Thromb Haemost 1999; 82(02): 337-344
DOI: 10.1055/s-0037-1615851
Research Article
Schattauer GmbH

Integrin Polymorphisms as Risk Factors for Thrombosis

Paul F. Bray
1   Departments of Medicine and Pathology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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Publikationsdatum:
09. Dezember 2017 (online)

Introduction

By the year 2020, ischemic heart disease will become the number one public health problem on the planet, surpassing lower respiratory infections, diarrheal disease, perinatal problems, and unipolar major depression.1 Acute myocardial infarction, the most feared complication of coronary artery disease, results from the formation of an occlusive thrombus at the site of a ruptured atherosclerotic plaque. The 1990s have seen an increased awareness of the contribution of inherited disorders of hemostasis as risks for coronary thrombosis. Consideration for potential hypercoagulable states in patients with these disorders would seem justified, since, for example, the risk for an acute coronary event is considerably greater with an abnormally elevated fibrinogen level than with an elevated total cholesterol level.2,3 The clinical benefit of thrombolytic therapy in acute myocardial infarction provides further support for the importance of fibrin formation or dissolution in this setting.4,5 An appropriate hypercoagulable evaluation of an unusual arterial thrombosis, particularly in a young patient, would include assays for hyperhomocysteinemia, the lupus anticoagulant, anticardiolipin antibodies, as well as assays for fibrinogen and plasminogen activator inhibitor-1. Currently, less evidence exists to support measurements of tissue plasminogen activator, von Willebrand factor (vWF), factors VII or XIII, or those factors associated with venous thrombosis, such as activated protein C resistance/factor V Leiden or deficiencies of antithrombin III, protein C, or protein S.

There is also abundant evidence that platelet thrombi play a crucial role in the development of acute myocardial infarction. In 1974, Chandler et al summarized a series of pathologic studies examining coronary arteries of patients with acute myocardial infarction and reaffirmed the basic understanding that coronary artery thrombi can cause acute ischemia and myocardial infarction.6 DeWood et al provided in vivo evidence to corroborate pathologic data,7 and Trip et al correlated platelet hyperreactivity with coronary events and mortality in patients with established coronary artery disease.8 The clinical arena has also provided additional support for the central role of platelets in the acute ischemic coronary syndromes, myocardial infarction, and unstable angina. Antiplatelet therapy with aspirin, ticlopidine, clopidogrel, and inhibitors of integrin αIIbβ3 (e.g., abciximab and integrilin) has demonstrated beneficial effects in a number of coronary artery disease settings.9-11

Platelet physiology is arbitrarily divided into phases of adhesion, activation, secretion, and aggregation. When arterial subendothelium is exposed, vWF molecules are rapidly localized to these areas, and the initial platelet contact with the wound is a tethering to this insoluble form of vWF via glycoprotein (GP) Ibα.12,13 Stable adhesion and platelet activation is then mediated through integrin α2β1 binding to exposed collagen and integrin αIIbβ3 binding to vWF and fibrinogen.14 Fibrinogen has multiple αIIbβ3 binding sites, and an expanding thrombus ensues when platelets aggregate via the intercellular bridging of fibrinogen and vWF binding to the activated conformation of αIIbβ3. Three platelet membrane glycoprotein receptors, αIIbβ3, α2β1, and GP Ib-IX, have highly interactive and additive adhesive effects, ultimately resulting in stable thrombus formation.

Attempts to educate both physicians and the lay public about the so-called “traditional” risk factors for coronary artery disease and acute ischemic coronary syndromes have been successful,15 and there are now established preventive therapies, such as blood pressure control, cessation of cigarette smoking, and cholesterol lowering. Genetic variations confer a potent risk for coronary artery disease in many families, and, although these risks fall outside the domain of preventive medicine, an emerging concept in the field is that targeted genetic testing may be used to direct therapeutic decisions. Although inherited alterations of hemostatic factors are believed to be important in the development of acute ischemic coronary syndromes, until recently, inherited platelet risk factors had not been considered. This review will focus on the potential link between the genetic and platelet components of arterial thrombosis, in particular, coronary artery disease.

