Influence of hemorheological factors on the development of retinal vein occlusion

Abstract

OBJECTIVE: The aim of this article was to present the influence of hemorheological factors on appearance of Retinal Vein Occlusion (RVO). Article explains which factors predispose to the occurrence of RVO.

STUDY SELECTION: Data presented in the article were collected from both review articles and research articles as well as other sources concerning hemorheology, pharmacology and ophthalmology.

RESULTS: Appearance of RVO is connected with blood viscosity and hemorheological parametres like aggregation of red blood cells, deformability of red blood cells, fibrinogen concentrations and haematocrit, and platelet activity. In the pathogenesis of retinal vein occlusion other risk factors were also indicated: age, systemic diseases and smoking. Such correlation has been indicated in numerous researches which were conducted over the last years. RVO is usually accompanied by macular oedema. RVO may successfully be treated using intravitreal dexamethasone implant.

CONCLUSION: Quick diagnosis and therapy create a possibility for successful treatment. Corticosteroid positive influence on visual acuity improvement has been indicted in two randomized, double-blind controlled studies – CRUISE and BRAVO. In both studies, the improvement of vision has been accompanied by a significant reduction of oedema in the vicinity of macula, reflected in the central retinal thickness.

Keywords

Hemorheology retinal vein occlusion blood viscosity thrombosis

Hemorheology is the science examining the phenomenon of the flow of blood as viscous fluid and the interaction between elements of the blood itself and the walls of blood vessels [11]. Mainly plasma viscosity, aggregation of red blood cells, deformability of red blood cells, fibrinogen concentrations and haematocrit, and platelet activity [26] affect the viscosity of the blood.

In the development of venous thrombosis three basic factors included in the so-called Virchow’s triad play a role, i.e. the slowdown of the venous blood flow, abnormalities in coagulation and in the fibrinolytic system and impaired function of the vascular endothelium. A particularly important factor is the slowdown of the blood flow or haemostasis in the veins, but the stasis itself is not enough to develop a blood clot and systemic activation of the coagulation system is also necessary. Maintaining proper haemostasis is possible due to the balance between natural pro- and anti-coagulant factors. Prothrombotic factors include, inter alia: a deficiency of antithrombin III, protein C, protein S, prothrombin gene mutation, a high titre of anti-phospholipid antibodies, thrombocythaemia of more than 700,000 cells/mm 3, occurring, e.g. after removal of the spleen. A deficiency of tissue plasminogen activator (t-PA) or an excess of plasminogen activator inhibitor 1 (PAI-1) is also conducive to the development of venous thrombosis. Endothelial dysfunctions make binding sites of factors IX and X expose, and then the formation of thrombin is possible directly on the endothelium. In addition, damage to the endothelial cells reduces or removes its negative charge and reduces the repellence properties of blood platelets, which significantly impairs the body’s natural antithrombotic defence of endothelial cells [7 , 21].

Retinal vein thrombosis is a retinal vascular disease, the second most frequent after diabetic retinopathy. Factors predisposing to the formation of clots can be divided into systemic and local. The first group includes factors that increase blood viscosity: Waldenström’s macroglobulinemia [18, 29], proliferative diseases of the haematopoietic system, sickle cell anaemia, thrombophilia, diabetes, hypertension [18], hyperlipidemia, cardio-vascular diseases, obesity, oral contraceptives, smoking and dehydration, especially in young people and in hot climates [12]. The second group includes: glaucoma [20], hypermetropia, inflammation of the eye, bends and oppression of the eye veins and a large number of crossings of veins and arteries of the eye [9, 14]. The common course of the cribriform plate of the central retinal artery (CRA) and the central retinal vein (CRV) also predispose to blood clot forming in the central retinal vein. Atherosclerotic changes of the CRA disturbe the flow of blood within the veins in the form of spin currents and the slow-down of the blood flow. This also leads to damage to the endothelial cells and the formation of thrombin in the CRV. As a result of damage to the vascular endothelium, penetration of fluid from the capillaries into the external space occurs, which leads to swelling of the retina, including the macula lutea, which determines the central visual acuity. Depending on their location the following are distinguished: central retinal vein occlusion (CRVO) and branch retinal vein occlusion (BRVO) [19]. The presence or absence of disturbances in the blood flow through the retinal capillaries of CRVO allows to divide CRVO into the ischaemic form, if there are areas of tissue perfusion absence and the non-ischaemic form, if the capillary flow is maintained. Untreated RVO leads to the deterioration of visual acuity and the development of eye complications. Although visual acuity in untreated patients with BRVO moderately deteriorates and then improves over time even without intervention (in 37–74% of patients), it rarely reaches the value 20/40 or better. In patients with CRVO visual acuity is poor from the beginning of the disease, and a lack of treatment over time brings its further decline. Furthermore, in the CRVO ischaemic form, visual acuity is worse from the diagnosis through the whole process of treatment, compared to the non-ischaemic CRVO form [16].

