Physiological platelet aggregation assay to mitigate drug-induced thrombocytopenia using a microphysiological system.
Platelet Aggregation
/ drug effects
Humans
Thrombocytopenia
/ chemically induced
Blood Platelets
/ drug effects
Collagen
/ metabolism
Endothelial Cells
/ drug effects
Platelet Adhesiveness
/ drug effects
Syk Kinase
/ metabolism
Platelet-Rich Plasma
/ metabolism
Human Umbilical Vein Endothelial Cells
/ drug effects
Microphysiological Systems
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
19 06 2024
19 06 2024
Historique:
received:
08
03
2024
accepted:
05
06
2024
medline:
20
6
2024
pubmed:
20
6
2024
entrez:
19
6
2024
Statut:
epublish
Résumé
Developing a reliable method to predict thrombocytopenia is imperative in drug discovery. Here, we establish an assay using a microphysiological system (MPS) to recapitulate the in-vivo mechanisms of platelet aggregation and adhesion. This assay highlights the role of shear stress on platelet aggregation and their interactions with vascular endothelial cells. Platelet aggregation induced by soluble collagen was detected under agitated, but not static, conditions using a plate shaker and gravity-driven flow using MPS. Notably, aggregates adhered on vascular endothelial cells under gravity-driven flow in the MPS, and this incident increased in a concentration-dependent manner. Upon comparing the soluble collagen-induced aggregation activity in platelet-rich plasma (PRP) and whole blood, remarkable platelet aggregate formation was observed at concentrations of 30 µg/mL and 3 µg/mL in PRP and whole blood, respectively. Moreover, ODN2395, an oligonucleotide, induced platelet aggregation and adhesion to vascular endothelial cells. SYK inhibition, which mediated thrombogenic activity via glycoprotein VI on platelets, ameliorated platelet aggregation in the system, demonstrating that the mechanism of platelet aggregation was induced by soluble collagen and oligonucleotide. Our evaluation system partially recapitulated the aggregation mechanisms in blood vessels and can contribute to the discovery of safe drugs to mitigate the risk of thrombocytopenia.
Identifiants
pubmed: 38898080
doi: 10.1038/s41598-024-64063-y
pii: 10.1038/s41598-024-64063-y
doi:
Substances chimiques
Collagen
9007-34-5
Syk Kinase
EC 2.7.10.2
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
14109Informations de copyright
© 2024. The Author(s).
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