ORIGINAL PAPER

Risk factors associated with retinal vein occlusion F. Mart
ınez,1,2 E. Furi
o,1 M. J. Fabi
a,1 A. V. P
erez,3 V. Gonz
alez-Albert,4,5 G. Rojo-Mart
ınez,5,6 M. T. Mart
ınez-Larrad,5,7 F. J. Mena-Mart
ın,8 F. Soriguer,5,6 M. Serrano-R
ıos,5,7 F. J. Chaves,4,5 J. C. Mart
ın-Escudero,8 J. Red
on,1,2 M. J. Garc
ıa-Fuster1

1

SUMMARY

What’s known

Aims: Retinal vein occlusion (RVO) is the most frequent retinal vascular disease after diabetic retinopathy in which arterial risk factors are much more relevant than venous factors. The objective was to evaluate the role of risk factors in the development of the first episode of RVO. Subjects and Methods: One hundred patients with RVO [mean age 56 years, 42% females and mean body mass index (BMI) 27.5 kg/m2] were recruited consecutively from the outpatient clinic of a tertiary hospital in Valencia (Spain). All subjects underwent clinical assessment including anthropometric and blood pressure measurements and laboratory test including homocysteine, antiphospholipid antibodies (aPLAs) and thrombophilia studies. In half of the subjects, a carotid ultrasonography was performed. Three control populations matched by age, sex and BMI from different population-based studies were used to compare the levels and prevalence of arterial risk factors. One cohort of young patients with venous thromboembolic disease was used to compare the venous risk factors. Results: Blood pressure levels and the prevalence of hypertension were significantly higher in the RVO population when compared with those for the general populations. There was also a large proportion of undiagnosed hypertension within the RVO group. Moreover, carotid evaluation revealed that a large proportion of patients with RVO had evidence of subclinical organ damage. In addition, homocysteine levels and prevalence of aPLAs were similar to the results obtained in our cohort of venous thromboembolic disease. Conclusions: The results indicate that hypertension is the key factor in the development of RVO, and that RVO can be the first manifestation of an undiagnosed hypertension. Furthermore, the majority of these patients had evidence of atherosclerotic disease. Among the venous factors, a thrombophilia study does not seem to be useful and only the prevalence of hyperhomocysteinaemia and aPLAs is higher than in the general population.

Introduction In recent years, knowledge of the pathophysiology and risk factors for retinal vein occlusion (RVO) has aroused great interest since they represent potential advances in prophylaxis and treatment (1– 3). Retinal vein occlusion is the most common retinal vascular disease after diabetic retinopathy. The occlusion can occur both at the level of the central retinal vein (CRVO) adjacent to the lamina cribrosa of the optic nerve, as well as at the distal retinal branches (BRVO) typically in arteriovenous intersections. Central retinal vein occlusion is a common cause of unilateral sight loss, and BRVO can produce different levels of visual impairment which ª 2014 John Wiley & Sons Ltd Int J Clin Pract, July 2014, 68, 7, 871–881. doi: 10.1111/ijcp.12390

• • • •

RVO is a common cause of blindness. Arterial factors are most important for RVO than venous factors. Inherited thrombophilia important role.

does

not

play

an

New treatments such as vascular endothelial growth factor inhibitors are being developed.

What’s new

• • •

RVO can be the first manifestation undiagnosed arterial risk factors, especially essential hypertension.

of

Comparison of risk factors with several suitable populations for the arterial as well as for venous part. Inherited thrombophilia study is no longer needed for RVO cases.

generally progress during the natural evolution of the disease (4). The real incidence of RVO is difficult to assess because of the high percentage of asymptomatic cases that only are discovered a posteriori, when RVO occur. For Fontela et al. (5), this incidence would be 2.14/1000 patients for a population over 40 years and 5.36/1000 in one over the age of 64. It is estimated that around 16 million people in the world may have RVO in at least one eye (6,7). Branch retinal vein occlusion is four times more frequent than is CRVO, and the bilateral event rate is very rare, accounting for 5% of cases (3,4,8). Systemic and local factors have been implicated in RVO. Among the local factors, short longitudinal

Internal Medicine Department, Fundaci
on de Investigaci
on del Hospital Cl
ınico de ValenciaINCLIVA, Hospital Cl
ınico Universitario, Universidad de Valencia, Valencia, Spain 2 “Centro de Investigaci
on Biom
edica en Red (CIBER) de Fisiopatolog
ıa, Obesidad y Nutrici
on (CIBEROB)”, Institute of Health Carlos III, Minister of Health, Madrid, Spain 3 Hospital de Cl
ınicas, Internal Medicine Department, Universidad de la Rep
ublica, Montevideo, Uruguay 4 Genotyping and Genetic Diagnosis Unit, Fundaci
on de Investigaci
on del Hospital Cl
ınico de Valencia-INCLIVA, Valencia, Spain 5 “Centro de Investigaci
on Biom
edica en Red (CIBER) de Diabetes y Enfermedades Metab
olicas Asociadas (CIBERDEM)”, Institute of Health Carlos III, Minister of Health, Madrid, Spain 6 Endocrinology and Nutrition Department, Carlos Haya University Hospital, M
alaga, Spain 7 Department of Internal Medicine II, Hospital Cl
ınico San Carlos, Madrid, Spain 8 Internal Medicine Department, Hospital Rio Hortega, University of Valladolid, Valladolid, Spain Correspondence to: Fernando Martinez, Hypertension Clinic, Internal Medicine, Hospital Clinico, University of Valencia, Avda Blasco Iba~nez, 17, Valencia 46010, Spain Tel: + (34) 96 3806302 Fax: (+34) 96 3862647 E-mail: [email protected] Disclosures None.

