Overcoming limitations of current antiplatelet drugs: A concerted effort for more profitable strategies of intervention

References

• Wasserman EJ, Shipley NM. Atherothrombosis in acute coronary syndromes: mechanisms, markers, and mediators of vulnerability. Mt Sinai J Med. 2006;73:431–9.
   PubMed Web of Science ®Google Scholar
• Brass LF. Thrombin and platelet activation. Chest. 2003; 124(3 suppl):18S–25S.
   PubMed Web of Science ®Google Scholar
• Offermanns S. Activation of platelet function through G protein coupled receptors. Circ Res. 2006;99:1293–304.
   PubMed Web of Science ®Google Scholar
• Varga-Szabo D, Pleines I, Nieswandt B. Cell adhesion mechanisms in platelets. Arterioscler Thromb Vasc Biol. 2008;28:403–12.
   PubMed Web of Science ®Google Scholar
• Montalescot G. Platelet biology and implications for antiplatelet therapy in atherothrombotic disease. Clin Appl Thromb Hemost. 2010 Jun 21 (Epub ahead of print).
   Web of Science ®Google Scholar
• Cattaneo M. New P2Y12 blockers. J Thromb Haemost. 2009;7 Suppl 1:262–5.
   PubMedGoogle Scholar
• Raymenants E, Yang B, Nicolini F, Behrens P, Lawson D, Mehta JL. Verapamil and aspirin modulate platelet-mediated vasomotion in arterial segments with intact or disrupted endothelium. J Am Coll Cardiol. 1993;22:684–9.
   PubMed Web of Science ®Google Scholar
• Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005; 3:1800–14.
   PubMed Web of Science ®Google Scholar
• De Candia E, Hall SW, Rutella S, Landolfi R, Andrews RK, De Cristofaro R. Binding of thrombin to glycoprotein Ib accelerates the hydrolysis of Par-1 on intact platelets. J Biol Chem. 2001;276:4692–8.
   PubMed Web of Science ®Google Scholar
• Shah R. Protease-activated receptors in cardiovascular health and diseases. Am Heart J. 2009;157:253–62.
   PubMed Web of Science ®Google Scholar
• Jennings LK. Role of platelets in atherothrombosis. Am J Cardiol. 2009;103(3 suppl):4A–10A.
   PubMedGoogle Scholar
• Davì G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med. 2007;357:2482–94.
   PubMed Web of Science ®Google Scholar
• ; Antithrombotic Trialists’ (ATT) CollaborationBaigent C, Blackwell L, Collins R, Emberson J, Godwin J, Peto R, . Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Antithrombotic Trialists’ (ATT) Collaboration. Lancet. 2009;373:1849–60.
   PubMed Web of Science ®Google Scholar
• Di Minno G, Cerbone AM, Mattioli PL, Turco S, Iovine C, Mancini M. Functionally thrombasthenic state in normal platelets following the administration of ticlopidine. J Clin Invest. 1985;75:328–38.
   PubMed Web of Science ®Google Scholar
• Hass WK, Easton JD, Adams HP Jr, Pryse-Phillips W, Molony BA, Anderson S, . A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients: Ticlopidine Aspirin Stroke Study Group. N Engl J Med. 1989;321:501–7.
   PubMed Web of Science ®Google Scholar
• Urban P, Macaya C, Rupprecht HJ, Kiemeneij F, Emanuelsson H, Fontanelli A, . Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the multicenter aspirin and ticlopidine trial after intracoronary stenting (MATTIS). Circulation. 1998;98:2126–32.
   PubMed Web of Science ®Google Scholar
• A randomized, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet. 1996;348:1329–39.
   PubMedGoogle Scholar
• Hankey GJ, Sudlow CL, Dunbabin DW. Thienopyridine derivatives (ticlopidine, clopidogrel) versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients. Cochrane Database Syst Rev. 2000; CD001246.
   PubMedGoogle Scholar
• Peters RJ, Mehta SR, Fox KA, Zhao F, Lewis BS, Kopecky SL, . Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003;108:1682–7.
