Analysis of platelet α2-adrenergic receptor activity in stable coronary artery disease patients on dual antiplatelet therapy

Bernát János Béres; Emese Tóth-Zsámboki; Katarína Vargová; Ádám László; Tamás Masszi; Gábor Kerecsen; István Préda; Róbert Gábor Kiss

doi:10.1160/TH08-03-0158

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2008; 100(05): 829-838
DOI: 10.1160/TH08-03-0158

Platelets and Blood Cells

Schattauer GmbH

Analysis of platelet α2-adrenergic receptor activity in stable coronary artery disease patients on dual antiplatelet therapy

Authors

Bernát János Béres^*

¹Research Group for Inflammation Biology and Immunogenomics of Hungarian Academy of Sciences and Semmelweis University Budapest, Hungary
Emese Tóth-Zsámboki^*

¹Research Group for Inflammation Biology and Immunogenomics of Hungarian Academy of Sciences and Semmelweis University Budapest, Hungary

²State Health Center, Department of Cardiology, Budapest, Hungary
Katarína Vargová

¹Research Group for Inflammation Biology and Immunogenomics of Hungarian Academy of Sciences and Semmelweis University Budapest, Hungary
Ádám László

³Szent László Hospital, Department of Bone Marrow Transplantation, Budapest, Hungary
Tamás Masszi

³Szent László Hospital, Department of Bone Marrow Transplantation, Budapest, Hungary
Gábor Kerecsen

²State Health Center, Department of Cardiology, Budapest, Hungary
István Préda

¹Research Group for Inflammation Biology and Immunogenomics of Hungarian Academy of Sciences and Semmelweis University Budapest, Hungary

²State Health Center, Department of Cardiology, Budapest, Hungary
Róbert Gábor Kiss

¹Research Group for Inflammation Biology and Immunogenomics of Hungarian Academy of Sciences and Semmelweis University Budapest, Hungary

²State Health Center, Department of Cardiology, Budapest, Hungary

Abstract

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Summary

Combined antiplatelet therapy reduces recurrent atherothrombotic events in stable coronary disease patients; however, high residual platelet reactivity measured ex vivo still raises concerns as a condition related to treatment failure. Alpha-2 adrenoceptor enhances platelet reactivity and might contribute to this phenomenon. For the present study, 121 stable angina patients on standard dual antiplatelet therapy (75 mg clopidogrel and 100 mg acetylsalicylic acid) were recruited. Born aggregometry was performed with adenosine diphosphate (ADP),collagen and epnephrine. To verify platelet adrenergic activity, potentiation by low-dose epinephrine and inhibition by selective alpha-2 receptor blocker atipamezole were determined. To assess the P2Y₁₂-specific residual activity, cangrelor was used. Plasma norepinephrine, soluble CD40-ligand, high-sensitivity-C-reactive protein (hsCRP) - and in 24 subjects platelet P-selectin positivity were measured. Epinephrine - at very low concentration (10^-9g/ml) - significantly potentiates (1.25 µM ADP: 26.5% vs. 43%; 5 µM ADP: 53% vs. 64.5%; collagen: 17% vs 42%, p<0.001) while atipamezole inhibits ADP- and collagen-induced platelet aggregations (1.25 µM ADP: 26.5% vs. 23%; 5 µM ADP: 53% vs. 47%;collagen:17% vs.11%,p<0.001).Patients with high adrenergic activity have significantly increased baseline ADP- and collagen-induced platelet aggregation. Based on cangrelor’s efficacy, these patients have significantly more residual P2Y₁₂ activity as well.HsCRP and soluble CD40-ligand levels were similar.In conclusion, stable coronary heart disease patients with prominent adrenoceptor activity in vitro have significantly increased platelet aggregability and more functional P2Y₁₂ receptor, indicating poor inhibitory response to thienopyridines.Therefore,platelet adrenergic receptor represents a considerable, dynamic factor of high residual platelet reactivity and might contribute to cardiovascular events indicating failure of antiplatelet therapy.

