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The Function and Regulation of Platelet P2Y12 Receptor

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Abstract

In addition to the key role in hemostasis and thrombosis, platelets have also been wildly acknowledged as immune regulatory cells and involving in the pathogenesis of inflammation-related diseases. Since purine receptor P2Y12 plays a crucial role in platelet activation, P2Y12 antagonists such as clopidogrel, prasugrel, and ticagrelor have been widely used in cardiovascular diseases worldwide in recent decades due to their potent antiplatelet and antithrombotic effects. Meanwhile, the role of P2Y12 in inflammatory diseases has also been extensively studied. Relatively, there are few studies on the regulation of P2Y12. This review first summarizes the various roles of P2Y12 in the process of platelet activation, as well as downstream effects and signaling pathways; then introduces the effects of P2Y12 in inflammatory diseases such as sepsis, atherosclerosis, cancer, autoimmune diseases, and asthma; and finally reviews the current researches on P2Y12 regulation.

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References

  1. Wong C, et al. Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance. Nat Immunol. 2013;14(8):785–92.

    Article  CAS  Google Scholar 

  2. Yeung J, Li W, Holinstat M. Platelet signaling and disease: targeted therapy for thrombosis and other related diseases. Pharmacol Rev. 2018;70(3):526–48.

    Article  CAS  Google Scholar 

  3. Mezger M, et al. Platelets and immune responses during thromboinflammation. Front Immunol. 2019;10:1731.

    Article  CAS  Google Scholar 

  4. Eriksson O, et al. The human platelet as an innate immune cell: interactions between activated platelets and the complement system. Front Immunol. 2019;10:1590.

    Article  CAS  Google Scholar 

  5. Cattaneo M. P2Y12 receptors: structure and function. J Thromb Haemost. 2015;13:S10–6.

    Article  CAS  Google Scholar 

  6. Hollopeter G, et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature. 2001;409(6817):202–7.

    Article  CAS  Google Scholar 

  7. Zhang FL, et al. ADP is the cognate ligand for the orphan G protein-coupled receptor SP1999. J Biol Chem. 2001;276(11):8608–15.

    Article  CAS  Google Scholar 

  8. Ohlmann P, et al. The platelet P2Y(12) receptor under normal and pathological conditions. Assessment with the radiolabeled selective antagonist [(3)H]PSB-0413. Purinergic Signal. 2013;9(1):59–66.

    Article  CAS  Google Scholar 

  9. Haynes SE, et al. The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci. 2006;9(12):1512–9.

    Article  CAS  Google Scholar 

  10. Wihlborg AK, et al. ADP receptor P2Y12 is expressed in vascular smooth muscle cells and stimulates contraction in human blood vessels. Arterioscler Thromb Vasc Biol. 2004;24(10):1810–5.

    Article  CAS  Google Scholar 

  11. Hogberg C, et al. The reversible oral P2Y12 antagonist AZD6140 inhibits ADP-induced contractions in murine and human vasculature. Int J Cardiol. 2010;142(2):187–92.

    Article  Google Scholar 

  12. Ben Addi A, et al. Role of the P2Y12 receptor in the modulation of murine dendritic cell function by ADP. J Immunol. 2010;185(10):5900–6.

    Article  CAS  Google Scholar 

  13. Kronlage M, et al. Autocrine purinergic receptor signaling is essential for macrophage chemotaxis. Sci Signal. 2010;3(132):ra55.

    Article  Google Scholar 

  14. Neves JS, Radke AL, Weller PF. Cysteinyl leukotrienes acting via granule membrane-expressed receptors elicit secretion from within cell-free human eosinophil granules. J Allergy Clin Immunol. 2010;125(2):477–82.

    Article  CAS  Google Scholar 

  15. Muniz VS, et al. Purinergic P2Y12 receptor activation in eosinophils and the schistosomal host response. PLoS One. 2015;10(10):e0139805.

    Article  Google Scholar 

  16. Su X, et al. The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling. J Clin Invest. 2012;122(10):3579–92.

    Article  CAS  Google Scholar 

  17. Mediero A, et al. Ticagrelor regulates osteoblast and osteoclast function and promotes bone formation in vivo via an adenosine-dependent mechanism. FASEB J. 2016;30(11):3887–900.

    Article  CAS  Google Scholar 

  18. Elaskalani O, et al. Antiplatelet drug ticagrelor enhances chemotherapeutic efficacy by targeting the novel P2Y12-AKT pathway in pancreatic cancer cells. Cancers. 2020;12(1):250.

    Article  CAS  Google Scholar 

  19. Sarangi S, et al. P2Y12 receptor inhibition augments cytotoxic effects of cisplatin in breast cancer. Med Oncol. 2013;30(2):567.

    Article  Google Scholar 

  20. Krzemiński P, et al. Expression and functional characterization of P2Y1 and P2Y12 nucleotide receptors in long-term serum-deprived glioma C6 cells. FEBS J. 2007;274(8):1970–82.

    Article  Google Scholar 

  21. Jin J, et al. The C6–2B glioma cell P2Y(AC) receptor is pharmacologically and molecularly identical to the platelet P2Y(12) receptor. Br J Pharmacol. 2001;133(4):521–8.

    Article  CAS  Google Scholar 

  22. Hechler B, et al. The P2Y1 receptor, necessary but not sufficient to support full ADP-induced platelet aggregation, is not the target of the drug clopidogrel. Br J Haematol. 1998;103(3):858–66.

