Abstract
Purpose
The aim of this study was to examine the relation of late-stage age-related macular degeneration (AMD) with markers of systemic atherothrombosis.
Methods
A hospital-based case–control study of AMD was undertaken in London, UK. Cases of AMD (n=81) and controls (n=77) were group matched for age and sex. Standard protocols were used for colour fundus photography and to classify AMD; physical examination included height, weight, history of or treatment for vascular-related diseases and smoking status. Blood samples were taken for measurement of fibrinogen, factor VIIc (FVIIc), factor VIIIc, prothrombin fragment F1.2 (F1.2), tissue plasminogen activator, and von Willebrand factor. Odds ratios from logistic regression analyses of each atherothrombotic marker with AMD were adjusted for age, sex, and established cardiovascular disease risk factors, including smoking, blood pressure, body mass index, and total cholesterol.
Results
After adjustment FVIIc and possibly F1.2 were inversely associated with the risk of AMD; per 1 standard deviation increase in these markers the odds ratio were, respectively, 0.62 (95% confidence interval 0.40, 0.95) and 0.71 (0.46, 1.09). None of the other atherothrombotic risk factors appeared to be related to AMD status. There was weak evidence that aspirin is associated with a lower risk of AMD.
Conclusions
This study does not provide strong evidence of associations between AMD and systematic markers of arterial thrombosis, but the potential effects of FVIIc, and F1.2 are worthy of further investigation.
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References
Bunce C, Evans J, Fraser S, Wormald R . BD8 certification of visually impaired people. Br J Ophthalmol 1998; 82: 72–76.
Evans JR, Fletcher AE, Wormald RP . Age-related macular degeneration causing visual impairment in people 75 years or older in Britain: an add-on study to the Medical Research Council Trial of Assessment and Management of Older People in the Community. Ophthalmology 2004; 111: 513–517.
Congdon N, O’Colmain B, Klaver CC, Klein R, Muñoz B, Friedman DS et al. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol 2004; 122: 477–485.
Owen CG, Fletcher AE, Donoghue M, Rudnicka AR . How big is the burden of visual loss caused by age related macular degeneration in the United Kingdom? Br J Ophthalmol 2003; 87: 312–317.
Friedman DS, O’Colmain BJ, Munoz B, Tomany SC, McCarty C, de Jong PT et al. Prevalence of age-related macular degeneration in the United States. Arch Ophthalmol 2004; 122: 564–572.
de Jong PT . Age-related macular degeneration. N Engl J Med 2006; 355: 1474–1485.
Smith W, Assink J, Klein R, Mitchell P, Klaver CC, Klein BE et al. Risk factors for age-related macular degeneration: pooled findings from three continents. Ophthalmology 2001; 108: 697–704.
Evans JR, Fletcher AE, Wormald RP . 28 000 Cases of age related macular degeneration causing visual loss in people aged 75 years and above in the United Kingdom may be attributable to smoking. Br J Ophthalmol 2005; 89: 550–553.
Thornton J, Edwards R, Mitchell P, Harrison RA, Buchan I, Kelly SP et al. Smoking and age-related macular degeneration: a review of association. Eye 2005; 19: 935–944.
Klein R, Deng Y, Klein BE, Hyman L, Seddon J, Frank RN et al. Cardiovascular disease, its risk factors and treatment, and age-related macular degeneration: Women's Health Initiative Sight Exam ancillary study. Am J Ophthalmol 2007; 143: 473–483.
Sperduto RD, Hiller R . Systemic hypertension and age-related maculopathy in the Framingham Study. Arch Ophthalmol 1986; 104: 216–219.
Chaine G, Hullo A, Sahel J, Soubrane G, Espinasse-Berrod MA, Schutz D et al. Case-control study of the risk factors for age related macular degeneration. France-DMLA Study Group. Br J Ophthalmol 1998; 82: 996–1002.
Mares-Perlman JA, Brady WE, Klein R, VandenLangenberg GM, Klein BE, Palta M . Dietary fat and age-related maculopathy. Arch Ophthalmol 1995; 113: 743–748.
Smith W, Mitchell P, Leeder SR, Wang JJ . Plasma fibrinogen levels, other cardiovascular risk factors, and age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol 1998; 116: 583–587.
Hyman L, Schachat AP, He Q, Leske MC . Hypertension, cardiovascular disease, and age-related macular degeneration. Age-Related Macular Degeneration Risk Factors Study Group. Arch Ophthalmol 2000; 118: 351–358.
Delcourt C, Michel F, Colvez A, Lacroux A, Delage M, Vernet MH et al. Associations of cardiovascular disease and its risk factors with age-related macular degeneration: the POLA study. Ophthalmic Epidemiol 2001; 8: 237–249.