   PubMed Web of Science ®Google Scholar
• Aronow HD, Steinhubl SR, Brennan DM, Berger PB, Topol EJ; CREDO Investigators. Bleeding risk associated with 1 year of dual antiplatelet therapy after percutaneous coronary intervention: insights from the Clopidogrel for the Reduction of Events During Observation (CREDO) trial. Am Heart J. 2009;157:369–74.
   PubMed Web of Science ®Google Scholar
• Angiolillo DJ. Variability in responsiveness to oral antiplatelet therapy. Am J Cardiol. 2009;103 Suppl:27A–34A.
   PubMedGoogle Scholar
• Krasopoulos G, Brister SJ, Beattie WS, Buchanan MR. Aspirin ‘resistance’ and risk of cardiovascular morbidity: a systematic review and meta-analysis. BMJ. 2008;336: 195–8.
   PubMed Web of Science ®Google Scholar
• Eikelboom JW, Hirsh J, Weitz JI, Johnston M, Yi Q, Yusuf S. Aspirin resistant thromboxane B biosynthesis and risk of myocardial infarction or cardiovascular death in patients at high risk of for cardiovascular events. Circulation. 2002; 105:1650–5.
   PubMed Web of Science ®Google Scholar
• Sofi F, Marcucci R, Gori AM, Giusti B, Abbate R, Gensini GF. Clopidogrel non-responsiveness and risk of cardiovascular morbidity. An updated meta-analysis. Thromb Haemost. 2010;103:841–8.
   PubMed Web of Science ®Google Scholar
• Heras M, Bueno H, Bardají A, Fernández-Ortiz A, Martí H, Marrugat J, . Magnitude and consequences of undertreatment of high-risk patients with non-ST segment elevation acute coronary syndromes: insights from the DESCARTES Registry. Heart. 2006;92:1571–6.
   PubMed Web of Science ®Google Scholar
• Kuliczkowski W, Witkowski A, Polonski L, Watala C, Filipiak K, Budaj A, . Interindividual variability in the response to oral antiplatelet drugs: a position paper of the Working Group on antiplatelet drugs resistance appointed by the Section of Cardiovascular Interventions of the Polish Cardiac Society, endorsed by the Working Group on Thrombosis of the European Society of Cardiology. Eur Heart J. 2009; 30:426–35.
   PubMed Web of Science ®Google Scholar
• Di Minno G, Silver MJ, Cerbone AM, Murphy S. Trial of repeated low-dose aspirin in diabetic angiopathy. Blood. 1986;68:886–91.
   PubMed Web of Science ®Google Scholar
• Maree AO, Curtin RJ, Chubb A, Dolan C, Cox D, O'Brien J, . Cycloxygenase-1 haplotype modulates platelet response to aspirin. J Thromb Haemost. 2005;3:2340–5.
   PubMed Web of Science ®Google Scholar
• Simon T, Verstuyft C, Mary-Krause M, Quteineh L, Drouet E, Méneveau N, . Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360:363–75.
   PubMed Web of Science ®Google Scholar
• Di Minno G, Silver MJ, Murphy S. Monitoring the entry of new platelets into the circulation after ingestion of aspirin. Blood. 1983;61:1081–5.
   PubMed Web of Science ®Google Scholar
• Zimmermann N, Gams E, Hohlfeld T. Aspirin in coronary artery bypass surgery: new aspects of and alternatives for an old antithrombotic agent. Eur J Cardiothorac Surg. 2008; 34:93–108.
   PubMed Web of Science ®Google Scholar
• Grove EL, Hvas AM, Mortensen SB, Larsen SB, Kristensen SD. Effect of platelet turnover on whole blood platelet aggregation in patients with coronary artery disease. J Thromb Haemost. 2011;9:185–91.
   PubMed Web of Science ®Google Scholar
• Di Minno G, Violi F. Aspirin resistance and diabetic angiopathy: back to the future. Thromb Res. 2004;113:97–9.
