Modulation of endothelial organelle size as an antithrombotic strategy.
J Thromb Haemost
; 18(12): 3296-3308, 2020 12.
Article
in English
| MEDLINE | ID: covidwho-1066732
ABSTRACT
BACKGROUND:
It is long established that von Willebrand factor (VWF) is central to hemostasis and thrombosis. Endothelial VWF is stored in cell-specific secretory granules, Weibel-Palade bodies (WPBs), organelles generated in a wide range of lengths (0.5-5.0 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 hypothesized 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 hours. RESULTS ANDCONCLUSIONS:
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-hemostatic activity of secreted VWF. This set of compounds acting at a very early stage of the hemostatic 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.Keywords
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Weibel-Palade Bodies
/
Organelle Size
/
Human Umbilical Vein Endothelial Cells
/
Fibrinolytic Agents
Type of study:
Prognostic study
Topics:
Traditional medicine
Limits:
Humans
Language:
English
Journal:
J Thromb Haemost
Journal subject:
Hematology
Year:
2020
Document Type:
Article
Affiliation country:
Jth.15084
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