    Article  CAS  Google Scholar 

  23. Jin J, Daniel JL, Kunapuli SP. Molecular basis for ADP-induced platelet activation. II. The P2Y1 receptor mediates ADP-induced intracellular calcium mobilization and shape change in platelets. J Biol Chem. 1998;273(4):2030–4.

    Article  CAS  Google Scholar 

  24. Turner NA, Moake JL, McIntire LV. Blockade of adenosine diphosphate receptors P2Y(12) and P2Y(1) is required to inhibit platelet aggregation in whole blood under flow. Blood. 2001;98(12):3340–5.

    Article  CAS  Google Scholar 

  25. Gachet C. P2Y(12) receptors in platelets and other hematopoietic and non-hematopoietic cells. Purinergic Signal. 2012;8(3):609–19.

    Article  CAS  Google Scholar 

  26. Cattaneo M, et al. Released adenosine diphosphate stabilizes thrombin-induced human platelet aggregates. Blood. 1990;75(5):1081–6.

    Article  CAS  Google Scholar 

  27. Storey RF, et al. The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol. 2000;110(4):925–34.

    Article  CAS  Google Scholar 

  28. Shankar H, et al. P2Y12 receptor-mediated potentiation of thrombin-induced thromboxane A2 generation in platelets occurs through regulation of Erk1/2 activation. J Thromb Haemost. 2006;4(3):638–47.

    Article  CAS  Google Scholar 

  29. Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev. 2009;23(4):177–89.

    Article  CAS  Google Scholar 

  30. Ponomarev ED. Fresh evidence for platelets as neuronal and innate immune cells: their role in the activation, differentiation, and deactivation of Th1, Th17, and Tregs during tissue inflammation. Front Immunol. 2018;9:406.

    Article  Google Scholar 

  31. Thomas MR, Storey RF. Effect of P2Y12 inhibitors on inflammation and immunity. Thromb Haemost. 2015;114(3):490–7.

    Google Scholar 

  32. Anderson R, et al. ADP-mediated upregulation of expression of CD62P on human platelets is critically dependent on co-activation of P2Y1 and P2Y12 receptors. Pharmaceuticals. 2020;13(12):420.

    Article  CAS  Google Scholar 

  33. Suzuki J, et al. Cytokine secretion from human monocytes potentiated by P-selectin-mediated cell adhesion. Int Arch Allergy Immunol. 2013;160(2):152–60.

    Article  CAS  Google Scholar 

  34. Neumann F, et al. Induction of cytokine expression in leukocytes by binding of thrombin-stimulated platelets. Circulation. 1997;95(10):2387–94.

    Article  CAS  Google Scholar 

  35. Carestia A, et al. Platelets promote macrophage polarization toward pro-inflammatory phenotype and increase survival of septic mice. Cell Rep. 2019;28(4):896-908.e5.

    Article  CAS  Google Scholar 

  36. Badrnya S, et al. Platelets mediate oxidized low-density lipoprotein-induced monocyte extravasation and foam cell formation. Arterioscler Thromb Vasc Biol. 2014;34(3):571–80.

    Article  CAS  Google Scholar 

  37. Etulain J, et al. P-selectin promotes neutrophil extracellular trap formation in mice. Blood. 2015;126(2):242–6.

    Article  CAS  Google Scholar 

  38. Barnard M, et al. Effects of platelet binding on whole blood flow cytometry assays of monocyte and neutrophil procoagulant activity. J Thromb Haemost. 2005;3(11):2563–70.

    Article  CAS  Google Scholar 

  39. Evangelista V, et al. Clopidogrel inhibits platelet-leukocyte adhesion and platelet-dependent leukocyte activation. Thromb Haemost. 2005;94(3):568–77.

    CAS  Google Scholar 

  40. Totani L, et al. Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse. Thromb Haemost. 2012;107(06):1130–40.

    Article  CAS  Google Scholar 

  41. Leon C, et al. Differential involvement of the P2Y1 and P2Y12 receptors in platelet procoagulant activity. Arterioscler Thromb Vasc Biol. 2003;23(10):1941–7.

    Article  CAS  Google Scholar 

  42. Dorsam RT, Tuluc M, Kunapuli SP. Role of protease-activated and ADP receptor subtypes in thrombin generation on human platelets. J Thromb Haemost. 2004;2(5):804–12.

    Article  CAS  Google Scholar 

  43. van der Meijden PE, et al. Platelet P2Y12 receptors enhance signalling towards procoagulant activity and thrombin generation. A study with healthy subjects and patients at thrombotic risk. Thromb Haemost. 2005;93(6):1128–36.

    Article  Google Scholar 

  44. Leon C, et al. Platelet ADP receptors contribute to the initiation of intravascular coagulation. Blood. 2004;103(2):594–600.

    Article  CAS  Google Scholar 

  45. Gąsecka A, et al. Role of P2Y receptors in platelet extracellular vesicle release. Int J Mol Sci. 2020;21(17):6065.

    Article  Google Scholar 

  46. Rosinska J, Lukasik M, Kozubski W. The impact of vascular disease treatment on platelet-derived microvesicles. Cardiovasc Drugs Ther. 2017;31(5–6):627–44.

    Article  CAS  Google Scholar 

  47. Giacomazzi A, et al. Antiplatelet agents inhibit the generation of platelet-derived microparticles. Front Pharmacol. 2016;7:314.

