Impaired fibrinolysis in retinal vein occlusion: a role for genetic determinants of PAI-1 levels

Summary

Few and contrasting data are available on the presence of a thrombophilic state in patients with retinal vein occlusion (RVO), and we have previously demonstrated a role of elevated PAI-1 activity as a risk factor for this condition. The present study was undertaken to investigate whether PAI 4G/5G and ACE I/D polymorphisms are independent risk factors for RVO and whether they account for elevated PAI-1 activity levels. We studied 112 RVO patients (52 males and 60 females; range 18–83 years; median age 60 years) and 112 healthy subjects (52 males and 60 females; range 20–84 years; median age 57 years). PAI-1 activity was determined by a chromogenic assay and ACE I/D and PAI-1 4G/5G polymorphisms by polymerase chain reaction (PCR) and restriction length fragment polymorphism (RLFP) methods. Elevated PAI-1 activity (above 95th percentile of the controls) was significantly associated with RVO at multivariate analysis after adjustment for age, sex, traditional cardiovascular risk factors and haemostasis-related risk factors (OR = 4.93, 95% CI 1.70–14.30; p = 0.003).The homozygosity for ACE DD was found to be an independent risk factor for RVO at multivariate analysis (OR = 1.98, 95% CI 1.013.83; p = 0.049), whereas no significant association between homozygosity for PAI-1 4G4G and risk of RVO was observed. Subjects carrying both ACE DD genotype and PAI-1 4G4G genotype showed an increased risk for RVO at multivariate analysis (OR = 4.82, 95% CI 1.89–12.29; p = 0.001). In 45/112 patients without the established risk factors for RVO (hypertension, hypercholesterolemia and diabetes) or characteristics known to be associated to increased PAI-1 activity (overweight, hypertriglyceridemia, and smoking habit) the contemporary presence of ACE DD and PAI-1 4G4G genotype was significantly associated with a risk for RVO (OR = 8.26, 95% CI 1.1857.92; p = 0.034). In conclusion, in our study: 1-indicates that ACE DD genotype is a risk factor for RVO in the whole group of patients, and in the subgroup of patients without the established risk factors for RVO or characteristics influencing the PAI-1 activity, when associated to PAI-1 4G4G genotype, and 2-confirms the role of hypofibrinolysis, documented by high levels of PAI-1 activity, in the occurrence of patients with RVO.

Keywords

Retinal vein occlusion - plasminogen activator inhibitor-1 (PAI-1) - angiotensin converting enzyme (ACE) - genetic polymorphisms - risk factors

