MAEDICA – a Journal of Clinical Medicine

Mædica - a Journal of Clinical Medicine 2024; 19(2): 380-387

https://doi.org/10.26574/maedica.2024.19.2.380
R eview

Systemic Risk Factors in

Branch Retinal Vein Occlusion:
a Comprehensive Review
Christina GARNAVOU-XIROUa, b, Georgios BONTZOSa,
Georgios SMOUSTOPOULOSa, Stavros VELISSARISa, Alexandros PAPADOPOULOSa,
Efstathios GEORGOPOULOSa, Panagiotis STAVRAKASb,
Constantinos GEORGAKOPOULOSb, Tina XIROUa, Vasileios KOZOBOLISb
a
Department of Ophthalmology, Korgialenio-Benakio General Hospital, Athens, Greece
b
Department of Ophthalmology, University Hospital of Patras, Patras, Greece

ABSTRACT
Background: Retinal vein occlusion (RVO) is a major cause of vision impairment globally. Obstruction
in the retinal venous system is often due to thrombus formation at arteriovenous crossing points, leading
to symptoms localized to the affected retinal area. Systemic conditions like hypertension, diabetes mellitus,
dyslipidemia and heart disease are recognized risk factors for RVO, influencing the components of Virchow's
triad.
Objective: This work aims to provide an updated overview of systemic risk factors associated with
branch retinal vein occlusion (BRVO) development and to explore management options for the prevention
or modification of associated risks.
Methods: Review of the literature concerning the pathogenesis and risk factors of BRVO, including
diabetes mellitus, hyperlipidemia, hematologic conditions, hormonal factors, thyroid disease, and the impact
of COVID-19 and related vaccines on BRVO incidence.
Results: Diabetes mellitus contributes to BRVO through mechanisms like endothelial dysfunction and
thrombogenesis. Hyperlipidemia – through lipid-mediated vascular changes – and hematologic conditions
– by predisposing to hypercoagulability – significantly increase BRVO risk. Hormonal imbalances and
thyroid diseases also influence BRVO development through their effects on vascular and hemostatic systems.
Furthermore, COVID-19 has been identified as a potential risk factor for BRVO, possibly due to its pro-
thrombotic effects.
Conclusion: Branch retinal vein occlusion represents a complex interplay of systemic and local vascular
factors, necessitating comprehensive management strategies. Early detection and modification of risk factors
is crucial for preventing vision impairment associated with BRVO. The ongoing pandemic and its systemic
implications underscore the importance of continued research into the multifactorial etiology of BRVO and
optimization of management strategies to improve patient outcomes.
Keywords: BRVO, vein occlusion, risk factors, diabetes, hypertension.

Address for correspondence:

Georgios Bontzos, MD, PhD
Postal address: Korgialenio – Benakio General Hospital, Atanasaki 11, 11526, Athens, Greece
Tel: +2132068754; email: [email protected]

Article received on the 11th of March and accepted for publication on the 17th of May 2024

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Systemic Risk Factors in BRVO

ABBREVIATIONS this vascular occlusion. As the prevalence of

RVO: retinal vein occlusion BRVO is notably higher than that of CRVO and
BRVO: branch retinal vein occlusion given the aging global population, the need for
CRVO: central retinal vein occlusion effective screening, prevention and treatment
COVID-19: coronavirus disease 2019 strategies is more critical than ever (15). Such ef-
forts are essential not only for mitigating the im-
mediate effects of RVO on vision but also for ad-
INTRODUCTION