    Article  Google Scholar 

  48. Gasecka A, et al. P2Y12 antagonist ticagrelor inhibits the release of procoagulant extracellular vesicles from activated platelets. Cardiol J. 2019;26(6):782–9.

    Article  Google Scholar 

  49. Zhang Y, et al. Contact- and agonist-regulated microvesiculation of human platelets. Thromb Haemost. 2013;110(2):331–9.

    CAS  Google Scholar 

  50. França CN, et al. Endothelial progenitor cell mobilization and platelet microparticle release are influenced by clopidogrel plasma levels in stable coronary artery disease. Circ J. 2012;76(3):729–36.

    Article  Google Scholar 

  51. Kafian S, et al. Association between platelet reactivity and circulating platelet-derived microvesicles in patients with acute coronary syndrome. Platelets. 2015;26(5):467–73.

    Article  CAS  Google Scholar 

  52. Kalantzi KI, et al. The platelet hyporesponsiveness to clopidogrel in acute coronary syndrome patients treated with 75 mg/day clopidogrel may be overcome within 1 month of treatment. Platelets. 2012;23(2):121–31.

    Article  CAS  Google Scholar 

  53. Gasecka A, et al. Ticagrelor attenuates the increase of extracellular vesicle concentrations in plasma after acute myocardial infarction compared to clopidogrel. J Thromb Haemost. 2020;18(3):609–23.

    Article  CAS  Google Scholar 

  54. Hafiane A, Daskalopoulou SS. Extracellular vesicles characteristics and emerging roles in atherosclerotic cardiovascular disease. Metabolism. 2018;85:213–22.

    Article  CAS  Google Scholar 

  55. Chyrchel B, et al. Platelet reactivity and circulating platelet-derived microvesicles are differently affected by P2Y12 receptor antagonists. Int J Med Sci. 2019;16(2):264–75.

    Article  CAS  Google Scholar 

  56. Zhang S, et al. P2Y12 protects platelets from apoptosis via PI3k-dependent Bak/Bax inactivation. J Thromb Haemost. 2013;11(1):149–60.

    Article  CAS  Google Scholar 

  57. Meng X, et al. Ticagrelor prevents tumor metastasis via inhibiting cell proliferation and promoting platelet apoptosis. Anticancer Drugs. 2020;31(10):1012–7.

    Article  CAS  Google Scholar 

  58. Ouseph MM, et al. Autophagy is induced upon platelet activation and is essential for hemostasis and thrombosis. Blood. 2015;126(10):1224–33.

    Article  CAS  Google Scholar 

  59. Malaver E, et al. NF-kappaB inhibitors impair platelet activation responses. J Thromb Haemost. 2009;7(8):1333–43.

    Article  CAS  Google Scholar 

  60. Cattaneo M, et al. Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate. Blood. 1992;80(11):2787–96.

    Article  CAS  Google Scholar 

  61. Nurden P, et al. An inherited bleeding disorder linked to a defective interaction between ADP and its receptor on platelets. Its influence on glycoprotein IIb-IIIa complex function. J Clin Invest. 1995;95(4):1612–22.

    Article  CAS  Google Scholar 

  62. Cattaneo M, et al. Platelets from a patient heterozygous for the defect of P2CYC receptors for ADP have a secretion defect despite normal thromboxane A2 production and normal granule stores: further evidence that some cases of platelet ‘primary secretion defect’ are heterozygous for a defect of P2CYC receptors. Arterioscler Thromb Vasc Biol. 2000;20(11):E101–6.

    Article  CAS  Google Scholar 

  63. Cattaneo M, et al. Molecular bases of defective signal transduction in the platelet P2Y12 receptor of a patient with congenital bleeding. Proc Natl Acad Sci U S A. 2003;100(4):1978–83.

    Article  CAS  Google Scholar 

  64. Shiraga M, et al. Impaired platelet function in a patient with P2Y12 deficiency caused by a mutation in the translation initiation codon. J Thromb Haemost. 2005;3(10):2315–23.

    Article  CAS  Google Scholar 

  65. Daly ME, et al. Identification and characterization of a novel P2Y 12 variant in a patient diagnosed with type 1 von Willebrand disease in the European MCMDM-1VWD study. Blood. 2009;113(17):4110–3.

    Article  CAS  Google Scholar 

  66. Nisar S, et al. An intact PDZ motif is essential for correct P2Y12 purinoceptor traffic in human platelets. Blood. 2011;118(20):5641–51.

    Article  CAS  Google Scholar 

  67. Patel YM, et al. A novel mutation in the P2Y12 receptor and a function-reducing polymorphism in protease-activated receptor 1 in a patient with chronic bleeding. J Thromb Haemost. 2014;12(5):716–25.

    Article  CAS  Google Scholar 

  68. Lecchi A, et al. Inherited dysfunctional platelet P2Y(12) receptor mutations associated with bleeding disorders. Hamostaseologie. 2016;36(4):279–83.

    Article  Google Scholar 

  69. Mundell SJ, et al. Receptor homodimerization plays a critical role in a novel dominant negative P2RY12 variant identified in a family with severe bleeding. J Thromb Haemost. 2018;16(1):44–53.

    Article  CAS  Google Scholar 

  70. Zhang K, et al. Structure of the human P2Y12 receptor in complex with an antithrombotic drug. Nature. 2014;509(7498):115–8.