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axis, open-angle glaucoma and ocular hypertension are all situations that could compromise retinal venous flow. The potential role of thrombophilia including proteins C and S, antithrombin III deficiencies, Factor V Leiden, hyperhomocysteinaemia and antiphospholipid syndrome (APS) has been analysed in several studies (9–11). Branch retinal vein occlusion at the junction of sclerotic arteries highlights the importance of arterial risk factors in the aetiology of RVO and, therefore, numerous studies have assessed the possible role of hypertension, dyslipidaemia, obesity and diabetes (11). Retinal bleeding, oedema and neovascularisation of the iris, anterior chamber angle and of the retina are all complications of the RVO leading to a partial or total loss of sight (3,12). Related to the therapy of RVO, some local treatments such as laser photocoagulation (13,14), corticoids (15,16) or vascular endothelial growth factor (VEGF) inhibitors (17) had been applied. Among the general treatments: isovolemic haemodilution (18), antiplatelet drugs (19–21), low molecular weight heparins (20,21) and fibrinolytics (22) had all been used with different results. Although the evidence is still scarce, the results of some of the above-mentioned studies might suggest that LMWH can be superior to other general treatments (1). However, none of them is totally effective (23,24), so a good prophylaxis achieved by a thorough knowledge of the associated risk factors is needed in order to decrease the incidence of RVO. Taking into account the magnitude of the problem and the necessity of preventive actions, our aim is not only to describe the risk factors already present in a consecutive series of patients with RVO, but also to compare the levels and prevalence of these risk factors with suitable populations for both arterial and venous factors.

Material and methods One hundred consecutive patients with new onset retinal venous occlusion either CRVO or BRVO were recruited in the internal medicine outpatient clinic of a tertiary hospital in Valencia, Spain, from May 2004 to October 2010. After the diagnosis of RVO (CRVO or BRVO), the description of the eye fundus and the measurement of ocular pressure by an ophthalmologist, the patient was referred to the Internal Medicine outpatient clinic department for assessment of risk factors and systemic treatment if needed. For all the patients, a complete anamnesis focusing on cardiovascular and venous risk factors was performed, along with a clinical examination including anthropometric and

blood pressure (BP) measurements. Blood pressure was assessed by a semiautomatic device, OMRON M6 (Omron Healthcare Europe B.V. Kruisweg 577, 2132 NA, Hoofddorp, The Netherlands), with the appropriate cuff size for the patient arm circumference and following the recommendations of the European Society of Hypertension (ESH) (25). Three BP measurements were taken for each patient with 5 min rest, with the average of the last two measurements taken as the real BP value. Body mass index (BMI) was calculated using the following formula ‘weight (Kg)/height (m2)’. Weight was assessed without shoes and wearing light clothing. Height was determined in a similar way. A subject was classified as obese if his/her BMI was ≥ 30 kg/m2. Basic serum biochemistry and lipid profile (total cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides) were measured with an Hitachi 917 autoanalyzer (Boehringer, Germany). Glucose was measured using the glucose oxidase method, and low-density lipoprotein (LDL) cholesterol was calculated using the Friedewald formula. Hypertension, dyslipidaemia and type 2 diabetes were classified according to the ESH (25), ATPIII (26) and American Diabetes Association (27) criteria, respectively. Subjects were classified as having hypertension, type 2 diabetes or dyslipidaemia if they had been previously diagnosed or were under medications for any of these conditions. Individuals were later on reclassified according to the following criteria: hypertension, if their levels of BP were ≥ 140/90 for systolic/diastolic BP; type 2 diabetes, if their fasting glucose was ≥ 126 mg/dl; or dyslipidaemia, if their levels for total cholesterol, LDL cholesterol, or triglycerides were higher than 220, 160 and 150 mg/ dl, respectively or HDL cholesterol lower than 40 mg/dl. Additionally, a complete thrombophilic study was performed in all the subjects. Antigenic antithrombin was assessed by radial immunodiffusion. The activity of antithrombin and protein C values were determined by the ‘Coamatic Antithrombin Kit and Coamate PC and Chromogenix AB, M€ olndal, Suecia)’. Total protein S and free antigen were determined by enzyme immunoassay, while the protein S activity was determined using the Instrumentation Laboratory test (IL, Izasa S.A. Placßa d’Europa 21-23 L’Hospitalet de Llobregat, 08908 Barcelona, Spain). Functional tests were assessed by the ‘Automated Coagulation Analyzer 6000’, with the normal range 60–120% of the reference value. The analysis of activated protein C was performed by the method of Jorquera, while factor V Leiden and G20210A mutations of the prothrombin gene were done by polymerase chain reaction. As to the acquired ª 2014 John Wiley & Sons Ltd Int J Clin Pract, July 2014, 68, 7, 871–881

Factors associated with retinal vein occlusion

thrombophilia, the lupus anticoagulant (LA) was assessed according to the criteria proposed by the Subcommittee of the International Society on Thrombosis and Haemostasis, while the antiphospholipid antibodies (aPLAs) were assessed through enzyme immunoassay. The normal values for anticardiolipin and antiphosphatidylserine antibodies IgG or IgM were 0–15 U/ml and for the anti-beta-2 glycoprotein antibodies IgM 0 and 4 U/ml and IgG 0–25 U/ml. When positive, the results were repeated after 2 months. Homocysteinaemia and D-dimer were also measured, with thresholds for hyperhomocysteinaemia and elevated D-dimer at ≥ 18.5 lmol/l and 250 mg/dl, respectively (28).

Control populations Venous factors For comparison of the main venous factors, we used the estimated prevalence for thrombophilic factors in general population and in some of the main cohorts of DVT/PE published in the literature (29–32). We also compared the main venous risk factors with the results from our own cohort which includes 293 patients under 50 years old with deep venous thrombosis and/or pulmonary embolism. This cohort is well characterised and is being followed in the outpatient clinic. In 2004, we published preliminary results with 100 of these young patients with thromboembolic disease (mean age 34  10 years, 48% females, BMI 25.5  4.2 kg/m2) and since then we have almost tripled the number of individuals in this cohort (33,34). According to our previous results, 37% of them had inherited factors and 19% had aPLAs. Among the inherited factors, the most frequent were factor V Leiden (15%), mutation G20210A of prothrombin (12%) and protein C or S deficiency (14%). Patients with inherited thrombophilia tend to have more familial thrombotic history and fewer acquired factors.

