for 24 h. RESULTS AND CONCLUSIONS: A novel approach to identification of antithrombotic compounds generated a significant number of candidates with the ability to shorten WPBs. In vitro assays of two selected compounds confirm that they inhibit the pro-haemostatic activity of secreted VWF. This set of compounds acting at a very early stage of the haemostatic process could well prove to be a useful adjunct to current antithrombotic therapeutics. Further, in the current SARS-CoV-2 pandemic, with a considerable fraction of critically ill COVID-19 patients affected by hypercoagulability, these WPB size-reducing drugs might also provide welcome therapeutic leads for frontline clinicians and researchers.

Type: Article
Title: Modulation of endothelial organelle size as an antithrombotic strategy
Location: England
Open access status: An open access version is available from UCL Discovery
DOI: 10.1111/jth.15084
Publisher version: http://dx.doi.org/10.1111/jth.15084
Language: English
Additional information: This article is protected by copyright. All rights reserved. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Keywords: COVID-19, Drug repurposing, Thrombosis, Von Willebrand Factor, Weibel-Palade bodies
UCL classification: UCL
UCL > Provost and Vice Provost Offices
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 Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10110044
Downloads since deposit
2Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item