960333

research-article2020
EJO0010.1177/1120672120960333European Journal of OphthalmologyChen et al.

EJO European
Journal of
Ophthalmology
Original research article

European Journal of Ophthalmology

Risk factors for central retinal

1­–10
© The Author(s) 2020
Article reuse guidelines:
vein occlusion in young adults sagepub.com/journals-permissions
https://doi.org/10.1177/1120672120960333
DOI: 10.1177/1120672120960333
journals.sagepub.com/home/ejo

Tony Y. Chen , Aditya Uppuluri, Marco A. Zarbin

and Neelakshi Bhagat

Abstract
Purpose: Several risk factors have been identified for central retinal vein occlusion (CRVO) in older population. CRVO
in young is uncommon, and the risk factors for this group are unclear. This large retrospective, cross-sectional study used
the National Inpatient Sample (NIS) database to evaluate the risk factors for CRVO in patients 18 to 40 years of age.
Methods: The 2002 to 2014 NIS database was used. All patients 18 to 40 years of age with a primary diagnosis of CRVO
were identified. Age- and gender-matched non-CRVO controls were randomly selected. The primary outcome was
identification of risk factors for CRVO. Chi-square analysis and Firth logistic regression were performed with IBM SPSS
23 and R packages versions 3.4.3, respectively. p < 0.05 was considered significant.
Results: A total of 95 weighted young CRVO patients were identified. The average age was 31.44 ± 6.41 years with no
gender predilection. Systemic and ocular conditions found to have statistically significant associations with CRVO included
primary open-angle glaucoma (POAG) (OR 836.72, p < 0.001), retinal vasculitis (OR 705.82, p < 0.001), pseudotumor
cerebri (OR 35.94, p < 0.001), hypercoagulable state (OR 25.25, p < 0.001), history of deep vein thrombosis/pulmonary
embolism (DVT/PE) (OR 21.88, p < 0.001), and hyperlipidemia (OR 3.60, p = 0.003).
Conclusion: The most significant risk factors for CRVO in young adults were POAG, retinal vasculitis, and pseudotumor
cerebri. Hypercoagulable states and DVT/PE were also associated with CRVO in this population. Systemic inflammatory
conditions were not associated with CRVO. Traditional risk factors such as hypertension and diabetes did not pose
significant risks, whereas hyperlipidemia was deemed a significant risk factor.

Keywords
Retina, venous occlusive disease, CRVO – medical therapies, retinal vascular disease, retinal degenerations associated
with systemic disease, arterial occlusive disease

