Role of haemorheological factors in patients with retinal vein occlusion.

Abstract

Retinal vein occlusion (RVO) is an important cause of permanent visual loss. Hyperviscosity, due to alterations of blood cells and plasma components, may play a role in the pathogenesis of RVO. Aim of this case-control study was to evaluate the possible association between haemorheology and RVO. In 180 RVO patients and in 180 healthy subjects comparable for age and gender we analysed the whole haemorheological profile: [whole blood viscosity (WBV), erythrocyte deformability index (DI), plasma viscosity (PLV), and fibrinogen]. WBV and PLV were measured using a rotational viscosimeter, whereas DI was measured by a microcomputer-assisted filtrometer. WBV at 0.512 sec(-1) and 94.5 sec(-1) shear rates as well as DI, but not PLV, were found to be significantly different in patients as compared to healthy subjects. At the logistic univariate analysis, a significant association between the highest tertiles of WBV at 94.5 sec(-1) shear rate (OR: 4.91, 95% CI 2.95-8.17; p < 0.0001), WBV at 0.512 sec(-1) shear rate (OR: 2.31, 95% CI 1.42-3.77; p < 0.0001), and the lowest tertile of DI (OR: 0.18, 95% CI 0.10-0.32; p < 0.0001) and RVO was found. After adjustment for potential confounders, the highest tertiles of WBV at 0.512 sec(-1) shear rate (OR: 3.23, 95% CI 1.39-7.48; p = 0.006), WBV at 94.5 sec(-1) shear rate (OR: 6.74, 95% CI 3.06-14.86; p < 0.0001) and the lowest tertile of DI (OR: 0.20,95% CI 0.09-0.44, p < 0.0001) remained significantly associated with the disease. In conclusion, our data indicate that an alteration of haemorheological parameters may modulate the susceptibility to the RVO, by possibly helping to identify patients who may benefit from haemodilution.

Full text

Page 1

Role of haemorheological factors in patients with retinal vein
occlusion
Francesco Sofi1, Lucia Mannini1, Rossella Marcucci1, Paola Bolli2,Andrea Sodi3, Barbara Giambene3, Ugo Menchini3,
Gian Franco Gensini1,2, RosannaAbbate1, Domenico Prisco1
1Department of Medical and Surgical Critical Care,Thrombosis Centre, University of Florence,Azienda Ospedaliero-Universitaria Careggi,
Florence, Italy; Center for the study at molecular and clinical level of chronic, degenerative and neoplastic diseases to DEvelop NOvel
THErapies, University of Florence, Italy;2Don Carlo Gnocchi Foundation, IRCCS, Florence, Italy;3Department of Oto-Neuro-
Ophthalmological Surgical Sciences, University of Florence,Azienda Ospedaliero-Universitaria Careggi, Florence, Italy
Summary
Retinal vein occlusion (RVO) is an important cause of perma-
nent visual loss.Hyperviscosity,due to alterations of blood cells
and plasma components,may play a role in the pathogenesis of
RVO. Aim of this case-control study was to evaluate the possi-
ble association between haemorheology and RVO.In 180 RVO
patients and in 180 healthy subjects comparable for age and
gender we analysed the whole haemorheological profile:[whole
blood viscosity (WBV), erythrocyte deformability index (DI),
plasma viscosity (PLV), and fibrinogen]. WBV and PLV were
measured using a rotational viscosimeter, whereas DI was
measured by a microcomputer-assisted filtrometer. WBV at
0.512 sec-1and 94.5 sec-1shear rates as well as DI,but not PLV,
were found to be significantly different in patients as compared
tohealthysubjects.Atthelogisticunivariateanalysis,asignificant
Keywords
Blood viscosity, haemodilution, haemorheology, retinal vein
occlusion
association between the highest tertiles of WBV at 94.5 sec-1
shearrate(OR:4.91,95%CI2.95–8.17;p<0.0001),WBVat0.512
sec-1shear rate (OR:2.31,95%CI 1.42–3.77;p<0.0001),and the
lowest tertile of DI (OR:0.18,95%CI 0.10–0.32;p<0.0001) and
RVOwasfound.Afteradjustmentforpotentialconfounders,the
highest tertiles of WBV at 0.512 sec-1shear rate (OR: 3.23,
95%CI 1.39–7.48; p=0.006),WBV at 94.5 sec-1shear rate (OR:
6.74,95%CI 3.06–14.86;p<0.0001) and the lowest tertile of DI
(OR:0.20,95%CI0.09–0.44,p<0.0001)remainedsignificantlyas-
sociatedwiththedisease.Inconclusion,ourdataindicatethatan
alteration of haemorheological parameters may modulate the
susceptibility to the RVO,by possibly helping to identify patients
who may benefit from haemodilution.