    Article  CAS  Google Scholar 

  71. Gao Y, et al. The role of P2Y12 receptor in ischemic stroke of atherosclerotic origin. Cell Mol Life Sci. 2018;76(2):341–54.

    Article  Google Scholar 

  72. Ito Y, et al. Vasodilator-stimulated phosphoprotein (VASP) is not a major mediator of platelet aggregation, thrombogenesis, haemostasis, and antiplatelet effect of prasugrel in rats. Sci Rep. 2018;8(1):9955.

    Article  Google Scholar 

  73. Massberg S, et al. Enhanced in vivo platelet adhesion in vasodilator-stimulated phosphoprotein (VASP)-deficient mice. Blood. 2004;103(1):136–42.

    Article  CAS  Google Scholar 

  74. Aszódi A, et al. The vasodilator-stimulated phosphoprotein (VASP) is involved in cGMP- and cAMP-mediated inhibition of agonist-induced platelet aggregation, but is dispensable for smooth muscle function. Embo j. 1999;18(1):37–48.

    Article  Google Scholar 

  75. Schwarz UR, et al. Flow cytometry analysis of intracellular VASP phosphorylation for the assessment of activating and inhibitory signal transduction pathways in human platelets–definition and detection of ticlopidine/clopidogrel effects. Thromb Haemost. 1999;82(3):1145–52.

    Article  CAS  Google Scholar 

  76. Trumel C, et al. A key role of adenosine diphosphate in the irreversible platelet aggregation induced by the PAR1-activating peptide through the late activation of phosphoinositide 3-kinase. Blood. 1999;94(12):4156–65.

    Article  CAS  Google Scholar 

  77. Woulfe D, et al. Activation of Rap1B by G(i) family members in platelets. J Biol Chem. 2002;277(26):23382–90.

    Article  CAS  Google Scholar 

  78. Cattaneo M. The platelet P2Y(1)(2) receptor for adenosine diphosphate: congenital and drug-induced defects. Blood. 2011;117(7):2102–12.

    Article  CAS  Google Scholar 

  79. Garcia A, et al. Role of phosphoinositide 3-kinase beta in platelet aggregation and thromboxane A2 generation mediated by Gi signalling pathways. Biochem J. 2010;429(2):369–77.

    Article  CAS  Google Scholar 

  80. Miao J, Liu R, Li Z. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360(21):2250–1.

    CAS  Google Scholar 

  81. Sugidachi A, et al. The in vivo pharmacological profile of CS-747, a novel antiplatelet agent with platelet ADP receptor antagonist properties. Br J Pharmacol. 2000;129(7):1439–46.

    Article  CAS  Google Scholar 

  82. Kamran H, et al. Oral Antiplatelet Therapy After Acute Coronary Syndrome: A Review. JAMA. 2021;325(15):1545–55.

    Article  CAS  Google Scholar 

  83. You S, et al. Association of Ticagrelor vs Clopidogrel With Net Adverse Clinical Events in Patients With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention. JAMA. 2020;324(16):1640–50.

    Article  CAS  Google Scholar 

  84. Armstrong D, et al. Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1. J Cardiovasc Pharmacol Ther. 2014;19(2):209–19.

    Article  CAS  Google Scholar 

  85. Franchi F, et al. Platelet Inhibition With Cangrelor and Crushed Ticagrelor in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention. Circulation. 2019;139(14):1661–70.

    Article  CAS  Google Scholar 

  86. Wolf D, Ley K. Immunity and Inflammation in Atherosclerosis. Circ Res. 2019;124(2):315–27.

    Article  CAS  Google Scholar 

  87. Penz SM, et al. Glycoprotein Ibalpha inhibition and ADP receptor antagonists, but not aspirin, reduce platelet thrombus formation in flowing blood exposed to atherosclerotic plaques. Thromb Haemost. 2007;97(3):435–43.

    Article  CAS  Google Scholar 

  88. Nergiz-Unal R, et al. Stabilizing role of platelet P2Y(12) receptors in shear-dependent thrombus formation on ruptured plaques. PLoS One. 2010;5(4):e10130.

    Article  Google Scholar 

  89. Afek A, et al. Clopidogrel attenuates atheroma formation and induces a stable plaque phenotype in apolipoprotein E knockout mice. Microvasc Res. 2009;77(3):364–9.

    Article  CAS  Google Scholar 

  90. Heim C, et al. Clopidogrel significantly lowers the development of atherosclerosis in ApoE-deficient mice in vivo. Heart Vessels. 2016;31(5):783–94.

    Article  Google Scholar 

  91. Ganbaatar B, et al. Ticagrelor, a P2Y12 antagonist, attenuates vascular dysfunction and inhibits atherogenesis in apolipoprotein-E-deficient mice. Atherosclerosis. 2018;275:124–32.

    Article  CAS  Google Scholar 

  92. Li D, et al. Roles of purinergic receptor P2Y, G protein-coupled 12 in the development of atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 2012;32(8):e81–9.

    Article  CAS  Google Scholar 

  93. West LE, et al. Vessel wall, not platelet, P2Y12 potentiates early atherogenesis. Cardiovasc Res. 2014;102(3):429–35.

    Article  CAS  Google Scholar 

  94. Pi S, et al. The P2RY12 receptor promotes VSMC-derived foam cell formation by inhibiting autophagy in advanced atherosclerosis. Autophagy. 2021;17(4):980–1000.