Arterial factors For the comparison or arterial risk factors, we selected three subpopulations extracted from three different Spanish population-based studies: Hortega, Pizarra and Segovia-VIVA. The main aim of these studies was to study the cardiovascular risk factors at a population level. The subpopulations were matched by age, sex and BMI. The Hortega study is a population-based study performed in Valladolid, a city located in the centre of Spain (Hortega population) (35–37). Subjects > 18 years old were randomly selected from the public register of the Western Medical Area of Valladolid. The calculated minimal sample size to be ª 2014 John Wiley & Sons Ltd Int J Clin Pract, July 2014, 68, 7, 871–881

representative of the population was 1400, and 1504 individuals were recruited. The selection strategy and methodology of this study have been previously described (35–37). The Pizarra study is an epidemiological study of 7000 inhabitants of the ‘Bajo Guadalhorce’ region in Malaga, southern Spain. The characteristics of this population have also been previously published (38–40). Briefly, 2090 subjects aged 18–65 years were randomly selected from the municipal register. For 1119 of the 2090 individuals, demographic, anthropometric and blood samples were available. This population has a prevalence of obesity and of type 2 diabetes higher than those reported for other Spanish communities. Finally, the Segovia-VIVA study is a population-based epidemiological study performed in Segovia, which is located in the centre of Spain. A description of the sampling methodology and characteristics of this study were previously published (41,42). The three studies recorded not only anthropometric measurements, BP, glycaemia and lipid profile but also personal and family information about cardiovascular risk factors. The anthropometric parameters were recorded for all the individuals according to standard procedures. Body mass index was calculated as weight divided by height2, expressed in kg/m2. Obesity was defined as a BMI ≥ 30 kg/m2 and overweight as a BMI of 25.0–29.9 kg/m2. Blood pressure was assessed with automatic devices following the recommendations of the European Society of Hypertension. Blood samples were obtained in fasting conditions in Pizarra and Segovia and with a mean of 3 h fasting (range 0–17) in Hortega. Serum biochemistry was analysed by means of standard autoanalyzers. Glucose was measured by the glucose oxidase method. Total cholesterol, triglycerides and HDLc were assessed with an enzymatic method by means of standard analyzers, and LDL cholesterol was calculated using the Friedewald formula. All the studies were approved by their Local Ethics Committees, and all the participants gave written agreement to participate.

Ultrasound evaluation The carotid ultrasound evaluation was performed with the patient in the supine position and the head slightly turned to the other side using a high frequency linear probe (12 MHz) with an Aloka ProSound Alpha-10 ultrasound device (6-22-1, Mure, Mitaka-shi, Tokyo 181-8622 Japan). We considered a patient to have atherosclerosis if there were plaques according to the definition of the Mannheim Carotid Intima-Media Thickness (IMT) Consensus (2004– 2006) (43): intima-media thickness > 1.5 mm or a lumen encroachment > 0.5 mm or a thickness

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> 50% of the surrounding IMT value. We also grouped the subjects by their plaque characteristics: fibrolipidic, fibrocalcic or both. The majority of the studies were performed by the same operator who recorded the size and characteristics of the plaque.

Statistical analysis Quantitative traits were expressed as mean  SD. Qualitative traits were expressed as absolute number and percentage. The propensity score matching method (k-nearest neighbours matching) was used to select the three most similar individuals for each subject with RVO in each of the comparison populations based on age, sex and BMI variables. T-test was used to compare quantitative variables between the RVO group and the other groups. v2 test was used to compare categorical variables among groups. The binomial probability test was used to compare the observed frequencies of venous risk factors with those of a reference general population and also for comparing the new frequencies of cardiovascular risk factors after reclassification with the previous frequency. All the statistical analyses were made with the StataIC 11 software (Stata Corp, 4905 Lakeway Drive, College Station, TX 77845, USA).

Results One hundred patients with RVO were selected (mean age 59 years, 42% females, mean BMI 27.5 kg/m2). Of these, 26 had CRVO and 74 had BRVO. None of them had bilateral RVO, and the most affected eye was the left one. The main characteristics of the study population are shown in Table 1.

Local factors Among the local factors for RVO was ocular hypertension, for which only 15 were under treatment, and whose ocular pressure at the moment of the RVO were 20.8  4.3 mmHg for the right eye and 21.6  6.0 for the left eye. For those subjects without ocular hypertension, the mean ocular pressures were 15.9  3.9 and 15.8  3.0 for the right and left eye, respectively. These differences are highly significant when compared with the levels observed in those treated for ocular hypertension. The prevalence of elevated ocular pressure (ocular pressure ≥ 21 mmHg) was 7.6% among those without diagnosis of ocular hypertension and 33.3% among those 15 under treatment for ocular hypertension (p-value 0.003). In the two subjects with the highest ocular pressure values (42 and 40 mmHg), the affected eye was the unilateral one, whereas in those subjects with only mild elevations of the OP this concordance did not always occur. The funduscopy revealed cross signs in 17 patients.

Venous factors Only the prevalence of hyperhomocysteinaemia and aPLAs was similar to that observed in our cohort of young patients with DVT and/or PE or to the estimated prevalence observed in DVT or PE studies in the literature. It was significantly higher than that reported in the general population. For genetic thrombophilia, which includes factor V Leiden, G201210A mutation of prothrombin gene, protein C, S or antithrombin III deficiencies, the prevalence observed in the RVO group was similar to the one observed in the general population and was significantly lower than that observed in our cohort of DVT or for the estimated one in DVT/PE in the literature. For the D-dimer levels, only a small number of patients (17%) had abnormal levels (D-dimer ≥ 250 mg/dl). Because of the large differences in age between the RVO and the DVT groups, we have also included the comparison with the subgroup of RVO patients equal or younger than 50 years old. The results of the comparison of venous factors are shown in Table 2.

Arterial factors For matching, there were no differences in age, sex and BMI among the RVO and the comparison populations, except for age in the case of Pizarra. Individuals from this population were significantly younger than were the individuals with RVO (55.9 vs. 59.2, p < 0.05). Among the main arterial risk factors for atherosclerosis, the prevalence of hypertension was initially similar for all the populations; however, after a reclassification of hypertension status based on BP levels over 140/90 mmHg, this prevalence was markedly higher for the RVO group than for the other groups. Additionally, BP levels were significantly higher in the RVO group than in the others groups. The change in the prevalence of hypertension after reclassification was highly significant (from 47.4 to 80.8) indicating a large proportion of new diagnosed hypertension. In the case of type 2 diabetes, the prevalence was significantly higher in Pizarra than in the other groups, but there were no significant differences among the RVO, Hortega or Segovia. After reclassification, there was a trend towards a higher prevalence in the RVO group when compared with those of Hortega and Segovia, but these differences were not significant. The glucose levels were significantly higher in the RVO than in Hortega or Segovia, but were lower than those observed in the Pizarra group. These differences in glucose levels among RVO, Hortega and Segovia were especially prevalent in the non-diabetic patients, indicating a higher prevalence of intolerance fasting glucose. ª 2014 John Wiley & Sons Ltd Int J Clin Pract, July 2014, 68, 7, 871–881