In venous thromboembolism an increase of viscosity of plasma, erythrocyte aggregation and reduction of their formability occurs [22]. Similar phenomena accompany a stable and unstable coronary arterial disease, myocardial infarction, arterial occlusive disease, neurological complications of atherosclerosis, and also states conducive to atherogenesis, such as diabetes [25, 26], visceral obesity, overweight, hypertension, metabolic syndrome, increased levels of uric acid, lipid disorders [3, 26].

One of the causes of CRVO development is an increased expression of phosphatidylserine (PS) in the erythrocyte membrane and of the receptor for phosphatidylserine (PSR) in the endothelium, which correlates with an increased adhesion and aggregation of red blood cells (RBC) in the blood. The most effective blocker of the RBC adhesion under flow conditions is annexin V (2x more effective than under static conditions). Annexin V inhibits blood clotting by competition for binding phosphatidylserine with prothrombin. This strengthens the hypothesis that the expression of PS on RBC in CRVO is an important parameter of an increased adhesion of erythrocytes, as antibodies block a certain pool of PSR receptors, but still new PSR with PS are coming and connecting with other non-locked antibodies. Only a “sweep” of PS on the surface of RBCs by annexin V considerably reduces the adhesion of red blood cells. Therefore, PS and the PSR are responsible for an increased adhesion of RBCs in CRVO. This phenomenon may be one of the factors responsible for the formation of CRVO. Mechanisms of adhesion represented by different protein - antibody pairs observed in different diseases, such as diabetes, sickle cell anaemia, essential thrombocythemia, and responsible for vascular complications show that similar mechanisms occur in CRVO [27].

Confirmation of clinical association between CRVO and increased blood viscosity are hyperviscosity units (‘systemic’), which are frequently associated with disorders of retinal function and are similar or even indistinguishable from CRVO [1]. Moreover, retinopathy occurs only when blood viscosity is high and decreases when haemorheological parameters improve. Furthermore, a relationship between CRVO and systemic diseases such as hypertension and disorders haemorheological [24] is demonstrated.

In a study conducted by Tom H Williamson et al. on CRVO and blood viscosity, which involved 87 patients, various haemostatic abnormalities in patients with CRVO were demonstrated, such as an increase in factor VIII and fibrinopeptide A - procoagulant factors, reduction of antithrombin III (AT III) - an inhibitor of coagulation and resistance to activated protein C (APCR) was demonstrated. APCR occurs in 12% of patients with CRVO compared with 5% of patients in the general population. APCR has been identified in 18–60% of patients with congenital thrombophilia and it is considered the main cause of venous thrombosis. In comparison with other haemostatic agents, which only show differences between groups of patients, APCR is significantly incorrect and can be introduced into clinical practice. An increase in von Willebrand factor also indicates a relative tendency of forming a thrombus. Compared with the control group an increase in corrected haematocrit and a relative viscosity of the blood were also observed, suggesting that cellular factors, e.g. deformability of red blood cells, are responsible for the increased viscosity of the blood [24].