Date received: 8 June 2020; accepted: 27 August 2020

Introduction CRVO is generally considered a disease of the elderly,

Central retinal vein occlusion (CRVO) is a common retinal
vascular disease, which affects an estimated 0.1% to 0.5%
of the general population.1,2 Complications of CRVO
include macular edema and ocular neovascularization, the
latter of which can lead to neovascular glaucoma (NVG),
vitreous hemorrhage, and retinal detachment with signifi-
cant visual impairment. Traditional risk factors for CRVO
include advancing age, hypertension, diabetes mellitus,
hyperlipidemia, and glaucoma.3–6 Several studies have
also suggested potential roles of hypercoagulable and
inflammatory conditions in the pathogenesis of CRVO,5,7–9
although other reports have provided contradicting
results.10–14
most prevalent in adults older than 65 years of age.5,15
Approximately 10% to 15% of CRVOs occur in patients
under the age of 40 years.16–18 Conflicting reports exist in
the literature regarding the association of traditional risk
factors with CRVO in young patients. Many authors have
The Institute of Ophthalmology and Visual Science, Rutgers-New
Jersey Medical School, Newark, NJ, USA
Corresponding author:
Neelakshi Bhagat, The Institute of Ophthalmology and Visual Science,
Rutgers-New Jersey Medical School, Doctor’s Office Center, 90
Bergen Street, Suite 6100, Newark, NJ 07103, USA.
Email: bhagatne@njms.rutgers.edu
2 European Journal of Ophthalmology 00(0)
advocated for extensive hypercoagulability workup in this
patient group, although evidence favoring this approach is
limited.5,16,19
The aim of this study was to identify systemic and ocu-
lar risk factors associated with CRVO in young adults
between the ages of 18 to 40 years, who were admitted to
hospital for workup and management, using the National
Inpatient Sample (NIS) database from 2002 to 2014.
Methods
Data source
Patient data for this study were obtained from NIS data-
base, 2002 to 2014. This database is founded and managed
by the Agency for Healthcare Research and Quality
(AHRQ) as a component of the Healthcare Cost and
Utilization Project. It is the most extensive collection of
hospitalization data and the largest public source of dis-
charge information in the United States. The database rep-
resents a 20% sample of U.S. community hospitalization
record, excluding rehabilitation and long-term acute care
hospitals, that encompasses approximately 97% of the
U.S. population. Data accessible through the NIS include
up to 15 International Classification of Diseases, Ninth
Edition, Clinical Modification (ICD-9-CM) diagnosis
codes and 15 procedural codes per patient, along with
information on demographics, comorbidity measures,
length and cost of stay, and mortality rate.
Patient identification
This retrospective, cross-sectional, case-control, observa-
tional study was performed using the publicly available
NIS database. It was exempted for institutional review
board approval according to our institution’s policy. The
study complied with the tenets of the Declaration of
Helsinki. ICD-9 code 362.35 was used to identify all
patients with CRVO as the primary admitting diagnosis.
Only patients between the ages of 18 to 40 years were
included. Demographic and comorbidity data were then
extracted for each patient. Gender- and age-matched con-
trols without CRVO were randomly selected from the NIS
database using the “Select Random Cases” function in
IBM SPSS 23. The ratio of cases to controls was 1:43 after
the data was randomized and cases were weighted.
Diagnosis codes utilized for systemic disease variables are
listed in Table 1.
Outcome measures
The primary aim of this study was to evaluate systemic and
ocular risk factors for CRVO, specifically in young adults
between 18 and 40 years of age. The secondary goal of this
study was to determine demographic variables associated
with CRVO. Univariate and multivariable regression analy-
ses were performed, comparing CRVO subjects to age- and
gender-matched controls without CRVO to identify comor-
bidities associated with CRVO in young adults.
Risk factors selections
Systemic and ocular comorbidities selected for analysis in
this study were based on risk factors reported to be possi-
bly associated with CRVO in the literature.5,20 A total of 30
potential systemic and ocular comorbidities were selected.
Specific variables with their associated ICD-9 codes are
listed in Table 1.
Comorbidities in which ICD-9 codes were provided by
AHRQ included hypertension, diabetes mellitus, obesity,
congestive heart failure (CHF), bleeding diathesis, drug use
disorder, peripheral vascular disease (PVD), and rheumatoid
arthritis/collagen vascular diseases (RA/CVD). Although
comorbidities such as atherosclerosis (systemic except
carotid and coronary), cocaine use, oral contraceptive use,
open globe injury, and non-stroke cerebrovascular disease
were included, no cases of these variables were identified in
either case or control groups, and, thus, did not undergo sta-
tistical analysis. No other chronic cases of non-cerebral sys-
temic venous thrombosis besides deep vein thrombosis
(DVT) and pulmonary embolism (PE) were identified.
Systemic diseases with individual ICD-9 codes were
included as distinct variables. When specific ICD-9 codes
were not available for a disorder, a group of systemic con-
ditions were combined – for instance, primary and second-
ary hypercoagulable states were analyzed collectively as a
single variable. The ICD-9 diagnosis of primary hyperco-
agulable state comprised various coagulation factor abnor-
malities such as protein C and S deficiencies, antithrombin
III deficiency, antiphospholipid syndrome, Factor V
Leiden, prothrombin G20210A mutation, and anti-cardi-
olipin antibody, which do not have unique ICD-9 codes.
However, when specific ICD-9 codes were available for
some hypercoagulable conditions, such as DVT and PE,
they were analyzed separately. Importantly, hyperhomo-
cysteinemia could not be included in our study because it
does not have a specific ICD-9 code, and as per the NIS
website, it is not included in their comorbidity variable,
primary hypercoagulable state.
RA/CVD are systemic conditions known to produce
inflammatory effects in multiple organ systems21–23 and, in
this study, were analyzed as a combined independent varia-
ble. Comorbidity ICD-9 codes were provided by AHRQ.
Included in the CVD group were systemic lupus erythema-
tosus, sicca syndrome, scleroderma, dermatomyositis, sys-
temic sclerosis, polymyositis, various inflammatory
arthropathies or spondylopathies, other unspecified diffuse
connective tissue diseases, and polymyalgia rheumatica.
Inflammatory vascular diseases, such as systemic vasculitis
and retinal vasculitis, were evaluated as distinct variables.
Chen et al. 3

Table 1.  List of variables and corresponding ICD-9 codes.