Keywords

Antiplatelet agents - cardiology - platelet physiology - receptors

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References

References
1 Siegel-Axel DI, Gawaz M. Platelets and endothelial cells. Semin Thromb Hemost 2007; 33: 128-135.
2 Gachet C. P2 receptors, platelet function and pharmacological implications. Thromb Haemost 2008; 99: 466-472.
3 Catella-Lawson F, Reilly M, Kapoor S. et al. Cyclooxygenase inhibitors and the antiplatelet effects of aspirin. N Eng J Med 2001; 345: 1809-1817.
4 Silber S, Albertsson P, Avilés FF. et al. Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology Guidelines for percutaneous coronary interventions The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology. Eur Heart J 2005; 26: 804-847.
5 Smith SC, Feldman TE, Hirshfeld JW. et al. American College of Cardiology/American Heart Association Task Force on Practice Guidelines; ACC/AHA/ SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention ACC/ AHA/SCAI 2005 Guideline Update for Percutaneous Coronary Intervention-Summary Article: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/ AHA/SCAI Writing Committee to Update the 2001 Guidelines for Percutaneous Coronary Intervention). J Am Coll Cardiol 2006; 47: 216-235.
6 Steinhubl SR, Berger PB, Mann 3rd JT. et al. CREDO Investigators Clopidogrel for the Reduction of Events During Observation Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. J Am Med Assoc 2002; 288: 2411-2420.
7 Mehta SR, Yusuf S, Peters RJ. et al. Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358: 527-533.
8 Wang TH, Bhatt DL, Topol EJ. Aspirin and clopidogrel resistance: an emerging clinical entity. Eur Heart J 2006; 27: 647-654.
9 Lepäntalo A, Mikkelsson J, Reséndiz JC. et al. Polymorphisms of COX-1 and GPVI associate with the antiplatelet effect of aspirin in coronary artery disease patients Thromb Haemost. 2006; 95: 253-259.
10 Mustonen P, van Willigen G, Lassila R. Epinephrine—Via Activation of P38-Mapk—Abolishes the Effect of Aspirin on Platelet Deposition to Collagen. Thromb Res 2001; 104: 439-449.
11 Wallén NH, Held C, Rehnqvist N. et al. Effects of mental and physical stress on platelet function in patients with stable angina pectoris and healthy controls. Eur Heart J 1997; 18: 807-815.
12 Christiaens L, Macchi L, Herpin D. et al. Resistance to aspirin in vitro at rest and during exercise in patients with angiographically proven coronary artery disease. Thromb Res 2002; 108: 115-119.
13 Ikarugi H, Taka T, Nakajima S. et al. Norepinephrine, but not epinephrine, enhances platelet reactivity and coagulation after exercise in humans. J Appl Physiol 1999; 86: 133-138.
14 Li N, Wallén NH, Hjemdahl P. Evidence for prothrombotic effects of exercise and limited protection by aspirin. Circulation 1999; 100: 1374-1379.
15 Perneby C, Wallén NH, Hu H. et al. Prothrombotic responses to exercise are little influenced by clopidogrel treatment. Thromb Res 2004; 114: 135-143.
16 Perneby C, Wallén NH, Hofman-Bang C. et al. Effect of clopidogrel treatment on stress-induced platelet activation and myocardial ischemia in aspirin-treated patients with stable coronary artery disease. Thromb Haemost 2007; 98: 1316-1322.
17 Aleil B, Ravanat C, Cazenave JP. et al. Flow cytometric analysis of intraplatelet VASP phosphorylation for the detection of clopidogrel resistance in patients with ischemic cardiovascular diseases. J Thromb Hae-most 2005; 03: 85-92.
18 Pampuch A, Cerletti C, de Gaetano G. Comparison of VASP-phosphorylation assay to light-transmission aggregometry in assessing inhibition of the platelet ADP P2Y12 receptor. Thromb Haemost 2006; 96: 767-773.
19 Mustonen P, Savola J, Lassila R. Atipamezole, an imidazoline-type alpha(2)-adrenoceptor inhibitor, binds to human platelets and inhibits their adrenaline-induced aggregation more effectively than yohimbine. Thromb Res 2000; 99: 231-237.
20 Pertovaara A, Haapalinna A, Sirviö J. et al. Pharmacological properties, central nervous system effects, and potential therapeutic applications of atipamezole, a selective alpha2-adrenoceptor antagonist. CNS Drug Rev 2006; 11: 273-288.
21 Zeymer U, Gitt AK, Jünger C. et al. Clopidogrel in addition to aspirin reduces in-hospital major cardiac and cerebrovascular events in unselected patients with acute ST segment elevation myocardial. Thromb Hae-most 2008; 99: 155-160.