An increase in blood viscosity creates a risk of CRVO, and abnormalities of haemostasis are particularly associated with the development of neovascularisation. In patients with rubeosis iridis a lower level of antithrombin III, Factor VII, Factor IX and tissue plasminogen activator was found compared with patients with CRVO, but who had not developed symptoms of iris neovascularisation. Ring et al. suggested that “rheological obstacle” in the form of increased viscosity of the blood, leading to haemostasis of venous blood may be present in patients with CRVO. Therefore, lowering of blood viscosity by applying isovolemic hemodilution or troxerutin, which is also called a rheological drug, leads to the reversion of vision in some patients [24].

More detailed understanding of the relationship between CRVO and platelet aggregation requires extensive testing, despite the fact that a formed clot plays an important role in the development of CRVO, and different antiplatelet drugs were used in the treatment of CRVO.

A new aggregometer quantifies platelet aggregates as a function of the scattered light intensity, and can quantify them without stimulation by aggregating agents. This is a huge advance compared with the older methods of measuring optical density. A scattered light measurement method was used to evaluate spontaneous platelet aggregation and the effectiveness of several antiplatelet drugs with different action mechanisms. In most studies a classical unrated quantitative method of measuring aggregation was used, especially for small aggregates formed in the early stages of a thrombus formation. Ticlopidine (a P2Y12 blocker which increases the amount of cAMP intracellularly), beraprost (a synthetic analogue of prostacyclin) and acetylsalicylic acid (an irreversible inhibitor of cyclooxygenase) were analysed. Patients with CRVO (significant) and BRVO (insignificantly) have a higher spontaneous platelet aggregation compared with the control group, which implies that it may be involved in the pathogenesis of CRVO and possibly BRVO. The use of the light scattering method has revealed that both diabetic patients and heavy smokers have a statistically significantly higher number of small platelet aggregates than people without diabetes and non-smokers. The effectiveness of the antiplatelet therapy in patients with CRVO is controversial. In the study presented by Takimi Y. et al. it was demonstrated that ASA did not inhibit spontaneous formation of platelet aggregates of any size. Other studies have also not shown any ASA influence on the first phase of the formation of platelet aggregates (small aggregates), although the inhibition by ASA of the progression of medium into larger aggregates, which is stimulated by collagen and ADP, was demonstrated. The most likely explanation for the inconsistency is the different size of aggregates produced in vivo and in vitro under different stimulants. Ticlopidine significantly inhibits the formation of small platelet aggregates, but not medium and large ones. Upon stimulation with collagen or ADP, ticlopidine inhibits the formation of aggregates of any size. Similarly, beraprost inhibits the formation of aggregates of any size. A limitation of the study is a relatively short period of time (2 weeks from the initiation of the drug), after which measurements were taken. Taking into account the increase of small platelet aggregates count in patients with RVO, it is suggested that oral administration of beraprost and ticlopidine, which inhibit the development of small aggregates, can be useful therapeutically in patients with RVO. In order to assess whether they can be used routinely in the treatment or prevention of RVO further research isneeded [23].

RVO is manifested by a sudden painless unilateral decrease in visual acuity, which depends on the size of the macular area occupied by a thrombus. There are metamorphopsias and relative scotoma. Patients with peripheral thrombus may have no symptoms. At the eye fundus retinal edema, cotton wool spots, blurring of the border of the optic nerve head, intraretinal haemorrhages and broadened, winding veinscan be observed. Neovascularisation can be a RVO complication, which develops within 6–12 months, but can develop at any time. NVE develops more often than NVD and it is formed most often on the border of areas with no perfusion, drained by a closed vein. Proliferating blood vessels may be the cause of recurrent haemorrhages into the vitreous body, traction retinal detachment [12] and can lead to the development of neovascular glaucoma, which occurs more frequently in the CRVO ischemic form [16].

After 6–12 months sheaths with residual vascular haemorrhage of different size may appear. A collateral circulation with winding vessels passing through the horizontal seam between the upper and lower vascular arches or the optic nerve head can be developed. We also observe microaneurysms and hard exudates, sometimes with accompanying crystalline deposits of cholesterol. Degeneration of the pigmentary retina layer and epiretinal membrane can also occur.