B
dressing the broader social and economic
ranch retinal vein occlusion (BRVO) is implications of this condition. The purpose of
a significant cause of vision impair- the present work is to provide a comprehensive
ment worldwide, ranking as the se­ update on the systemic risk factors associated
cond leading cause of blindness re- with BRVO development and explore manage-
sulting from retinal vascular diseases ment options associated with the prevention or
(1). Globally, over 20 million individuals suffer modification of associated risks. q
from BRVO, a figure expected to rise due to
population aging (1, 2). Advancing age is a recog­ METHODS
nized risk factor for BRVO, suggesting an inevi-
table increase in the incidence of this condition
(3, 4). The impact of BRVO extends beyond the W e looked through PubMed and Google
Scholar databases for articles published
between January 2010 and January 2024, using
individual, affecting the quality of life and impo­
sing significant economic burdens on society. the following query terms: (retinal vein occlu-
Retinal occlusion encompasses two primary sion) OR (BRVO) AND (risk factors). We found
forms: BRVO and central retinal vein occlusion 620 articles. After abstract screening, all articles
(CRVO), with BRVO showing a prevalence be- that were not available in English, all studies on
tween 0.5% and 2.0%, while CRVO is less com- animals, in vitro models were excluded. For the
mon, with a prevalence ranging from 0.1% to purpose of the review, we also included syste­ma­
0.2% (5). The obstruction in the retinal venous tic reviews and meta-analyses. In total, 157 arti-
system, which is the hallmark of RVO, can be at- cles focusing on the systemic risk factors for
tributed to thrombus formation. This blockage BRVO were further considered for analysis. q
might occur in the central, hemi-central, or
branch retinal vein, often resulting from com- RESULTS
pression by adjacent sclerotic retinal arteries,
e­xternal forces, or diseases affecting the vein wall
such as vasculitis (6). S everal risk factors were found, as described
below.
Virchow’s triad, which includes endothelial
injury, abnormal blood flow and hypercoagula- Hypertension
bility, has been instrumental in understanding The role of hypertension as a primary factor in
the predisposition to thrombosis, including RVO. the pathogenesis of BRVO is complex and multi-
Conditions such as hypertension, diabetes mel- faceted, implicating various mechanistic path-
litus, dyslipidemia and heart disease, which in- ways that contribute to vascular compromise
fluence the components of Virchow's triad, have within the retinal circulation. The retinal vascula-
been linked to an increased risk of RVO in vari- ture is uniquely susceptible to systemic blood
ous studies (7-10). However, the role of hyperco- pressure alterations due to its autoregulatory ca-
agulability as a risk factor for RVO, especially its pacity designed to maintain constant blood flow
differential impact on BRVO versus CRVO, re- despite fluctuations in the systemic arterial pres-
mains a topic of ongoing research and debate sure (16, 17). Chronic hypertension challenges
(11-14). this autoregulation, leading to structural and
The management and understanding of RVO functional changes in the retinal arterioles, in-
requires a comprehensive approach that consi­ cluding wall thickening, luminal narrowing and
ders the various risk factors, including systemic increased vascular tone. These alterations exa­
conditions that may predispose individuals to cerbate the vascular shear stress and contribute

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Systemic Risk Factors in BRVO