   PubMed Web of Science ®Google Scholar
• Farré AJ, Tamargo J, Mateos-Cáceres PJ, Azcona L, Macaya C. Old and new molecular mechanisms associated with platelet resistance to antithrombotics. Pharm Res. 2010; 27:2365–73.
   PubMed Web of Science ®Google Scholar
• Coccheri S. Antiplatelet drugs—do we need new options? With a reappraisal of direct thromboxane inhibitors. Drugs. 2010;70:887–908.
   PubMed Web of Science ®Google Scholar
• Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Fox KA, Granger CB, . Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J. 2008;156:1080–8.
   PubMed Web of Science ®Google Scholar
• Bonello L, Camoin-Jau L, Armero S, Com O, Arques S, Burignat-Bonello C, . Tailored clopidogrel loading dose according to platelet reactivity monitoring to prevent acute and subacute stent thrombosis. Am J Cardiol. 2009; 1;103:5–10.
   Google Scholar
• Bonello L, Camoin-Jau L, Arques S, Boyer C, Panagides D, Wittenberg O, . Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol. 2008;51:1404–11.
   PubMed Web of Science ®Google Scholar
• Price MJ, Berger PB, Angiolillo DJ, Teirstein PS, Tanguay JF, Kandzari DE, . Evaluation of individualized clopidogrel therapy after drug-eluting stent implantation in patients with high residual platelet reactivity: design and rationale of the GRAVITAS trial. Am Heart J. 2009;157:818–24.
   PubMed Web of Science ®Google Scholar
• Gajos G, Rostoff P, Undas A, Piwowarska W. Effects of polyunsaturated omega-3 fatty acids on responsiveness to dual antiplatelet therapy in patients undergoing percutaneous coronary intervention: the OMEGA-PCI (OMEGA-3 fatty acids after pci to modify responsiveness to dual antiplatelet therapy) study. J Am Coll Cardiol. 2010;55:1671–8.
   PubMed Web of Science ®Google Scholar
• Goto S. Cilostazol: potential mechanism of action for antithrombotic effects accompanied by a low rate of bleeding. Atheroscler Suppl. 2005;6:3–11.
   PubMed Web of Science ®Google Scholar
• Angiolillo DJ, Capranzano P, Goto S, Aslam M, Desai B, Charlton RK, . A randomized study assessing the impact of cilostazol on platelet function profiles in patients with diabetes mellitus and coronary artery disease on dual antiplatelet therapy: results of the OPTIMUS-2 study. Eur Heart J. 2008;29:2202–11.
   PubMed Web of Science ®Google Scholar
• Kamal AK, Naqvi I, Husain MR, Khealani BA. Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin. Cochrane Database Syst Rev. 2011:CD008076. DOI:10.1002/14651858.CD008076.pub2.
   PubMed Web of Science ®Google Scholar
• Angiolillo DJ, Bhatt DL, Gurbel PA, Jennings LK. Advances in antiplatelet therapy: agents in clinical development. Am J Cardiol. 2009;103 Suppl:40A–51A.
   PubMedGoogle Scholar
• Brandt JT, Payne CD, Wiviott SD, Weerakkody G, Farid NA, Small DS, . A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007;153:66.e9–e16.
   PubMed Web of Science ®Google Scholar
• Wiviott SD, Antman EM, Winters KJ, Weerakkody G, Murphy SA, Behounek BD, . Randomized comparison of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 antagonist, with clopidogrel in percutaneous coronary intervention: results of the Joint Utilization of Medications to Block Platelets Optimally (JUMBO)-TIMI 26 trial. Circulation. 2005;111:3366–73.
   PubMed Web of Science ®Google Scholar
• Wiviott SD, Trenk D, Frelinger AL, O'Donoghue M, Neumann FJ, Michelson A, . Prasugrel compared with high loading- and maintenance-dose clopidogrel in patients with planned percutaneous coronary intervention. The prasugrel in comparison to clopidogrel for inhibition of platelet activation and aggregation thrombolysis in myocardial infarction 44 trial. Circulation. 2007;116:2923–32.