The most common cause of poor visual acuity after retinal vein thromboses is chronic macular oedema [12].

The development of RVO depends on the age. The incidence rate in the population over 40 is 0.3–2.1% and increases in people over 50 years of age and over 65 years of age it reaches 2.9% [13, 16]. Based on a 15-year study, it was found that the frequency of BRVO is greater than CRVO (0.5–2.0% vs. 0.1–0.2% vs), i.e. BRVO occurs 3–10 times more often than CRVO. Binocular RVO is not common and is less than 10% of all cases of RVO. Frequency of RVO is similar in both men and women, in all studies in which gender was taken into account. Prevalence of RVO seems to be uniform in all countries and in all ethnic groups. Most patients with CRVO have already got macular oedema at diagnosis and in patients with BRVO (in approx. 5–15% eyes) it develops within a year. It is estimated that macular oedema occurs within 15 months in approx. 30% of patients with CRVO without ischaemia and in as many as approx. 73% of patients with the ischaemic CRVO form. Conversion of the form without ischaemia into the form with ischaemia is above 34%. Haemorrhages into the vitreous chamber occur in 40% of patients with BRVO at an unspecified time, while as many as 10% of patients develop vitreous haemorrhage within 9 months after diagnosis [16].

So far, the main RVO therapeutic methods reducing oedema of the retina and affecting the haemorheological parameters are:

Anti-VEGF therapy (ranibizumab, aflibercept, bevacizumab - off-label)

Intravitreal corticosteroids (triamcinolone - off-label)

Periocular corticosteroids

Dexamethasone in the form of a biodegradable implant of a diameter approx. 0.46 mm and a length of 6 mm administered intravitreally (more often) [2, 19].

One of the methods of therapy conducted in a prospective, randomised, multi-centre clinical study is haemodilution through erythrocytopheresis. Haemodilution reduces the number of RBC, hematocrit, blood viscosity, thereby improving the blood flow through the vessels. Haemodilution in CRVO has proved to be most effective at the early stage after the onset of CRVO, i.e. under three weeks from the incident occurrence. Improvement in visual acuity by 1.7 ETDRS was found, compared to a decline in visual acuity by 2.3 lines in the control group. The number of conversions into ischaemic CRVO decreased in patients after haemodilution (11%) compared with the control group (50%). Central retinal thickness was also reduced. The average thickness in the treated group was 289 um, and in the control group 401 um. Measurements were taken using optical coherence tomography (OCT).

Haemodilution directly affects the blood flow through the retina and is characterised by a long-term effect in the treatment of CRVO. Automated aphaeresis of erythrocytes decreases blood and plasma viscosity and interrupts the vicious cycle leading to the enhanced aggregation and CRVO progression. Haemodilution improves the prognosis in CRVO, but does not eliminate the cause of the thrombus.

Summing up, isovolemic haemodilution can improve visual acuity reaching a better therapeutic effect in patients with the non-ischaemic CRVO form compared to the ischaemic form. Clinical improvement is affected by reducing the total blood viscosity, which leads to an improvement in the blood flow through the areas of the retina with disturbed microcirculation [6, 28].

In the retinal venous thrombus corticosteroids reduce macular oedema, stabilise the blood-retinal barrier and improve hemorheological parameters in the vessels of the retina by reducing the inflammation, inhibiting deposition of fibrin, reducing the influx of leukocytes and inflammatory cells. They inhibit prostaglandin synthesis, proinflammatory cytokines, among them interleukin-1, interleukin-6, TNF-alpha. Interleukin-1 is a factor stimulating inflammation, interleukin-6 and TNF-alpha are involved in relaxation of tight junctions between retinal vascular endothelial cells, and also between retinal pigmentary epithelial cells. Apart from participation in inflammatory processes TNF-alpha plays a significant role in neovascularisation and vasomotor responses [5 , 15]. Administration of a corticosteroid directly into the vitreous body allows to achieve optimal therapeutic concentration in the eye tissues. The use of biodegradable implants with dexamethasone, which has a prolonged operating time, makes it possible to use them less frequently. In the available literature the improvement of the treated eye functions was visible after a week from intravitreous injection of Ozurdex and further improvement was noted in a monthly observation. A significant reduction in retinal macular oedema was also observed, confirmed in an optical coherence tomography (OCT) examination [15].

