Author + information
- S1936879815020725-3d48134338ce09dc6644242144467b1aJayaprakash Kotha1,
- S1936879815020725-4c671e6edd090466432a2161bff5444dMason L.A. Dixon1,
- S1936879815020725-9cacd60020ae5afd848a475b2735b47aJay M. Jalenak1,
- S1936879815020725-fd3a3eed68724b9e6a63d50cfe8070e8Paige S. Dunphy1,
- S1936879815020725-6abac5f3da1a16fe08692123b3936259James E. Tcheng2,
- S1936879815020725-c2f6299f1968a0871f5c628eea60018fJorge F. Saucedo3 and
- S1936879815020725-4435460377149ae1b50f68043b298b5fLisa K. Jennings4
Platelet-mediated thrombus formation is influenced by local hemodynamic events and numerous spatial and temporal events that rely on mediators of platelet reactivity. Two classes of anti-platelet agents, the P2Y12 and the GPIIb-IIIa antagonists, play a significant role in reducing platelet activation and aggregation. The purpose of this study was to evaluate how each class of platelet antagonists contribute to reducing platelet reactivity and thrombus burden, particularly as it pertains to the setting of percutaneous coronary intervention (PCI).
In vitro platelet aggregometry studies were performed to assess the capability of a parenteral P2Y12 antagonist, AR-C69931MX (cangrelor, Kengreal®) versus a GPIIb-IIIa antagonist, tirofiban (Aggrastat®), to inhibit platelet aggregation as well as disengage pre-formed aggregates (n=5). Primary platelet agonists collagen (2 μg/mL) and TRAP (25 μM) and secondary agonist ADP (20 μM) were used to evaluate platelet aggregation inhibition. Antagonist concentrations reflect levels similar to that achieved when administered therapeutically. Collagen (2 μg/mL) was used as agonist for evaluating the effects of these agents in disengaging pre-formed platelet aggregates. Platelet aggregates after antagonist treatment were examined by microscopy to evaluate aggregate size.
We demonstrated that tirofiban inhibited platelet aggregation >80% to platelet agonists ADP, collagen, and TRAP, whereas cangrelor inhibited ADP-induced platelet aggregation by >80% but to a lesser degree with the other agonists (∼40%). Cangrelor appeared to disrupt the loosely-associated discoid platelets that made up the outer portion of a developing aggregate, but not the stable core. Tirofiban had a greater effect on aggregate destabilization. The total number of larger aggregates upon antagonist treatment were 3.6-fold lower in tirofiban vs. cangrelor treated samples.
Our data support the administration of a parenteral P2Y12 antagonist to curb thrombus formation in vivo primarily by inhibiting platelet activation by secreted ADP. As tirofiban has a wide-ranging effect on platelet aggregate formation and aggregate size, these data suggest that GPIIb-IIIa plays a dynamic, continuous role in the formation and stability of platelet-rich thrombi. Utilization of a GPIIb-IIIa antagonist in the acute setting may provide added protection to not only limit platelet thrombus propagation but also to reduce thrombus burden.