   PubMed Web of Science ®Google Scholar
• Wiviott SD, Braunwald E, McCabe CH, Montalescot G, Ruzyllo W, Gottlieb S, . Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–15.
   PubMed Web of Science ®Google Scholar
• Wiviott SD, Braunwald E, McCabe CH, Horvath I, Keltai M, Herrman JP, . Intensive oral antiplatelet therapy for reduction of ischaemic events including stent thrombosis in patients with acute coronary syndromes treated with percutaneous coronary intervention and stenting in the TRITON-TIMI 38 trial: a subanalysis of a randomised trial. Lancet. 2008;371:1353–63.
   PubMed Web of Science ®Google Scholar
• Chin CT, Roe MT, Fox KA, Prabhakaran D, Marshall DA, Petitjean H, . Study design and rationale of a comparison of prasugrel and clopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial. Am Heart J. 2010;160:16–22.
   PubMed Web of Science ®Google Scholar
• Greenbaum AB, Ohman EM, Gibson CM, Borzak S, Stebbins AL, Lu M, . Preliminary experience with intravenous P2Y12 platelet receptor inhibition as an adjunct to reduced-dose alteplase during acute myocardial infarction: results of the Safety, Tolerability and Effect on Patency in Acute Myocardial Infarction (STEP-AMI) angiographic trial. Am Heart J. 2007;154:702–9.
   PubMed Web of Science ®Google Scholar
• Harrington RA, Stone GW, McNulty S, White HD, Lincoff AM, Gibson CM, . Platelet inhibition with cangrelor in patients undergoing PCI. N Engl J Med. 2009;361:2318–29.
   PubMed Web of Science ®Google Scholar
• Bhatt DL, Lincoff AM, Gibson CM, Stone GW, McNulty S, Montalescot G, . Intravenous platelet blockade with cangrelor during PCI. N Engl J Med. 2009;361:2330–41.
   PubMed Web of Science ®Google Scholar
• Anderson SD, Shah NK, Yim J, Epstein BJ. Efficacy and safety of ticagrelor: a reversible P2Y12 receptor antagonist. Ann Pharmacother. 2010;44:524–37.
   PubMed Web of Science ®Google Scholar
• Storey RF, Husted S, Harrington RA, Heptinstall S, Wilcox RG, Peters G, . Inhibition of platelet aggregation by AZD6140, a reversible oral P2Y12 receptor antagonist, compared with clopidogrel in patients with acute coronary syndromes. J Am Coll Cardiol. 2007;50:1852–6.
   PubMed Web of Science ®Google Scholar
• Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27:1038–47.
   PubMed Web of Science ®Google Scholar
• Tantry US, Bliden KP, Wei C, Storey RF, Armstrong M, Butler K, . First analysis of the relation between CYP2C19 genotype and pharmacodynamics in patients treated with ticagrelor versus clopidogrel: The ONSET/OFFSET and RESPOND genotype studies. Circ Cardiovasc Genet. 2010;3:556–66.
   PubMed Web of Science ®Google Scholar
• Cannon CP, Husted S, Harrington RA, Scirica BM, Emanuelsson H, Peters G, . Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-ST segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial. J Am Coll Cardiol. 2007;50:1844–51.
   PubMed Web of Science ®Google Scholar
• Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C, . Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361: 1045–57.
   PubMed Web of Science ®Google Scholar
• Serebruany VL, Stebbing J, Atar D. Dyspnoea after antiplatelet agents: the AZD6140 controversy. Int J Clin Pract. 2007;61:529–33.
   PubMed Web of Science ®Google Scholar
• Bhatt DL. Intensifying platelet inhibition—navigating between Scylla and Charybdis. N Engl J Med. 2007;357: 2078–81.
   PubMed Web of Science ®Google Scholar
• Gurbel PA, Bliden KP, Butler K, Tantry US, Gesheff T, Wei C, . Randomized double-blind assessment of the ONSET and OFFSET of the antiplatelet effects of ticagrelor versus clopidogrel in patients with stable coronary artery disease. The ONSET/OFFSET Study. Circulation. 2009; 120:2577–85.