Factors associated with retinal vein occlusion

Table 1 Main characteristics of the retinal vein occlusion population

Age Sex (male/female) Thrombosis localisation (N/%) Left eye Right eye Ocular pressure Ocular pressure right eye (mmHg) Ocular pressure left eye (mmHg) Ocular pressure right eye (patients under treatment) (mmHg) Ocular pressure left eye (patients under treatment) (mmHg) Ocular pressure right eye (patients without treatment; mmHg) Ocular pressure left eye (patients without treatment; mmHg) Ocular Hypertension under treatment (N/%) Ocular pressure ≥ 21 mmHg (N/%) Cross signs (N/%) BMI (kg/m2) SBP (mmHg) DBP (mmHg) Glucose (mg/dl) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl) Triglycerides (mg/dl) Hypertension (N/%) Type 2 diabetes (N/%) Dyslipidaemia (N/%) Total cholesterol ≥ 200 mg/dl LDL cholesterol ≥ 160 mg/dl HDL cholesterol ≤ 40 mg/dl Triglycerides ≥ 150 mg/dl Overweight (N/%) Obesity (N/%) Hyperhomocysteinaemia (≥ 18.5 lmol/) (N/%) D-dimer (mg(dl) D-dimer ≥ 250 mg/dl, N (%) Antiphospholipid antibodies (N/%) Inherited thrombophilia (N/%) FVL (N/%) Prothrombin G20210A mutation (N/%) C- protein deficiency S-protein deficiency Antithrombin III deficiency

All (N = 100)

CRVO (N = 26)

BRVO (N = 74)

59.26 (12.6) 58/42

60.0 (13.5) 18/8

59.0 (12.4) 40/34

45 (45.0) 55 (55.0)

11 (42.3) 15 (57.7)

34 (45.9) 40 (54.1)

16.6  4.2 16.7  4.2 20.2  4.2 21.6  6.0 15.9  3.9 15.8  3.0 15 (15.5) 11 (11.0) 17 (17.3) 27.5  4.4 158.8  24.5 88.6  16.1 106.9  27.4 212.0  41.4 56.9  22.7 130.2  33.8 138.5  93.0 80 (80.8) 20 (20.2) 67 (72.8) 56 (56.6) 19 (19.2) 10 (10.1) 28 (28.3) 40 (40.4) 28 (28.3) 16 (16.3) 318.9  739.3 17 (17.7) 13 (13.5) 10 (10.4) 7 (7.29) 3 (3.13) 0 (0.0) 0 (0.0) 0 (0.0)

17.6  6.5 16.9  5.8 21.2  6.4 22.7  11.5 16.9  3.5 15.8  3.4 4 (15.3) 4 (16.6) 1 (3.8) 27.3  3.9 152.2  25.4 85.2  16.7 102.1  18.2 219.7  42.9 62.0  24.8 133.2  36.4 139.3  101.4 19 (73.1) 4 (15.3) 17 (65.4) 16 (61.5) 8 (30.7) 2 (7.7) 6 (23.1) 12 (46.1) 6 (23.8) 2 (7.7) 259.1  447.9 3 (12.0) 1 (4.0) 1(4.0) 0 (0.0) 1 (4.0) 0 (0.0) 0 (0.0) 0 (0.0)

16.3  3.04 16.6  3.5 19.9  3.4 21.2  2.7 15.6  2.5 15.8  3.0 11 (15.07) 7(10.1) 16 (22.2) 27.6  4.6 161.2  23.9 89.8  15.7 108.6  19.9 209.3  40.7 55.0  21.8 129.1  33.0 138.2  90.6 61(83.5) 16 (21.9) 50 (75.7) 40 (54.9) 11 (15.1) 8 (10.9) 22 (30.1) 28 (38.4) 22 (30.1) 14(19.4) 340.0  819.2 14 (19.7) 12 (16.9) 9 (12.7) 7 (9.9) 2 (2.8) 0(0.0) 0(0.0) 0(0.0)

*Quantitative variables are expressed as mean  SD; Qualitative variables are expressed as absolute number and percentage; CRVO, central retinal vein occlusion; BRVO, branch retinal vein occlusion; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; FVL, factor V Leiden.

Finally, for lipid metabolism, the prevalence of dyslipidaemia under treatment was significantly higher in the RVO as compared with that for the Hortega group and was similar to the one observed in the Segovia group. Both LDL and HDL cholesterol were significantly higher in the RVO than in Hortega, whereas the opposite trend was observed for triglycerides. The ª 2014 John Wiley & Sons Ltd Int J Clin Pract, July 2014, 68, 7, 871–881

results for the comparison of arterial factors are shown in Table 3 and Figures 1 and 2.

Carotid evaluation A carotid ultrasound evaluation was performed in 48 patients. It showed evidence of atherosclerosis in a large number of subjects [36 (75%)]. Fifteen subjects

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Table 2 Comparison of venous risk factors among populations

Age (years) Sex (male/female) (N/%) BMI (kg/m2) Glucose (mg/dl) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Triglycerides (mg/dl) Homocysteine (lmol/l) Hyperhomocysteinemia (≥ 18.5 lmol/) D-dimer (mg/dl) D-dimer ≥ 250 mg/dl, N (%) Antiphospholipid antibodies (N/%) Inherited thrombophilia FVL (N/%) Prothrombin G20210A mutation (N/%) C- protein deficiency S-protein deficiency Antithrombin III deficiency

RVO Study (N = 100)

Subjects ≤ 50 years from RVO study (N = 28) DVT (N = 293)

Estimated prevalence Estimated prevalence in general in venous population (%) thrombosis (%)

59.26  12.61 58(58)/42(42) 27.56  4.43 106.90  27.41 212.01  41.40 130.25  33.79 56.89  22.72 138.52  93.02 14.64  6.95 16 (16.33) 318.97  739.28 17 (17.71) 13 (13.54) 10 (10.42) 7 (7.29) 3 (3.13) 0 (0) 0 (0) 0 (0)

43.2  5.6 17(60.1)/11(39.3) 27.6  4.2 104.3  26.4 213.3  45.8 132.7  31.9 52.5  18.9 141.7  82.1 14.9  7.3 5 (17.9) 472.3  1312.4 5 (19.2) 4 (15.4) 1 (3.70) 1 (3.70) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)

5 (20)***/*

10 (20)*

1–5 (19)**/* – 5 (20) 2 (20) 0.2–0.4 (20) – 0.2 (20)