    Article  CAS  Google Scholar 

  95. Chen X, et al. Endothelial Cell-Specific Deletion of P2Y2 Receptor Promotes Plaque Stability in Atherosclerosis-Susceptible ApoE-Null Mice. Arterioscler Thromb Vasc Biol. 2017;37(1):75–83.

    Article  CAS  Google Scholar 

  96. Mendolicchio GL, et al. Variable effect of P2Y12 inhibition on platelet thrombus volume in flowing blood. J Thromb Haemost. 2011;9(2):373–82.

    Article  CAS  Google Scholar 

  97. Chen Y, et al. Effect of aspirin plus clopidogrel on inflammatory markers in patients with non-ST-segment elevation acute coronary syndrome. Chin Med J. 2006;119(1):32–6.

    Article  CAS  Google Scholar 

  98. Lowenstern A, et al. Platelet-related biomarkers and their response to inhibition with aspirin and p2y(12)-receptor antagonists in patients with acute coronary syndrome. J Thromb Thrombolysis. 2017;44(2):145–53.

    Article  CAS  Google Scholar 

  99. Sakata T, Kario K. Antiplatelet therapy effectively reduces plasma plasminogen activator inhibitor-1 levels. Atherosclerosis. 2011;214(2):490–1.

    Article  CAS  Google Scholar 

  100. Yi X, et al. A comparative study of dual versus monoantiplatelet therapy in patients with acute large-artery atherosclerosis stroke. J Stroke Cerebrovasc Dis. 2014;23(7):1975–81.

    Article  Google Scholar 

  101. An X, et al. Inhibition of platelets by clopidogrel suppressed Ang II-induced vascular inflammation, oxidative stress, and remodeling. J Am Heart Assoc. 2018;7(21):e009600.

    Article  CAS  Google Scholar 

  102. Liu O, et al. Clopidogrel, a platelet P2Y12 receptor inhibitor, reduces vascular inflammation and angiotensin II induced-abdominal aortic aneurysm progression. PLoS One. 2012;7(12):e51707.

    Article  CAS  Google Scholar 

  103. Wang Y, et al. Platelet activation and antiplatelet therapy in sepsis: A narrative review. Thromb Res. 2018;166:28–36.

    Article  CAS  Google Scholar 

  104. Assinger A, et al. Platelets in sepsis: an update on experimental models and clinical data. Front Immunol. 2019;10:1687.

    Article  CAS  Google Scholar 

  105. Soriano AO, et al. Levels of endothelial and platelet microparticles and their interactions with leukocytes negatively correlate with organ dysfunction and predict mortality in severe sepsis. Crit Care Med. 2005;33(11):2540–6.

    Article  Google Scholar 

  106. Naime ACA, Ganaes JOF, Lopes-Pires ME. Sepsis: the involvement of platelets and the current treatments. Curr Mol Pharmacol. 2018;11(4):261–9.

    Article  Google Scholar 

  107. Hamzeh-Cognasse H, et al. Platelets and infections - complex interactions with bacteria. Front Immunol. 2015;6:82.

    Article  Google Scholar 

  108. Hannachi N, et al. Antiplatelet agents have a distinct efficacy on platelet aggregation induced by infectious bacteria. Front Pharmacol. 2020;11:863.

    Article  CAS  Google Scholar 

  109. Wang XL, et al. Clopidogrel reduces lipopolysaccharide-induced inflammation and neutrophil-platelet aggregates in an experimental endotoxemic model. J Biochem Mol Toxicol. 2019;33(4):e22279.

    Article  Google Scholar 

  110. Rahman M, et al. Ticagrelor reduces neutrophil recruitment and lung damage in abdominal sepsis. Platelets. 2014;25(4):257–63.

    Article  CAS  Google Scholar 

  111. Liverani E, et al. P2Y12 receptor modulates sepsis-induced inflammation. Arterioscler Thromb Vasc Biol. 2016;36(5):961–71.

    Article  CAS  Google Scholar 

  112. Li X, et al. The protective effect of ticagrelor on renal function in a mouse model of sepsis-induced acute kidney injury. Platelets. 2018;30(2):199–205.

    Article  Google Scholar 

  113. Seidel M, et al. Beneficial effect of clopidogrel in a mouse model of polymicrobial sepsis. J Thromb Haemost. 2009;7(6):1030–2.

    Article  CAS  Google Scholar 

  114. Liverani E, et al. LPS-induced systemic inflammation is more severe in P2Y12 null mice. J Leukoc Biol. 2014;95(2):313–23.

    Article  Google Scholar 

  115. Claushuis TAM, et al. Platelet-dense granules worsen pre-infection thrombocytopenia during gram-negative pneumonia-derived sepsis. J Innate Immun. 2019;11(2):168–80.

    Article  CAS  Google Scholar 

  116. Albayati S, et al. P2Y(12) antagonism results in altered interactions between platelets and regulatory T cells during sepsis. J Leukoc Biol. 2020;110(1):141–53.

    Article  Google Scholar 

  117. Thomas MR, et al. Platelet P2Y12 inhibitors reduce systemic inflammation and its prothrombotic effects in an experimental human model. Arterioscler Thromb Vasc Biol. 2015;35(12):2562–70.

    Article  CAS  Google Scholar 

  118. Schoergenhofer C, et al. Potent irreversible P2Y12 inhibition does not reduce LPS-induced coagulation activation in a randomized, double-blind, placebo-controlled trial. Clin Sci. 2016;130(6):433–40.