to endothelial dysfunction, a pivotal early event meability and thrombogenesis. These processes
in the pathogenesis of BRVO (18, 19). are instrumental in the pathophysiological pro-
Endothelial cells, lining the interior surface of gression toward BRVO, as they exacerbate endo-
blood vessels, play a critical role in maintaining thelial cell injury and disrupt normal blood flow
vascular homeostasis by regulating blood flow, within the retinal venous system (24-26). Simi-
thrombosis and inflammatory responses. Hyper- larly to hypertension, the severity of diabetes is
tension-induced endothelial dysfunction is cha­ important. Patients with diabetes and systematic
racterized by a diminished production of nitric complications have an increased risk of develo­
oxide (NO), a potent vasodilator, and an in- ping BRVO (20).
creased expression of endothelial adhesion mo­ Diabetes induces hemodynamic changes
lecules, promoting leukocyte adhesion and mi- characterized by increased blood viscosity and
gration. This dysfunctional state favors a altered blood flow dynamics, contributing to the
pro-thrombotic and pro-inflammatory milieu, venous stasis component of Virchow's triad. The
conducive to the formation of venous thrombi at hyperglycemia-induced upregulation of inflam-
arteriovenous crossing sites where the retinal matory mediators and pro-coagulant factors fur-
vein is compressed by a sclerotic arteriole (16). ther predisposes individuals with diabetes to
Furthermore, hypertension accelerates the thrombosis within the retinal veins (27). Concu­
process of arteriolosclerosis, leading to the rrently, oxidative stress plays a critical role in dia-
thicke­ning of arteriolar walls and contributing to betic vascular disease. Similarly to hypertension,
the mechanical compression of the adjacent excessive production of reactive oxygen species
veins. This compression, particularly at arteriove- (ROS) in DM impairs NO bioavailability, a crucial
nous crossings where the shared adventitial vasodilator, compounding endothelial dysfunc-
sheath is present, is a critical mechanical factor tion and promoting a pro-thrombotic state con-
in the development of BRVO. The resulting ve- ducive to BRVO (28).
nous stasis, coupled with endothelial injury and The intersection of diabetes and BRVO is fur-
a hypercoagulable state, fulfills the criteria of ther illuminated by the inflammatory pathways
Virchow’s triad for thrombus formation (20). Al- that underlie diabetic retinopathy, a common
though there is not a direct correlation between microvascular complication of diabetes. Pro-in-
arterial pressure values and risk for BRVO deve­ flammatory cytokines, such as tumor necrosis
lopment, research has shown that the severity of factor-alpha (TNF-α) and interleukin-1 beta (IL-1β),
hypertension has a significant impact on the as- are elevated in the diabetic state, fostering an
sociated risk. Complicated hypertension has a environment of vascular inflammation that can
three-fold increased risk for BRVO development precipitate venous occlusive events (29). These
compared to uncomplicated cases (20). cytokines, along with VEGF-driven vascular per-
meability, create a retinal milieu prone to the
Diabetes mellitus development of BRVO (30, 31).
A large meta-analysis has previously revealed
that there was no significant association between Hyperlipidemia
diabetes mellitus (DM) and BRVO, as opposed to Hyperlipidemia, characterized by elevated levels
CRVO (21, 22). However, there is gathering evi- of lipids in the bloodstream, including chole­
dence that DM has a significant role in BRVO sterol and triglycerides, has been implicated as a
pathogenesis (23). Hyperglycemia, which is at significant risk factor for BRVO (7, 32, 33). Un-
the core of diabetes-related vascular complica- like the mechanisms associated with hyperten-
tions, instigates a cascade of biochemical disrup- sion and diabetes, which predominantly involve
tions leading to endothelial dysfunction and mi- direct vascular and endothelial alterations, hy-
crovascular damage. Persistent elevation of perlipidemia contributes to BRVO through li­ -
blood glucose levels promotes the non-enzyma­ pid-mediated vascular changes and indirect ef-
tic glycation of proteins and lipids, forming ad- fects on blood rheology and inflammatory
vanced glycation end products (AGEs) which en- pathways (34).
gage with their receptor (RAGE) on endothelial Hyperlipidemia facilitates the development
cells, activating intracellular signaling pathways of atherosclerotic plaques within the vasculature,
that foster vascular inflammation, increased per- including the retinal arterioles. Atherosclerosis in

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Systemic Risk Factors in BRVO