15 (22) 25–35 (21) 20 (20)**/* 6 (20) 3 (20) 1–2 1 (20)

35.58  8.9***/*** 168 (57.93)/122 (42.07) 26.30  4.91* 102.89  36.57 193.24  45.07***/* 122.04  36.15 48.98  26.00** 140.45  75.91 13.90  9.92 44 (18.33) 1249.57  1842.87***/* 179 (69.92)***/*** 43 (15.14) 75 (26.41)**/** 41 (15.53)* 24 (9.13) (0.056) 12 (4.58)* 7 (2.66) 4 (1.52)

*p < 0.05 for the differences between RVO study and the other groups; **p < 0.01 for the differences between RVO study and the other groups; ***p < 0.001 for the differences between RVO study and the other groups; The asterisk before the forward slash is for the comparison of the whole group of RVO patients with other groups; the asterisk after the forward slash is for the comparison of the RVO patients ≤ 50 years old with the other groups; RVO, retinal vein occlusion; BMI, body mass index; DVT, deep venous thrombosis.

had fibrolipidic plaques, eight had fibrocalcic ones and 10 had both types of plaque. The most affected carotid was the left, in 33 patients, with the majority of the plaques located at the bifurcation. The mean size of these plaques on the left side was 1.93, 2.21 and 2.36 mm for distal common carotid artery, bifurcation and internal carotid artery, respectively. The right carotid system was affected in 27 subjects, with an average plaque size of 1.8, 2.3, 2.0 and 2.5 mm for distal common carotid artery, bifurcation, internal carotid artery and external carotid artery, respectively. Nor were there significant differences in sex, SBP, DBP, glucose or lipid levels among those subjects with or without carotid atherosclerosis. In the patients with carotid atherosclerosis, the RVO was in the right eye in 20 subjects (55.5%) and in the left eye in 16 (44.4%).

Discussion In this study, the characteristics of a series of patients with a first episode of RVO and the impact of potential associated risk factors were described. Subsequently, we compared the observed prevalence for

these factors in the RVO population with three different general populations in the case of arterial risk factors, and with those for one cohort of young patients with DVT/PE or with those found in the literature in the case of venous factors. Among the arterial risk factors, hypertension and overall BP levels were the main associated factors, whereas only hyperhocysteinaemia and aPLAs were relevant among the venous risk factors for thrombosis. Vascular diseases, especially coronary heart disease and stroke, are the leading causes of morbidity and mortality in industrialised countries. Although retinal vascular disease does not compromise lifespan, it can have a deleterious effect on the quality of life of those affected and, therefore, it is important to determine the main associated risk factors in order to prevent the disease. Both arterial and venous risk factors are thought to be involved in RVO, based on the fact that the retinal veins and arteries share a common adventitious. In this study, there were more affected males than females (58% vs. 42%), with a mean age of 59 years. This indicates that it is not a disease only of the elderly people, but that it also affects active middleaged subjects and, therefore, can have a significant ª 2014 John Wiley & Sons Ltd Int J Clin Pract, July 2014, 68, 7, 871–881

Factors associated with retinal vein occlusion

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Table 3 Comparison of arterial risk factors among populations

*p < 0.05 for the differences between RVO study and the other studies; **p < 0.01 for the differences between RVO study and the other studies; ***p < 0.001 for the differences between RVO study and the other studies; Significant changes in the percentage after the reclassification; RVO, retinal vein occlusion; BMI, body mass index; HTN, Hypertension; BP, blood pressure; SBP, systolic blood pressure; † Adjusted by antihypertensive treatment and also by age in Pizarra; DBP, diastolic blood pressure.

impact on productivity. The CRVO or BRVO can, in the short term, lead to macular oedema with or without a decrease in perfusion, and in the long ª 2014 John Wiley & Sons Ltd Int J Clin Pract, July 2014, 68, 7, 871–881

term, to neovascularisation, retinal deterioration, neovascular glaucoma or vitreous haemorrhaging, all of which are causes of vision loss (3).

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Figure 1 Prevalence of the main arterial risk factors in the

Figure 2 Box plot for the systolic and diastolic blood

retinal vein occlusion group and the comparison groups. Horizontal lines inside the bars mean the prevalence of the risk factor previous to the reclassification (see main text)

pressure factors in the retinal vein occlusion (RVO) group and the comparison groups grouped by the presence or absence of antihypertensive treatment. *,**,*** are statistically significant differences (p < 0.05, 0.01 and 0.001, respectively) between the RVO group and the other groups

The BRVO is three to five times more frequent than is CVRO, and it normally occurs as a result of compression at the crossroads junctions with an adjacent artery. A similar ratio was observed in this study and has been described in previous studies (8). The venous stasis caused by the increase in pressure or stiffness of the adjacent artery seems to be one of the main predisposing factors for RVO. This hypothesis easily explains why the central retinal vein is less affected, and this is related to its large calibre and location. This study did not have any bilateral occlusion that supports localised stasis problems. The presence of ocular hypertension as a cause of RVO is discarded, since only a few patients (11) had high ocular pressure (≥ 21 mmHg) at the moment of the event. Even in those 15 previously diagnosed with ocular hypertension and under treatment, only five (33.3%) had high ocular pressure. From our data, it is possible to speculate that ocular hypertension could be particularly relevant in those subjects with very high ocular pressure levels in one eye, as has been shown by the fact that the affected eye was the unilateral one. The presence of inherited thrombophilia in our series was very rare and similar to that observed in the general population. In fact, none of the patients suffered from protein C, S or antithrombin III deficiency, only seven had Factor V Leiden, and three the G20210A mutation of the prothrombin gene. These percentages are significantly lower than the ones observed in our cohort of young patients with DVTPE or than the estimations for populations with DVT or PE in the literature. These results seem to be the

same even for the young patients with RVO, although this subsample was quite small and still the differences in age as compared with the DVT group were highly significant. Therefore, our results confirm the findings of previous studies (9,44,45) in which inherited thrombophilia had little influence on RVO, so its determination would not be justified a priori. Hypercoagulability, as a result of immune-complexes against the membrane phospholipids or plasmatic proteins (LA, aPLAs) can also lead to RVO. This can be related to the inhibition of the production of prostacyclin by the vascular endothelium, the increase in thromboxane production by the platelet, the increase in the release of tissue factor and the presence of vascular endothelium adhesion molecules that interfere with the fibrinolytic process (29,46). In the present study, there were 13 patients with prevalence significantly higher than the one observed in general population and similar to that observed in the cohort of DVT/PE or the estimated one for thrombosis populations (47). Carbone et al. (48) found that patients with aPLAs and retinal thrombosis had a greater frequency of antinuclear antibodies, low levels of factor 4 of the complement (C4) and the presence of circulating immune-complexes, something that could be the first manifestation of APS or a Systemic Lupus Erythematosus with severe repercussions in other target organs. Homocysteine, which can be considered both an arterial, as well as a venous risk factor, was elevated in 16 patients. Again, this prevalence is significantly higher than that reported for the genª 2014 John Wiley & Sons Ltd Int J Clin Pract, July 2014, 68, 7, 871–881

