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ADP-induced Platelet-associated Tissue Factor Expression: Unique Involvement of the P2Y12 Receptor and Modulation by Clopidogrel Treatment

M. Brambilla1, P. Canzano1, G. Rovati2, N. Cosentino1, A. Becchetti1, J. Campodonico1, M. Cattaneo3, D. Trabattoni1, C. Pinna2, E. Tremoli1, M. Camera2

1Centro Cardiologico Monzino IRCCS, Milan, Italy, 2Dept of Pharmaceutical Sciences, Università degli Studi di Milano, Milan, Italy, 3Unità di Medicina II, ASST Santi Paolo e Carlo, Dept of Scienze della Salute, Università degli Studi di Milano, Milan, Italy

Abstract Number: LPB0008

Meeting: ISTH 2021 Congress

Theme: Coagulation and Natural Anticoagulants » Tissue Factor Pathway

Background: Clopidogrel treatment is effective, besides inhibiting platelet aggregation, also in impairing platelet procoagulant activity which is supported by both phosphatidylserine and Tissue Factor (TF) exposure. Platelet-ADP stimulation results in TF expression. However, the role of the 2 ADP purinergic receptors in platelet-TF modulation is still unknown.

Aims: To assess:
1) whether P2Y1 and P2Y12 receptors equally contribute to ADP-induced TF expression;
2) whether clopidogrel treatment modulate TF exposure;
3) TF intracellular localization through a pharmacological approach.

Methods: Platelets from healthy subjects were treated with the P2Y1 antagonist MRS-2250 or the P2Y12 antagonist AR-C69931MX (1pM–100nM). Expression of platelet-TF and P-selectin, as marker of alpha-granule secretion, were analyzed by flow cytometry upon ADP stimulation (10µM) and pA2 of the two P2Y-antagonists to inhibit their expression was calculated. The relationship between TF expression and the clopidogrel antiplatelet effect, assessed by the VASP-assay, was investigated in 106 coronary artery disease (CAD) patients.

Results: P2Y12-antagonist, but not P2Y1-antagonist, concentration-dependently prevented ADP-induced TF exposure. TF-activity, measured by thrombin generation assay, behaved similarly, being completely inhibited at 100nM AR-C69931MX. Platelet-TF expression in CAD patients with poor clopidogrel response (VASP>50%) was significantly higher compared to good-responders. Conversely, the extent of P-selectin inhibition was comparable between the two groups indicating that clopidogrel concentration able to inhibit P-selectin are less effective in reducing TF exposure. Indeed, AR-C69931MX pA2 to inhibit TF is 150-times lower than that of P-selectin. Inhibition of open canalicular system (OCS) by cytochalasin D impaired ADP-induced TF expression but it did not affect P-selectin, suggesting a different intracellular localization of the two proteins.

Conclusions: Data indicate that 1) P2Y12 only regulates surface expression of OCS-stored TF; 2) the therapeutic benefits of clopidogrel may also rely on inhibition of platelet-TF expression, although at higher concentrations than those required to regulate alpha-granule secretion.

To cite this abstract in AMA style:

Brambilla M, Canzano P, Rovati G, Cosentino N, Becchetti A, Campodonico J, Cattaneo M, Trabattoni D, Pinna C, Tremoli E, Camera M. ADP-induced Platelet-associated Tissue Factor Expression: Unique Involvement of the P2Y12 Receptor and Modulation by Clopidogrel Treatment [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/adp-induced-platelet-associated-tissue-factor-expression-unique-involvement-of-the-p2y12-receptor-and-modulation-by-clopidogrel-treatment/. Accessed May 19, 2022.

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