Lack of association between the 807 C/T polymorphism of glycoprotein Ia gene and post-treatment platelet reactivity after aspirin and clopidogrel in patients with acute coronary syndrome

Thomas Cuisset; Corinne Frere; Jacques Quilici; Pierre-Emmanuel Morange; Noémie Saut; Marie Romero-Barra; Laurence Camoin; Marc Lambert; Irène Juhan-Vague; Jean-Louis Bonnet; Marie-Christine Alessi

doi:10.1160/TH06-10-0583

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 97(02): 212-217
DOI: 10.1160/TH06-10-0583

Platelets and Blood Cells

Schattauer GmbH

Lack of association between the 807 C/T polymorphism of glycoprotein Ia gene and post-treatment platelet reactivity after aspirin and clopidogrel in patients with acute coronary syndrome

Thomas Cuisset

¹Department of Cardiology, CHU Timone, Marseille, France;

,

Corinne Frere

²INSERM, UMR 626, Faculté de Médecine CHU Timone, Marseille, France

,

Jacques Quilici

¹Department of Cardiology, CHU Timone, Marseille, France;

,

Pierre-Emmanuel Morange

²INSERM, UMR 626, Faculté de Médecine CHU Timone, Marseille, France

,

Noémie Saut

²INSERM, UMR 626, Faculté de Médecine CHU Timone, Marseille, France

,

Marie Romero-Barra

²INSERM, UMR 626, Faculté de Médecine CHU Timone, Marseille, France

,

Laurence Camoin

³Laboratory of Haematology, CHU Conception, Marseille, France

,

Marc Lambert

¹Department of Cardiology, CHU Timone, Marseille, France;

,

Irène Juhan-Vague

²INSERM, UMR 626, Faculté de Médecine CHU Timone, Marseille, France

,

Jean-Louis Bonnet

¹Department of Cardiology, CHU Timone, Marseille, France;

,

Marie-Christine Alessi

²INSERM, UMR 626, Faculté de Médecine CHU Timone, Marseille, France

› Author Affiliations

Abstract

Summary

Variability in platelet response to antiplatelet therapy and its clinical relevance have been well described. However, the underlying mechanisms remain unclear. It was the aim of the present study to assess whether the response to aspirin and clopidogrel may be influenced by the 807 C/T polymorphism of the glycoprotein Ia (GpIa) gene in patients with non-ST elevation acute coronary syndrome (NSTE ACS). Six hundred one NSTE ACS patients were included in our study and were divided into three groups: CC homozygotes, CT heterozygotes ad TT homozygotes. All patients received loading doses of 600 mg clopidogrel and 250 mg aspirin at least 12 hours before blood samples were drawn. Post-treatment platelet reactivity was assessed by post treatment ADP 10 µM-induced platelet aggregation (ADP-Ag), VASP phosphorylation (PRI VASP) and P-selectin expression. Non-response to dual antiplatelet therapy was defined by high post-treatment platelet reactivity (HPPR= ADP-Ag>70%). Significant variability in the distribution of platelet parameters was observed in the overall study population. No significant difference in platelet parameters profiles was observed within patients having the same genotype, for ADP-Ag (p=0.33), PRIVASP (p=0.72) and P-selectin expression (p=0.37). The genotype frequencies of the 807 C/T polymorphism of the GpIa gene were similar in responders and non-responders defined by persistent HPPR (p=0.104). In conclusion, our study did not show any influence of 807 C/T polymorphism of GpIa gene on post-treatment platelet reactivity assessed by ADP-Ag, PRI VASP or P-selectin expression in 601 NSTE ACS patients.