 
  • References

  • 1 Lopez AD, Murray CCJL. The global burden of disease, 1990-2020. Nat Med. 1998; 4: 1241-1243.
  • 2 Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet. 1986; 2: 533-537.
  • 3 Ernst E, Ludwig RK. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med. 1993; 118: 956-963.
  • 4 The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993; 329: 673-682.
  • 5 Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet. 1994; 343: 311-322.
  • 6 Chandler AB, Chapman I, Erhardt LR, Roberts WM, Schwartz CJ, Sinapius D, Spain DM, Sherry S, Ness PM, Simon TL. Coronary thrombosis in myocardial infarction: report of a workshop on the role of coronary thrombosis in the pathogenesis of acute myocardial infarction. Am J Card. 1974; 34: 823-833.
  • 7 DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med. 1980; 303: 897-902.
  • 8 Trip MD, Cats VM, van Capelle FJ, Vreeken J. Platelet hyperreactivity and prognosis in survivors of myocardial infarction. N Engl J Med. 1990; 322: 1549-1554.
  • 9 Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy—I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J. 1994; 308: 81-106.
  • 10 The EPILOG Investigators. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med. 1997; 336: 1689-1696.
  • 11 The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. Platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy. N Engl J Med. 1998; 339: 436-443.
  • 12 Bolhuis PA, Sakariassen KS, Sander HJ, Bouma BN, Sixma JJ. Binding of factor VIII-von Willebrand factor to human arterial subendothelium precedes increased platelet adhesion and enhances platelet spreading. J Lab Clin Med. 1981; 97: 568-576.
  • 13 Fredrickson BJ, Dong JF, McIntire LV, Lopez JA. Shear-dependent rolling on von Willebrand factor of mammalian cells expressing the platelet glycoprotein Ib-IX-V complex. Blood 1998; 92: 3684-3693.
  • 14 Savage B, Alums-Jacobs F, Ruggeri ZM. Specific synergy of multiple substrate-receptor interactions in platelet thrombus formation under flow. Cell. 1998; 94: 657-666.
  • 15 Cleeman JI, Lenfant C. The National Cholesterol Education Program: progress and prospects. JAMA. 1998; 280: 2099-2104.
  • 16 Sing CF, Haviland MB, Templeton AR, Zerba KE, Reilly SL. Biological complexity and strategies for finding DNA variations responsible for inter-individual variation in risk of a common chronic disease, coronary artery disease. Ann Med. 1992; 24: 539-547.
  • 17 Doggen CJ, Cats VM, Bertina RM, Rosendaal FR. Interaction of coagulation defects and cardiovascular risk factors: increased risk of myocardial infarction associated with factor V Leiden or prothrombin 20210A. Circulation. 1998; 97: 1037-1041.
  • 18 Kunicki TJ, Newman PJ. The molecular immunology of human platelet proteins. Blood 1992; 80: 1386-1404.
  • 19 Valentin N, Newman PJ. Human platelet alloantigens. Curr Opin Hematol. 1994; 1: 381-387.
  • 20 van Leeuwen EF, Leeksma OC, van Mourik JA, Engelfriet CP, von dem Borne AE. Effect of the binding of anti-Zwa antibodies on platelet function. Vox Sang. 1984; 47: 280-289.
  • 21 Kunicki TJ. Biochemistry of platelet-associated isoantigens and alloantigens. In: Kunicki TJ, George JN. eds. Platelet Immunobiology: Molecular and Clinical Aspects. Lippincott-Raven; Philadelphia: 1989: 99-120.