Variable Code
Aortic dissection/Aneurysm 441.0-441.7, 441.9, 441.00-441.03, 437.3
Arterial thromboembolic disease + coronary artery 444.0-444.2, 444.8-444.9, 444.01, 444.09, 444.21-444.22, 444.81, 444.89,
disease 445.0, 445.8, 445.01-445.02, 445.81, 445.89, 414.0, 414.00-414.07
Bleeding diathesis AHRQ comorbidity measure
Cocaine use 305.6, 305.60, 305.61, 305.62, 305.63
Congestive heart failure AHRQ comorbidity measure
Deep venous thrombosis and pulmonary embolism V12.51, V12.55
(history)
Diabetes mellitus AHRQ comorbidity measure
Drug use disorder (non-intravenous) AHRQ comorbidity measure
Drug use disorder (intravenous) Utilizes algorithm detailed in “Methods” section
Glaucoma 365.10-365.15, 365.20-365.24, 365.31, 365.32, 365.41-365.44, 365.51,
365.52, 365.59-365.65, 365.70-365.74, 365.81-365.82, 365.89, 365.1-
365.6, 265.8, 365.9
Hypercoagulable state (primary) 289.81
Hyperlipidemia 272.0-272.4
Hypertension AHRQ comorbidity measure
Lyme disease 088.81
Migraine 346.00-346.03, 346.10-346.13, 346.20-346.23, 346.40-346.43, 346.50-
346.53, 346.70-346.73, 346.80-346.83, 346.90-346.93, 346.0-346.9
Obesity AHRQ comorbidity measure
Ocular trauma 365.65, 366.20-366.22, 376.47, 376.52
Oral contraceptive use V25.41
Peripheral vascular disease AHRQ comorbidity measure
Pregnancy V22.0, V22.1, 651.00, 630, 631.8, 632, 633.10, 633.90, 634.90, 637.90,
640.00, 656.40
Pseudotumor cerebri 348.20
Central retinal vein occlusion 362.35
Retinal vasculitis 362.18
Rheumatoid arthritis/collagen vascular disease AHRQ comorbidity measure
Sickle cell disease and trait 282.41-282.42, 282.5, 282.6, 282.60-282.64, 282.68, 282.69
Stroke (history) V12.54
Syphilis 090.0-097.9
Systemic vasculitis 446.0-446.2, 446.20-446.21, 446.29, 446.3-446.7
Tobacco use V15.82, 305.1, 305.10, 305.12, 305.13

Bleeding diathesis comorbidity variable (same as the
comorbidity “coagulopathy” defined by AHRQ) contains a
group of systemic conditions to be bleeding disorders in
which blood cannot clot appropriately. Conditions within this
group include various congenital or acquired coagulation fac-
tor disorders, von Willebrand disease, acquired hemophilia,
platelet disorders, and other non-specified clotting disorders.
A history of both ischemic and non-ischemic strokes
was included in the variable “stroke.” Acute cases of stroke
were separately included in the concurrent in-hospital
thrombotic complications in Table 2.
Diagnosis codes for drug use disorder is provided by
AHRQ, although no ICD-9 code specifically indicates intra-
venous (IV) drug use. Thus, we utilized an algorithm used by
Tookes et al. to identify cases of IV drug use.24 We assumed
that any patient with documented “drug use” in addition to
one or more conditions classically associated with IV drug
use (septicemia, endocarditis, soft tissue or skin infections,
or osteomyelitis) had a history of IV drug use.
Lastly, only primary open angle glaucoma (POAG)
cases were included; neovascular glaucoma (NVG), which
is more likely a complication of CRVO was not included in
the variable “glaucoma.”
Statistical analysis
Demographic descriptive analyses were performed
using chi-square tests, with case and control groups
controlled for age and gender. Chi-square analysis and
Logistic Regression were performed using IBM SPSS
25 and R package version 3.4.3, respectively. Logistic
Regression was performed using the Firth Logistic
Regression Model instead of the Standard Model to
account for statistical separation that was observed
between the cases and controls. Adjusted odds-ratios
(ORs) were calculated with multivariable regression
analysis. p < 0.05 was considered significant for all sta-
tistical analyses.
4 European Journal of Ophthalmology 00(0)
Table 2.  Results of chi square analysis for acute in-hospital complications and medications.
 