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eral population, slightly higher than the estimated one for thrombosis populations and similar to the one observed in our group with DVT/PE. Hyperhomocysteinaemia produces a blockade of the union of the tissue plasminogen activator to the endothelial cell and, therefore, can block the release of thrombomodulin by the endothelial cell, activate coagulation factors V and VII and inhibit protein C (49,50). These findings, observed in our cohort, were confirmed by the meta-analysis performed by Janssen and colleagues (9) in patients with RVO, including 11 case– control studies. The odds ratio was 8.9 (95% Cl 5.7– 13.7) for hyperhomocysteinaemia and 3.9 (95% Cl 2.3–6.7) for anticardiolipin antibodies. Hyperhomocysteinaemia has also been associated with BP in the literature (51–54), and therefore the effect of these two factors could be closely related. In this sense, we did not find differences in homocystein levels or for the prevalence of hyperhomocysteinaemia in the RVO group for those with or without hypertension (15.2 vs. 13.9 lmol, p-value 0.34 and 14.8 vs. 14.6 lmol, p-value 0.90, for normotensives and hypertensives before and after reclassification of the hypertension status; 19.6 vs. 12.7%, p-value 0.3 and 15.7 vs. 16.4%, p-value 0.9 for the prevalence of hyperhomocysteinaemia for normotensives and hypertensives before and after reclassification of the hypertension status). Another important issue is that the D-dimer, which is of great value in the diagnosis of an acute episode of DVT/PE (55) or in ischaemic stroke (56), is only elevated in a minority of patients with RVO (only 17 subjects had D-dimer ≥ 250 mg/dl). This parameter has been studied very little in relation to retinal vascular pathology (57), and therefore a more comprehensive evaluation would be necessary. As an arterial risk factor, initially only 47 patients (47%) were diagnosed with hypertension. After reclassification, taking into account BP levels over 140/90, a significant increase in this prevalence was observed (from 47 to 80%). Although we cannot assume a correct diagnosis for all of them, surely among them are many with undiagnosed hypertension. This is important because RVO could be the first clinical manifestation of an essential hypertension in many patients. Moreover, the high systolic and diastolic BP levels seen in both groups, the supposed normotensives and the hypertensives, when compared with those in studies of the general population, indicate a lack of BP control. This is confirmed by the meta-analysis performed by O’Mahoney and collaborators (12), which included 2916 subjects with RVO. In this meta-analysis, the prevalence of hypertension was 63%, significantly higher than the prevalence observed in the comparaª 2014 John Wiley & Sons Ltd Int J Clin Pract, July 2014, 68, 7, 871–881

tive population (36.2%), with an OR for hypertension of 3.5 (95% CI 2.5–5.1). Taking into account our findings and the results of the meta-analysis (12), hypertension seems to be a key factor in the development of RVO. Probably, the increase in arterial stiffness as a result of high BP levels facilitates the venous stasis because the artery lies next to the vein in the retina. For type 2 diabetes, the results were not as evident as for those with hypertension. We only observed a trend towards a higher prevalence, especially after reclassification, based on fasting glucose levels ≥ 126 mg/dl. Fasting glucose levels were also significantly higher in the RVO group when compared with two of the populations (Hortega and Segovia), and these differences were more evident in subjects without type 2 diabetes than in those with it. This may indicate that some kind of carbohydrate metabolism abnormality might also play a role in the development of RVO. In the O’Mahoney meta-analysis (12), of 2877 patients with RVO, 14.6% were diabetic as compared with 11.1% in the general population, which is in agreement with our results. In the O’Mahoney study, however fasting glucose was not evaluated, so some new type 2 diabetes diagnoses could have gone undetected. The lipid abnormalities results were quite inconsistent. There could be a trend towards high LDL cholesterol in the RVO group, but only when compared with one of the populations; the same trend was observed for HDL cholesterol. These confusing results were also observed in the multicentre study of O’Mahoney et al. (12) and could be related to the different criteria used in defining dyslipidaemia or the different thresholds for normal lipid levels. In this study, however, there was a noticeable twofold increase in the incidence of dyslipidaemia in patients with RVO as compared with the general population (12). Finally, in 48 patients with RVO who underwent a carotid intima-media thickness evaluation, this study noted a high prevalence of arteriosclerotic lesions. This result reinforces the hypothesis of arterial risk factors as triggers of RVO. An association among ischaemic stroke, retinal thrombosis and carotid stenosis has been recently described (58–60). Among the strengths of this study is the use of several populations for comparing the arterial factors. This minimises the possibility that the observed findings were by chance. Moreover, the comparison populations were matched by age, sex and BMI to reduce the impact of said variables on the prevalence of the main cardiovascular risk factors. In the case of the venous factors, we took advantage of one large series of young patients with DVT/PE who are perfectly characterised regarding the risk factors for

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venous thrombosis. Additionally, the observed prevalence of venous risk factors in the literature for both populations with DVT/PE and population-based studies was reviewed. Among the main weaknesses is that which derives from the differences in the methodology of the different studies used for comparison. This is especially important in the case of dyslipidaemia, not only because of the different definitions of dyslipidaemia but also because of the lack of information. As examples, in the Segovia population, lipids data were missing in a large number of patients, and in the Pizarra one, we did not have a register of those subjects who were already dyslipidaemics or under hypolipaemic treatment. Taking into account the characteristics of the Pizarra population, which has a very high prevalence of obesity and type 2 diabetes, one higher than that reported for other Spanish populations, we can assume that the low lipid levels observed in this population were probably related to a high use of statins or other hypolipaemic treatments. In conclusion, arterial factors in special hypertension and high BP levels are the main contributors to the development of RVO. Another important point is that RVO may be the first manifestation of an undiagnosed hypertension. Therefore, the early detection of hypertensive patients and good control of BP levels can help prevent the development of RVO. Moreover, the diagnosis of RVO in the context of

