Pl^A polymorphism of the glycoprotein IIIa and efficacy of reperfusion therapy in patients with acute myocardial infarction

Summary

The Pl^A polymorphism of the platelet glycoprotein IIIa gene is associated with altered platelet function and response to antiplatelet drugs. We sought to assess whether the Pl^A polymorphism influences myocardial salvage achieved by reperfusion therapy in patients with acute myocardial infarction. We analyzed 292 patients enrolled in 2 randomized trials that compared stenting plus abciximab with thrombolysis (alteplase alone or alteplase plus abciximab) in acute myocardial infarction. Patients were genotyped for the Pl^A polymorphism using polymerase chain reaction with fluorogenic probes. Technetium-99m sestamibi was injected before and 1-2 weeks after reperfusion treatment. The scintigrams enabled the calculation of the initial perfusion defect, final infarct size, and the proportion of initial defect salvaged by reperfusion (salvage index). Clinical follow-up was done up to 18 months after primary treatment. The genotype distribution was as follows: Pl^A2/A2 in 3.4%, Pl^A1/A2 in 24.7% and Pl^A1/A1 in 71.9% of patients. There were no significant differences between Pl^A2 allele carriers and Pl^A1/A1 patients in salvage index (0.46±0.50 vs. 0.41±0.43, respectively, P=0.48), final infarct size (16.8±20.8% vs. 18.4±19.1% of left ventricle, respectively, P=0.46) as well as 18-month mortality (8.5% vs.7.1%, respectively, P=0.69). The lack of relationship between Pl^A2 allele and myocardial salvage was observed for both reperfusion strategies, stenting and thrombolysis. Thus, these findings show that the functional Pl^A polymorphism of platelet glycoprotein IIIa has no influence on the degree of myocardial salvage achieved by reperfusion therapies in patients with acute myocardial infarction.

Keywords

Pl^A polymorphism - glycoprotein IIIa - platelets - acute myocardial infarction - reperfusion