 
 
Acute Complication
 DVT/PE
  Myocardial infarction
  Stroke (hemorrhagic)
  Stroke (ischemic)
 TIA
  Cerebral venous sinus thrombosis
  Non-cerebral systemic venous thrombosis
Medicationsa
 Anticoagulants
 Antiplatelets
 Aspirin
a
For medications, it is not clear when the medication was started.
b
As per NIS Database guidelines, cells in which the count is between 1 and 10 must be redacted; “*” has been placed instead of the numerical value.
For variables that have a redacted cell and for which there is a statistically significant difference, the cell value in bold represents the cell with the
higher prevalence.
Results
Patient demographics
A weighted total of 95 patients between the ages of 18 to
40 years with a primary admitting diagnosis of CRVO
were identified in the NIS database (Table 3). The average
age of the case group was 31.44 ± 6.41 years. Among cases
of CRVO, 57.1% occurred in women. The prevalence of
CRVO in women was calculated to be 2.30% and 2.25% in
men; gender did not confer any additional risk per regres-
sion analysis (p = 0.924). We stratified these patients by
age groups, which showed an increasing prevalence of
CRVO with age. Nearly half (48%) of all young CRVO
patients were between the ages of 33 to 40 years and 84%
were between 25 and 40 years.
In the age- and gender-matched control group, a
weighted total of 4076 patients without CRVO were
selected randomly as described in the “Patient identifica-
tion” section. The average age of the control group was
30.89 ± 6.31 years, comparable to the study group. The
age distribution of control group was also similar to the
study group, indicating good matching and randomization.
Women comprised of 56% of the control group.
Comorbidities
Chi-square analysis identified the following comorbidities
to have significantly increased prevalence in young adults
with CRVO compared to those with no history of CRVO
(Table 3): History of DVT/PT (p < 0.001), hypercoagulable
CRVO p-value
No Yes
(Weighted N = 4076) (Weighted N = 95)
Count (%) Count (%)
50 (1.2%) 0 (0.0%) 0.277
*b 0 (0.0%) 0.733
* 0 (0.0%) 0.733
0 (0.0%) 0 (0.0%) –
* 0 (0.0%) 0.733
0 (0.0%) 0 (0.0%) –
14 (0.3%) 0 (0.0%) 0.567
28 (0.7%) * <0.001
0 (0.0%) 0 (0.0%) –
* 0 (0.0%) 0.733
state (p < 0.001), diabetes mellitus (p = 0.013), migraine
(p < 0.001), hyperlipidemia (p < 0.001), glaucoma (POAG)
(p < 0.001), RA/CVD (p < 0.001), pseudotumor cerebri
(p < 0.001), retinal vasculitis ( p < 0.001). Non-IV drug use
was not seen in patients with CRVO (p = 0.004).
Multivariable regression analysis in this study found
POAG (OR 836.72, CI 36.28–19295.13, p < 0.001), retinal
vasculitis (OR 705.82, CI 28.55–17448.63, p < 0.001), and
pseudotumor cerebri (OR 35.94 CI 9.03–142.99; p < 0.001)
to be the most significant associated comorbidities for
CRVO. Other significant comorbidities included hyperco-
agulable states (OR 25.25, CI 7.78–81.97, p < 0.001),
DVT/PE (OR 21.88, CI 10.58–45.26, p < 0.001), and
hyperlipidemia (OR 3.60, CI 1.57–8.30, p = 0.003).
Univariate, but not multivariable, regression analysis
revealed the following comorbidities to be significantly
associated with CRVO: RA/CVD (OR 9.98, CI 3.84–25.97,
p < 0.001), migraine (OR 8.95, CI 4.45–18.00, p < 0.001),
diabetes mellitus (OR 2.39, CI 1.24–4.61, p = 0.010), and
non-IV drug use (OR 0.06, 0.00–0.95, p = 0.046). A com-
plete list of significant variables using univariate and multi-
variable regression analyses can be found in Table 4.
Furthermore, chi-square analysis for acute in-hospital
complications shows no cases of thrombotic complications
such as DVT/PE, myocardial infarction, ischemic and non-
ischemic strokes, transient ischemic attack, cerebral venous
sinus thrombosis, or non-cerebral systemic venous throm-
bosis. A small percent (5.3%) of patients with CRVO were
on anticoagulants. None of the study cases were on anti-
platelets or aspirin during the course of hospitalization.
Chen et al. 5

Table 3.  Results of chi-square analysis.

