A platelet target for venous thrombosis? P2Y1 deletion or antagonism protects mice from vena cava thrombosis.

Journal of Thrombosis and Thrombolysis
J Eileen BirdWilliam A Schumacher

Abstract

A role for platelets in the pathogenesis of venous thrombosis was suggested by clinical and preclinical studies. However, examination of the platelet receptor, P2Y1, in this area has been limited. The goal of the current study was to examine effects of P2Y1 deletion, or selective antagonism with MRS2500, in oxidative venous thrombosis in mice. The P2Y12 antagonist, clopidogrel, was included as a reference agent. Anesthetized C57BL/6 or genetically modified mice underwent 3.5 or 5 % FeCl(3)-induced vena cava thrombosis. Pharmacokinetic properties of MRS2500 were defined for dose selection. Platelet aggregation and renal or tail bleeding times (BT) were measured to put antithrombotic effects into perspective. P2Y1 deletion significantly reduced (p < 0.001) venous thrombus weight by 74 % in 3.5 % FeCl(3) injury compared to P2Y1(+/+) littermates. MRS2500 (2 mg/kg, i.v.) significantly decreased (p < 0.001) thrombus weight 64 % in C57BL/6 mice. In the more severe 5 % FeCl(3)-induced injury model, thrombus weight significantly (p < 0.001) decreased 68 % in P2Y1(-/-) mice versus P2Y1(+/+) mice, and MRS2500 (2 mg/kg) was also beneficial (54 % decrease, p < 0.01). Renal BT doubled in P2Y1(-/-) versus P2Y1(+/+) mice, and increased threefo...Continue Reading

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Citations

Dec 15, 2015·Journal of Thrombosis and Thrombolysis·Pancras C WongEarl J Crain
Nov 26, 2013·Bioorganic & Medicinal Chemistry Letters·Réjean RuelPatrick Y S Lam
May 15, 2013·Bioorganic & Medicinal Chemistry Letters·Réjean RuelPatrick Y S Lam
Jun 8, 2013·Bioorganic & Medicinal Chemistry Letters·Zulan PiPatrick Y S Lam
Dec 3, 2014·The Journal of Allergy and Clinical Immunology·Richard T AmisonSimon C Pitchford
Apr 23, 2013·Bioorganic & Medicinal Chemistry Letters·Tammy C WangPatrick Y S Lam
Jun 17, 2014·Journal of Medicinal Chemistry·Wu YangPatrick Y S Lam
Jun 22, 2018·Pharmacological Reviews·Jennifer YeungMichael Holinstat
Aug 18, 2020·ChemMedChem·Veronica Salmaso, Kenneth A Jacobson

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