Association Between Anemia and Cerebral

Venous Thrombosis
CaseControl Study
Jonathan M. Coutinho, MD, PhD; Susanna M. Zuurbier, MD; Aafke E. Gaartman, BSc;
Arienne A. Dikstaal; Jan Stam, MD, PhD; Saskia Middeldorp, MD, PhD;
Suzanne C. Cannegieter, MD, PhD

Downloaded from http://stroke.ahajournals.org/ by guest on November 15, 2016

Background and PurposeAnemia is often considered to be a risk factor for cerebral venous thrombosis (CVT),
but this assumption is mostly based on case reports. We investigated the association between anemia and CVT in a
controlled study.
MethodsUnmatched casecontrol study: cases were adult patients with CVT included in a single-center, prospective
database between July 2006 and December 2014. Controls were subjects from the control population of the Multiple
Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis (MEGA) study. Anemia was defined
according to World Health Organization criteria: nonpregnant women hemoglobin <7.5 mmol/L, pregnant women
<6.9 mmol/L, and men <8.1 mmol/L. We used logistic regression analysis, adjusting for age, sex, malignancy, oral
contraceptive use, and pregnancy/puerperium.
ResultsWe included 152 cases and 2916 controls. Patients with CVT were younger (mean age, 40 versus 48 years) and
more often women (74% versus 53%) than controls. Anemia was more frequent in cases (27.0%) than in controls (6.5%;
P<0.001). Anemia was associated with CVT, both in univariate analysis (odds ratio, 5.3; 95% confidence interval [CI],
3.67.9) and after adjustment for potential confounders (adjusted odds ratio, 4.4; 95% CI, 2.86.9). Hemoglobin as a
continuous variable was inversely associated with CVT (adjusted odds ratio per 1 mmol/L change 0.53; 95% CI, 0.42
0.66). Stratification by sex showed a stronger association between anemia and CVT in men (adjusted odds ratio, 9.9; 95%
CI, 4.123.8) than in women (3.6; 95% CI, 2.16.0).
ConclusionOur data suggest that anemia is a risk factor for CVT.(Stroke. 2015;46:2735-2740. DOI: 10.1161/
STROKEAHA.115.009843.)
Key Words: anemia case-control studies pregnancy risk factors sinus thrombosis, intracranial

erebral venous thrombosis (CVT) is a rare cause of stroke

with an incidence of 1.3 per 100000 among adults.1,2
Unlike arterial stroke, CVT mainly affects young to middleaged adults and children, and >90% are <60 years.3 Various
risk factors for CVT have been identified, such as local infections of the head, acquired and genetic thrombophilia, and
cancer, especially hematologic malignancies. Because of
women-specific risk factors (oral contraceptives, pregnancy,
and puerperium), CVT is 3 more common among women
than among men.4
Anemia is also often considered to be a risk factor for
CVT,57 but the evidence for this assumption is mainly based
on case reports and case series.8,9 In cohort studies, anemia is
indeed prevalent in patients who present with CVT, with estimates between 7% and 18% in adults10,11 and even higher percentages in children.12 However, because anemia could also
be associated with underlying diseases that increase the risk

for CVT, it is inconclusive whether anemia is indeed a risk

factor by itself.
Only 1 controlled study has addressed the association
between anemia and CVT in adults.13 After adjustment for
potential confounders, mild anemia was not associated with
CVT. The authors did find an association between severe anemia and CVT, but it is was weak (odds ratio [OR], 1.1; 95%
confidence interval [CI], 1.01 to 2.22). The aim of our study
was to examine the association between anemia and CVT in a
large casecontrol study.

Methods
Study Design and Patient Selection
Cases were adult patients with CVT who were included in a prospective database of consecutive patients admitted to the Academic
Medical Center between July 2006 and December 2014.14 As controls, we assessed subjects who were included in the control group of

Received April 22, 2015; final revision received July 10, 2015; accepted July 15, 2015.
From the Departments of Neurology (J.M.C., S.M.Z., A.E.G., A.A.D., J.S.) and Vascular Medicine (S.M.), Academic Medical Center, Amsterdam, The
Netherlands; and Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands (S.C.C.).
Correspondence to Jonathan M. Coutinho, MD, PhD, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. E-mail j.coutinho@amc.nl
2015 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org