    Article  CAS  Google Scholar 

  119. Kiers D, et al. A randomised trial on the effect of anti-platelet therapy on the systemic inflammatory response in human endotoxaemia. Thromb Haemost. 2017;117(9):1798–807.

    Article  Google Scholar 

  120. Dewitte A, et al. Correction to: Blood platelets and sepsis pathophysiology: A new therapeutic prospect in critically ill patients? Ann Intensive Care. 2018;8(1):32.

    Article  Google Scholar 

  121. Sexton TR, et al. Ticagrelor reduces thromboinflammatory markers in patients with pneumonia. JACC Basic Transl Sci. 2018;3(4):435–49.

    Article  Google Scholar 

  122. Tsai MJ, et al. Association of prior antiplatelet agents with mortality in sepsis patients: a nationwide population-based cohort study. Intensive Care Med. 2015;41(5):806–13.

    Article  CAS  Google Scholar 

  123. Kim T, et al. Clopidogrel may decrease the risk of post-stroke infection after ischaemic stroke. Eur J Neurol. 2019;26(2):261–7.

    Article  CAS  Google Scholar 

  124. Butt J, et al. Ticagrelor and the risk of staphylococcus aureus bacteremia and other infections. Eur Heart J Cardiovasc Pharmacother. 2020. https://www.ncbi.nlm.nih.gov/pubmed/32750138/Ticagrelor and The Risk of Staphylococcus Aureus Bacteremia and Other Infections. Accessed 4 Aug 2020.

  125. Storey R, et al. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets. 2014;25(7):517–25.

    Article  CAS  Google Scholar 

  126. Long H, et al. Risk of infections in patients treated with ticagrelor versus clopidogrel: a systematic review and meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2021;7(3):171–9.

  127. Huang B, et al. Ticagrelor inhibits the NLRP3 inflammasome to protect against inflammatory disease independent of the P2Y(12) signaling pathway. Cell Mol Immunol. 2020;18(5):1278–89.

    Article  Google Scholar 

  128. Lancellotti P, et al. Antibacterial activity of ticagrelor in conventional antiplatelet dosages against antibiotic-resistant gram-positive bacteria. JAMA Cardiol. 2019;4(6):596–9.

    Article  Google Scholar 

  129. Elaskalani O, et al. Targeting platelets for the treatment of cancer. Cancers (Basel). 2017;9(7):94.

    Article  Google Scholar 

  130. Gresele P, Malvestiti M, Momi S. Anti-platelet treatments in cancer: Basic and clinical research. Thromb Res. 2018;164:S106–11.

    Article  CAS  Google Scholar 

  131. Cho MS, et al. Role of ADP receptors on platelets in the growth of ovarian cancer. Blood. 2017;130(10):1235–42.

    Article  CAS  Google Scholar 

  132. Bambace NM, Levis JE, Holmes CE. The effect of P2Y-mediated platelet activation on the release of VEGF and endostatin from platelets. Platelets. 2010;21(2):85–93.

    Article  CAS  Google Scholar 

  133. Battinelli EM, Markens BA, Italiano JE Jr. Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis. Blood. 2011;118(5):1359–69.

    Article  CAS  Google Scholar 

  134. Wu H, et al. The angiogenic responses induced by release of angiogenic proteins from tumor cell-activated platelets are regulated by distinct molecular pathways. IUBMB Life. 2015;67(8):626–33.

    Article  CAS  Google Scholar 

  135. Holmes CE, et al. Platelet phenotype changes associated with breast cancer and its treatment. Platelets. 2016;27(7):703–11.

    Article  CAS  Google Scholar 

  136. Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20(5):576–90.

    Article  CAS  Google Scholar 

  137. Kubota SI, et al. Whole-organ analysis of TGF-β-mediated remodelling of the tumour microenvironment by tissue clearing. Commun Biol. 2021;4(1):294.

    Article  CAS  Google Scholar 

  138. Chen H, et al. Direct TGF-β1 signaling between activated platelets and pancreatic cancer cells primes cisplatin insensitivity. Cell Biol Int. 2013;37(5):478–84.

    Article  CAS  Google Scholar 

  139. Kalinichenko, Vladimir V, et al. Platelet P2Y12 is involved in murine pulmonary metastasis. PLoS ONE. 2013;8(11):e80780.

    Article  Google Scholar 

  140. Wang D, et al. Prostaglandin E2 promotes colorectal cancer stem cell expansion and metastasis in mice. Gastroenterology. 2015;149(7):1884-1895.e4.

    Article  CAS  Google Scholar 

  141. Nandi P, et al. PGE2 promotes breast cancer-associated lymphangiogenesis by activation of EP4 receptor on lymphatic endothelial cells. BMC Cancer. 2017;17(1):11.

    Article  Google Scholar 

  142. Guillem-Llobat P, et al. Aspirin prevents colorectal cancer metastasis in mice by splitting the crosstalk between platelets and tumor cells. Oncotarget. 2016;7(22):32462–77.

    Article  Google Scholar 

  143. Gebremeskel S, et al. The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer. Int J Cancer. 2015;136(1):234–40.

    Article  CAS  Google Scholar 

  144. Gareau AJ, et al. Ticagrelor inhibits platelet-tumor cell interactions and metastasis in human and murine breast cancer. Clin Exp Metastasis. 2018;35(1–2):25–35.

