ENGLISH
Retinal vein occlusion (RVO) is the second most common retinal vascular disease after diabetic retinopathy. It occurs most commonly in individuals over the age of 40 [1, 2]. The precise pathogenesis is still unknown [3]. Risk factors include arterial hypertension, hyperlipidemia, diabetes mellitus, stroke, and cigarette smoking [3-6]. The risk of RVO increases with age [1, 2].
Epidemiological studies indicate that the prevalence of RVO is between 0.6% and 1.1% in the Caucasian population [7] and up to 2.74% in Asian countries such as Nepal [8].
RVO can be divided into two types: branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO). Outcomes in terms of improvement in visual acuity are more favorable for BRVO.
Importantly, RVO can develop in patients younger than 50 years old. The present paper also explores other prothrombotic factors that could be relevant in this patient group.
Although the precise pathogenesis of RVO is unknown, the condition may be associated with systemic factors referred to as Virchow’s triad:
compression of retinal veins by retinal arteries at vessel crossings,
degenerative changes in retinal vessels,
hematological factors [9].
Retinal vein compression: sclerotization of arterial vessels due to factors such as arterial hypertension or hyperlipidemia can lead to venous compression. Venous compression was observed in 99% of eyes affected by RVO [10]. Mechanical compression of retinal veins at arteriovenous crossings can cause turbulent blood flow. Turbulence can damage both the endothelium and the vascular tunica media (the intima-media complex), initiating the thrombotic cascade [11].
Degenerative changes in the retinal vasculature are caused primarily by arterial hypertension, hyperlipidemia, and diabetes mellitus. The relative risk of RVO in patients with the systemic diseases listed above is reported as 3.0, 2.3, and 1.1, respectively, according to a 2014 meta-analysis involving 492,488 patients [13]. This implies that hypertension is the main culprit contributing to the development of RVO. The meta-analysis also identified no correlation between the development of RVO and diabetes mellitus without systemic complications. However, in individuals with complicated diabetes mellitus, the risk of RVO was shown to increase by 36%. No correlation was found between isolated hyperlipidemia and the disorder, but the risk of RVO is known to increase in hyperlipidemic patients with comorbid metabolic syndrome [14].
Hematological factors: elevated hematocrit levels are linked to an increased incidence of thrombosis [12]. Hematocrit and fibrinogen impact blood viscosity. Increased blood viscosity is generally not problematic when blood flow is fast. However, in situations where blood flow is slow, e.g. in venous vessels, the risk of blood clot formation increases [15, 16]. Multiple studies have demonstrated an association between elevated fibrinogen levels and cardiovascular diseases [17]. Thrombophilia has also been identified as a potential cause of RVO [18-20].
Furthermore, many studies have highlighted the role of homocysteine in the pathogenesis of RVO. The enzyme that affects homocysteine levels is methylenetetrahydrofolate reductase (MTHFR). It catalyzes the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate. The resulting 5-methyltetrahydrofolate is essential for the subsequent reaction, which converts the amino acid homocysteine into methionine. The activity of MTHFR involves converting folic acid into its active form and reducing elevated levels of homocysteine [21, 22]. Hyperhomocysteinemia can arise from a genetic defect in MTHFR production, and it is associated with RVO [23-25].
Several polymorphisms of the MTHFR gene have been identified, of which two are of the greatest importance: MTHFR C677T and MTHFR A1298C. The MTHFR C677T variant decreases MTHFR activity by 60% in homozygous individuals, resulting in hyperhomocysteinemia [26]. The MTHFR A1298C variant results in a 40% reduction in enzyme activity in homozygotes, but does not lead to hyperhomocysteinemia. However, in individuals who are heterozygous both for the A1298C and C677T variants, hyperhomocysteinemia may occur [21].
The prevalence of the homozygous MTHFR C677T variant is 20% in the Chinese and 15% in the North American population. In Europe, the prevalence rates are 4% in Finland, 26% in the southern part of Italy, and 11.8% in Spain [27]. The prevalence of heterozygous MTHFR C677T mutations is estimated at 6.6% in Africa, 26–37% in Japan, 24–40% in Europe, and 30–40% in the North American population [28].
Severe hyperhomocysteinemia is uncommon, whereas milder forms occur in approximately 5% of the general population [25]. The association between hyperhomocysteinemia and RVO is well documented [23-25, 29], as is the relationship between the MTHFR gene polymorphism and RVO [31]. However, an isolated MTHFR gene defect alone may not induce hyperhomocysteinemia. Factors that influence blood homocysteine levels include age, gender, folic acid intake, smoking, vitamin B intake, vascular diseases, and treatment with antihypertensive agents [30].