• References

• 1 Margaglione M, Di Minno G, Grandone E. et al. Abnormally high circulation levels of tissue plasminogen activator and plasminogen activator inhibitor-1 in patients with a history of ischemic stroke. Arterioscler Thromb 1994; 14: 1741-5.
• 2 Thompson SG, Kienast J, Pyke SDN. et al. Haemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995; 332: 635-41.
• 3 Schulman S, Wilman B. The duration of anticoagulation (DURAC) Trial Study Group. The significance of hypofibrinolysis for the risk of recurrence of venous thrombosis. Thromb Haemost 1996; 75: 601-11.
• 4 Soeki T, Tamura Y, Shinohara H. et al. Plasma concentrations of fibrinolytic factors in the subacute phase of myocardial infarction predict recurrent myocardial infarction or sudden cardiac death. Int J Cardiol 2002; 85: 277-83.
• 5 Vaya A, Mira Y, Ferrando F. et al. Hyperlipidaemia and venous thromboembolism in patients lacking thrombophilic risk factors. Br J Haematol 2002; 118: 255-9.
• 6 Dawson S, Hamsten A, Wiman B. et al. Genetic variation at the plasminogen activator inhibitor-1 locus is associated with altered levels of plasminogen activator inhibitor-1 activity. Arterioscler Thromb 1991; 11: 183-90.
• 7 Dawson SJ, Wiman B, Hamsten A. et al. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268: 10739-145.
• 8 Margaglione M, Grandone E, Vecchione G. et al. Plasminogen activator inhibitor-1 (PAI-1) antigen plasma levels in subjects attending a metabolic ward: relation to polymorphisms of PAI-1 and angiotensin converting enzyme (ACE) genes. Arterioscler Thromb Vasc Biol 1997; 17: 2082-7.
• 9 Matsubara Y, Hayakawa T, Tsuda T. et al. Angiotensin converting enzyme insertion/ deletion polymorphism is associated with plasma antigen levels of plasminogen activator inhibitor-1 in healthy Japanese population. Blood Coagul Fibrinolysis 2000; 11: 115-20.
• 10 Iacoviello L, Burzotta F, Di Castelnuovo A. et al. The 4G/5G polymorphism of PAI-1 promoter gene and the risk of myocardial infarction: a meta-analysis. Thromb Haemost 1998; 80: 1029-30.
• 11 Jackson A, Brown K, Langdown J. et al. Effect of the angiotensin-converting enzyme gene deletion polymorphism on the risk of venous thromboembolism. Br J Haematol 2000; 111: 562-4.
• 12 Gonzàles AJOrdonez, Fernàndez JMCarreira, Medina JMRodrìguez. et al. Risk of venous thromboembolism associated with the insertion/deletion polymorphism in the angiotensin-converting enzyme gene. Blood Coagul Fibrinolysis 2000; 11: 485-90.
• 13 Agerholm-Larsen B, Nordestgaard BG, Tybjaerg-Hansen A. ACE gene polymorphism in cardiovascular disease: a meta-analysis of small and large studies in whites. Arterioscl Thromb Vasc Biol 2000; 20: 484-92.
• 14 Seguì R, Estelles A, Mira Y. et al. PAI-1 promoter 4G/5G genotype as an additional risk factor for venous thrombosis in subjects with genetic thombophilic defects. Br J Haematol 2000; 111: 122-8.
• 15 Fong AC, Schatz H, Mc Donald HR. et al. Central retinal vein occlusion in young adults (papillophlebitis). Retina 1992; 12: 3-11.
• 16 Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in Australia. The Blue Muntains Eye Study. Arch Ophthalmol 1996; 114: 1243-7.
• 17 Williamson TH. Central retinal vein occlusion: what’s the story?. British Journal of Ophthalmology 1997; 81: 698-704.
• 18 Rath EZ, Frank RN, Shin DH. et al. Risk factors for retinal vein thrombosis: a case-control study. Ophthalmology 1992; 99: 509-14.
• 19 Elman MJ, Bhatt AK, Quinlan PM. et al. The risk for systemic vascular diseases and mortality in patients with central retinal vein occlusion. Ophthalmology 1990; 97: 1543-8.
• 20 Laatikanen L, Kohner EM, Khoury D. Panretinal photocoagulation in central retinal vein occlusion: a randomized controlled clinical study. Br J Ophthalmol 1977; 61: 741-53.
• 21 Bernard AG, Chanabel A, Lelong F. Elevated erythrocyte aggregation in patients with central retinal vein occlusion and without conventional risk factors. Ophthalmology 1994; 101: 1483-7.
• 22 Salomon O, Moisseiev J, Rosemberg N. et al. Analysis of genetic polymorphism related to thrombosis and other risk factors in patients with retinal vein occlusion. Blood Coagul Fibrinol 1998; 09: 617-22.
• 23 Bhagat N, Goldberg MF, Gascon P. et al. Central retinal vein occlusion: review of management. Eur J Ophthalmol 1999; 09: 165-80.
• 24 Prisco D, Marcucci R, Bertini L. et al. Cardiovascular and thrombophilic risk factors for central retinal vein occlusion. Eur J Intern Med 2002; 13: 163-9.