CRVO p-value

  No Yes

  (Weighted N = 4076) (Weighted N = 95)

  Count Column N% Count Column N%

Sex 0.924
 Men 1779 43.6% 41 42.9%  
 Women 2297 56.4% 54 57.1%  
Average Age (years) 30.89 ± 6.31 – 31.44 ± 6.41 – 0.403
Age (years) 0.270
 18–24 850 20.8% 15 15.6%  
 25–32 1218 29.9% 45 36.3%  
 33–40 2008 49.3% 46 48.1%  
Systemic Comorbidities
  Aortic dissection/aneurysm *a * 0 0.0% 0.647
  Arterial thromboembolic disease + coronary artery disease 57 1.4% 0 0.0% 0.246
  Bleeding diathesis 90 2.2% 0 0.0% 0.142
  Congestive heart failure 20 0.5% 0 0.0% 0.492
  DVT/PE (history) 34 0.8% 16 16.5% <0.001
  Diabetes mellitus 198 4.9% 10 10.5% 0.013
  Drug use (IV) 36 0.9% 0 0.0% 0.356
  Drug use (non-IV) 332 8.2% 0 0.0% 0.004
  Hypercoagulable state (primary) * * * * <0.001
 Hyperlipidemia 115 2.8% * * <0.001
 Hypertension 413 10.2% 15 15.4% 0.076
  Lyme disease * * 0 0.0% 0.733
 Migraine 55 1.3% * * <0.001
 Obesity 208 5.1% * * 0.954
  Peripheral vascular disease * * 0 0.0% 0.628
 Pregnancy 25 0.6% 0 0.0% 0.444
  Pseudotumor cerebri * * * * <0.001
  Rheumatoid arthritis and collagen vascular disease 24 0.6% * * <0.001
  Sickle cell trait and disease 67 1.7% 0 0.0% 0.208
  Tobacco use 763 18.7% 15 16.3% 0.469
  Ischemic and hemorrhagic stroke (history) * * 0 0.0% 0.453
 Syphilis * * 0 0.0% 0.733
  Systemic vasculitis * * 0 0.0% 0.733
Ocular findings
  Glaucoma (POAG) (excludes neovascular glaucoma) 0 0.0% * * <0.001
  Retinal vasculitis 0 0.0% * * <0.001

Variables with n = 0 in both the case group and control group were excluded:
- Atherosclerosis (systemic except carotid and coronary).
- Cocaine use.
- Oral contraceptive use.
- Open-globe injury.
- Non-stroke cerebrovascular disease.
a
As per NIS Database guidelines, cells in which the count is between 1 and 10 must be redacted; “*” has been placed instead of the numerical value.
For variables that have a redacted cell and for which there is a statistically significant difference, the cell value in bold represents the cell with the
higher prevalence.

Discussion Compared to older adults, hypertension and diabetes are not

prevalent in young adults with CRVO.5,25,26 Hypertension
Systemic diseases and CRVO and diabetes mellitus was noted in 15.4% and 10.5% of
Hypertension, diabetes mellitus, and hyperlipidemia are weighted cases, respectively, in our study, but regression
well-documented risk factors for CRVO in older patients.2–6 analysis showed that these conditions were not significant
6 European Journal of Ophthalmology 00(0)

Table 4.  Results of univariate and multivariable firth logistic regression.