  • 22 Newman PJ, Derbes R, Aster RH. The human platelet alloantigens, P1A1 and P1A2, are associated with a leucine33/proline33 amino acid polymorphism in membrane glycoprotein IIIa, and are distinguishable by DNA typing. J Clin Invest. 1989; 83: 1778-1781.
  • 23 Weiss EJ, Bray PF, Tayback MT, Schulman SP, Kickler TS, Becker LC, Weiss JL, Gerstenblith G, Goldschmidt-Clermont PJ. The platelet glycoprotein IIIa polymorphism PlA2: An inherited platelet risk factor for coronary thrombotic events. N Engl J Med. 1996; 334: 1090-1094.
  • 24 Ridker PM, Hennekens CH, Schmitz C, Stampfer MJ, Lindpaintner K. PlA1/A2 polymorphism of platelet glycoprotein IIIa and risks of myocardial infarction, stroke, and venous thrombosis. Lancet. 1997; 349: 385-388.
  • 25 Zotz RB, Winkelmann BR, Nauck M, Giers G, Maruhn-Debowski B, Marz W, Scharf RE. 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: 731-735.
  • 26 Pastinen T, Perola M, Niini P, Terwilliger J, Salomaa V, Vartiainen E, Peltonen L, Syvanen A. Array-based multiplex analysis of candidate genes reveals two independent and additive genetic risk factors for myocardial infarction in the Finnish population. Hum Mol Genet. 1998; 7: 1453-1462.
  • 27 Carter AM, Ossei-Gerning N, Wilson IJ, Grant PJ. Association of the platelet PlA polymorphism of glycoprotein IIb/IIIa and the fibrinogen Bβ 448 polymorphism with myocardial infarction and extent of coronary disease. Circulation. 1997; 96: 1424-1431.
  • 28 Walter DH, Schachinger V, Elsner M, Dimmeler S, Zeiher AM. Platelet glycoprotein IIIa polymorphisms and risk of coronary stent thrombosis. Lancet. 1997; 350: 1217-1219.
  • 29 Abbate R, Marcucci R, Camacho-Vanegas O, Pepe G, Gori AM, Capanni M, Simonetti I, Prisco D, Gensini GF. Role of platelet glycoprotein PL(A1/A2) polymorphism in restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol. 1998; 82: 524-525.
  • 30 Gardemann A, Humme J, Stricker J, Nguyen QD, Katz N, Philipp M, Tillmanns H, Hehrlein FW, Rau M, Haberbosch W. Association of the platelet glycoprotein IIIa PlA1/A2 gene polymorphism to coronary artery disease but not to nonfatal myocardial infarction in low risk patients. Thromb Haemost. 1998; 80: 214-217.
  • 31 Garcia-Ribes M, Gonzalez-Lamuno D, Hernandez-Estefania R, Colman T, Pocovi M, Delgado-Rodriguez M, Garcia-Fuentes M, Revuelta JM. Polymorphism of the platelet glycoprotein IIIa gene in patients with coronary stenosis. Thromb Haemost. 1998; 79: 1126-1129.
  • 32 Herrmann SM, Poirier O, Marques-Vidal P, Evans A, Arveiler D, Luc G, Emmerich J, Cambien F. The Leu33/Pro polymorphism (PlA1/PlA2) of the glycoprotein IIIa (GPIIIa) receptor is not related to myocardial infarction in the ECTIM Study. Etude Cas-Temoins de l’Infarctus du Myocarde. Thromb Haemost. 1997; 77: 1179-1181.
  • 33 Samani N, Lodwick D. Glycoprotein IIIa polymorphism and risk of myocardial infarction. Cardiovasc Res. 1997; 33: 693-697.
  • 34 Durante-Mangoni E, Davies GJ, Ahmed N, Ruggiero G, Tuddenham EG. Coronary thrombosis and the platelet glycoprotein IIIA gene PLA2 polymorphism. Thromb Haemost. 1998; 80: 218-219.
  • 35 Hato T, Minamoto Y, Fukuyama T, Fujita S. Polymorphisms of HPA-1 through 6 on platelet membrane glycoprotein receptors are not a genetic risk factor for myocardial infarction in the Japanese population. Am J Cardiol. 1997; 80: 1222-1224.