the context of BRVO involves the accumulation tipping the balance toward thrombogenesis (41).
of lipids within the vascular wall, leading to in- Factor V Leiden, for instance, renders Factor V
creased rigidity and narrowed lumen diameter resistant to inactivation by activated protein C,
(35, 36). These changes can exacerbate the me- leading to unchecked thrombin generation and
chanical compression at arteriovenous crossing fibrin clot formation. Such mutations can signifi-
points, a critical site for BRVO pathogenesis. The cantly increase the risk of venous thromboembo-
accumulation of lipids, particularly low-density lism in the systemic circulation and are implica­
lipoprotein (LDL) cholesterol and its oxidized ted in the occlusion of retinal veins (42).
forms (oxLDL), can directly injure the vascular Acquired conditions such as antiphospholipid
endothelium, promoting an inflammatory res­ syndrome (APS), characterized by the presence
ponse and contributing to the thrombogenic en- of antiphospholipid antibodies like lupus antico-
vironment conducive to vein occlusion (37). agulant, anti-cardiolipin and anti-β2 glycopro-
Hyperlipidemia impacts blood viscosity and tein I, also predispose individuals to thrombotic
platelet function, both of which playing crucial events, including BRVO. These antibodies pro-
roles in the development of BRVO. Additionally, mote thrombosis by interfering with the phos-
hyperlipidemia is known to enhance platelet ag- pholipid-dependent steps of coagulation, acti-
gregation and activation, further increasing the vating endothelial cells and impairing the
risk of thrombus formation within the retinal ve- function of natural anticoagulants. The role of
nous system (38). The interaction between lipids APS in retinal vascular occlusions highlights the
and the coagulation cascade, including the up- complex interactions between autoimmune res­
regulation of procoagulant factors and downre­ ponses and coagulation pathways (43, 44).
gulation of fibrinolytic activity, accentuates the The pathophysiological impact of hypercoa­
hypercoagulable state (39). gulable states on the retinal venous system in-
The role of inflammation in the pathogenesis volves both direct and indirect mechanisms. Di-
of BRVO under hyperlipidemic conditions can- rectly, the propensity for clot formation within
not be overstated. Lipids, especially oxLDL, are the retinal veins leads to venous occlusion and
potent mediators of vascular inflammation, ca- subsequent retinal ischemia. Indirectly, hyperco-
pable of activating macrophages and endothelial agulability can cause a secondary inflammatory
cells to release inflammatory cytokines and che- response, further damaging the vascular endo-
mokines. This inflammatory milieu not only thelium and exacerbating the conditions condu-
damages the vascular endothelium but also pro- cive to BRVO. The resultant hypoxia and is­
motes the recruitment and adhesion of leuko- chemia trigger compensatory mechanisms,
cytes to the vascular wall, exacerbating endothe- including neovascularization, which can worsen
lial dysfunction and contributing to the sequence the prognosis by leading to complications such as
of events leading to venous occlusion (40). vitreous hemorrhage and tractional retinal de-
tachment (45-47).
Hematologic conditions
Hematologic conditions that predispose to hy- Hormonal factors
percoagulability play a critical role in the patho- Estrogens and other sex hormones exert signifi-
genesis of BRVO, presenting a complex interplay cant effects on vascular endothelial function. Es-
between clotting mechanisms and vascular in- trogens, for example, have been shown to pro-
tegrity. These conditions, ranging from inherited mote vasodilation through the enhancement of
thrombophilias to acquired disorders, contribute endothelial nitric oxide synthase (eNOS) activity,
to an increased risk of thrombus formation with- leading to increased production of NO, a potent
in the retinal venous system. vasodilator. However, the imbalance of hor-
Inherited conditions such as Factor V Leiden mones, either through natural menopause or
mutation, prothrombin G20210A mutation and other endocrine disorders, can lead to endothe-
deficiencies in natural anticoagulants like protein lial dysfunction, characterized by reduced NO
C, protein S and antithrombin III have all been availability and increased production of vaso-
identified as significant contributors to hyperco- constrictors such as endothelin-1. This dysfunc-
agulability and, by extension, to BRVO. These tion predisposes to vascular occlusive diseases,
genetic variations alter the coagulation cascade, including BRVO, by promoting a state of in-

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Systemic Risk Factors in BRVO