According to the Royal College of Ophthalmologists in the case of BRVO with the secondary macular oedema, the efficacy of laser photocoagulation of retinal grid-pattern was demonstrated. In the case of CRVO with the secondary macular oedema no benefits of using laser photocoagulation of the retina were proven, and there are good results of clinical application of corticosteroids or after intravitreal administration of anti-VEGF preparation [16].

According to J. A. Haller et al. in patients with BRVO (291 eyes) after the intravitreal administration of 0.7 mg of dexamethasone a significant improvement of visual acuity (VA) was noted, compared with visual acuity in the control group after 90 days from the beginning of treatment (24% in the treated group vs. 15% in the control group) which, however, did not last to 180 days after injection. In patients with CRVO (136 eyes) after 60 days a significant improvement in VA was reported in 29% of treated eyes vs. 9% of eyes from the control group. Ozurdex therapy is repeatable and after 6 months in the case of recurrent macular oedema, there are indications for re-injection of an dexamethasone-eluting implant [8, 17].

In a multicenter randomised GENEVA study an intravitreal implant was applied, containing a slow release dexamethasone in a dose of 0.7 mg. 3 months after the administration in patients with CRVO and BRVO the effectiveness of treatment was 18%. BCVA improved by at least 15 letters, i.e. 3 lines compared with patients with sham injections, whose improvement was 12%. The Royal College of Ophthalmologists recommend administration of dexamethasone as an implant into the vitreous chamber and ranibizumab in the treatment of macular oedema in the course of CRVO and BRVO [16].

In the Merkoudis N. and Granstam E. study patients with CRVO and BRVO received dexamethasone in the form of an implant into the vitreous chamber. The analysis included patients with decreased visual acuity and an increase in the central retinal thickness of at least 320 mm and sometimes more than 10 months from the initiation of the therapy. Clinical improvement occurred after 2 months after the beginning of the therapy, visual acuity improved by at least 2 lines (0.2 logMAR) in 73% of patients and at least 3 lines (0.3 logMAR) in 55% without any observable increase in the central retinal thickness. On average reoccurring macular oedema was reported 3.8 months in the case of CRVO and 3.5 months for BRVO. Therefore, close monitoring of patients is necessary in order to identify recurrence of macular oedema and consideration of dexametazon re-implantation into the vitreous body after 4 months from the first administration of a prolonged release corticosteroid. Careful monitoring of intraocular pressure (IOP) is necessary in patients treated with a dexamethasone implant, since an average increase of IOP of 5 mmHg after 1 month of the drug administration was observed and its normalisation only after administration of a local drug lowering IOP. No patient required a surgical intervention in order to lower intraocular pressure [19].

Benefits of intravitreal re-implantation of prolonged release dexamethasone (Ozurdex) were shown in the Coscas G. et al. study. 58 patients with CRVO and 70 patients with BRVO participated in the study. Repeated injections were performed on average 5.9 months after the first injection of dexamethasone, and 8.7 months after the second. Improvement in visual acuity of more than 15 letters was observed in 34 patients with CRVO and in 16 patients with BRVO, but it was not statistically significant. Reduction of the central retinal thickness was statistically significant and averaged 214.6 mm in patients with BRVO and 355.1 mm in patients with CRVO. The incidence of complications was very low. A standard procedure in RVO is currently steroidtherapy by intravitreal injection and use of anti-VEGF preparations. In the case of BRVO benefits of laser treatment are comparable to the effects of intravitreal pharmacotherapy. A long-term Ozurdex therapy requires fewer injections than a therapy using drugs of the anti-VEGF group, which requires a monthly injection. A repeated therapy with intravitreal administration of dexamethasone is safe, but it leads to post-steroid cataracts – 29.8% vs. 10.5%, but only in 1.3% of patients surgical treatment was necessary. An increase of intraocular pressure was temporary, local medications reducing intraocular pressure were effective and there was no glaucoma damage to the optic nerve or loss of vision. Other complications occur very rarely. After the second intravitreal administration Ozurdex exerted a greater effect on visual acuity than after the first administration (the difference not statistically significant), probably because at the first administration the disease was uncontrollable and more aggressive. Intravitreal dexamethasone injections in the form of an implant should be performed in the case of an increase in the central retinal thickness and vision decrease, on average every 4-5 months [4].