Schaumberg DA, Christen WG, Hankinson SE, Glynn RJ . Body mass index and the incidence of visually significant age-related maculopathy in men. Arch Ophthalmol 2001; 119: 1259–1265.
Klein R, Klein BE, Tomany SC, Moss SE . Ten-year incidence of age-related maculopathy and smoking and drinking: the Beaver Dam Eye Study. Am J Epidemiol 2002; 156: 589–598.
Klein R, Klein BE, Marino EK, Kuller LH, Furberg C, Burke GL et al. Early age-related maculopathy in the cardiovascular health study. Ophthalmology 2003; 110: 25–33.
Vingerling JR, Dielemans I, Bots ML, Hofman A, Grobbee DE, de Jong PT . Age-related macular degeneration is associated with atherosclerosis. The Rotterdam Study. Am J Epidemiol 1995; 142: 404–409.
Sato E, Feke GT, Appelbaum EY, Menke MN, Trempe CL, McMeel JW . Association between systemic arterial stiffness and age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2006; 244: 963–971.
Wong TY, Tikellis G, Sun C, Klein R, Couper DJ, Sharrett AR . Age-related macular degeneration and risk of coronary heart disease: the Atherosclerosis Risk in Communities Study. Ophthalmology 2007; 114: 86–91.
Duan Y, Mo J, Klein R, Scott IU, Lin HM, Caulfield J et al. Age-related macular degeneration is associated with incident myocardial infarction among elderly Americans. Ophthalmology 2007; 114: 732–737.
Klein R, Clegg L, Cooper LS, Hubbard LD, Klein BE, King WN et al. Prevalence of age-related maculopathy in the Atherosclerosis Risk in Communities Study. Arch Ophthalmol 1999; 117: 1203–1210.
Cheung N, Liao D, Islam FM, Klein R, Wang JJ, Wong TY . Is early age-related macular degeneration related to carotid artery stiffness? The Atherosclerosis Risk in Communities Study. Br J Ophthalmol 2007; 91: 430–433.
Lip PL, Blann AD, Hope-Ross M, Gibson JM, Lip GY . Age-related macular degeneration is associated with increased vascular endothelial growth factor, hemorheology and endothelial dysfunction. Ophthalmology 2001; 108: 705–710.
Dasch B, Fuhs A, Behrens T, Meister A, Wellmann J, Fobker M et al. Inflammatory markers in age-related maculopathy: cross-sectional analysis from the Muenster Aging and Retina Study. Arch Ophthalmol 2005; 123: 1501–1506.
Schaumberg DA, Christen WG, Buring JE, Glynn RJ, Rifai N, Ridker PM . High-sensitivity C-reactive protein, other markers of inflammation, and the incidence of macular degeneration in women. Arch Ophthalmol 2007; 125: 300–305.
Wu KH, Tan AG, Rochtchina E, Favaloro EJ, Williams A, Mitchell P et al. Circulating inflammatory markers and hemostatic factors in age-related maculopathy: a population-based case-control study. Invest Ophthalmol Vis Sci 2007; 48: 1983–1988.
Seddon JM, Gensler G, Milton RC, Klein ML, Rifai N . Association between C-reactive protein and age-related macular degeneration. JAMA 2004; 291: 704–710.
Klein R, Klein BE, Knudtson MD, Wong TY, Shankar A, Tsai MY . Systemic markers of inflammation, endothelial dysfunction, and age-related maculopathy. Am J Ophthalmol 2005; 140: 35–44.
Seddon JM, Gensler G, Klein ML, Milton RC . C-reactive protein and homocysteine are associated with dietary and behavioral risk factors for age-related macular degeneration. Nutrition 2006; 22: 441–443.
Shankar A, Mitchell P, Rochtchina E, Tan J, Wang JJ . Association between circulating white blood cell count and long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Am J Epidemiol 2007; 165: 375–382.
Meade TW, North WR, Chakrabarti R, Stirling Y, Haines AP, Thompson SG et al. Haemostatic function and cardiovascular death: early results of a prospective study. Lancet 1980; 1: 1050–1054.
Cooper JA, Miller GJ, Bauer KA, Morrissey JH, Meade TW, Howarth DJ et al. Comparison of novel hemostatic factors and conventional risk factors for prediction of coronary heart disease. Circulation 2000; 102: 2816–2822.
Rudnicka AR, Mt-Isa S, Meade TW . Associations of plasma fibrinogen and factor VII clotting activity with coronary heart disease and stroke: prospective cohort study from the screening phase of the Thrombosis Prevention Trial. J Thromb Haemost 2006; 4: 2405–2410.
De Stavola BL, Meade TW . Long-term effects of hemostatic variables on fatal coronary heart disease: 30-year results from the first prospective Northwick Park Heart Study (NPHS-I). J Thromb Haemost 2007; 5: 461–471.
Fibrinogen Studies Collaboration. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis. JAMA 2005; 294: 1799–1809.