creased vascular tone and susceptibility to and hemostasis, potentially influencing the risk
thrombosis (48, 49). of thrombotic events within the retinal circula-
The use of hormone replacement therapy tion.
(HRT), particularly estrogen-alone or estro­ - Hypothyroidism is associated with athero-
gen-plus-progestin regimens, has been associa­ sclerotic changes, increased cholesterol levels
ted with an increased risk of thromboembolic and altered coagulation, all of which can contri­
events, including deep vein thrombosis and pul- bute to vascular occlusive diseases. The hypothy-
monary embolism (49). The pro-thrombotic ef- roid state leads to increased levels of total chole­
fects of HRT are attributed to alterations in co- sterol, LDL and possibly, lipoprotein (a), which
agulation factors, leading to increased levels of are known risk factors for atherosclerosis. Addi-
procoagulant factors (such as Factors VII and VIII, tionally, hypothyroidism can induce a hyperco-
and fibrinogen) and decreased anticoagulant ac- agulable state characterized by elevated fibrino-
tivity (e.g., protein S levels). These alterations gen levels and increased platelet aggregability,
may similarly contribute to the pathogenesis of enhancing the propensity for thrombus forma-
BRVO by enhancing the propensity for thrombus tion. These changes, coupled with endothelial
formation within the retinal venous circulation dysfunction, may contribute to the pathogenesis
(50, 51). of BRVO by promoting venous occlusion in the
Oral contraceptives, which typically contain retinal circulation (56, 57).
combinations of estrogen and progestin, have Conversely, hyperthyroidism is characterized
been implicated in altering the hemostatic ba­ by a state of enhanced metabolic rate leading to
lance and endothelial function, thereby contri­ weight loss, increased blood pressure and a
buting to thrombotic risks. Oral contraceptives heightened risk of atrial fibrillation. The increased
induce a prothrombotic state through several he- cardiac output and elevated systolic blood pres-
mostatic changes, including increased levels of sure in hyperthyroidism can exacerbate endo-
coagulation factors (Factor VII, VIII, and X), re- thelial damage and contribute to vascular re-
duced anticoagulant protein S levels, and en- modeling (58). Moreover, hyperthyroidism has
hanced platelet aggregability. These modifica- been linked to alterations in coagulation para­
tions contribute to a hypercoagulable state, meters, including reduced levels of protein C
predisposing to thrombus formation (52, 53). and protein S as well as increased levels of von
Estrogen components in oral contraceptives are Willebrand factor, potentially contributing to a
known to affect endothelial health directly. While prothrombotic state. These hemodynamic and
physiological estrogen levels support endothelial hemostatic changes may increase the risk of de-
function and NO production, the pharmacologi- veloping BRVO by promoting conditions condu-
cal doses in contraceptives can have variable ef- cive to venous stasis and thrombosis in the retina
fects on endothelial integrity and vasomotor (59).
function, potentially leading to vascular constric-
tion and increased vascular resistance (54). Hor- COVID-19
mones in oral contraceptives impact the The emergence of COVID-19 as a global pan-
renin-angiotensin system and endothelin-1 le­ demic in 2020 has prompted extensive research
vels, both of which play critical roles in vascular into its systemic implications, including its asso-
tone regulation. Alterations in these systems can ciation with the development of BRVO. Recent
lead to vasoconstriction and impaired venous studies have elucidated the role of SARS-CoV-2,
outflow, contributing to conditions favorable for the virus responsible for COVID-19, in precipi-
BRVO development (55). tating a pro-thrombotic state, attributable to di-
rect viral effects and secondary inflammatory res­
Thyroid disease ponses. The precise mechanisms remain under
The relationship between thyroid disease and active investigation, but evidence suggests that
the development of BRVO encapsulates a nu- COVID-19 facilitates thrombogenesis through
anced interplay of metabolic, vascular and he- the elevation of pro-thrombotic and inflamma-
mostatic factors inherent to thyroid dysfunction. tory biomarkers such as von Willebrand factor,
Both hypothyroidism and hyperthyroidism exert fibrinogen, ferritin and interleukin-6 (IL-6),
profound effects on the cardiovascular system alongside the augmentation of both innate

