Platelets contribute fundamentally to ischemic heart disease, and antiplatelet therapy has been critical to reducing acute thrombotic complications of atherosclerotic disease. Thrombin, by acting on protease activated receptors (PAR), is one of the most potent platelet activators. PAR-1 antagonists may therefore provide more comprehensive antithrombotic effects. We review the pathophysiology of atherothrombosis, platelet activation by thrombin, the role of platelet protease activated receptors (PAR), and the clinical data supporting their use.
References
[1]
ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988, 2, 349–360.
[2]
Yusuf, S.; Zhao, F.; Mehta, S.R.; Chrolavicius, S.; Tognoni, G.; Fox, K.K. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 2001, 345, 494–502, doi:10.1056/NEJMoa010746.
[3]
Wallentin, L.; Becker, R.C.; Budaj, A.; Cannon, C.P.; Emanuelsson, H.; Held, C.; Horrow, J.; Husted, S.; James, S.; Katus, H.; et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 2009, 361, 1045–1057, doi:10.1056/NEJMoa0904327.
[4]
Wiviott, S.D.; Braunwald, E.; McCabe, C.H.; Montalescot, G.; Ruzyllo, W.; Gottlieb, S.; Neumann, F.J.; Ardissino, D.; De Servi, S.; Murphy, S.A.; et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 2007, 357, 2001–2015, doi:10.1056/NEJMoa0706482.
[5]
Lloyd-Jones, D.; Adams, R.; Carnethon, M.; De Simone, G.; Ferguson, T.B.; Flegal, K.; Ford, E.; Furie, K.; Go, A.; Greenlund, K.; et al. Heart disease and stroke statistics—2009 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2009, 119, 480–486, doi:10.1161/CIRCULATIONAHA.108.191259.
[6]
Lincoff, A.M.; Kleiman, N.S.; Kereiakes, D.J.; Feit, F.; Bittl, J.A.; Jackman, J.D.; Sarembock, I.J.; Cohen, D.J.; Spriggs, D.; Ebrahimi, R.; et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs. heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA 2004, 292, 696–703, doi:10.1001/jama.292.6.696.
[7]
Leger, A.J.; Covic, L.; Kuliopulos, A. Protease-activated receptors in cardiovascular diseases. Circulation 2006, 114, 1070–1077, doi:10.1161/CIRCULATIONAHA.105.574830.
Camerer, E.; Duong, D.N.; Hamilton, J.R.; Coughlin, S.R. Combined deficiency of protease-activated receptor-4 and fibrinogen recapitulates the hemostatic defect but not the embryonic lethality of prothrombin deficiency. Blood 2004, 103, 152–154, doi:10.1182/blood-2003-08-2707.
[10]
Gawaz, M.; Langer, H.; May, A.E. Platelets in inflammation and atherogenesis. J. Clin. Invest. 2005, 115, 3378–3384, doi:10.1172/JCI27196.
[11]
Borissoff, J.I.; Spronk, H.M.; ten Cate, H. The hemostatic system as a modulator of atherosclerosis. N. Engl. J. Med. 2011, 364, 1746–1760, doi:10.1056/NEJMra1011670.
[12]
Vu, T.K.; Hung, D.T.; Wheaton, V.I.; Coughlin, S.R. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 1991, 64, 1057–1068, doi:10.1016/0092-8674(91)90261-V.
[13]
Coughlin, S.R. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost. 2005, 3, 1800–1814, doi:10.1111/j.1538-7836.2005.01377.x.
[14]
Ossovskaya, V.S.; Bunnett, N.W. Protease-activated receptors: contribution to physiology and disease. Physiol. Rev. 2004, 84, 579–621, doi:10.1152/physrev.00028.2003.
[15]
Kahn, M.L.; Nakanishi-Matsui, M.; Shapiro, M.J.; Ishihara, H.; Coughlin, S.R. Protease-activated receptors 1 and 4 mediate activation of human platelets by thrombin. J. Clin. Invest. 1999, 103, 879–887, doi:10.1172/JCI6042.
[16]
Cornelissen, I.; Palmer, D.; David, T.; Wilsbacher, L.; Concengco, C.; Conley, P.; Pandey, A.; Coughlin, S.R. Roles and interactions among protease-activated receptors and P2ry12 in hemostasis and thrombosis. Proc. Natl. Acad. Sci. USA 2010, 107, 18605–18610, doi:10.1073/pnas.1013309107.
[17]
Kato, Y.; Kita, Y.; Hirasawa-Taniyama, Y.; Nishio, M.; Mihara, K.; Ito, K.; Yamanaka, T.; Seki, J.; Miyata, S.; Mutoh, S. Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig. Eur. J. Pharmacol. 2003, 473, 163–169, doi:10.1016/S0014-2999(03)01973-3.
