Abstract Number: PB1468
Meeting: ISTH 2020 Congress
Background: MultiDrug Resistance-Protein 4 (MRP4) as part of the physiological mechanism of elimination of cyclic nucleotides in human platelets and its inhibition, when coupled with phosphodiesterase (PDE) inhibition, strongly impairs platelet aggregation.
Aims: To determine whether platelet nitric oxide (NO) resistance correlates with MRP4 expression and if cilostazol (an inhibitor of both MRP4 mediated transport and PDE) in vitro treatment reduces both NO resistance and ADP-induced platelet reactivity.
Methods: Platelet NO resistance was evaluated with ADP-induced aggregation in sodium nitroprusside (SNP)-treated platelets, obtained from aspirin treated patients.
The role of cilostazol on ADP-induced platelet aggregation was performed in high on aspirin residual platelet reactivity (HARPR) patients and compared to healthy volunteers (HV), and a control cohort (CTR).
Results: Aspirin treated patients were divided into quartiles for MRP4 expression. Aspirinated patients belonging to the 4th quartiles ( > 0.015 ΔΔCt ), with high levels of MRP4, had reduced SNP inhibition when platelets were stimulated with ADP compared to those belonging to the 1st-3rd quartiles ( from 0.005 ΔΔCt to 0.014 ΔΔCt ), with low levels of MRP4, (32±18 % vs 22±15 %; respectively; p>0.05). Cilostazol treatment enhanced NO inhibition by approximately 60%.
MRP4 inhibition by cilostazol significantly reduced ADP-induced platelet aggregation in the HARPR (36±25% vs 74±15%; p>0.0001), in HV (15±11% vs 55±15%) and CTR (17±16% vs 62±17% ) populations.
Conclusions: MRP4 inhibition by cilostazol can mitigate the hyper-reactive platelet phenotype of HARPR patients by reducing residual ADP-induced platelet aggregation and increasing NO-dependent endothelial antiplatelet effects. Aspirin plus cilostazol may represent a novel antithrombotic strategy to reduce cardiovascular events, particularly among patients with MRP4 platelet overexpression.
To cite this abstract in AMA style:Guarino ML, Massimi I, Alemanno L, Conti L, Angiolillo DJ, Pulcinelli FM. Role of Multidrug Resistance Protein 4 on Both Platelet Nitric Oxide Resistance and ADP Induced Platelet Aggregation [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/role-of-multidrug-resistance-protein-4-on-both-platelet-nitric-oxide-resistance-and-adp-induced-platelet-aggregation/. Accessed January 27, 2022.
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