   PubMed Web of Science ®Google Scholar
• Leonardi S, Rao SV, Harrington RA, Bhatt DL, Gibson CM, Roe MT, . Rationale and design of the randomized, double-blind trial testing INtraveNous and Oral administration of elinogrel, a selective and reversible P2Y(12)-receptor inhibitor, versus clopidogrel to eVAluate Tolerability and Efficacy in nonurgent Percutaneous Coronary Interventions patients (INNOVATE-PCI). Am Heart J. 2010;160:65–72.
   PubMed Web of Science ®Google Scholar
• Shinohara Y, Nishimaru K, Sawada T, Terashi A, Handa S, Hirai S, ; S-ACCESS Study Group. Sarpogrelate-SarpoAspirin comparative clinical study for efficacy and safety in secondary prevention of cerebral infarction (S-ACCESS): a randomized, double-blind, aspirin controlled trial. Stroke. 2008;39:1827–33.
   Google Scholar
• Zafar MU, Ibáñez B, Choi BG, Vorchheimer DA, Piñero A, Jin X, . A new oral antiplatelet agent with potent antithrombotic properties: comparison of DZ-697b with clopidogrel in a randomized phase I study. Thromb Haemost. 2010;103:205–12.
   PubMed Web of Science ®Google Scholar
• Goto S, Ogawa H, Takeuchi M, Flather MD, Bhatt DL; J-LANCELOT (Japanese-Lesson from Antagonizing the Cellular Effect of Thrombin) Investigators. Double-blind, placebo-controlled phase II studies of the protease-activated receptor 1 antagonist E5555 (atopaxar) in Japanese patients with acute coronary syndrome or high-risk coronary artery disease. Eur Heart J. 2010;31:2601–13.
   PubMed Web of Science ®Google Scholar
• Angiolillo DJ, Capranzano P. Pharmacology of emerging novel platelet inhibitors. Am Heart J. 2008;156(2 Suppl):S10–5.
   PubMed Web of Science ®Google Scholar
• Becker RC, Moliterno DJ, Jennings LK, Pieper KS, Pei J, Niederman A, . Safety and tolerability of SCH 530348 in patients undergoing non-urgent percutaneous coronary intervention: a randomised, double-blind, placebo-controlled phase II study. Lancet. 2009;373:919–28.
   PubMed Web of Science ®Google Scholar
• Day JR, Punjabi PP, Randi AM, Haskard DO, Landis RC, Taylor KM. Clinical inhibition of the seven-transmembrane thrombin receptor (PAR1) by intravenous aprotinin during cardiothoracic surgery. Circulation. 2004;110:2597–600.
   PubMed Web of Science ®Google Scholar
• Goto S, Yamaguchi T, Ikeda Y, Kato K, Yamaguchi H, Jensen P. Safety and exploratory efficacy of the novel thrombin receptor (PAR-1) antagonist SCH530348 for non-ST-segment elevation acute coronary syndrome. J Ateroscler Thromb. 2010;17:156–64.
   PubMed Web of Science ®Google Scholar
• TRA*CER Executive and Steering Committees. The thrombin receptor antagonists for clinical event reduction in acute coronary syndrome (TRA*CER) trial: study design end rationale. Am Heart J. 2009;158:327–34.
   PubMed Web of Science ®Google Scholar
• Morrow DA, Scirica BM, Fox KA, Berman G, Strony J, Veltri E, . Evaluation of a novel antiplatelet agent for secondary prevention in patients with a history of atherosclerotic disease: Design and rationale for the Thrombin-Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-TIMI 50 trial. Am Heart J. 2009;158:335–41.
   PubMed Web of Science ®Google Scholar
• Ishimoto Y, Nakano T. Release of a product of growth arrest-specific gene 6 from rat platelets. FEBS Lett. 2000;466: 197–9.