Thromb Haemost 2007; 98: 1215–1219
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Correspondence to:
Francesco Sofi, MD, PhD
Department of Medical and Surgical Critical Care
Thrombosis Centre, University of Florence
Viale Morgagni 85, 50134 Florence, Italy
Tel.: +39 055 7949420, Fax: +39 055 7949418
E-mail: francescosofi@gmail.com
ReceivedApril 4, 2007
Accepted after revision October 3, 2007
Prepublished online November 9, 2007
doi :10.1160/TH07–04–0247
© 2007 Schattauer GmbH, Stuttgart
1215
Introduction
Retinal vein occlusion (RVO) is one of the commonest vision-
threateningretinalvasculardisorders(1,2).Despiteitsrelatively
uncommonprevalenceamongthegeneralpopulation,RVOhasa
clinicalrelevancesinceitisanimportantcauseofpermanentvis-
ual loss, especially in elderly people, and it has been reported to
beassociatedwithanincreasedriskofmortalityfromcardiovas-
cular diseases (3).To date, the pathogenesis of RVO has not yet
been determined. Atherosclerosis is considered to be the most
important underlying condition and several risk factors associ-
ated to the atherosclerotic process, including hypertension, dia-
betes, and smoking habit, have been identified to play a role in
thepathogenesisofthedisease(2).Inaddition,severaloftheac-
quired and inherited risk factors for arterial and venous throm-
botic diseases have been reported to be highly prevalent in RVO
patients (4). We have previously demonstrated a significant as-
sociation between some thrombophilic parameters and the oc-
currence of RVO (5–7).
An open issue in the pathogenesis of RVO is, to date, blood
viscosity. Blood viscosity is a relevant factor in venous circu-
lation and an impaired blood flow in a branch of the central reti-
nal vein may be able to favour and/or precipitate RVO. Over the
last few years, an increasing interest for the possible association

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Sofi et al. Haemorheology in retinal vein occlusion
betweenalterationsofbloodrheologyandRVOhasbeendemon-
strated, but no conclusive data have been obtained (8–16). Some
studieshavereportedincreasedlevelsofsomehaemorheological
variablesinRVOpatientsascomparedtohealthycontrols(8,10,
15,16),whereasothersdidnotsupportthesefindings(9,11,12).
Inaddition,someotherpapersreportedabeneficialroleforhae-
modilution therapy and rheologic drugs in RVO patients, also
through the improvement of haemorheological parameters (11,
17–19). Currently, to the best of our knowledge, no studies are
available in the literature which evaluate the whole haemorheo-
logicalprofileinaconsiderablegroupofRVO.Aimofthisretro-
spectivecase-controlstudywasthentoevaluate,inalargepopu-
lationofRVOpatients,thewholehaemorheologicalprofileinre-
lation to the occurrence of RVO.
Material and methods
Study population
Thestudypopulationcomprised180consecutivepatientswitha
diagnosis of RVO who had been referred to the Thrombosis
Centre of the University of Florence, Italy. RVO was diagnosed
in all patients within a period ranging from one to three months
before the examination, at the Department of Oto-Neuro-Oph-
thalmogical Surgical Sciences of the University of Florence,
Italy. RVO was diagnosed by ophthalmoscopic fundus examin-
ation revealing disc swelling, venous dilation or tortuosity, reti-
nal haemorrhages, and cotton-wool spots. The control popu-
lation was comprised 180 healthy subjects selected to be com-
parableforageandgenderwithpatientsfromthestaffoftheUni-
versity of Florence and/or from their friends or partners.