• References

• 1 Lincoff AM, Topol EJ. Illusion of reperfusion. Does anyone achieve optimal reperfusion during acute myocardial infarction? Circulation 1993; 88: 1361-74.
• 2 Roe MT, Ohman EM, Maas AC. et al. Shifting the open-artery hypothesis downstream: the quest for optimal reperfusion. J Am Coll Cardiol 2001; 37: 9-18.
• 3 Ito H, Maruyama A, Iwakura K. et al. Clinical implications of the ‘no reflow’ phenomenon. A predictor of complications and left ventricular remodeling in reperfused anterior wall myocardial infarction. Circulation 1996; 93: 223-8.
• 4 Wu KC, Zerhouni EA, Judd RM. et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation 1998; 97: 765-72.
• 5 Dong J, Ndrepepa G, Schmitt C. et al. Early resolution of ST-segment elevation correlates with myocardial salvage assessed by Tc-99m sestamibi scintigraphy in patients with acute myocardial infarction after mechanical or thrombolytic reperfusion therapy. Circulation 2002; 105: 2946-9.
• 6 Gavin JB, Maxwell L, Edgar SG. Microvascular involvement in cardiac pathology. J Mol Cell Cardiol 1998; 30: 2531-40.
• 7 Gawaz M, Neumann FJ, Ott I. et al. Platelet function in acute myocardial infarction treated with direct angioplasty. Circulation 1996; 93: 229-37.
• 8 Kastrati A, Schömig A, Seyfarth M. et al. PlA polymorphism of platelet glycoprotein IIIa and risk of restenosis after coronary stent placement. Circulation 1999; 99: 1005-10.
• 9 Kastrati A, Koch W, Gawaz M. et al. PlA polymorphism of glycoprotein IIIa and risk of adverse events after coronary stent placement. J Am Coll Cardiol 2000; 36: 84-9.
• 10 Weiss EJ, Bray PF, Tayback M. et al. A polymorphism of a platelet glycoprotein receptor as an inherited risk factor for coronary thrombosis. N Engl J Med 1996; 334: 1090-4.
• 11 Zotz RB, Winkelmann BR, Nauck M. et al. Polymorphism of platelet membrane glycoprotein IIIa: human platelet antigen 1b (HPA-1b/PlA2) is an inherited risk factor for premature myocardial infarction in coronary artery disease. Thromb Haemost 1998; 79: 731-5.
• 12 Feng D, Lindpaintner K, Larson MG. et al. Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism: the Framingham Offspring Study. Arterioscler Thromb Vasc Biol 1999; 19: 1142-7.
• 13 Undas A, Brummel K, Musial J. et al. Pl(A2) polymorphism of beta(3) integrins is associated with enhanced thrombin generation and impaired antithrombotic action of aspirin at the site of microvascular injury. Circulation 2001; 104: 2666-72.
• 14 Schömig A, Kastrati A, Dirschinger J. et al. Coronary stenting plus platelet glycoprotein IIb/IIIa blockade compared with tissue plasminogen activator in acute myocardial infarction. N Engl J Med 2000; 343: 385-91.
• 15 Kastrati A, Mehilli J, Dirschinger J. et al. Myocardial salvage after coronary stenting plus abciximab versus fibrinolysis plus abciximab in patients with acute myocardial infarction: a randomised trial. Lancet 2002; 359: 920-5.
• 16 Livak KJ. Allelic discrimination using fluorogenic probes and the 5’ nuclease assay. Genet Anal 1999; 14: 143-9.
• 17 Ryan TJ, Antman EM, Brooks NH. et al. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol 1999; 34: 890-911.
• 18 Mukherjee D, Moliterno DJ. Achieving tissuelevel perfusion in the setting of acute myocardial infarction. Am J Cardiol 2000; 85: 39C-46C.
• 19 Massberg S, Enders G, Leiderer R. et al. Platelet-endothelial cell interactions during ischemia/reperfusion: the role of P-selectin. Blood 1998; 92: 507-15.
• 20 Massberg S, Enders G, Matos FC. et al. Fibrinogen deposition at the postischemic vessel wall promotes platelet adhesion during ischemia-reperfusion in vivo. Blood 1999; 94: 3829-38.
• 21 Serebruany VL, Gurbel PA. Effect of thrombolytic therapy on platelet expression and plasma concentration of PECAM-1 (CD31) in patients with acute myocardial infarction. Arterioscler Thromb Vasc Biol 1999; 19: 153-8.
• 22 Gurbel PA, Serebruany VL, Shustov AR. et al. Increased baseline levels of platelet P-selectin, and platelet-endothelial cell adhesion molecule-1 in patients with acute myocardial infarction as predictors of unsuccessful thrombolysis. Coron Artery Dis 1998; 09: 451-6.
• 23 Gawaz M, Neumann FJ, Ott I. et al. Changes in membrane glycoproteins of circulating platelets after coronary stent implantation. Heart 1996; 76: 166-72.
• 24 Gawaz M, Neumann FJ, Dickfeld T. et al. Vitronectin receptor (alpha(v)beta3) mediates platelet adhesion to the luminal aspect of endothelial cells: implications for reperfusion in acute myocardial infarction. Circulation 1997; 96: 1809-18.
• 25 Nurden AT. Polymorphisms of human platelet membrane glycoproteins: structure and clinical significance. Thromb Haemost 1995; 74: 345-51.
• 26 Vijayan KV, Goldschmidt-Clermont PJ, Roos C. et al. The Pl(A2) polymorphism of integrin beta(3) enhances outside-in signaling and adhesive functions. J Clin Invest 2000; 105: 793-802.
• 27 Goodall AH, Curzen N, Panesar M. et al. Increased binding of fibrinogen to glycoprotein IIIa-Proline33 (HPA-1b, PlA2, Zwb) positive platelets in patients with cardiovascular disease. Eur Heart J 1998; 20: 742-7.
• 28 Szczeklik A, Sanak M, Undas A. Platelet glycoprotein IIIa pl(a) polymorphism and effects of aspirin on thrombin generation. Circulation 2001; 103: E33-4.
• 29 Ridker PM, Hennekens CH, Scmitz C. et al. Pl^A1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet 1997; 349: 385-8.
• 30 Bray PF, Cannon CP, Goldschmidt-Clermont P. et al. The platelet Pl(A2) and angiotensinconverting enzyme (ACE) D allele polymorphisms and the risk of recurrent events after acute myocardial infarction. Am J Cardiol 2001; 88: 347-52.
• 31 Zotz RB, Klein M, Dauben HP. et al. Prospective analysis after coronary-artery bypass grafting: platelet GP IIIa polymorphism (HPA-1b/PIA2) is a risk factor for bypass occlusion, myocardial infarction, and death. Thromb Haemost 2000; 83: 404-7.
• 32 Walter DH, Schächinger V, Elsner M. et al. Platelet glycoprotein IIIa polymorphisms and risk of coronary stent thrombosis. Lancet 1997; 350: 1217-9.
• 33 Laule M, Cascorbi I, Stangl V. et al. A1/A2 polymorphism of glycoprotein IIIa and association with excess procedural risk for coronary catheter interventions: a case-controlled study. Lancet 1999; 353: 708-12.
• 34 Goldschmidt-Clermont PJ, Cooke GE, Eaton GM. et al. PlA2, a variant of GPIIIa implicated in coronary thromboembolic complications [editorial]. J Am Coll Cardiol 2000; 36: 90-3.
• 35 Brscic E, Bergerone S, Gagnor A. et al. Acute myocardial infarction in young adults: prognostic role of angiotensin-converting enzyme, angiotensin II type I receptor, apolipoprotein E, endothelial constitutive nitric oxide synthase, and glycoprotein IIIa genetic polymorphisms at medium-term follow-up. Am Heart J 2000; 139: 979-84.
• 36 Walter DH, Schachinger V, Elsner M. et al. Statin therapy is associated with reduced restenosis rates after coronary stent implantation in carriers of the Pl(A2)allele of the platelet glycoprotein IIIa gene. Eur Heart J 2001; 22: 587-95.
• 37 Wheeler GL, Braden GA, Bray PF. et al. Reduced inhibition by abciximab in platelets with the PlA2 polymorphism. Am Heart J 2002; 143: 76-82.
• 38 Unkelbach K, Kalb R, Santoso S. et al. Genomic RFLP typing of human platelet alloantigens Ww(Pl^A), Ko, Bak and Br (HPA-1, 2, 3, 5). Br J Haematol 1995; 89: 169-76.
• 39 Legler TJ, Kohler M, Mayr WR. et al. Genotyping of the human platelet antigen systems 1 through 5 by multiplex polymerase chain reaction and ligation-based typing. Transfusion 1996; 36: 426-31.
• 40 Samani NJ, Lodwick D. Glycoprotein IIIa polymorphism and risk of myocardial infarction. Cardiovasc Res 1997; 33: 693-7.