    Article  CAS  Google Scholar 

  145. Rodríguez-Miguel A, et al. Clopidogrel and low-dose aspirin, alone or together, reduce risk of colorectal cancer. Clin Gastroenterol Hepatol. 2019;17(10):2024-2033.e2.

    Article  Google Scholar 

  146. Leader A, et al. The effect of combined aspirin and clopidogrel treatment on cancer incidence. Am J Med. 2017;130(7):826–32.

    Article  CAS  Google Scholar 

  147. Kuan YC, et al. Effects of aspirin or clopidogrel on colorectal cancer chemoprevention in patients with type 2 diabetes mellitus. Cancers (Basel). 2019;11(10):1468.

    Article  CAS  Google Scholar 

  148. Hayashi T, et al. Antiplatelet therapy improves the prognosis of patients with hepatocellular carcinoma. Cancers (Basel). 2020;12(11):3215.

    Article  CAS  Google Scholar 

  149. Cairat M, et al. Antiplatelet drug use and breast cancer risk in a prospective cohort of postmenopausal women. Cancer Epidemiol Biomarkers Prev. 2021;30(4):643–52.

    Article  CAS  Google Scholar 

  150. Elmariah S, et al. Impact of clopidogrel therapy on mortality and cancer in patients with cardiovascular and cerebrovascular disease: a patient-level meta-analysis. Circulation Cardiovascular interventions. 2018;11(1):e005795.

    Article  CAS  Google Scholar 

  151. Hicks B, et al. Clopidogrel use and cancer-specific mortality: a population-based cohort study of colorectal, breast and prostate cancer patients. Pharmacoepidemiol Drug Saf. 2015;24(8):830–40.

    Article  CAS  Google Scholar 

  152. Raposeiras-Roubín S, et al. Risk of cancer after an acute coronary syndrome according to the type of P2Y12 inhibitor. Thromb Res. 2019;174:51–8.

    Article  Google Scholar 

  153. Duffau P, et al. Platelet CD154 potentiates interferon-alpha secretion by plasmacytoid dendritic cells in systemic lupus erythematosus. Sci Transl Med. 2010;2(47):47ra63.

    Article  Google Scholar 

  154. Wang L, et al. Transcriptional down-regulation of the platelet ADP receptor P2Y(12) and clusterin in patients with systemic lupus erythematosus. J Thromb Haemost. 2004;2(8):1436–42.

    Article  CAS  Google Scholar 

  155. Harifi G, Sibilia J. Pathogenic role of platelets in rheumatoid arthritis and systemic autoimmune diseases. Perspectives and therapeutic aspects. Saudi Med J. 2016;37(4):354–60.

    Article  Google Scholar 

  156. Lukasik ZM, Makowski M, Makowska JS. From blood coagulation to innate and adaptive immunity: the role of platelets in the physiology and pathology of autoimmune disorders. Rheumatol Int. 2018;38(6):959–74.

    Article  CAS  Google Scholar 

  157. Frey O, et al. Erosive arthritis and hepatic granuloma formation induced by peptidoglycan polysaccharide in rats is aggravated by prasugrel treatment. PLoS ONE. 2013;8(7):e69093.

    Article  Google Scholar 

  158. Garcia AE, et al. Clopidogrel, a P2Y12 receptor antagonist, potentiates the inflammatory response in a rat model of peptidoglycan polysaccharide-induced arthritis. PLoS One. 2011;6(10):e26035.

    Article  CAS  Google Scholar 

  159. Takeda T, et al. Recent advances in understanding the roles of blood platelets in the pathogenesis of allergic inflammation and bronchial asthma. Allergol Int. 2018;67(3):326–33.

    Article  CAS  Google Scholar 

  160. Mansour A, et al. P2Y12 inhibition beyond thrombosis: effects on inflammation. International Journal of Molecular Sciences. 2020;21(4):1391.

    Article  CAS  Google Scholar 

  161. Paruchuri S, et al. Leukotriene E4-induced pulmonary inflammation is mediated by the P2Y12 receptor. J Exp Med. 2009;206(11):2543–55.

    Article  CAS  Google Scholar 

  162. Suh DH, et al. P2Y12 antagonist attenuates eosinophilic inflammation and airway hyperresponsiveness in a mouse model of asthma. J Cell Mol Med. 2016;20(2):333–41.

    Article  CAS  Google Scholar 

  163. Laidlaw TM, et al. A trial of type 12 purinergic (P2Y12) receptor inhibition with prasugrel identifies a potentially distinct endotype of patients with aspirin-exacerbated respiratory disease. J Allergy Clin Immunol. 2019;143(1):316-324.e7.

    Article  CAS  Google Scholar 

  164. Lussana F, et al. Effect of prasugrel in patients with asthma: results of PRINA, a randomized, double-blind, placebo-controlled, cross-over study. J Thromb Haemost. 2015;13(1):136–41.

    Article  CAS  Google Scholar 

  165. Mundell SJ, et al. Rapid resensitization of purinergic receptor function in human platelets. J Thromb Haemost. 2008;6(8):1393–404.

    Article  CAS  Google Scholar 

  166. Hardy AR, et al. P2Y1 and P2Y12 receptors for ADP desensitize by distinct kinase-dependent mechanisms. Blood. 2005;105(9):3552–60.