Patientsand healthysubjects withapersonalhistoryofglau-
comaorcardiovasculardiseasewereexcludedfromthestudy.In
order to identify symptom-free subjects and patients to exclude
whoweresuspectedofhavinganyformofvasculardisease,ade-
tailed interview addressed to personal and familial history was
performed.
The subjects were classified as having hypertension accord-
ingtotheguidelinesofEuropeanSocietyofHypertension/Euro-
peanSocietyofCardiology(20)oriftheyreportedtakingantihy-
pertensive medications, as verified by the interviewer. Diabetic
subjects were defined in line with the American Diabetes As-
sociation(21)oronthebasisofself-reportdata(ifconfirmedby
medication or chart review). Dyslipidemia was defined follow-
ing the criteria of the ATP III Expert Panel of the US National
Cholesterol Education Program (22). Current smoking status
was determined at the time of physical examination.All partici-
pants gave signed informed consent; the study was approved by
the local Ethics Committee and applies with the Declaration of
Helsinki.
Blood measurements
Blood samples were collected from the antecubital vein into
evacuated plastic tubes (Vacutainer) in the morning, after an
overnight fasting. Plasma sample was obtained by centrifuging
blood at 2000 g for 10 minutes at 4°C.
Complete blood cell count was measured by using the Sys-
mex XE-2100 hematology analyser (Sysmex, Kobe, Japan) and
fibrinogen was assessed according to the method by von Clauss.
Whole blood viscosity (WBV) and plasma viscosity (PLV) were
measured at 37°C using the Rotational Viscosimeter LS 30
(Contraves, Zurich, Switzerland). WBV was analysed at 0.512
sec-1and94.5sec-1shearrates.Theerythrocytefiltrationtestwas
used to determine erythrocyte deformability by a microcom-
puter-assistedfiltrometer(modelMF4;Myrenne,Roetgen,Ger-
many), as reported by Ramakrishnan et al. (23). Erythrocyte de-
formability index (DI) was estimated by a curve indicating ery-
throcyte filtration throughout a 10 min recording in order to de-
termine rheological properties of erythrocytes, passing them
through polycarbonate filters with 5 µm micropores (Nucleo-
pore, Pleasanton, CA, USA). The initial flow rate from the
microcomputer-generated curves was used for assessing ery-
throcyte DI. For the different haemorheological variables, intra-
assay coefficients of variation were <1.6%, and interassay coef-
ficients of variation were <4.5%.
Statistical analysis
Statistical analysis was performed using the SPSS (Statistical
Package for Social Sciences, Chicago USA) software for
Windows (Version 13.0). Log-transformed values for all circu-
latingparameterswereusedintheanalyses,andbacktransform-
ed for data presentation as median and range.The non-paramet-
ric Mann-Whitney test for unpaired data was used for compari-
sons between single groups.The χ2-test was used to test for pro-
portions.Correlationanalysesweremeasuredbyusing thePear-
son’s correlation test.A logistic regression analysis was used to
evaluate the risk of RVO according to the tertiles of distribution
of haemorheological variables measured within the healthy con-
trol group (WBV at 0.512 sec-1shear rate: 1sttertile < 24.22
MPa*s, 2ndtertile: 24.23–26.50 MPa*s, 3rdtertile: > 26.50
MPa*s; WBV at 94.5 sec-1shear rate: 1sttertile: < 4.29 MPa*s,
2ndtertile:4.29–4.34MPa*s,3rdtertile:>4.34MPa*s;DI:1stter-
tile < 6.86, 2ndtertile 6.87–10.16, 3rdtertile > 10.16). Variables
showing, at the univariate logistic regression analysis, a signifi-
cant association with the disease were introduced in the multi-
variate model.At multivariate analysis, a first model (Model 1)
was performed by adjusting for age, gender, smoking habit, dia-
betesandhypertension.Subsequently,asecondmodel(Model2)
was performed by adjusting also for white blood cells. Finally, a
further fully-adjusted model was performed by introducing he-
matocrit, and fibrinogen levels into the model. Odds ratios (OR)
and 95% confidence intervals (CI) are presented. A p-value <
0.05 was considered to indicate statistical significance.