Whincup PH, Danesh J, Walker M, Lennon L, Thomson A, Appleby P et al. von Willebrand factor and coronary heart disease: prospective study and meta-analysis. Eur Heart J 2002; 23: 1764–1770.
Lowe GD, Danesh J, Lewington S, Walker M, Lennon L, Thomson A et al. Tissue plasminogen activator antigen and coronary heart disease. Prospective study and meta-analysis. Eur Heart J 2004; 25: 252–259.
Bird AC, Bressler NM, Bressler SB, Chisholm IH, Coscas G, Davis MD et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol 1995; 39: 367–374.
von Clauss A . Rapid physiological coagulation method in determination of fibrinogen. Acta Haematol 1957; 17: 237–246.
Miller GJ, Stirling Y, Esnouf MP, Heinrich J, van de Loo J, Kienast J et al. Factor VII-deficient substrate plasmas depleted of protein C raise the sensitivity of the factor VII bio-assay to activated factor VII: an international study. Thromb Haemost 1994; 71: 38–48.
Armstrong BG . The effects of measurement errors on relative risk regressions. Am J Epidemiol 1990; 132: 1176–1184.
MacCallum PK, Cooper JA, Martin J, Howarth DJ, Meade TW, Miller GJ . Haemostatic and lipid determinants of prothrombin fragment F1.2 and D-dimer in plasma. Thromb Haemost 2000; 83: 421–426.
Anderssen T, Halvorsen H, Bajaj SP, Osterud B . Human leukocyte elastase and cathepsin G inactivate factor VII by limited proteolysis. Thromb Haemost 1993; 70: 414–417.
Klein R, Klein BE, Tomany SC, Cruickshanks KJ . Association of emphysema, gout, and inflammatory markers with long-term incidence of age-related maculopathy. Arch Ophthalmol 2003; 121: 674–678.
Christen WG, Glynn RJ, Ajani UA, Schaumberg DA, Chew EY, Buring JE et al. Age-related maculopathy in a randomized trial of low-dose aspirin among US physicians. Arch Ophthalmol 2001; 119: 1143–1149.
Klein R, Klein BEK, Jensen SC, Cruickshanks KJ, Lee KE, Danforth LG et al. Medication use and the 5-year incidence of early age-related maculopathy—the Beaver Dam eye study. Arch Ophthalmol 2001; 119: 1354–1359.
Wang JJ, Ross RJ, Tuo J, Burlutsky G, Tan AG, Chan CC et al. The LOC387715 polymorphism, inflammatory markers, smoking, and age-related macular degeneration. A population-based case-control study. Ophthalmology 2008; 115: 693–699.
Klein R, Klein BE, Jensen SC, Mares-Perlman JA, Cruickshanks KJ, Palta M . Age-related maculopathy in a multiracial United States population: the National Health and Nutrition Examination Survey III. Ophthalmology 1999; 106: 1056–1065.
The eye disease case-control study group. Risk factors for neovascular age-related macular degeneration. The eye disease case-control study group. Arch Ophthalmol 1992; 110: 1701–1708.
Malukiewicz-Wisniewska G, Rosc D, Kaluzny B, Kaluzny JJ . von Willebrand factor in plasma of patients with age related macular degeneration. (Polish). Klinika Oczna 2005; 107: 70–72.
Tao Y, Jonas JB . Refractive error and smoking habits in exudative age-related macular degeneration in a hospital-based setting. Eye 2009. e-pub ahead of print; doi: 10.1038/eye.2009.160.
Klein R, Klein BE, Tomany SC, Cruickshanks KJ . The association of cardiovascular disease with the long-term incidence of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 2003; 110: 1273–1280.
Hirvela H, Luukinen H, Laara E, Sc L, Laatikainen L . Risk factors of age-related maculopathy in a population 70 years of age or older. Ophthalmology 1996; 103: 871–877.
Acknowledgements
We thank Liz McCabe for recruitment of the participants in the study, Jackie Cooper for monitoring matching during recruitment, and Homeira Sheikh for performing all the laboratory analyses. We also thank Mr Ivor Levy (deceased) for his contribution in interpretation of the retinal photographs and Bob Tapper for performing the photographs. This research was funded by the Medical Research Council.
Author contributions: All authors contributed to the formulation of the hypothesis. PM, RW, and TWM were responsible for the design and conduct of the study. ARR performed the statistical analyses and drafted the paper, to which all authors contributed. PM and TWM supervised the laboratory analyses. All authors approved the final version. PM and ARR had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
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Rudnicka, A., MacCallum, P., Whitelocke, R. et al. Circulating markers of arterial thrombosis and late-stage age-related macular degeneration: a case–control study. Eye 24, 1199–1206 (2010). https://doi.org/10.1038/eye.2010.8
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DOI: https://doi.org/10.1038/eye.2010.8