    Article  CAS  Google Scholar 

  167. Chaudhary P, et al. Role of GRK6 in the regulation of platelet activation through selective G protein-coupled receptor (GPCR) desensitization. Int J Mol Sci. 2020;21(11):3932.

    Article  CAS  Google Scholar 

  168. Nagy B Jr, et al. Contribution of the P2Y12 receptor-mediated pathway to platelet hyperreactivity in hypercholesterolemia. J Thromb Haemost. 2011;9(4):810–9.

    Article  CAS  Google Scholar 

  169. Haberstock-Debic H, et al. A clopidogrel-insensitive inducible pool of P2Y12 receptors contributes to thrombus formation: inhibition by elinogrel, a direct-acting, reversible P2Y12 antagonist. J Pharmacol Exp Ther. 2011;339(1):54–61.

    Article  CAS  Google Scholar 

  170. Koessler J, et al. The role of agonist-induced activation and inhibition for the regulation of purinergic receptor expression in human platelets. Thromb Res. 2018;168:40–6.

    Article  CAS  Google Scholar 

  171. Periayah MH, et al. Glycoprotein IIb/IIIa and P2Y12 induction by oligochitosan accelerates platelet aggregation. Biomed Res Int. 2014;2014:653149.

    Article  Google Scholar 

  172. Shanker G, et al. Nicotine upregulates the expression of P2Y12 on vascular cells and megakaryoblasts. J Thromb Thrombolysis. 2006;22(3):213–20.

    Article  CAS  Google Scholar 

  173. Hu L, et al. Platelets express activated P2Y12 receptor in patients with diabetes mellitus. Circulation. 2017;136(9):817–33.

    Article  CAS  Google Scholar 

  174. Fejes Z, et al. Hyperglycaemia suppresses microRNA expression in platelets to increase P2RY12 and SELP levels in type 2 diabetes mellitus. Thromb Haemost. 2017;117(3):529–42.

    Article  Google Scholar 

  175. Nagalla S, et al. Platelet microRNA-mRNA coexpression profiles correlate with platelet reactivity. Blood. 2011;117(19):5189–97.

    Article  CAS  Google Scholar 

  176. Szilagyi B, et al. Role of sepsis modulated circulating microRNAs. EJIFCC. 2019;30(2):128–45.

    CAS  Google Scholar 

  177. Shi R, et al. The emerging role of miR-223 in platelet reactivity: implications in antiplatelet therapy. Biomed Res Int. 2015;2015:981841.

    Article  Google Scholar 

  178. Shi R, et al. Decreased platelet miR-223 expression is associated with high on-clopidogrel platelet reactivity. Thromb Res. 2013;131(6):508–13.

    Article  CAS  Google Scholar 

  179. Zhang YY, et al. Decreased circulating microRNA-223 level predicts high on-treatment platelet reactivity in patients with troponin-negative non-ST elevation acute coronary syndrome. J Thromb Thrombolysis. 2014;38(1):65–72.

    Article  CAS  Google Scholar 

  180. Landry P, et al. Existence of a microRNA pathway in anucleate platelets. Nat Struct Mol Biol. 2009;16(9):961–6.

    Article  CAS  Google Scholar 

  181. Kaudewitz D, et al. Association of MicroRNAs and YRNAs with platelet function. Circ Res. 2016;118(3):420–32.

    Article  CAS  Google Scholar 

  182. Zhou M, et al. Long non-coding RNA metallothionein 1 pseudogene 3 promotes p2y12 expression by sponging miR-126 to activate platelet in diabetic animal model. Platelets. 2019;30(4):452–9.

    Article  CAS  Google Scholar 

  183. Rauch BH, et al. Regulation of functionally active P2Y12 ADP receptors by thrombin in human smooth muscle cells and the presence of P2Y12 in carotid artery lesions. Arterioscler Thromb Vasc Biol. 2010;30(12):2434–42.

    Article  CAS  Google Scholar 

  184. Li J-J, et al. Antiplatelet drug ticagrelor delays gastric ulcer healing in rats. Exp Ther Med. 2017;14(4):3774–9.

    Article  CAS  Google Scholar 

  185. Pels K, et al. Long-term clopidogrel administration following severe coronary injury reduces proliferation and inflammation via inhibition of nuclear factor-kappaB and activator protein 1 activation in pigs. Eur J Clin Invest. 2009;39(3):174–82.

    Article  CAS  Google Scholar 

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Acknowledgements

The authors would like to express their gratitude to EditSprings (https://www.editsprings.com/) for the expert linguistic services provided.

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This work was supported by the Youth Science Fund of The First Hospital of Jilin University (no. JDYY102019010).

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  1. Department of Infectious Diseases, The First Hospital of Jilin University, Changchun, 130021, Jilin, China

    Xiaohua Li

  2. Department of Pharmacology, School of Pharmacy, Jilin University, Fujin Road, Changchun, 130021, Jilin, China

    Xiaohua Li & Xia Cao

  3. ICU, Ji Lin Tumor Hospital, Changchun, China

    Guoxing Zhang

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Xiaohua Li collected, read the literature, and wrote this article; Guoxing Zhang collected literature and critically read this paper; Xia Cao critically read this paper.

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Li, X., Zhang, G. & Cao, X. The Function and Regulation of Platelet P2Y12 Receptor. Cardiovasc Drugs Ther 37, 199–216 (2023). https://doi.org/10.1007/s10557-021-07229-4

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