   PubMed Web of Science ®Google Scholar
• Manfioletti G, Brancolini C, Avanzi G, Schneider C. The protein encoded by a growth arrestspecific gene (gas6) is a new member of the vitamin K-dependent proteins related to protein S, a negative coregulator in the blood coagulation cascade. Mol Cell Biol. 1993;13:4976–85.
   PubMed Web of Science ®Google Scholar
• Chen C, Li Q, Darrow AL, Wang Y, Derian CK, Yang J, . Mer receptor tyrosine kinase signaling participates in platelet function. Arterioscler Thromb Vasc Biol. 2004; 24:1118–23.
   PubMed Web of Science ®Google Scholar
• Nagase H, Visse R, Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006;69:562–73.
   PubMed Web of Science ®Google Scholar
• Sawicki G, Sanders EJ, Salas E, Wozniak M, Rodrigo J, Radomski MW. Localization and translocation of MMP-2 during aggregation of human platelets. Thromb Haemost. 1998;80:836–9.
   PubMed Web of Science ®Google Scholar
• Falcinelli E, Guglielmini G, Torti M, Gresele P. Intraplatelet signaling mechanisms of the priming effect of matrix metalloproteinase-2 on platelet aggregation. J Thromb Haemost. 2005;3:2526–35.
   PubMed Web of Science ®Google Scholar
• Cheung PY, Sawicki G, Wozniak M, Wang W, Radomski MW, Schulz R. Matrix metalloproteinase-2 contributes to ischemia reperfusion injury in the heart. Circulation. 2000; 101:1833–9.
   PubMed Web of Science ®Google Scholar
• Hu YB, Li DG, Lu HM. Modified synthetic siRNA targeting tissue inhibitor of metalloproteinase-2 inhibits hepatic fibrogenesis in rats. J Gene Med. 2007;9:217–29.
   PubMed Web of Science ®Google Scholar
• Andre P, Prasad KS, Denis CV, He M, Papalia JM, Hynes RO, . CD40L stabilizes arterial thrombi by a b3 integrin-dependent mechanism. Nat Med. 2002;8: 247–52.
   PubMed Web of Science ®Google Scholar
• Kuwana M, Nomura S, Fujimura K, Nagasawa T, Muto Y, Kurata Y, . Effect of a single injection of humanized anti-CD154 monoclonal antibody on the platelet-specific autoimmune response in patients with immune thrombocytopenic purpura. Blood. 2004;103: 1229–36.
   PubMed Web of Science ®Google Scholar
• Otterdal K, Pedersen TM, Solum NO. Release of soluble CD40 ligand after platelet activation. Studies on the solubilization phase. Thromb Res. 2004;114:167–77.
   PubMed Web of Science ®Google Scholar
• Ma H, Hara A, Xiao CY, Okada Y, Takahata O, Nakaya K, . Increased bleeding tendency and decreased susceptibility to thromboembolism in mice lacking the prostaglandin E2 receptor subtype EP3. Circulation. 2001;104: 1176–80.
   PubMed Web of Science ®Google Scholar
• Fabre JE, Nguyen M, Athirakul K, Coggins K, McNeish JD, Austin S, . Activation of the murine EP3 receptor for PGE2 inhibits cAMP production and promotes platelet aggregation. J Clin Invest. 2001;107:603–10.
   PubMed Web of Science ®Google Scholar
• Singh J, Zeller W, Zhou N, Hategen G, Mishra R, Polozov A, . Antagonists of the EP3 receptor for prostaglandin E2 are novel antiplatelet agents that do not prolong bleeding. ACS Chem Biol. 2009;4:115–26.
   PubMed Web of Science ®Google Scholar
• Gresele P, Falcinelli E, Momi S. Potentiation and priming of platelet activation: a potential target for antiplatelet therapy. Trends Pharmacol Sci. 2008;29:352–60.
   PubMed Web of Science ®Google Scholar
• Angiolillo DJ, Capodanno D, Goto S. Platelet thrombin receptor antagonism and atherothrombosis. Eur Heart J. 2010;31:17–28.
   PubMed Web of Science ®Google Scholar