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Modulation of endothelial organelle size as an antithrombotic strategy
Author(s) -
Ferraro Francesco,
Patella Francesca,
Costa Joana R.,
Ketteler Robin,
KristonVizi Janos,
Cutler Daniel F.
Publication year - 2020
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.15084
Subject(s) - antithrombotic , modulation (music) , organelle , microbiology and biotechnology , chemistry , medicine , biology , cardiology , physics , acoustics
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 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‐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.