Variable Univariate Multivariable

OR (95% CI) p-value OR (95% CI) p-value

Sex
 Women REF – – –
 Men 0.97 (0.65–1.47) 0.903 – –
Age
 18–29 REF – – –
 30–40 0.88 (0.58–1.33) 0.538 – –
Systemic Comorbidities
  Aortic aneurysm/dissection 2.36 (0.12–48.11) 0.578 – –
  Arterial thromboembolic disease 0.37 (0.02–6.12) 0.484 – –
  Bleeding diathesis 0.23 (0.01–3.76) 0.301 – –
  Congestive heart failure 1.01 (0.06–18.04) 0.993 – –
  DVT/PE (History) 23.74 (12.57–44.83) <0.001 21.88 (10.58–45.26) <0.001
  Diabetes mellitus 2.39 (1.24–4.61) 0.010 1.21 (0.46–3.12) 0.694
  Drug use (IV) 0.58 (0.03–9.83) 0.704 – –
  Drug use (non-IV) 0.06 (0.00–0.95) 0.046 0.10 (0.01–1.65) 0.108
 Hyperlipidemia 4.18 (2.13–8.18) <0.001 3.60 (1.57–8.30) 0.003
  Hypercoagulable state 47.54 (19.28–117.19) <0.001 25.25 (7.78–81.97) <0.001
 Hypertension 1.64 (0.94–2.88) 0.081 – –
  Lyme disease 3.87 (0.16–92.94) 0.404 – –
 Migraine 8.95 (4.45–18.00) <0.001 2.53 (0.86–7.49) 0.092
 Obesity 1.12 (0.47–2.69) 0.797 – –
  Peripheral vascular disease 2.06 (0.10–40.91) 0.635 – –
 Pregnancy 0.82 (0.05–14.31) 0.891 – –
  Pseudotumor cerebri 45.28 (12.85–159.52) <0.001 35.94 (9.03–142.99) <0.001
  Rheumatoid arthritis/collagen vascular disease 9.98 (3.84–25.97) <0.001 0.91 (0.06–14.47) 0.949
  Sickle cell trait and disease 0.31 (0.02–5.13) 0.413 – –
 Smoking 0.87 (0.50–1.49) 0.601 – –
  Stroke (history) 2.21 (0.11–44.56) 0.603 – –
 Syphilis 3.57 (0.15–82.83) 0.428 – –
  Systemic Vasculitis 3.87 (0.16–92.94) 0.404 – –
Ocular findings
  Glaucoma (POAG) (excludes neovascular glaucoma) 558.86 (24.35–12824.38) <0.001 836.72 (36.28–19295.13) <0.001
  Retinal vasculitis 466.43 (18.96–11474.48) <0.001 705.82 (28.55–17448.63) <0.001

Variables in which n = 0 for both the CRVO and Non-CRVO groups were not included.
Firth Logistic Regression was used because of statistical separation that was present in the weighted data.
Variables with a p < 0.05 on univariate regression were included in the multivariable model.