• 25 Pandolfi M, Isacson S, Astedt B. Coagulation and fibrinolytic studies in 23 patients with occlusion of the retinal vessels. Acta Ophthalmol (Copenh) 1972; 50: 62-72.
• 26 Williamson TH, Rumley A, Lowe GD. Blood viscosity, coagulation and activated protein C resistance in central retinal vein occlusion: a population controlled study. Br J Ophthalmol 1996; 80: 203-8.
• 27 Abu El-Asrar AM, Abdel AGGader, Al-Amro S. et al. Fibrinolytic activity in retinal vein occlusion. Int Ophthalmol 1997; 98. 21: 343-8.
• 28 Lip PL, Blann AD, Jones AF. et al. Abnormalities in haemorheological factors and lipoprotein (a) in retinal vascular risk. Eye 1998; 12: 245-51.
• 29 Glueck CJ, Bell H, Vadlamani L. et al. Heritable thrombophilia and hypofibrinolysis. Possible causes of retinal vein occlusion. Arch Opthalmol 1999; 117: 43-9.
• 30 Marcucci R, Bertini L, Giusti B. et al. Thrombophylic risk factors in patients with central retinal vein occlusion. Thromb Haemost 2001; 86: 772-6.
• 31 Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26: S5-S20.
• 32 Rigat B, Hubert C, Corvol P. et al. PCR detection of the insertion/deletion polymorphism of the human angiotensin converting enzyme gene (DCP1) (dipeptidyl carboxypeptidase 1). Nucleic Acids Res 1992; 20: 1433.
• 33 Wiman B. Plasminogen activator inhibitor 1 (PAI-1) in plasma: its role in thrombotic disease. Thromb Haemost 1995; 74: 71-6.
• 34 Margaglione M, Capucci G, D’Addeddda M. et al. PAI-1 plasma levels in a general population without clinical evidence of atherosclerosis. Relation to enviromental and genetic determinants. Arterioscler Thromb Vasc Biol 1998; 18: 562-7.
• 35 Cambien F, Poirier O, Lecerf L. et al. Deletion polymorphism in the gene for angiotensinconverting enzyme is a potent risk factor for myocardial infarction. Nature 1992; 359: 641-4.
• 36 Fatini C, Abbate R, Pepe G. et al. Searching for a better assessment of the individual coronary risk profile. The role of angiotensin-converting enzyme, angiotensin II type 1 receptor and angiotensinogen gene polymorphisms. Eur Heart J 2000; 21: 633-8.
• 37 Agema WRP, Jukema JW, Zwinderman AH. et al. A meta-analysis of the angiotensin-converting enzyme gene polymorphism and restenosis after percutaneous transluminal coronary revascularization: evidence for publication bias. Am Heart J 2002; 144: 760-8.
• 38 Schunkert H, Hense HW, Holmer SR. et al. Association between a deletion polymorphism of the angiotensin-converting enzyme gene and left ventricular hypertrophy. N Engl J Med 1994; 330: 1634-8.
• 39 O’Donnel CJ, Lindpaintner K, Larson MG. et al. Evidence for association and genetic linkage of the angiotensin-converting enzyme locus with hypertension and blood pressure in men but not in women in the Framingham Heart Study. Circulation 1998; 97: 1766-72.
• 40 Fatini C, Gensini F, Sticchi E. et al. ACE DD genotype: an independent predisposition factor for venous thromboembolism. Eur J Clin Invest 2003; 33: 642-7.
• 41 Vaughan DE. Fibrinolytic balance, the renninangiotensin system and atherosclerotic disease. Eur Heart J 1998; 19: G9-G12.
• 42 Keidar S, Oiknine J, Leiba A. et al. Fosinopril reduces ADP-induced platelet aggregation in hypertensive patients. J Cardiovasc Pharmacol 1996; 27: 183-6.
• 43 Ridker PM, Gaboury CL, Conlin PR. et al. Stimulation of plasminogen activator inhibitor in vivo by infusion of angiotensin II. Evidence of a potential interaction between the reninangiotensin system and fibrinolytic function. Circulation 1993; 87: 1969-73.
• 44 Stratton JR, Chandler WL, Schwartz RS. et al. Effects of physical conditioning on fibrinolytic variables and fibrinogen in young and old healthy adults. Circulation 1991; 83: 1692-7.
• 45 Estelles A, Dalmau J, Falco C. et al. Plasma PAI-1 levels in obese children – effect of weight loss and influence of PAI-1 promoter 4G/5G genotype. Thromb Haemost 2001; 86: 647-52.
• 46 Brown NJ, Agirbasli MA, Williams GH. et al. Effect of activation and inhibition of the reninangiotensin system on plasma PAI-1. Hypertension 1998; 32: 965-71.
• 47 Vaughan DE, Rouleau JL, Ridker PM. et al. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Heart Study Investigators. Circulation 1997; 96: 442-7.
• 48 Pretorius M, Rosenbaum D, Vaughan DE. et al. Angiotensin-converting enzyme inhibition increases human vascular tissue-type plasminogen activator release through endogenous bradykinin. Circulation 2003; 107: 579-85.