References 1 Squizzato A, Manfredi E, Bozzato S, Dentali F, Ageno W. Antithrombotic and fibrinolytic drugs for retinal vein occlusion: a systematic review and a call for action. Thromb Haemost 2010; 103: 271–6. 2 Karia N. Retinal vein occlusion: pathophysiology and treatment options. Clin Ophthalmol 2010; 4: 809–16. 3 Wong TY, Scott IU. Clinical practice. Retinal-vein occlusion. N Engl J Med 2010; 363: 2135–44. 4 Hayreh SS. Prevalent misconceptions about acute retinal vascular occlusive disorders. Prog Retin Eye Res 2005; 24: 493–519. 5 Fontenla JR, Aranda A, Ferren M, Pita D. Obstrucci
on Venosa Retiniana. Barcelona: Alhambra, 2004: 3–19. 6 Cugati S, Wang JJ, Rochtchina E, Mitchell P. Ten-year incidence of retinal emboli in an older population. Stroke 2006; 37: 908–10. 7 Klein R, Moss SE, Meuer SM, Klein BE. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol 2008; 126: 513–8. 8 Rogers S, McIntosh RL, Cheung N et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology 2010; 117, 313– 9 e1.

hypertension raises the possibility of other target organ damage (TOD) such as carotid arteries, the heart and the kidney, given the large number of individuals with carotid plaques. If this is the case, these patients should be treated more aggressively in order to avoid the progression of TOD. Among the venous factors, only hyperhomocysteinaemia and the presence of aPLAs seem to play a role, so it would not be necessary to assess the inherited thrombophilia in those patients with new onset RVO.

Acknowledgements This study was supported by grants SAF2005-02883 of the Inter-ministry commission of Science and Technology (CICYT); PI07/0497, PI09/02014 and PI11/00726 from Carlos III Health Institute Madrid and of the Spanish Health Ministry; Net of biomedical research centers (CIBER) of physiopathology, obesity and nutrition (CIBEROB) and CIBER of diabetes and metabolic diseases (CIBERDEM), Carlos III Health Institute Madrid and of the Spanish Health Ministry; GRUPOS 03/101 and 2005/027 from the Valencian Government and European Network of Excellence Ingenious Hypercare (EPSS037093) from the European Commission; Bio bank grant from the National Health Institute Carlos III FEDER RD09/0076/00132 (Madrid, Spain).

9 Janssen MC, den Heijer M, Cruysberg JR, Wollersheim H, Bredie SJ. Retinal vein occlusion: a form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors. Thromb Haemost 2005; 93: 1021–6. 10 Fegan CD. Central retinal vein occlusion and thrombophilia. Eye 2002; 16: 98–106. 11 Soriano C, Hernandez-Lastras A. Trombosis retiniana en pacientes j
ovenes. Aspectos inmunol
ogicos y cl
ınicos. Archivos de la sociedad Espa~ nola de Oftalmologia 2001; 3: 181–88. 12 O’Mahoney PR, Wong DT, Ray JG. Retinal vein occlusion and traditional risk factors for atherosclerosis. Arch Ophthalmol 2008; 126: 692–9. 13 Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein Occlusion Study Group. Am J Ophthalmol 1984;98: 271–82. 14 Baseline and early natural history report. The Central Vein Occlusion Study. Arch Ophthalmol 1993; 111: 1087–95. 15 Blodi BA, Domalpally A, Scott IU et al. Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study system for evaluation of stereoscopic color fundus photographs and fluorescein angiograms: SCORE Study Report 9. Arch Ophthalmol 2010; 128: 1140–5. 16 Joshi L, Yaganti S, Gemenetzi M et al. Dexamethasone implants in retinal vein occlusion: 12-month clinical effectiveness using repeat injections as-needed. Br J Ophthalmol 2013; 97: 1040–4.

17 Campochiaro PA. Anti-vascular endothelial growth factor treatment for retinal vein occlusions. Ophthalmologica 2012; 227 (Suppl. 1): 30–5. 18 Glacet-Bernard A, Zourdani A, Milhoub M, Maraqua N, Coscas G, Soubrane G. Effect of isovolemic hemodilution in central retinal vein occlusion. Graefe’s Arch Clin Exp Ophthalmol 2001; 239: 909–14. 19 Houtsmuller AJ, Vermeulen JA, Klompe M et al. The influence of ticlopidine on the natural course of retinal vein occlusion. Agents Actions Suppl 1984; 15: 219–29. 20 Farahvash MS, Moghaddam MM, Moghimi S, Mohammadzadeh S. Dalteparin in the management of recent onset central retinal vein occlusion: a comparison with acetylsalicylic acid. Can J Ophthalmol 2008; 43: 79–83. 21 Ageno W, Cattaneo R, Manfredi E et al. Parnaparin versus aspirin in the treatment of retinal vein occlusion. A randomized, double blind, controlled study. Thromb Res 2010; 125: 137–41. 22 Hattenbach LO, Friedrich Arndt C, Lerche R et al. Retinal vein occlusion and low-dose fibrinolytic therapy (R.O.L.F.): a prospective, randomized, controlled multicenter study of low-dose recombinant tissue plasminogen activator versus hemodilution in retinal vein occlusion. Retina 2009; 29: 932–40. 23 McIntosh RL, Rogers SL, Lim L et al. Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010; 117: 1113–23, e15.

