Venous thrombosis affects one in 1000 individuals per year causing significant morbidity and mortality ¹. Its has a 'multiple hit' pathogenesis in which several adverse influences affecting the composition of the blood, the structure and function of the vessel wall and blood flow, together result in an acute thrombotic event ².
Retinal venous occlusion is a venous thrombotic disorder which also afflicts older subjects, 51% of cases occurring at more than 65 years of age ³. Undoubted associations exist with other conditions, especially hypertension, diabetes mellitus, sedentary lifestyle, and open angle glaucoma, each of which is also age related ⁴.
The Eye Disease Case Control Study Group identified a number of risk factors for branch, central, and hemiretinal vein occlusions including hypertension, diabetes, a history of cardiovascular disease, an increased body mass index at 20 years of age, and patients with open angle glaucoma ^5-7. Other risk factors include hyperviscosity syndromes, malignancy, pregnancy, and oestrogen therapy ^8-9.
Inherited defects in the coagulation pathways are also associated with retinal vein occlusion. Hypercoagulability can be the result of deficiencies in particular elements of the coagulation cascade such as protein C, protein S, or antithrombin III. These are rare disorders associated with increased incidence of venous thrombosis particularly in young adults ¹⁰.

The aim of this study is to investigate the relationship between central and branch vein occlusion and certain risk factors and whether these factors vary between the two conditions.

This study was conducted over a two year period between July 2003 and June 2005 in King Hussein Medical Center in Royal Medical Services. A total number of 96 patients with retinal vein occlusion (52 branch, 44 central) were investigated for certain factors. These variables included patient age, body mass index, smoking, presence of hypertension, diabetes, hyperlipidaemia, glaucoma, body mass index, refractive status and thrombophilia profile. The latter included APC-R, factor V Leiden, protein C, protein S, antithrombin III. Ophthalmologic examination included Snellen's visual acuity, anterior segment examination via slit lamp, Goldmann's applanation tonometry (measured at the same slit lamp by the same physician between 10-11 am), refraction, and posterior segment examination via +78 lens. Diagnosis of retinal vein occlusion was confirmed by fluorescein angiography. Patients with hemicentral venous occlusion were included in CRVO group. Results were compared with a control group of 96 patients of the same age distribution for the same variables. P-value was applied to determine significance of the variable.

The mean age for patients with central vein occlusion, branch vein occlusion and for control group was 67.4, 61.4, and 63.2 years respectively (Table 1). Table 2 shows the association between risk factors with retinal vein occlusion and Table 3 shows coagulation abnormalities; more than one fifth of patients with CRVO expressed reduced APC-R and factor V Leiden mutation. Hypertension and smoking were significantly associated with BRVO. Glaucoma, APC-R, factor V mutation, and MTHFR mutation were significantly associated with CRVO (Table 4).

Retinal vein occlusion is an established cause of visual loss in the middle-aged and elderly population. Studies have identified major medical conditions associated with retinal vein occlusion including hypertension, hyperlipidemia and diabetes mellitus, vasculitis, and hyperviscocity syndrome ^{6, 11}.

Hypertension was more frequent in BRVO than in CRVO or in control group in our study (53.8% vs. 40.9% and 29.2%). It was significantly associated with BRVO (p-value < 0.01). The explanation for this is that thickened arteriolar walls have been shown to compress and narrow the venous lumen at arteriovenous crossings, setting the stage for an occlusion. Factors that can cause arteriolar wall pathology such as smoking would be expected to be more closely associated with a branch vein occlusion. This also explains the higher prevalence of BRVO in smokers. These results had been previously found by Appiah and his colleague. They showed that hypertension is more closely associated with a branch as opposed to a central, or hemicentral retinal vein occlusion ¹².

Diabetes was more frequent in CRVO and BRVO than in controls, but this was not statistically significant. Both hypercholesterolaemia and hypertriglyceridaemia were associated with BRVO, while hypertriglyceridaemia only, was associated with CRVO more than in controls. Neither result proved to be statically significant, although they were more significant in BRVO than in CRVO (Table 4).