  • 36 Corral J, Gonzalez-Conejero R, Rivera J, Iniesta JA, Lozano ML, Vicente V. HPA-1 genotype in arterial thrombosis - role of HPA-1b polymorphism in platelet function. Blood Coagul Fibrinolysis. 1997; 8: 284-290.
  • 37 Garg UC, Arnett DK, Folsom AR, Province MA, Williams RR, Eckfeldt JH. Lack of association between platelet glycoprotein IIb/IIIa receptor PlA polymorphism and coronary artery disease or carotid intima-media thickness. Thromb Res. 1998; 89: 85-89.
  • 38 Sperr WR, Huber K, Roden M, Janisiw M, Lang T, Graf S, Maurer G, Mayr WR, Panzer S. Inherited platelet glycoprotein polymorphisms and a risk for coronary heart disease in young central Europeans. Thromb Res. 1998; 90: 117-123.
  • 39 Scaglione L, Bergerone S, Gaschino G, Imazio M, Maccagnani A, Gambino R, Cassader M, Di Leo M, Macchia G, Brusca A, Pagano G, Cavallo-Perin P. Lack of relationship between the P1A1/P1A2 polymorphism of platelet glycoprotein IIIa and premature myocardial infarction. Eur J Clin Invest. 1998; 28: 385-388.
  • 40 Mamotte CD, van Bockxmeer FM, Taylor RR. PIa1/a2 polymorphism of glycoprotein IIIa and risk of coronary artery disease and restenosis following coronary angioplasty. Am J Cardiol. 1998; 82: 131-136.
  • 41 Harvald B, Hauge M. Coronary occlusion in twins. Acta Genet Med Gemellol (Roma). 1970; 19: 248-250.
  • 42 Carter AM, Catto AJ, Bamford JM, Grant PJ. Platelet GP IIIa PlA and GP Ib variable number tandem repeat polymorphisms and markers of platelet activation in acute stroke. Arterioscler Thromb Vasc Biol. 1998; 18: 1124-1131.
  • 43 Carlsson LE, Greinacher A, Spitzer C, Walther R, Kessler C. Polymorphisms of the human platelet antigens HPA-1, HPA-2, HPA-3, and HPA-5 on the platelet receptors for fibrinogen (GPIIb/IIIa), von Willebrand factor (GPIb/IX), and collagen (GPIa/IIa) are not correlated with an increased risk for stroke. Stroke. 1997; 28: 1392-1395.
  • 44 Wagner KR, Giles WH, Johnson CJ, Ou CY, Bray PF, Goldschmidt-Clermont PJ, Croft JB, Brown VK, Stern BJ, Feeser BR, Buchholz DW, Earley CJ, Macko RF, McCarter RJ, Sloan MA, Stolley PD, Wityk RJ, Wozniak MA, Price TR, Kittner SJ. Platelet glycoprotein receptor IIIa polymorphism P1A2 and ischemic stroke risk: the Stroke Prevention in Young Women Study. Stroke. 1998; 29: 581-585.
  • 45 Zimmerman SA, Ware RE. Inherited DNA mutations contributing to thrombotic complications in patients with sickle cell anemia. Am J Hematol. 1998; 59: 267-272.
  • 46 Feng D, Lindpaintner K, Larson MD, Rao VS, O’Donnell CJ, Lipinska I, Schmitz C, Sutherland PA, Silbershatz H, D’Agostino RB, Muller JE, Myers RH, Levy D, Tofler GH. Increased platelet aggregability associated with platelet GPIIIa PlA2 polymorphism. The Framingham offspring study. Arterioscler Thromb Vasc Biol. 1999; 19: 1142-1147.
  • 47 Lasne D, Krenn M, Pingault V, Arnaud E, Fiessinger JN, Aiach M, Rendu F. Interdonor variability of platelet response to thrombin receptor activation: influence of PlA2 polymorphism. Br J Haematol. 1997; 99: 801-807.
  • 48 Bennett JS, Vilaire G, Catella-Lawson F, Rut AR, Fitzgerald G. The PlA2 alloantigen does not alter the affinity of GPIIb-IIIa for fibrinogen or RGD-containing peptides. Blood 1997; 90: 154a.
  • 49 Michelson AD, Furman MI, Coleman L, Hamlington J, Goldschmidt-Clermont P, Hendrix C, Mascelli MA, Barnard MR, Kickler T, Christie DJ, Kundu S, Bray PF. Integrin β3 (GPIIIa) PlA polymorphisms on platelets display different sensitivity to agonists and antagonists. Blood 1998; 92: 28a.