Results
Demographicandclinicalcharacteristicsofthestudypopulation
arereportedinTable1.Amongthetraditionalcardiovascularrisk
factors, hypertension, smoking habit and diabetes, but not dysli-
pidemia, were significantly more frequent in patients than in
healthysubjects.Withregardtolaboratoryparameters,asignifi-
cant difference for WBV at 94.5 and at 0.512 sec-1shear rates,
white blood cell, and DI, but not for PLV, haematological vari-
ables and fibrinogen, was observed between patients and con-
trols(Table2).Amongthepatientgroupsignificant correlations
between hematocrit andWBV at 0.512 sec-1shear rate (R=0.41;

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Sofi et al. Haemorheology in retinal vein occlusion
1217
p<0.0001) and fibrinogen and plasma viscosity (R=0.22;
p=0.02) were observed.
In order to investigate the possible association between RVO
and haemorheological parameters we measured the tertiles of
distribution ofWBV at 94.5 sec-1and 0.512 sec-1shear rates and
DIwithinthehealthycontrolgroup,andweperformedalogistic
regression analysis which showed, at the univariate analysis, a
significant association of the highest tertiles of WBV at 94.5
sec-1shear rate (OR: 4.91, 95%CI 2.95–8.17; p<0.0001), WBV
at 0.512 sec-1shear rate (OR: 2.31, 95%CI 1.42–3.77;
p<0.0001), and the lowest tertile of DI (OR: 5.53, 95%CI
3.13–9.75; p<0.0001) with the disease.
After adjustment for age, sex, hypertension, smoking habit
and diabetes (Table 3, model 1), white blood cells (Table 3,
model 2) as well as for hematocrit, and fibrinogen (Table 3,
model 3) the highest tertiles ofWBV at both shear rates, and the
lowesttertileofDIwerefoundtobesignificantlyassociatedwith
the disease.
Discussion
The present case-control study performed in a considerable
number of RVO patients reported a significant association be-
tween alterations of haemorheology and occurrence of the reti-
nal occlusive disease. Indeed, the highest tertiles ofWBV at dif-
ferent shear rates as well as the lowest tertile of red cell deform-
abilityhavebeenfoundtobeassociatedwithanincreasedriskof
RVO.
Tothebestofourknowledge,thisisthemostcomprehensive
assessment of the association between blood rheology parame-
ters and RVO. Some studies have reported an association be-
tween alterations of blood flow and retinal vascular disease but
no conclusive data have been obtained (8–16). Some reports, in
fact, showed an association between altered haemorheological
variables and the occurrence of RVO (8, 10, 15, 16), whereas
otherstudiesdidnotconfirmtheseobservations(9,11,12).Such
conflicting results can be explained either by the scanty number
of patients studied in most of these studies, or by the fact that
onlysomeofthesestudiesanalysedthewholepatternofhaemor-
heologyinassociationwiththedisease.Ourstudy,evaluatingthe
entire haemorheological profile together with fibrinogen, white
bloodcellsandhaematologicalvariables,inarelevantnumberof
RVO patients and healthy subjects, confirms the significant role
of haemorheological variables on the occurrence of RVO.
RVO is one of the commonest retinal vascular diseases with
ahighprevalenceinthegeneralpopulation(1,2).Duringthelast
years, findings demonstrating a significant association between
RVOandcardiovascularmortalityhavebeenreported,soconfer-
Table 1: Clinical characteristics of the
study population.
VariablePatients (n=180)Healthy subjects
(n=180)
65.5 (25–85)
79/101
34 (18.9)
26 (14.4)
40 (22.2)
10 (5.6)
p value
Age (years)*
Males/Females, n
Hypertension, n (%)
Smoking habit, n (%)
Dyslipidemia, n (%)
Diabetes, n (%)
66.5 (26–84)
78/102
77 (42.8)
51 (28.3)
41 (22.8)
22 (12.2)
0.07
0.9
< 0.0001
0.001
0.9
0.03
* Median and (range).
Table 2: Laboratory parameters.All values
are presented as median and (range).
