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

Abstract

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 95(th) 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 1.01-3.83; 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 (hyper-tension, 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 1.18-57.92; 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.

High lipoprotein (a) levels are associated with an increased risk of retinal vein occlusion

“…Subsequently, a second model (Model 2) was created by also adjusting for triglycerides' levels. Finally, a further fully adjusted model was created by introducing some thrombophilic risk factors such as homocysteine and PAI-1 levels, which have been demonstrated to be associated with RVO [5][6][7]. Odds ratios (OR) and 95% confidence intervals (CI) are presented.…”

“…Recently, a meta-analysis by Janssen et al [27] demonstrated that factors known to contribute to the risk of atherosclerosis might also be important in the pathogenesis of RVO, including some thrombophilic risk factors. In addition, we have also demonstrated in a large group of patients with RVO that homocysteine, as well as haemorheological variables and circulating vitamins, may predispose the occurrence of the disease [5][6][7][8]. Despite this, the full pattern of possible risk factors in its pathology has not been investigated and some issues remain open in terms of the pathological mechanisms that lead to the clinical thrombosis.…”

“…We have recently reported a role for emerging thrombophilic risk factors, haemorheology, and B-group vitamins on the occurrence of RVO [5][6][7][8], but an ongoing issue is the role of dyslipidemia and lipid parameters in the pathogenesis of RVO. Lipoprotein (a) [Lp(a)] is a specific class of lipoprotein particle composed of a single copy of apolipoprotein B-100 linked to an apo(a) component [9].…”

Role of angiotensin-converting enzyme insertion/deletion and plasminogen activator inhibitor-1 4G/5G gene polymorphisms in retinal vein occlusion

“…Yet only very limited and at least partly conflicting data on the role of gene polymorphism known to affect PAI-1 plasma levels are available [2][3][4]. Recently, Gori et al [2] investigating 112 patients with RVO suggested both homozygosity for the angiotensin converting enzyme insertion/deletion (ACE I/D) polymorphism and the combined presence of the PAI-1 4G/4G and ACE DD genotypes as novel risk factors.Homozygosity for the PAI-1 4G/5G gene polymorphism itself was not associated with an increased risk for RVO [2]. No significant difference in the PAI-1 4G/5G genotype distribution was also found in another study including 72 patients with either retinal artery or vein occlusion [4].…”

Retinal Vein Occlusion and Polymorphisms

“…Plazmadaki, plazminojen aktivator inhibitor-1 (PAI-1) konsantrasyonunun artması hipofibrinolize sebep olur. Gori ve arkadaş-ları, RVT olan hastalarda homozigotik anjiotensin konverting enzim (AKE) insersiyon/delesyon için, (PAI-1 4G/4G ve AKE DD) genotiplerinin bir risk faktörü olduğunu ileri sürmüşlerdir [18]. Ancak Mattes ve arkadaşları ise AKE DD genotipini RVT olan hastalarda önceki yayınla tersi şekilde yüksek bulamamışlar [19].…”