  • 50 Cooke GE, Bray PF, Hamlington J, Pham DM, Goldschmidt-Clermont PJ. PlA2 polymorphism and efficacy of aspirin. Lancet. 1998; 351: 1353.
  • 51 Senti M, Aubo C, Bosch M. The relationship between smoking and is modulated by genetic variation in the glycoprotein IIIa gene. Metabolism. 1998; 47: 1040-1041.
  • 52 Joven J, Simo JM, Vilella E, Camps J, Masana L, de Febrer G, Camprubi M, Richart C, Bardaji A, Casao E, Pocovi M, Civeira F. Lipoprotein(a) and the significance of the association between platelet glycoprotein IIIa polymorphisms and the risk of premature myocardial infarction. Atherosclerosis. 1998; 140: 155-159.
  • 53 Kritzik M, Savage B, Nugent DJ, Santoso S, Ruggeri ZM, Kunicki TJ. Nucleotide polymorphisms in the α2 gene define multiple alleles that are associated with differences in platelet α2β1 density. Blood 1998; 92: 2382-2388.
  • 54 Kunicki TJ, Kritzik M, Annis DS, Nugent DJ. Hereditary variation in platelet integrin α2β1 density is associated with two silent polymorphisms in the alpha 2 gene coding sequence. Blood 1997; 89: 1939-1943.
  • 55 Moshefegh K, Wuillemin WA, Redondo M, Lammle B, Beer JH, Liechti-Gallati S, Meyer BJ. Association of two silent polymorphisms of platelet glycoprotein Ia/IIa receptor with risk of myocardial infarction: a case-control study. Lancet. 1999; 353: 351-4.
  • 56 Santoso S, Kunicki T, Kroll H, Haberbosch W, Gardenmann A. Polymorphisms in the platelet GP Ia and GPIIIa and the risk of coronary heart disease. Blood 1998; 92: 305a.
  • 57 Mazzucato M, Pradella P, De Angelis V, Steffan A, De Marco L. Frequency and functional relevance of genetic threonine 145/ methionine 145 dimorphism in platelet glycoprotein Ibα in an Italian population. Transfusion. 1996; 36: 891-894.
  • 58 Afshar-Kharghan V, Khoshvevis-Asl M, Hopkins P, Lopez JA. Polymorphism of the platelet gycoprotein (GP) Ibα Kozak sequence determines the surface level of the GP Ib-IX-V complex and risk for early myocardial infarction. Blood 1998; 92: 702a.
  • 59 Corral J, Gonzalez-Conejero R, Lozano ML, Rivera J, Vicente V. New alleles of the platelet glycoprotein. Blood 1998; 92: 564a.
  • 60 Murata M, Matsubara Y, Kawano K, Zama T, Aoki N, Yoshino H, Watanabe G, Ishikawa K, Ikeda Y. Coronary artery disease and polymorphisms in a receptor mediating shear stress-dependent platelet activation. Circulation. 1997; 96: 3281-3286.
  • 61 Gonzalez-Conejero R, Lozano ML, Rivera J, Corral J, Iniesta JA, Moraleda JJ, Vicente V. Polymorphisms of platelet membrane glycoprotein Iba associated with arterial thrombotic disease. Blood 1998; 8: 2771-2776.
  • 62 Reilly SL, Ferrell RE, Kottke BA, Sing CF. The gender-specific apolipoprotein E genotype influence on the distribution of plasma lipids and apolipoproteins in the population of Rochester, Minnesota. II. Regression relationships with concomitants. Am J Hum Genet. 1992; 51: 1311-1324.
  • 63 Daley GQ, Cargill [first initials] Ireland J, Altshuler D, Sklar P, Ziaugra L, Kalyanaraman N, Lim E, Rosen S, Gaziano JM, Hennekens C, Murata M, Ikeda Y, Lander E. High throughput polymorphism discovery in genes related to thrombosis; a paradigm for linking common variants to common disease. Blood 1998; 92: 473a.