Keywords

ADP receptors - polymorphisms - coronary syndrome - collagen receptors - antiplatelet agents

Full Text

References

References
1 Yusuf S, Zhao F, Mehta SR. et al. Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without STsegment elevation. N Engl J Med 2001; 345: 494-502.
2 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.
3 Sanderson S, Emery J, Baglin T. et al. Narrative review: aspirin resistance and its clinical implications. Ann Intern Med 2005; 142: 370-380.
4 Gurbel PA, Bliden KP, Hiatt BL. et al. Clopidogrel for coronary stenting:response variability, drug resistance, and the effect of pretreatment platelet reactivity. Circulation 2003; 107: 2908-2913.
5 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Identification of low responders to a 300-mg clopidogrel loading dose in patients undergoing coronary stenting. Thromb Res 2005; 115: 101-108.
6 Jaremo P, Lindahl TL, Fransson SG. et al. Individual variations of platelet inhibition after loading doses of clopidogrel. J Intern Med 2002; 252: 233-238.
7 Muller I, Besta F, Schulz C. et al. Prevalence of clopidogrel non-responders among patients with stable angina pectoris scheduled for elective coronary stent placement. Thromb Haemost 2003; 89: 783-787.
8 Serebruany VL, Steinhubl SR, Berger PB. et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol 2005; 45: 246-251.
9 Barragan P, Bouvier JL, Roquebert PO. et al. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003; 59: 295-302.
10 Gurbel PA, Bliden KP, Samara W. et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST Study. J Am Coll Cardiol 2005; 46: 1827-1832.
11 Wenaweser P, Hess O. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol 2005; 46: CS5-6.
12 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.
13 Cuisset T, Frere C, Quilici J. et al. High post-treatment platelet reactivity identified low-responders to dual antiplatelet therapy at increased risk of recurrent cardiovascular events after stenting for acute coronary syndrome. J Thromb Haemost 2006; 4: 542-549.
14 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27: 2420-2425.
15 Hochholzer W, Trenk D, Bestehorn HP. et al. Impact of the degree of peri-interventional platelet inhibition after loading with clopidogrel on early clinical outcome of elective coronary stent placement. J Am Coll Cardiol 2006; 48: 1742-1750.
16 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Role of the 807 C/T polymorphism of glycoprotein Ia/Iia on platelet function following clopidogrel loading- dose in patients undergoing coronary stenting. Blood Coagul Fibrinolysis 2004; 15: 427-433.
17 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Variability in platelet aggregation following sustained aspirin and treatment in patients with coronary heart disease and influence polymorphism of the glycoprotein Ia gene. Am J Cardiol 2005; 96: 1095-1099.
18 Kastrati A, Mehilli J, Neumann FJ. et al. Intracoronary Stenting and Antithrombotic: Regimen Rapid Early Action for Coronary Treatment 2 (ISAR-REACT 2) Trial Investigators. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR-REACT 2 randomized trial. J Am Med Assoc 2006; 295: 1531-1538.
19 Jernberg T, Payne CD, Winters KJ. et al. Prasugrel achieves greater inhibition of platelet agregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J 2006; 27: 1166-1173.
20 Kastrati A, von Beckerath N, Joost A. et al. Loading with 600 mg clopidogrel in patients with coronary artery disease with and without chronic clopidogrel therapy. Circulation 2004; 110: 1916-1919.
21 Gurbel PA, Bliden KP, Hayes KM. et al. The relation of dosing to clopidogrel responsiveness and the incidence of high post-treatment platelet aggregation in patients undergoing coronary stenting. J Am Coll Cardiol 2005; 45: 1392-1396.
22 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. High clopidogrel loading dose during coronary stenting: effects on drug response and interindividual variability. Eur Heart J 2004; 25: 1903-1910.