Patients (n=180)Healthy subjects
(n=180)
4.3 (3.9–6.0)
25.2 (21.1–40.8)
1.32 (1.24–1.61)
8.71 (1.76–13.2)
43.7 (36.9–50.6)
14.2 ± 2.6
89.7 ± 5.4
29.8 ± 2.1
33.2 ± 1.9
p
WBV 94.5 sec-1shear rate, mPa.s
WBV, 0.512 sec-1shear rate, mPa.s
PLV, mPa.s
Erythrocyte deformability index
Hematocrit (%)
Hemoglobin, g/dL ^
Mean corpuscular volume, fL ^
Mean corpuscular haemoglobin, pg ^
Mean corpuscular haemoglobin
concentration, g/dL ^
White blood cells
Fibrinogen, mg/dL
4.4 (3.7–13.2)
27.6 (19.9–53.6)
1.35 (1.20–1.63)
4.10 (0.20–13.8)
42.5 (30.6–51.5)
14.4 ± 3.2
89.6 ± 8.2
29.6 ± 2.3
33.8 ± 2.2
< 0.0001
< 0.0001
0.1
< 0.0001
0.6
0.2
0.5
0.8
0.7
6230 (3600–17300)
304 (186–574)
5920 (3700–11200)
291 (208–439)
0.006
0.3
^ Mean ± standard deviation.

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Sofi et al. Haemorheology in retinal vein occlusion
ring to RVO an epidemiological relevance among vascular dis-
orders (3). However, despite this, the precise pathogenesis of
RVO has not been completely clarified.
The findings of our study are in keeping with some previous
studies evaluating haemorheological variables in the same type
of patients (8, 10, 12, 15). In 1976, for the first time, Ring et al.
reported increased WBV values in a limited group of RVO pa-
tients as compared to healthy controls (8). Subsequently, other
studies confirmed such preliminary finding in other and larger
(although limited) study populations (10, 12, 15). In our study,
WBV has been found to be associated with an increased risk of
RVOatbothshearratesinvestigated,aftermultiplestatisticalad-
justments.Thisallowsustostatethatbloodviscosityplaysarel-
evantroleinthepathogenesisofRVO.Indeed,haemorheologyin
RVOseemsimportantparticularlybecausealteredbloodfluidity
could lead to further decreased flow, initiating and/or causing
progression of vessel wall alterations.
Another relevant finding of the study is the observation that
an increased red cell DI is significantly protective against RVO.
Red cell deformability plays an important role in determining
bloodviscosityinthepresenceofslowvenousflowandhighvas-
cular resistance, conditions that are normally present in the cen-
tralretinalvein,especiallyattheleveloflaminacribrosa.Indeed,
erythrocyte morphology is extremely relevant in rheological
flow by affecting, under pathological circumstances, the rheo-
logic environment at microcirculatory level. This can be ob-
tainedbyboththemetabolicchangesoftheredcellthatoccurin
relation to the endothelial dysfunction present in such vascular
patients, and the haemostatic changes that can be observed con-
sequentlytothealteredhemodynamicshearstress.Hence,anal-
tered pattern of deformability for red cell can lead to a venous
stasisandthentoareducedbloodflow,bydeterminingocclusion
oftheretinalvessels.Inourstudy,abnormalitiesofDIhavebeen
foundtobepresentinahighpercentageofRVOpatientsascom-
pared to age- and gender-comparable healthy subjects, and have
been observed to be significantly associated with an increased
riskofthedisease.Previousstudiesinvestigatedredcelldeform-
ability in RVO patients but inconclusive data were obtained
(10–13). At variance with previous studies, conversely, we did
not find a significant association between plasma viscosity and
RVO (8, 10, 13, 14, 16).
These discrepancies can be explained by the differences
amongthedifferentstudiesintermsoftraditionalcardiovascular
risk factors and different methods used for measuring haemor-
heologicalparameters.Infact,redcelldeformabilityandplasma
viscosity are significantly influenced by several risk factors,
such as smoking habit, hypertension and diabetes.Thus, the dif-
ferent pattern of risk factors among the study patients and the
healthycontrolgroupcanexplain,atleastpartly,thedifferentre-
sults obtained. Moreover, different techniques (i.e. single ery-
throcyte rigidometer or red cells’filtrometer to measure red cell
deformability) have been used, hence causing a possible metho-
dological difference among the results of these studies.
Notably, however, the results obtained in the present study
can be helpful for the clinical management of RVO patients. Up
tonow,noestablishedtreatmentforRVOhasbeenavailable.The
increasing role of hypercoagulability in these patients supports
theroleofantithromboticdrugs,butmedicalmanagementofpa-
Table 3: Multivariate logistic regression analysis.