22 Lordkipanidzé M, Pharand C, Schampaert E. et al. A comparison of six major platelet function tests to determine the prevalence of aspirin resistance in patients with stable coronary artery disease. Eur Heart J 2007; 28: 1702-1708.
23 Gum PA, Kottke-Marchant K, Welsh PA. et al. A prospective, blinded determination of the natural history of aspirin resistance among stable patients with cardiovascular disease. J Am Coll Cardiol 2003; 41: 961-965.
24 Gurbel PA, Lau WC, Bliden KP. et al. Clopidogrel resistance: implications for coronary stenting. Curr Pharm Des 2006; 12: 1261-1269.
25 Matetzky S, Shenkman B, Guetta V. et al. Clopidogrel resistance is associated with increased risk of recurrent atherothrombotic events in patients with acute myocardial infarction. Circulation 2004; 109: 3171-3175.
26 Cuisset T, Frere C, Quilici J. et al. High post-treatment platelet reactivity is associated with a high incidence of myonecrosis after stenting for non-ST elevation acute coronary syndromes. Thromb Haemost 2007; 97: 282-287.
27 Marcucci R, Paniccia R, Antonucci E. et al. Residual platelet reactivity is an independent predictor of myocardial injury in acute myocardial infarction patients on antiaggregant therapy. Thromb Haemost 2007; 98: 844-851.
28 Lev EI, Patel RT, Maresh KJ. et al. Aspirin and clopidogrel drug response in patients undergoing percutaneous coronary intervention: the role of dual drug resistance. J Am Coll Cardiol 2006; 47: 27-33.
29 Yang J, Wu J, Jiang H. et al. Signaling through Gi family members in platelets Redundancy and specificity in the regulation of adenylyl cyclase and other effectors. J Biol Chem 2002; 277: 46035-46042.
30 Motulsky HJ, Shattil SJ, Ferry N. et al. Desensitization of epinephrine-initiated platelet aggregation does not alter binding to the alpha 2-adrenergic receptor or receptor coupling to adenylate cyclase. Mol Pharmacol 1986; 29: 1-6.
31 Johnston GI, Cook RG, MacEver RP. Cloning of GMP-140, a granule membrane protein of platelets and endothelium: sequence similarity to proteins involved in cell adhesion and inflammation. Cell 1989; 56: 1033-1044.
32 Shebuski RJ, Kilgore KS. Role of inflammatory mediators in thrombogenesis. J Pharmacol Exp Ther 2002; 300: 729-735.
33 Vandendries ER, Furie BC, Furie B. Role of P-selectin and PSGL-1 in coagulation and thrombosis. Thromb Haemost 2004; 92: 459-466.
34 Blann AD, Nadar SK, Lip GY. The adhesion molecule P-selectin and cardiovascular disease. Eur Heart J 2003; 24: 2166-2179.
35 Figures WR, Scearce LM, Wachtfogel Y. et al. Platelet ADP receptor and alpha 2-adrenoceptor interaction Evidence for an ADP requirement for epinephrine-induced platelet activation and an influence of epinephrine on ADP binding. J Biol Chem 1986; 261: 5981-5986.
36 Lahiri P, Chaudhuri U, Chattopadhyay A. et al. Structural insights in platelet receptor synergism - antiplatelet therapy in postischemic cerebrovascular events. Blood Cells Mol Dis 2005; 34: 248-256.
37 Ding Z, Kim S, Dorsam RT. et al. Inactivation of the human P2Y12 receptor by thiol reagents requires interaction with both extracellular cysteine residues, Cys17 and Cys270. Blood 2003; 101: 3908-3914.
38 Fugate SE, Cudd LA. Cangrelor for treatment of coronary thrombosis. Ann Pharmacother 2006; 40: 925-930.
39 Lanza F, Beretz A, Stierlé A. et al. Epinephrine potentiates human platelet activation but is not an aggregating agent. Am J Physiol 1988; 255: H1276-1288.
40 Poulsen TS, Kristensen SR, Korsholm L. et al. Variation and importance of aspirin resistance in patients with known cardiovascular disease. Thromb Res 2007; 120: 477-484.
41 Helgason CM, Bolin KM, Hoff JA. et al. Development of aspirin resistance in persons with previous ischemic stroke. Stroke 1994; 25: 2331-2336.
42 Merkely B, Tóth-Zsámboki E, Becker D. et al. Very late drug-eluting stent thrombosis after non-steroidal antiinflammatory drug treatment despite dual antiplatelet therapy. Can J Cardiol.Accepted on 23th June. 2007
43 Schäfer A, Bonz AW, Eigenthaler M. et al. Late thrombosis of a drug-eluting stent during combined anti-platelet therapy in a clopidogrel nonresponsive diabetic patient: Shall we routinely test platelet function?. Thromb Haemost 2007; 97: 862-865.
44 Meine TJ, Roe MT, Chen AY. et al. CRUSADE Investigators Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. Am Heart J 2005; 149: 1043-1049.
45 López-Sendón J, Swedberg K, McMurray J. et al. Task Force On Beta-Blockers of the European Society of Cardiology Expert consensus document on beta-adrenergic receptor blockers. Eur Heart J 2004; 25: 1341-1362.