23 Gurbel PA, Bliden KP, Zaman KA. et al. Clopidogrel loading with eptifibatide to arrest the reactivity of platelets: results of the Clopidogrel Loading With Eptifibatide to Arrest the Reactivity of Platelets (CLEAR PLATELETS) study. Circulation 2005; 111: 1153-1159.
24 von Beckerath N, Taubert D, Pogatsa-Murray G. et al. Absorption, metabolization, and antiplatelet effects of 300-, 600-, and 900-mg loading doses of clopidogrel: results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial. Circulation 2005; 112: 2946-2950.
25 Patti G, Colonna G, Pasceri V. et al. Randomized Trial of High Loading Dose of Clopidogrel for Reduction of Periprocedural Myocardial Infarction in Patients Undergoing Coronary Intervention. Results From the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) Study. Circulation 2005; 111: 2099-2106.
26 Cuisset T, Frere C, Quilici J. et al. Benefit of a 600 mg loading dose of clopidogrel on platelet reactivity and clinical outcomes in patients with non-ST elevation acute coronary syndrome undergoing coronary stenting. J Am Coll Cardiol 2006; 48: 1339-1345.
27 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Lack of association between the P2Y12 receptor gene polymorphism and platelet response to clopidogrel in patients with coronary artery disease. Thromb Res 2005; 116: 491-497.
28 von Beckerath N, von Beckerath O, Koch W. et al. A P2Y12 gene H2 haplotype is not associated with increased adenosine diphosphate-induced platelet aggregation after initiation of clopidogrel therapy with a high loading dose. Blood Coagul Fibrinolysis 2005; 16: 199-204.
29 Lev E, Patel RT, Guthikonda S. et al. Genetic polymorphisms of the platelet receptors P2Y12, P2Y1 and GP IIIa and response to aspirin and clopidogrel. Thromb Res. 2006. in press.
30 Hulot JS, Bura A, Villard E. et al. Cytochrome P450 2C19 loss-of-function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects. Blood. 2006. in press.
31 Angiolillo DJ, Fernandez-Ortiz A, Bernardo E. et al. Contribution of gene sequence variations of the hepatic cytochrome P450 3A4 enzyme to variability in individual responsiveness to clopidogrel. Arterioscler Thromb Vasc Biol 2006; 26: 1895-1900.
32 Clemetson KJ, Clemetson JM. Platelet collagen receptors. Thromb Haemost 2001; 86: 189-197.
33 Watson S, Berlanga O, Best D. et al. Update on collagen receptor interactions in platelets: is the twostate model still valid?. Platelets 2000; 11: 252-258.
34 Kuijpers MJ, Schulte V, Bergmeier W. et al. Complementary roles of glycoprotein VI and alpha2beta1 integrin in collagen-induced thrombus formation in flowing whole blood ex vivo. FASEB J 2003; 17: 685-687.
35 Kritzik M, Savage B, Nugent DJ. et al. Nucleotide polymorphisms in the alpha2 gene define multiple alleles that are associated with differences in platelet alpha2 beta1 density. Blood 1998; 92: 2382-2388.
36 Reiner AP, Aramaki KM, Teramura G. et al. Analysis of platelet glycoprotein Ia (alpha 2 integrin) allele frequencies in three North American populations reveals genetic association between nucleotide 807 C/T and amino acid 505 Glu/Lys (HPA-5) dimorphisms. Thromb Haemost 1998; 80: 449-456.
37 Kunicki TJ, Kritzik M, Annis DS. et al. Hereditary variation in platelet integrin alpha 2 beta 1 density is associated with two silent polymorphisms in the alpha 2 gene coding sequence. Blood 1997; 89: 1939-1943.
38 Kunicki TJ, Orchekowski R, Annis D. et al. Variability of integrin alpha 2 beta 1 activity on human platelets. Blood 1993; 82: 2693-2703.
39 Kunicki TJ. The influence of platelet collagen receptor polymorphisms in hemostasis and thrombotic disease. Arterioscler Thromb Vasc Biol 2002; 22: 14-20.
40 Luzak B, Golanski J, Rozalski M. et al. Effect of the 807 c/t polymorphism in glycoprotein Ia on blood platelets reactivity. J Biomed Sci 2003; 10: 731-737.
41 Samara WM, Bliden KP, Tantry US. et al. The difference between clopidogrel responsiveness and posttreatment platelet reactivity. Thromb Res 2005; 115: 89-94.