The venous thrombus of the retina leads to a number of changes within the vascular wall, as well as to haemorheological disorders in the form of abnormal blood flow and disorders of blood viscosity. As a result of these mechanisms stimulation of inflammatory processes occur leading to an increase in the release of angiogenic factors, in particular vascular endothelial growth factor VEGF, whose level in the serum and vitreous body positively correlates with the severity of macular oedema.

Safety of use and effectiveness of ranibizumab in patients with visual impairment due to macular oedema secondary to RVO was evaluated in a randomised, double-blind, controlled BRAVO and CRUISE studies, in which patients with BRVO (n = 397) and CRVO (n = 392) were included respectively. In both studies, patients received intravitreal injections of 0.3 mg or 0.5 mg or sham injections. After 6 months, patients from the sham group were transferred to the group receiving ranibizumab in a dose of 0.5 mg. In the BRAVO study, laser photocoagulation as a saving procedure was allowed in all stages of the trial from the third months.

In both studies, the improvement of vision was accompanied by a significant reduction of oedema in the vicinity of macula, reflected in the central retinal thickness. Patients with BRVO (BRAVO study and extension HORIZON study) who were treated with sham injections in the first 6 months and then with ranibizumab, after 2 years achieved a comparable improvement in VA (∼15 letters) compared to patients treated with ranibizumab from the beginning of treatment (∼16 letters). However, the number of patients treated for complete 2 years was limited and only in the HORIZON study quarterly monitoring visits were planned. Therefore, there is currently insufficient evidence to formulate recommendations regarding the timing of ranibizumab treatment initiation in patients with BRVO. Patients with CRVO (CRUISE study and extension HORIZON study) who were treated with sham injections in the first 6 months and then with ranibizumab after 2 years did not achieve a comparable improvement in VA (∼6 letters) compared to patients treated with ranibizumab from the beginning of treatment (∼12 letters). After 6 and 12 months of study in addition to the objective improvement of visual acuity in patients treated with ranibizumab, also subjective benefits were observed measured by a questionnaire of the National Eye Institute Visual Function Questionnaire (NEI VFQ-25) and referring to near and distance vision. The difference between the group treated with a medicinal product - Lucentis 0.5 mg and the control group was assessed at month 6, at p values ranging from 0.02 to 0.0002 [17]. In patients who used ranibizumab the quality of life as assessed by the above questionnaire (NEI VFQ-25) [12] also improved.

RVO is a disease whose causes include hemorheological disorders occurring in numerous systemic diseases, therefore, treatment of the retina venous thrombus is very difficult and protracted. Worse prognosis of the improvement of VA and retinal morphology and the amount and frequency of complications is in patients with CRVO. Moreover, RVO is a disease permanently damaging the structure of the retina and synaptic connections between its cells. In many cases it makes it impossible to obtain an improvement of VA, despite complete withdrawal of macular oedema. On the other hand, major structural changes associated with RVO in the macula prevent obtaining a sustainable improvement in retinal morphology, and thus VA [8]. Patients with RVO have a higher risk of serious cardiovascular complications, although there is insufficient evidence to consider RVO as a predictor of mortality from stroke or myocardial infarction. In clinical trials there was no increase in mortality due to cardiovascular causes, after adjustment for age, sex, BMI (body mass index,), hypertension diabetes and other age-related factors. The risk of death from cardiovascular causes in patients with RVO under 70 years of age is 2 times higher than in the population without the disease, but RVO is not a predictor of mortality [16].

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