Factors involved in the pathogenesis of RVO include mutations in coagulation factor V and prothrombin [32]. Factor V Leiden is a variant form of coagulation factor V that is caused by a genetic point mutation. Factor V Leiden is relatively common, occurring in approximately 5% of the European population. The altered protein is normally activated in the coagulation process; however, the process of inactivation by protein C is slowed down. It was found that the mutation increased the risk of thrombosis by 3-8 times in heterozygous individuals, and by up to 80 times in homozygous individuals, compared to the general population [33]. Factor V Leiden coexists with systemic venous thrombosis in 20% of cases [33] and with pulmonary embolism in 27.3% of cases [34, 35]. The prevalence of the mutation in heterozygous individuals with RVO is 8.2% [36]. Some authors, however, argue that factor V Leiden is not involved in the development of RVO [31, 38].
A mutation in the prothrombin gene can triple the risk of thrombosis by increasing prothrombin production. This mutation ranks among the most common, second only to the coagulation factor V mutation, occurring in approximately 1.2% of the population. Mutations are estimated to affect 17% of patients with systemic venous thrombosis and 18.2% of patients with pulmonary embolism [33]. The prevalence of mutations coexisting with RVO is evaluated at 4.2% [36]. A study focusing on patients with RVO under 60 years of age reported the prevalence of the mutation as 10% [37], suggesting that it may have a greater impact on younger patients. Other authors, however, challenge the claim that prothrombin gene mutations contribute to the risk of RVO [31].
A potential prothrombotic factor that might affect the development of RVO, particularly in younger patients, is PAI-1 polymorphism. The PAI-1 gene encodes the PAI-1 protein, which acts as an inhibitor of tissue plasminogen activator (tPA). Elevated levels of the PAI-1 protein slow down the process of blood clot dissolution, increasing the risk of blood vessel blockage.
There is a documented correlation between the occurrence of RVO and polymorphism in the PAI-1 gene. The polymorphism -675 (4G/5G) within the PAI-1 gene involves insertion/deletion of the nucleotide guanine (G). Depending on the allele, either four guanine repeats (4G) or five guanine repeats (5G) are present at the polymorphic site. In individuals with the homozygous 4G/4G genotype, serum PAI-1 levels are elevated, which inhibits the process of fibrinolysis compared to the population with the 5G/5G genotype. In individuals with the heterozygous genotype (4G/5G), the PAI-1 level is intermediate between those observed in the homozygous genotypes. The presence of polymorphism in the PAI-1 gene may elevate the risk of RVO by inhibiting fibrinolysis [39]. However, another publication refutes the link between RVO and PAI-1 gene mutation [31].
The risk of developing RVO can be assessed using biomarkers: platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) [43]. PLR and NLR can be used to monitor the treatment of certain types of cancer [44-46]. Some studies report that PLR and NLR can be employed to determine the risk of thromboembolic events [47, 48], and also to directly assess the risk of RVO [49]. It was shown that patients with RVO had elevated neutrophil counts and decreased lymphocyte counts compared to the control group. PLR and NLR values were found to be significantly higher in patients with RVO. In the discussion, the authors highlighted the role of neutrophils in releasing chemokines such as VEGF, IL-8, angiopoietin 1, and matrix metalloproteinase-9, all of which are prothrombotic factors. Lymphocytes play the opposite role to neutrophils. They can regulate inflammatory processes and induce cell apoptosis. Blood platelets release VEGF and participate in angiogenesis and inflammatory processes; hence, elevated NLR levels may be linked to poorer prognosis [49].
Other known prothrombotic factors include lupus anticoagulant, antiphospholipid antibodies, protein C and protein S deficiency, oral contraceptives, hormonal treatments, rheumatic diseases, infections, and hyperviscosity syndromes (polycythemia rubra, leukemia, lymphoma) [4]. These risk factors are especially important in young patients with RVO.
Studies focusing on the anatomy of the eye also suggest that certain factors may be implicated in the development of RVO. They include the axial length of the eye, depth of the posterior chamber, glaucoma, vitreous adhesion, and inadvertent perforation of the eye during ophthalmological procedures [50-52].
Documented factors contributing to the pathomechanism of RVO include glaucoma and elevated intraocular pressure, as reported in several publications [53, 54].
It is difficult to establish unequivocally which examination should be considered the most valuable in the diagnosis of the pathomechanisms of RVO, particularly in young patients. The available studies tend to present varying viewpoints, and there is currently no standardized algorithm for the diagnostic work-up of RVO. This is due to the complexity of pathomechanisms and the interplay of multiple interrelated factors.
When determining the causative mechanisms of RVO, particularly in young patients, antithrombin III and homocysteine level tests should be performed. In addition, testing for methylenetetrahydrofolate reductase (MTHFR), coagulation factor V, prothrombin, and PAI-1 gene mutations should be considered.
SUMMARY
RVO frequently leads to vision impairment. Often, an ophthalmologist is the first medical professional to diagnose venous thromboembolic disease, which is why understanding the pathomechanisms of RVO is so important. Young patients are a special concern because of challenges in identifying the pathomechanisms underlying the condition. The studies presented in the review can aid in identifying the cause, which is essential for selecting the right treatment approach. The intricate mechanisms contributing to the development of RVO remain incompletely understood and definitely warrant further research.