Dobree in 1957 described the mechanisms for obstruction of a vein in a glaucomatous optic cup. He suggested that an extensive cauldron-shaped excavation could lead to a considerable stretching and weakening of the walls of the vein, and that the vein walls, which have lost the support and protection of the optic nerve tissue, become directly exposed to the intraocular pressure ¹³. A popular theory exists that raised intraocular pressure causes external compression of the central retinal vein as it passes through the lamina cribrosa. This results in turbulent blood flow distal to the constriction and subsequent thrombus formation ¹⁴. We found glaucoma to be significantly associated with CRVO (p<0.01). It had been reported that primary open angle glaucoma or ocular hypertension occurs in 4% to 43% of patients with CRVO ^{12, 15}.

Hypermetropia was more frequent in BRVO patients. The mechanism for increase risk of BRVO is still not well understood ¹⁶. Higher body mass index (more than 30) was also more frequent in BRVO patients. The Eye Disease Case Control Study Group showed that increased body mass index is considered as risk factor for BRVO ⁷.

Two patients with BRVO had Behçet's disease. Behçet's disease is characterised in some patients by recurrent retinal vein occlusions probably due to a combination of retinal vasculitis and thrombus formation. Thrombosis in Behçet's disease carries a poor ocular and systemic prognosis, so the presence of an identifiable and significant risk factor could be an indicator for anticoagulant treatment in addition to an immunosuppressive regimen ¹⁷. One patient had non-arteritic anterior ischaemic optic neuropathy. This neuropathy is most probably caused by local factors which compromise the short posterior ciliary arteries, the pial circulation, and the retinal circulation at the optic nerve head and are most significant in the crowded disc ¹⁸. It may also, however, be associated with systemic factors, which increase the likelihood of occlusion of these vessels. Such factors include diabetes, increased body mass index, ischaemic heart disease, hypercholesterolaemia, and acute events such as systemic hypotension.

Activated protein C resistance was reported in 12-26% of patients with CRVO compared with 5% of controls taken from the general population ^19-20. We found APC-R in 22.7% of patients with CRVO and in 13.7% of those with BRVO compared to 5.2% of controls. It was statically significant in the CRVO group. In 95% of cases of APC resistance, the cause is a single point mutation in the factor V gene, called factor V Leiden ^21-22. Other causes of resistance to activated protein C exist including pregnancy, surgery, oral contraceptives, lupus anticoagulant, and elevated factor VIIIa in plasma. Factor V Leiden mutation (a point mutation in factor V rendering it resistant to the normal inactivation by activated protein C) is a common inherited mutation that is a significant risk factor for deep vein thrombosis. Factor V mutation was seen in 22.7% of CRVO (statistically significant), 11.5% of BRVO group and 4.2% of controls. Spagnolo, et al reported factor V Leiden in 29% and 19% in CRVO and BRVO patients respectively ²³.

Other coagulation abnormalities including protein C, protein S, and antithrombin III deficiencies are rarely reported in retinal vein occlusions ²⁴. In our study, protein C deficiency was found in one CRVO patient, protein S in one BRVO patient, and no patient had antithrombin III deficiency.

A variant of the methylenetetrahydrofolate reductase enzyme, caused by a C677T mutation, may result in hyperhomocysteinaemia. It has been implicated in central retinal vein occlusion ²⁵. A prevalence of 8.3% had been reported for the mutation in patients with CRVO compared with 0% for controls ²⁶. In this study, four CRVO patients (9.1%) and two BRVO patients (3.8%) had the mutation.

Ten patients with retinal vein occlusion were younger than 40 years, five with CRVO and five with BRVO. All of those with CRVO had APC-R and factor V Leiden mutation; two were hypertensive, and one had protein C deficiency. Three patients with BRVO were hypertensive, two had APC-R, two with factor V Leiden mutation, and one had protein S deficiency. These findings illustrate the importance to investigate young patients for coagulation abnormalities. In a study of 31 young adults with CRVO, 26% of patients younger than 50 years and 36% of patients younger than 45 years evidenced resistance to activated protein C ²⁷.

In conclusion, there are variable risk factors for both central and branch retinal vein occlusion. We found that glaucoma, APC-R, factor V mutation, and MTHFR mutation were significantly associated with CRVO, while hypertension and smoking were significantly associated with BRVO. Also it is advisable to investigate young patients with retinal vein occlusion for coagulation abnormalities.

Table 1. Age distribution of patients and control groups

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Table 2 Risk factors for vein occlusion in the three groups.

* More than 20 cigarettes/day since the last one year.
** include Behçet's disease and non-arteritic anterior ischemic optic neuropathy.
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Table 3 Coagulation abnormalities in the three groups.

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Table 4 P-value for both CRVO and BRVO groups in relation to controls.

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