[18]
Derian, C.K.; Damiano, B.P.; Addo, M.F.; Darrow, A.L.; D'Andrea, M.R.; Nedelman, M.; Zhang, H.C.; Maryanoff, B.E.; Andrade-Gordon, P. Blockade of the thrombin receptor protease-activated receptor-1 with a small-molecule antagonist prevents thrombus formation and vascular occlusion in nonhuman primates. J. Pharmacol. Exp. Ther. 2003, 304, 855–861, doi:10.1124/jpet.102.042663.
[19]
Chintala, M.; Shimizu, K.; Ogawa, M.; Yamaguchi, H.; Doi, M.; Jensen, P. Basic and translational research on proteinase-activated receptors: Antagonism of the proteinase-activated receptor 1 for thrombin, a novel approach to antiplatelet therapy for atherothrombotic disease. J. Pharmacol. Sci. 2008, 108, 433–438, doi:10.1254/jphs.08R06FM.
[20]
Kosoglou, T.; Kraft, W.K.; Kumar, B.; Statkevich, P.; Xuan, F.; Ma, L.; Jennings, L.K.; Schiller, J.E.; Langdon, R.B.; et al. Pharmacokinetics and pharmacodynamics of the novel PAR-1 antagonist vorapaxar in patients with end-stage renal disease. Eur. J. Clin. Pharmacol. 2012, 68, 1049–1056, doi:10.1007/s00228-012-1217-6.
Becker, R.C.; Moliterno, D.J.; Jennings, L.K.; Pieper, K.S.; Pei, J.; Niederman, A.; Ziada, K.M.; Berman, G.; Strony, J.; Joseph, D.; et al. 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, 919–928, doi:10.1016/S0140-6736(09)60230-0.
[23]
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. Atheroscler. Thromb. 2010, 17, 156–164, doi:10.5551/jat.3038.
[24]
Tricoci, P.; Huang, Z.; Held, C.; Moliterno, D.J.; Armstrong, P.W.; van de Werf, F.; White, H.D.; Aylward, P.E.; Wallentin, L.; Chen, E.; et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N. Engl. J. Med. 2012, 366, 20–33, doi:10.1056/NEJMoa1109719.
[25]
Morrow, D.A.; Braunwald, E.; Bonaca, M.P.; Ameriso, S.F.; Dalby, A.J.; Fish, M.P.; Fox, K.A.; Lipka, L.J.; Liu, X.; Nicolau, J.C.; et al. Vorapaxar in the secondary prevention of atherothrombotic events. N. Engl. J. Med. 2012, 366, 1404–1413, doi:10.1056/NEJMoa1200933.
[26]
Bonaca, M.P.; Scirica, B.M.; Creager, M.A.; Olin, J.W.; Bounameaux, H.; Dellborg, M.; Lamp, J.M.; Murphy, S.A.; Braunwald, E.; Morrow, D.A. Vorapaxar in Patients with Peripheral Artery Disease: Results from TRA2{degrees}P-TIMI 50. Circulation 2013, 127, 1522–1529, doi:10.1161/CIRCULATIONAHA.112.000679.
[27]
Takeuchi, M. Pharmacodynamics and safety of a novel Protease Activated Receptor-1 antagonist E5555 for healthy volunteers. In Proceedings of ESC Congress, Vienna, Austria, 1–5 September 2007.
[28]
Serebruany, V.; Sabaeva, E.; Booze, C.; Atar, O.D.; Eisert, C.; Hanley, D. Distribution of dipyridamole in blood components among post-stroke patients treated with extended release formulation. Thromb. Haemost. 2009, 102, 538–543.
[29]
Goto, S.; Ogawa, H.; Takeuchi, M.; Flather, M.D.; Bhatt, D.L. 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, 2601–2613, doi:10.1093/eurheartj/ehq320.
[30]
O'Donoghue, M.L.; Bhatt, D.L.; Wiviott, S.D.; Goodman, S.G.; Fitzgerald, D.J.; Angiolillo, D.J.; Goto, S.; Montalescot, G.; Zeymer, U.; Aylward, P.E.; et al. Safety and tolerability of atopaxar in the treatment of patients with acute coronary syndromes: The lessons from antagonizing the cellular effects of Thrombin-Acute Coronary Syndromes Trial. Circulation 2011, 123, 1843–1853, doi:10.1161/CIRCULATIONAHA.110.000786.