risk factors for CRVO in young adults. The pathogenesis of
CRVO is likely multifactorial, but thrombosis of central reti-
nal vein due to mechanical compression by atherosclerotic
central retinal artery has been postulated to be an underlying
etiology.27 Hypertension and diabetes mellitus can accelerate
atherosclerosis.28 However, we postulate that in young
patients the atherosclerotic changes may be early, not clini-
cally severe enough to cause significant total vein occlusion,
although with time, progressive cumulative changes will
cause CRVO in an older adult.
In contrast, multiple reports have suggested hyperlipi-
demia to be an important underlying systemic comorbidity in
young CRVO patients.5,26,29–31 Our multivariable regression
analysis also showed that hyperlipidemia increased the odds
of having CRVO three-fold (OR of 3.60). Hyperlipidemia
may predispose to CRVO by promoting thrombosis through
the release of β-thromboglobulin and platelet factor IV.5,30,32
Hypercoagulable states and CRVO
Hypercoagulable disorders have been implicated to pro-
mote CRVO. The most common of these conditions
include hyperhomocysteinemia, anticardiolipin antibod-
ies, Factor V Leiden, anticardiolipin antibodies, protein C
or protein S deficiencies, prothrombin mutation, and oth-
ers.33–35 Extensive hypercoagulability workup is usually
suggested if older patients do not possess any of the tradi-
tional risk factors, or if the patient is younger than 50 years,
or has bilateral CRVO, or a prior history or family history
of thrombosis.5,16,19,34,36
Hypercoagulable disorders were significantly more
prevalent in CRVO patients under the age of 45 years.37 In
young CRVO patients, hyperhomocysteinemia and
antiphospholipid antibodies are more commonly seen
compared with age-matched controls without the disease.34
Chen et al. 7
We analyzed hypercoagulable state as a single independent
variable comprising all primary and secondary causes of
hypercoagulability; however, no cases of secondary hyper-
coagulable state were identified in our study. Our result
revealed hypercoagulable state to be an important risk fac-
tor for CRVO in young patients. It is important to note that
hyperhomocysteinemia was not included in this study
since it does not have a specific ICD-9 code. However, this
underlying pathology may have caused various other
hypercoagulable comorbidities (as PE or DVT) and may
have been indirectly included in our analyses.
DVT/PE was analyzed as a grouped risk factor. As
stated in “Risk factors selections,” only “history of” DVT/
PE was considered in this study in order to evaluate this
comorbidity as a risk factor. Our data revealed that DVT/
PE was an independent risk factor for CRVO with a OR of
21.88, further reaffirming the role of hypercoagulable con-
ditions in the pathogenesis of CRVO in these patients.
CRVO may develop from direct mechanical compres-
sion by the adjacent atherosclerotic central retinal artery
causing turbulent flow and thrombosis of central retinal
vein.27 In younger patients without known cardiovascular
risk factors or significant atherosclerosis, the pathophysi-
ology of CRVO remains unclear. However, it was hypoth-
esized that unprovoked thrombus formation in the central
retinal vein secondary to a hypercoagulable state may con-
tribute to developing CRVO in these patients.38
It is worth noting that pregnancy and sickle cell trait or
disease, conditions that can potentially predispose to
hypercoagulable states, did not increase the risk CRVO.
Furthermore, no cases of oral contraceptive use were
found in both study and control groups and thus it was not
included in the analysis.
Inflammatory conditions and CRVO
Inflammatory conditions such as RA and CVD have
been associated with CRVO in young patients.5,39–42 In
this study, RA/CVD was analyzed as a single variable to
evaluate for the effect of systemic inflammation on
CRVO. While various CVDs were included in our analy-
sis, SLE and sicca syndrome accounted for all cases in
this group. The association of RA/CVD with CRVO was
statistically significant only in the univariate analysis
but not multivariable regression analysis after adjusting
for confounding variables. Systemic vasculitis was simi-
larly shown not to be a significant risk factor for CRVO
in the univariate analysis.
Interestingly, a strong and significant association was
found between retinal vasculitis and CRVO, with an OR
over 700. As opposed to systemic vasculitis, the direct
inflammatory effect on retinal vessels may underlie the
predisposition to CRVO. The magnitude of adjusted OR,
however, should be interpreted with caution because of the
wide confidence interval, which was a result of low preva-
lence in both control and study groups. The association
between retinal vasculitis and CRVO had been described
previously in a patient with Crohn disease-related retinal
vasculitis, and it was posited that severe inflammation of
the retinal vasculature can have occlusive effect on arteries
and veins, resulting in CRVO.43 Retinal vasculitis has not
been studied extensively and is not a well-recognized risk
factor for CRVO in older populations. Our result suggested
a potentially unique risk factor of CRVO in young adults
that warrants further investigation.
Central nervous system and CRVO
Pseudotumor cerebri was the most significant systemic
comorbidity of CRVO in the present study with an OR of
35.94. It occurs most commonly in patients age 20 to 50 and
may be a unique risk factor in young patients. Association
between pseudotumor cerebri and CRVO has been previ-
ously reported.44,45 While the pathophysiology is not entirely
understood, it is hypothesized that optic nerve swelling sec-
ondary to increased intracranial pressure impedes retinal
venous return and can precipitate CRVO.
Migraine headache has also been associated with young
CRVO patients in multiple studies, with a prevalence of 4%
to 12%.17,46 Benninger et al. reported a young woman with
history of migraine headache who presented with new
CRVO with a negative systemic work up for cardiovascular,
autoimmune, and coagulation abnormalities.47 It has been
speculated that platelet abnormalities related to migraine
may predispose to CRVO.48 Our multivariable regression
analysis showed an OR of 2.64 with a p-value that was near
statistical significance. Further studies would be helpful in
elucidating this potential risk factor association.
Glaucoma and CRVO
Elevated IOP and glaucoma are well-known risk factors