ª 2014 John Wiley & Sons Ltd Int J Clin Pract, July 2014, 68, 7, 871–881

Factors associated with retinal vein occlusion

24 Lazo-Langner A, Hawel J, Ageno W, Kovacs MJ. Low molecular weight heparin for the treatment of retinal vein occlusion: a systematic review and meta-analysis of randomized trials. Haematologica 2010; 95: 1587–93. 25 Mancia G, De Backer G, Dominiczak A et al. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25: 1105–87. 26 Kuhar MB. Update on managing hypercholesterolemia. The new NCEP guidelines. AAOHN J 2002; 50: 360–4. 27 Diagnosis and classification of diabetes mellitus. Diabetes Care 2011; 34 (Suppl. 1): S62–9. 28 Kang SS, Wong PW, Malinow MR. Hyperhomocyst (e)inemia as a risk factor for occlusive vascular disease. Annu Rev Nutr 1992; 12: 279–98. 29 Levine JS, Branch DW, Rauch J. The antiphospholipid syndrome. N Engl J Med 2002; 346: 752–63. 30 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167–73. 31 Rosendaal FR. Thrombosis in the young: epidemiology and risk factors. A focus on venous thrombosis. Thromb Haemost 1997; 78: 1–6. 32 Eschwege V, Peynaud-Debayle E, Wolf M et al. Prevalence of antiphospholipid-related antibodies in unselected patients with history of venous thrombosis. Blood coagulation & fibrinolysis: an international journal in haemostasis and thrombosis 1998; 9: 429–34. 33 Garcia-Fuster MJ, Fernandez C, Forner MJ, Vaya A. Risk factors and clinical characteristics of thromboembolic venous disease in young patients: a prospective study. Med Clin 2004; 123: 217–9. 34 Garcia-Fuster MJ, Forner MJ, Fernandez C, Gil J, Vaya A, Maldonado L. Long-term prospective study of recurrent venous thromboembolism in patients younger than 50 years. Pathophysiol Haemost Thromb 2005; 34: 6–12. 35 Mena Martin FJ, Martin Escudero JC, Simal Blanco F, Carretero Ares JL, Herreros Fernandez V. [Cardiovascular risk factors in diabetic patients. Cross-sectional study in general population: Hortega study]. An Med Interna 2003; 20: 292–6. 36 Mansego ML, Redon J, Marin R et al. Renin polymorphisms and haplotypes are associated with blood pressure levels and hypertension risk in postmenopausal women. J Hypertens 2008; 26: 230–7.

ª 2014 John Wiley & Sons Ltd Int J Clin Pract, July 2014, 68, 7, 871–881

37 Mena-Martin FJ, Martin-Escudero JC, Simal-Blanco F, Carretero-Ares JL, Arzua-Mouronte D, Herreros-Fernandez V. Health-related quality of life of subjects with known and unknown hypertension: results from the population-based Hortega study. J Hypertens 2003; 21: 1283–9. 38 Soriguer F, Rojo-Martinez G, Almaraz MC et al. Incidence of type 2 diabetes in southern Spain (Pizarra Study). Eur J Clin Invest 2008; 38: 126–33. 39 Morcillo S, Rojo-Martinez G, Cardona F et al. Effect of the interaction between the fatty acid binding protein 2 gene Ala54Thr polymorphism and dietary fatty acids on peripheral insulin sensitivity: a cross-sectional study. Am J Clin Nutr 2007; 86: 1232–7. 40 Soriguer-Escofet F, Esteva I, Rojo-Martinez G et al. Prevalence of latent autoimmune diabetes of adults (LADA) in Southern Spain. Diabetes Res Clin Pract 2002; 56: 213–20. 41 Galan JJ, Buch B, Pedrinaci S et al. Identification of a 2244 base pair interstitial deletion within the human ESR1 gene in the Spanish population. J Med Genet 2008; 45: 420–4. 42 Martinez-Larrad MT, Fernandez-Perez C, Gonzalez-Sanchez JL et al. [Prevalence of the metabolic syndrome (ATP-III criteria). Population-based study of rural and urban areas in the Spanish province of Segovia]. Med Clin (Barc) 2005; 125: 481–6. 43 Touboul PJ, Hennerici MG, Meairs S et al. Mannheim intima-media thickness consensus. Cerebrovasc Dis 2004; 18: 346–9. 44 Hodgkins PR, Perry DJ, Sawcer SJ, Keast-Butler J. Factor V and antithrombin gene mutations in patients with idiopathic central retinal vein occlusion. Eye (Lond) 1995; 9 (Pt 6): 760–2. 45 Linna T, Ylikorkala A, Kontula K, Puska P, Tervo T. Prevalence of factor V Leiden in young adults with retinal vein occlusion. Thromb Haemost 1997; 77: 214–6. 46 Khamashta MA, Cuadrado MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the antiphospholipid-antibody syndrome. N Engl J Med 1995; 332: 993–7. 47 Hegde VA, Vivas Y, Shah H et al. Cardiovascular surgical outcomes in patients with the antiphospholipid syndrome–a case-series. Heart Lung Circ 2007; 16: 423–7. 48 Carbone J, Sanchez-Ramon S, Cobo-Soriano R et al. Antiphospholipid antibodies: a risk factor for occlusive retinal vascular disorders. Comparison

49

50

51

52

53

54

55 56

57

58

59

60

881

with ocular inflammatory diseases. J Rheumatol 2001; 28: 2437–41. Falcon CR, Cattaneo M, Panzeri D, Martinelli I, Mannucci PM. High prevalence of hyperhomocyst (e)inemia in patients with juvenile venous thrombosis. Arterioscler Thromb 1994; 14: 1080–3. Cattaneo M. Hyperhomocysteinemia, atherosclerosis and thrombosis. Thromb Haemost 1999; 81: 165–76. Dinavahi R, Falkner B. Relationship of homocysteine with cardiovascular disease and blood pressure. J Clin Hypertens 2004; 6: 494–8; quiz 9-500. Lim U, Cassano PA. Homocysteine and blood pressure in the Third National Health and Nutrition Examination Survey, 1988–1994. Am J Epidemiol 2002; 156: 1105–13. Sutton-Tyrrell K, Bostom A, Selhub J, Zeigler-Johnson C. High homocysteine levels are independently related to isolated systolic hypertension in older adults. Circulation 1997; 96: 1745–9. Nygard O, Vollset SE, Refsum H et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. JAMA 1995; 274: 1526–33. Agnelli G, Becattini C. Acute pulmonary embolism. N Engl J Med 2010; 363: 266–74. Montaner J, Perea-Gainza M, Delgado P et al. Etiologic diagnosis of ischemic stroke subtypes with plasma biomarkers. Stroke 2008; 39: 2280–7. Mukha AI. [The content of D-dimer in peripheral blood as observed studied in thrombohemorrhagic lesions of the retina]. Vestn oftalmol 2004; 120: 14–6. De Silva DA, Liew G, Wong MC et al. Retinal vascular caliber and extracranial carotid disease in patients with acute ischemic stroke: the Multi-Centre Retinal Stroke (MCRS) study. Stroke 2009; 40: 3695–9. Wong TY. Is retinal photography useful in the measurement of stroke risk? Lancet Neurol 2004; 3: 179–83. Wong TY, Kamineni A, Klein R et al. Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the cardiovascular health study. Arch Intern Med 2006; 166: 2388–94.

Paper received September 2013, accepted December 2013