384 Maedica A Journal of Clinical Medicine, Volume 19, No. 2, 2024

Systemic Risk Factors in BRVO

(e.g., complement system activation) and adap- cytopenia’ (VITT) by experts, leads to the forma-
tive immune responses, and disturbances in the tion of thrombi in sites such as arteries, cerebral
renin-angiotensin system. The hypercoagulable sinuses and splanchnic veins, in persons carrying
state associated with COVID-19 is characterized the anti-PF4 antibody (67). In addition to VITT,
by increased D-dimer levels, prolonged pro- other proposed pathophysiological mechanisms
thrombin time, activated partial thromboplastin of vaccine-induced BRVOs include the triggering
time and elevated fibrinogen and cytokine le­ of thrombi in individuals with retinal vasculitis
vels, collectively fostering the conditions condu- and in those with a background of homocystein-
cive to RVO development, independent of tradi- aemia (68). Despite the above evidence, the
tional systemic risk factors. scarcity of available data in combination with the
Anecdotal evidence and case reports have heterogenous nature of the various studies
begun to highlight a potential correlation be- means that more research regarding the side-ef-
tween COVID-19 and BRVO. In 2023, Kapsis fect profile of COVID-19 vaccines is required, as
et al (60) reported a case involving a 65-year-old it is vital to establish the risk-benefit profile, espe-
male who developed BRVO two days post-re- cially in susceptible individuals. q
covery from COVID-19, in the absence of other
risk factors. Similarly, Duff et al (61) described CONCLUSIONS
the development of BRVO in a 74-year-old fe-
male, otherwise in good health, concurrent with
a COVID-19 infection. Furthermore, a signifi- T he profound impact of BRVO on global vi-
sion health cannot be overstated (5, 69). As a
leading cause of vision impairment and the se­
cant cohort study by Modjtahedi et al (62) re-
vealed an uptick in the incidence of post-COVID cond most common retinal vascular disease
retinal vein occlusions compared to the pre-pan- leading to blindness, BRVO represents a signifi-
demic era. The authors suggested that these cant public health challenge (1). The condition's
findings might be attributable to secondary fac- prevalence, influenced by demographic trends
tors related to the pandemic, such as increased such as an aging population, underscores an ur-
sedentary lifestyles, diminished management of gent need for comprehensive strategies encom-
systemic comorbidities like diabetes and hyper- passing early detection, risk factor modification
tension and delays in seeking medical attention. and targeted treatment to mitigate its conse-
Parallel to the implications of SARS-CoV-2 it- quences.
self, there has been speculative evidence regar­ The pathogenesis of BRVO is multifaceted,
ding the potential role of COVID-19 vaccines in involving mechanical compression at arteriove-
BRVO onset. Case reports include an instance nous crossings, endothelial dysfunction and a
published by Pur et al (63), detailing a 34-year-old hypercoagulable state as delineated by Virchow’s
healthy male who experienced BRVO two days triad. These mechanisms highlight the critical
following administration of the BNT162b2 mRNA role of systemic conditions such as hypertension,
vaccine. In a subsequent report, Gironi et al (64) diabetes mellitus, hyperlipidemia and hemato-
documented a case of a 50-year-old male, with logic disorders in predisposing individuals to this
moderate risk factors, developing bilateral BRVO occlusive vascular event (26, 33, 37, 38).
within 24 hours post-immunization with the Emerging evidence also points to the contri-
mRNA-1273 vaccine. Efforts to establish a com- bution of less conventional risk factors, including
prehensive understanding of the relationship be- hormonal imbalances, thyroid diseases and even
tween COVID-19 vaccines and BRVO have the global pandemic of COVID-19, further com-
been undertaken by researchers such as Singh plicating the BRVO risk landscape (60, 66). The
et al (65) and Feltgen et al (66), with the former early identification of BRVO is paramount for
identifying a weak temporal association and the several reasons. Firstly, it allows for the initiation
latter finding no substantive link between vacci- of timely and appropriate treatment strategies
nation and BRVO incidence. Recent evidence aimed at preserving or restoring visual function.
suggested that vaccines may induce thrombosis Secondly, it provides an opportunity for the
with thrombocytopenia in susceptible indivi­ modification of underlying risk factors, poten-
duals. This novel syndrome, which has been tially preventing the occurrence of BRVO in the
termed ‘vaccine induced thrombotic thrombo- contralateral eye or the development of other

Maedica A Journal of Clinical Medicine, Volume 19, No. 2, 2024 385

Systemic Risk Factors in BRVO

vascular complications. Thirdly, early detection In conclusion, BRVO presents a complex cli­
enables prompt referral to low vision services, nical challenge that requires a proactive manage-
ensuring patients receive the necessary support ment approach. The interconnection between
for lifestyle adjustments and minimizing the risk systemic health and ocular pathology in BRVO
of secondary complications such as falls (70). emphasizes the need for interdisciplinary col-
Given the potential for BRVO to lead to se- laboration in patient care. As we advance our
vere complications like retinal neovasculariza-
understanding of BRVO's multifactorial etiology
tion, vitreous hemorrhage and tractional retinal
and harness the potential of innovative diagnos-
detachment, the role of early intervention cannot
be overstated. The evolving landscape of BRVO tic and therapeutic modalities, the prospect of
management, characterized by the integration of improving visual outcomes and quality of life for
systemic and ocular treatment approaches, high- affected individuals remains promising. q
lights the need for ongoing research to refine our
understanding of its pathophysiology and opti- Conflicts of interest: none declared.
mize therapeutic strategies. Financial support: none declared.

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