[31]
Wiviott, S.D.; Flather, M.D.; O'Donoghue, M.L.; Goto, S.; Fitzgerald, D.J.; Cura, F.; Aylward, P.; Guetta, V.; Dudek, D.; Contant, C.F.; et al. Randomized trial of atopaxar in the treatment of patients with coronary artery disease: The lessons from antagonizing the cellular effect of Thrombin-Coronary Artery Disease Trial. Circulation 2011, 123, 1854–1863, doi:10.1161/CIRCULATIONAHA.110.001404.
[32]
Chatterjee, S.; Ghose, A.; Sharma, A.; Guha, G.; Mukherjee, D.; Frankel, R. Comparing newer oral anti-platelets prasugrel and ticagrelor in reduction of ischemic events-evidence from a network meta-analysis. J. Thromb. Thrombolysis 2012, doi:10.1007/s11239-012-0838-z.
[33]
Diener, H.C.; Bogousslavsky, J.; Brass, L.M.; Cimminiello, C.; Csiba, L.; Kaste, M.; Leys, D.; Matias-Guiu, J.; Rupprecht, H.J.; investigators, M. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 2004, 364, 331–337, doi:10.1016/S0140-6736(04)16721-4.
[34]
Sacco, R.L.; Diener, H.C.; Yusuf, S.; Cotton, D.; Ounpuu, S.; Lawton, W.A.; Palesch, Y.; Martin, R.H.; Albers, G.W.; Bath, P.; et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N. Engl. J. Med. 2008, 359, 1238–1251, doi:10.1056/NEJMoa0805002.
[35]
Falcone, G.J.; Brouwers, H.B.; Rosand, J. Risk of intracranial hemorrhage with protease-activated receptor-1 antagonists. Stroke 2012, 43, 3158–3159, doi:10.1161/STROKEAHA.112.676932.
[36]
Siller-Matula, J.M.; Krumphuber, J.; Jilma, B. Pharmacokinetic, pharmacodynamic and clinical profile of novel antiplatelet drugs targeting vascular diseases. Br. J. Pharmacol. 2010, 159, 502–517, doi:10.1111/j.1476-5381.2009.00555.x.
[37]
Zhang, P.; Gruber, A.; Kasuda, S.; Kimmelstiel, C.; O'Callaghan, K.; Cox, D.H.; Bohm, A.; Baleja, J.D.; Covic, L.; Kuliopulos, A. Suppression of arterial thrombosis without affecting hemostatic parameters with a cell-penetrating PAR1 pepducin. Circulation 2012, 126, 83–91, doi:10.1161/CIRCULATIONAHA.112.091918.
[38]
Connolly, S.J.; Ezekowitz, M.D.; Yusuf, S.; Eikelboom, J.; Oldgren, J.; Parekh, A.; Pogue, J.; Reilly, P.A.; Themeles, E.; Varrone, J.; Wang, S.; et al. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2009, 361, 1139–1151, doi:10.1056/NEJMoa0905561.
[39]
Granger, C.B.; Alexander, J.H.; McMurray, J.J.; Lopes, R.D.; Hylek, E.M.; Hanna, M.; Al-Khalidi, H.R.; Ansell, J.; Atar, D.; Avezum, A.; et al. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 2011, 365, 981–992, doi:10.1056/NEJMoa1107039.
[40]
Patel, M.R.; Mahaffey, K.W.; Garg, J.; Pan, G.; Singer, D.E.; Hacke, W.; Breithardt, G.; Halperin, J.L.; Hankey, G.J.; Piccini, J.P.; et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 2011, 365, 883–891, doi:10.1056/NEJMoa1009638.
[41]
Schulman, S.; Kearon, C.; Kakkar, A.K.; Schellong, S.; Eriksson, H.; Baanstra, D.; Kvamme, A.M.; Friedman, J.; Mismetti, P.; Goldhaber, S.Z.; et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N. Engl. J. Med. 2013, 368, 709–718, doi:10.1056/NEJMoa1113697.
[42]
EINSTEIN Investigators; Bauersachs, R.; Berkowitz, S.D.; Brenner, B.; Buller, H.R.; Decousus, H.; Gallus, A.S.; Lensing, A.W.; Misselwitz, F.; Prins, M.H.; et al. Oal rivaroxaban for symptomatic venous thromboembolism. N. Engl. J. Med. 2010, 363, 2499–2510, doi:10.1056/NEJMoa1007903.
[43]
Mega, J.L.; Braunwald, E.; Wiviott, S.D.; Bassand, J.P.; Bhatt, D.L.; Bode, C.; Burton, P.; Cohen, M.; Cook-Bruns, N.; Fox, K.A.; et al. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med. 2012, 366, 9–19, doi:10.1056/NEJMoa1112277.