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Cited by 19Platelet Disorders and TreatmentsBlood Coagulation and Thrombosis MechanismsBlood properties and coagulation

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Modulation of endothelial organelle size as an antithrombotic strategy

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Ferraro, Francesco, Patella, Francesca, Costa, Joana R., Ketteler, Robin, Kriston‐Vizi, Janos, Cutler, Daniel F.·2020·Journal of Thrombosis and Haemostasis
DOI 10.1111/jth.15084PMC PMC8436738

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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.

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Metadata

Authors
Ferraro, F., Patella, F., Costa, J. R., Ketteler, R., Kriston‐Vizi, J., & Cutler, D. F.
Affiliations
MRC Laboratory for Molecular Cell Biology (GB)
Corresponding author
  • Ferraro, Francesco
  • Cutler, Daniel F.
ORCID
Venue
Journal of Thrombosis and Haemostasis
Publisher
Elsevier BV
Published
2020-12
Volume
18
Issue
12
Pages
3296-3308
ISSN
1538-7836 (ISSN-L)
DOI
10.1111/jth.15084
PMC
PMC8436738
OpenAlex
W3081683736
Cited by
19
References
2
Citations by year
2024: 6 · 2023: 4 · 2022: 2 · 2021: 5 · 2020: 2
FWCI
2.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Thrombosis and Haemostasis (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
Medical Research Council (MC_U12266B, MC_UU_12018/2)
Topics
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
  • Health Sciences › Medicine › Hematology › Blood properties and coagulation
Keywords
von Willebrand factor, Weibel-Palade bodies, antithrombotic therapy, VWF secretion, platelet adhesion, hemostasis, thrombosis, hypercoagulability, COVID-19 pandemic, SARS-CoV-2, drug screening
MeSH terms
Cells, Cultured, Drug Evaluation, Preclinical, Fibrinolytic Agents, Hemostasis, Humans, von Willebrand Factor, Weibel-Palade Bodies, Organelle Size, Drug Repositioning, Human Umbilical Vein Endothelial Cells

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