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Thrombus remodelling by reversible and irreversible P2Y12 inhibitors
Kjersti Tunströmer1, Lars Faxälv1, Pia Larsson1,2
1Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.
Platelets
|January 11, 2023
Summary
Irreversible P2Y12 inhibitors like prasugrel active metabolite (PAM) offer gradual thrombus inhibition, while reversible inhibitors like ticagrelor provide rapid blockade. Even with a small fraction of uninhibited platelets, PAM maintains its antithrombotic effect.
Area of Science:
- Cardiovascular Pharmacology
- Hematology
- Thrombosis Research
Background:
- Platelet P2Y12 receptor inhibition is crucial for preventing atherothrombotic events in acute coronary syndrome (ACS).
- Irreversible P2Y12 inhibitors (e.g., clopidogrel, prasugrel) form active metabolites with short half-lives, potentially leading to ADP-responsive platelets between doses.
- Reversible P2Y12 inhibitors (e.g., ticagrelor, cangrelor) offer complete platelet inhibition.
Purpose of the Study:
- To compare the impact of irreversible (prasugrel active metabolite, PAM) and reversible (ticagrelor) P2Y12 inhibition on thrombus formation.
- To quantify the role of inhibited versus uninhibited platelets in thrombus growth and consolidation.
- To analyze the kinetics of platelet inhibition and recruitment under different pharmacological strategies.
Main Methods:
- Utilized an ex vivo flow chamber model to simulate thrombus formation.
- Employed a customized image analysis pipeline for automated, large-scale identification and tracking of single platelets within thrombi.
- Conducted comparative experiments using prasugrel active metabolite (PAM) and ticagrelor.
Main Results:
- Prasugrel active metabolite (PAM) demonstrated a more gradual inhibition of thrombus platelet recruitment compared to ticagrelor, with a slower onset.
- A small fraction (<10%) of uninhibited platelets did not significantly compromise the antithrombotic efficacy of PAM.
- Observed a progressive enrichment of inhibited platelets in the thrombus periphery, suggesting selective recruitment to the outer shell.
Conclusions:
- Pharmacological differences between irreversible and reversible P2Y12 inhibitors significantly impact thrombus formation dynamics.
- Reversible P2Y12 inhibition provides a rapid and complete blockade, while irreversible agents offer sustained inhibition with gradual onset.
- The study highlights the importance of considering platelet turnover and inhibitor pharmacokinetics in managing atherothrombotic risk.
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