Model 1*Model 2†Model 3§
OR (95%CI)
0.99 (0.98–1.02)
1.08 (0.68–1.69)
3.15 (1.94–5.12)
2.09 (0.93–4.73)
2.34 (1.35–4.07)
pOR (95%CI)
0.99 (0.97–1.02)
1.27 (0.78–2.07)
3.19 (1.91–5.23)
2.29 (0.97–5.4)
2.24 (1.24–4.03)
pOR (95%CI)
0.99 (0.96–1.02)
1.23 (0.68–2.23)
3.20 (1.74–5.88)
2.91 (1.11–7.68)
2.05 (1.02–4.12)
p
Age
Gender (males vs. females)
Hypertension
Diabetes
Smoking habit
WBV at 94.5 sec-1shear rate, mPa.s
1sttertile
2ndtertile
3rdtertile
0.9
0.7
0.8
0.3
0.7
0.5
< 0.0001
0.07
0.002
< 0.0001
0.06
0.007
< 0.0001
0.03
0.04
WBV at 0.512 sec-1shear rate, mPa.s
1sttertile
2ndtertile
3rdtertile
Erythrocyte Deformability Index
1sttertile
2ndtertile
3rdtertile
Reference
0.55 (0.29–1.04)
2.78 (1.15–6.72)
Reference
0.57 (0.29–1.09)
1.73 (1.00–3.00)
Reference
1.17 (0.48–2.84)
2.78 (1.15–6.72)
0.06
0.005
0.9
0.05
0.7
0.02
4.99 (2.76–9.05)
1.20 (0.61–2.36)
Reference
< 0.0001
0.6
4.75 (2.53–8.94)
1.13 (0.54–2.34)
Reference
< 0.0001
0.7
4.84 (2.05–11.44)
1.02 (0.37–2.79)
Reference
< 0.0001
0.9
*Adjusted for age, gender, hypertension, diabetes, smoking habit; †Adjusted for age, gender, hypertension, diabetes, smoking habit and white blood cells;§Adjusted for age, gender, hypertension, diabetes, smok-
ing habit, white blood cells, hematocrit, and fibrinogen.
Reference
1.6 (0.82–3.16)
4.29 (2.52–7.31)
Reference
1.68 (0.82–3.45)
4.08 (2.30–7.21)
Reference
1.90 (0.72–5.06)
8.97 (3.72–21.63)
0.20.2
0.006
0.2
< 0.0001 < 0.0001

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Sofi et al. Haemorheology in retinal vein occlusion
1219
tients with RVO consists primarily of the treatment of the under-
lying systemic diseases.The presence of an altered haemorheo-
logical profile, on the other hand, can give physicians a further
therapeutic option for the treatment of RVO patients. Currently,
some reports indicating a possible beneficial role of haemodilu-
tion therapy in the management of RVO have been reported, but
data are limited (11, 17). Furthermore, a beneficial effect of
treatmentswithpentoxyfillineandtroxerutin,therapeuticagents
able to determine a significant improvement of perfusion to oc-
cluded vessels, as well as of haemorheology, has been proposed
in RVO patients, by hypothesising a relevant role for pro-hae-
morheologicalagentsintheclinicalmanagementofsuchocclus-
ivedisease,butthereisalackofdatatosupporttheseapproaches
(18, 19).
To date, statins and antiplatelet drugs have been reported to
significantly influence haemorheological profile (24, 25) and,
interestingly, a recent report showed a role for platelet activation
in the pathogenesis of RVO (26). Thus, the results of our study
suggestapossibleusefulnessoftheapproachwiththesedrugsto
these patients.This is also in line with a recent meta-analysis of
studies evaluating thrombophilia in RVO, which suggests that
these patients have a risk profile of “arterial” more than of “ve-
nous” type (27).
Inconclusion,recentliteratureandourfindingsindicateapos-
sibleapproachtoRVOwithhaemodilution,statins,andantiplatelet
drugs.Randomizedcontrolledclinicaltrialsarewarrantedinorder
to confirm the usefulness of such treatments in these patients.
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