for CRVO in the general population.6,49,50 Their associa-
tion specifically in younger patients has been reported
but not well-established.51 It is hypothesized that IOP
can cause external compression of the central retinal
vein at the level of lamina cribrosa, resulting in turbulent
flow and subsequent thrombus formation.52 Presumably,
deformation of the lamina cribrosa associated with glau-
comatous optic atrophy also contributes to vein com-
pression and thrombus formation. All identified cases of
glaucoma in this study were POAG. Using multivariable
regression analysis, we showed that POAG was the most
significant risk factor for CRVO in young patients with
an OR over 800. However, the large OR and wide confi-
dence interval resulted from low prevalence in study and
control groups, the magnitude of OR should be inter-
preted with caution.
8 European Journal of Ophthalmology 00(0)
Cardiovascular risk factors and CRVO
Studies on the association between CRVO and various car-
diovascular conditions such as stroke, PVD, arterial throm-
boembolic disease and coronary artery diseases, and CHF
have yielded conflicting results.2,15,38,53 Such discrepancy
may suggest underlying weak associations of these risk
factors. Limited studies have evaluated these risk factors
in younger population. Our statistical analysis did not
show significant associations between CRVO and any of
these cardiovascular risk factors.
Social lifestyle and CRVO
Cigarette smoking had been suggested by many reports to
be a potential risk factor for branch retinal vein occlusion30,54;
however, a statistically significant association had not been
demonstrated consistently. Klein et al. presented data show-
ing an increased risk of BRVO and all-type RVO in current
smokers, but none was found for CRVO.3 In contrast, data
from other studies have provided contradicting results.2,6
We included both current and former users of tobacco in our
study, and did not find cigarette smoking to be a significant
risk factor for CRVO.
Non-IV illicit drug use was associated with decreased risk
of CRVO in the univariate analysis; however, after adjusting
for confounding variables, a statistically significant associa-
tion was not found in the multivariable regression analysis.
This variable consisted of illicit drug use as well as various
substance abuse-associated complications such as intoxica-
tion, withdrawal, dependence, and altered mental status,
among others. Use of IV drugs was also shown to have no
significant association with CRVO in our study.
Acute in-hospital thrombotic complications
Patients are not routinely admitted to hospital for workup or
management for acute CRVO. We performed a chi-square
analysis on various acute thrombotic complications to pro-
vide an insight regarding the need for inpatient management
(Table 2), but no cases of acute thrombotic events were identi-
fied in the study group. Our data showed that the use of anti-
coagulants was more prevalent in patients with CRVO than
those without. No antiplatelet or aspirin use were identified in
the study group. Using the database, it was unclear if antico-
agulant was a part of patients’ pre-hospitalization medication
or was initiated in the hospital. The reason for hospitalization
is still unclear but we postulate that these patients may have
had an atypical presentation of CRVO or have other medical
conditions that necessitate inpatient management.
Limitations of the study
While this study uses a large database, it has a number of
limitations. First, all primary and comorbid diagnoses
were identified through ICD-9 codes used on hospital
discharge. The validity of the study results depends
largely on the accuracy and specificity of the ICD codes.
Second, ICD-9 codes contain less-specific diagnoses
than ICD-10 codes, which limits the analysis undertaken
in this study. For example, various coagulation factor
deficiencies have no specific diagnosis codes, and they
must be coded under the less specific primary hyperco-
agulable state diagnosis. Third, this study included only
those patients who were hospitalized with a primary
diagnosis of CRVO. CRVO patients are not routinely
admitted for workup unless a concurrent severe comor-
bidity needs urgent management (for example, pseudo-
tumor cerebri or medically uncontrolled high blood
pressure). The results of this study may not be applicable
to a different patient population. Lastly, this study only
reveals associations between CRVO and various comor-
bidities. A causal relationship cannot be established on
this basis. However, when possible, we included ICD-9
codes that distinguished between prior history and acute
events in order to evaluate comorbidities as risk factors
rather than simple associations.
Conclusion
The pathogenesis of CRVO is likely multifactorial. It is
postulated that atherosclerotic change of central retinal
artery causes stasis and thrombosis of the adjacent reti-
nal vein within the same adventitia, leading to CRVO.27
The risk of central retinal vein thrombosis potentially
increases with underlying hypercoagulable diseases.
The results of our study demonstrated that, except for
hyperlipidemia, traditional risk factors such as hyper-
tension and diabetes may not be as significant in young
patients. Additionally, hypercoagulable states, DVT/
PE, pseudotumor cerebri, retinal vasculitis, and glau-
coma may play important roles in the pathogenesis of
CRVO in this population. Given the results of our
study, we believe that systemic workup for hypercoag-
ulable risk factors are indicated for patients younger
than 40  years of age, along with treatment of
hyperlipidemia.
Declaration of conflicting interests
The author(s) declared the following potential conflicts of
interest with respect to the research, authorship, and/or publi-
cation of this article: M.Z. reports personal fees from
Genentech/Roche, personal fees from Novartis Pharma AG,
personal fees and other from Iveric bio, personal fees from
Ophthotech, other from NVasc, personal fees from Healios
KK, personal fees and other from Frequency Therapeutics,
personal fees from Chengdu Kanghong Biotech, grants from
Aerie Pharmaceuticals, personal fees from Iridex, outside the
submitted work. No conflicting relationship exists for the other
authors.
Chen et al. 9
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
ORCID iD
Tony Y. Chen https://orcid.org/0000-0001-9079-3443
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