Physiological platelet aggregation assay to mitigate drug-induced thrombocytopenia using a microphysiological system

Area of Science:

• Biomedical Engineering
• Pharmacology
• Hematology

Background:

• Predicting drug-induced thrombocytopenia is crucial for drug discovery.
• Existing methods often fail to fully replicate in-vivo platelet behavior.
• Microphysiological systems (MPS) offer a promising platform for studying complex biological processes.

Purpose of the Study:

• To develop and validate a novel MPS-based assay for predicting thrombocytopenia.
• To investigate the role of shear stress in platelet aggregation and adhesion.
• To assess the utility of the assay in drug discovery for identifying compounds that may cause thrombocytopenia.

Main Methods:

• An MPS was utilized to simulate in-vivo conditions, including shear stress and interactions with vascular endothelial cells.
• Platelet aggregation was induced by soluble collagen and an oligonucleotide (ODN2395).
• The effect of SYK inhibition on platelet aggregation was evaluated.

Main Results:

• The MPS assay detected shear-dependent platelet aggregation induced by soluble collagen.
• Platelet aggregates adhered to vascular endothelial cells in a concentration-dependent manner under flow.
• The assay demonstrated differential responses in platelet-rich plasma versus whole blood.
• ODN2395 also induced platelet aggregation and adhesion, with effects mitigated by SYK inhibition.

Conclusions:

• The developed MPS assay partially recapitulates in-vivo platelet aggregation mechanisms.
• This system can serve as a valuable tool for early detection of thrombocytopenia risk during drug development.
• The findings highlight the importance of shear stress in platelet activation and adhesion relevant to thrombotic events.