DOI: 10.1161/STROKEAHA.115.009843

2735

2736StrokeOctober 2015
the Dutch Multiple Environmental and Genetic Assessment of Risk
Factors for Venous Thrombosis (MEGA) study. The MEGA study is
a casecontrol study performed in the Netherlands that included 4956
consecutive patients with a first deep-vein thrombosis of the leg or
pulmonary embolism between March 1999 and September 2004.15
Partners of patients were invited as control subjects and 3297 participated. An additional 3000 controls were recruited by random digit
dialing. These participants were between the ages of 18 and 70 years
and had no history of venous thrombosis.
We excluded 4 cases and 3381 controls for whom no hemoglobin concentration was available. The excluded control subjects were
mostly recruited after June 2002, when, for logistic reasons; blood
sampling was no longer performed in the MEGA study. In cases, diagnosis of CVT was confirmed with computed tomography-venography, magnetic resonance imaging/magnetic resonance-venography,
catheter angiography, or autopsy. Written informed consent was obtained from cases if plasma and DNA of the patient were stored. In
patients for whom only clinical data were stored, informed consent
was not obtained because this is not required under Dutch law. All
controls from the MEGA study provided written informed consent.
Downloaded from http://stroke.ahajournals.org/ by guest on November 15, 2016

Data Collection and Laboratory Measurements

Data on clinical manifestations, imaging, and outcome were recorded
with a standardized case report form for cases. We extracted hemoglobin concentration and mean corpuscular volume (MCV) from the
medical records. All laboratory measurements were done as a part of
routine diagnostic work-up within 48 hours of admission. For laboratory measurements, a Sysmex XE-5000 Automated Hematology
System (maximal imprecision 1.5%, inaccuracy, 2%) was used for
cases, and a Coulter MD-II Series Analyzer (maximal imprecision
2%, inaccuracy, 2%) for controls.
Control subjects in the MEGA study completed a questionnaire
with information on demographics, previous medical history, and
risk factors for thrombosis. Blood was collected into vacuum tubes
containing 0.106 mmol/L trisodium citrate and processed within 4
hours. The final concentration of hemoglobin was multiplied by a
factor of 1.1 to adjust for the dilution by the trisodium citrate, as done
previously.16,17

Definition of Anemia
We used the World Health Organization definitions for anemia: nonpregnant women hemoglobin <7.5 mmol/L, pregnant women <6.9
mmol/L, and men <8.1 mmol/L (http://www.who.int/vmnis/indicators/hemoglobin.pdf). Severe anemia is defined as hemoglobin
<5.0 mmol/L for men and nonpregnant women or hemoglobin <4.3
mmol/L for pregnant women. Anemia is categorized as microcytic
(MCV <80 fL), normocytic (MCV 80100 fL), or macrocytic anemia
(MCV >100 fL).

diagnosis of inflammatory bowel disease. We could not adjust for

these potential confounders in the model because these conditions
were not scored in the controls.

Results
Within the study period, 156 adult patients with CVT were
admitted to our hospital. A total of 6297 control subjects participated in the MEGA study. After exclusion of subjects with
missing baseline hemoglobin, 152 cases and 2916 controls
were included in the analysis.
Cases were younger (mean age, 40 versus 48 years), more
often women (74.3 versus 52.6%), and more often had been
diagnosed with cancer (9.2 versus 3.7%) compared with controls (Table1). Oral contraceptive use (69.7% versus 21.1%)
and pregnancy/puerperium (5.3% versus 1.4%) were more
frequent in female cases. The baseline clinical manifestations
of patients with CVT are provided in Table1.
Mean hemoglobin concentration was lower in cases than
in controls (8.06 versus 8.68 mmol/L; P<0.001; Table2).
Anemia was present in 27.0% (41/152) of the cases, significantly more frequently than in controls (6.5%; 189/2916; absolute difference, 20.5%; 95% CI, 14 to 28). Severe anemia was
present in 2.6% of cases versus none in the controls (absolute
difference, 2.6%; 95% CI, 1.0 to 6.6). Increased hemoglobin
concentration was rare in both cases and controls (0.7 versus
0.2%; absolute difference, 0.5%; 95% CI, 0.8 to 1.8).
After adjustment for potential confounders, anemia was
significantly associated with CVT (adjusted OR, 4.4; 95%
CI, 2.8 to 6.9; Table3). Similarly, hemoglobin concentration
was inversely associated with CVT risk (adjusted OR per 1
mmol/L increase, 0.53; 95% CI, 0.42 to 0.66). Stratification
by sex showed a stronger association between anemia and
CVT in men (adjusted OR, 9.9; 95% CI, 4.123.8) than in
women (adjusted OR, 3.6; 95% CI, 2.1 to 6.0). Stratification
by MCV indicated that the risk of CVT was most clearly
Table 1. Baseline Characteristics and Risk Factors
Cases (n=152)

Controls (n=2916)

40 (14)

48 (12)

74.3

52.6

Demographics
Mean age, y (SD)
Women, %

Data Analysis

Risk factors for thrombosis, %

We analyzed categorical data with the 2 test or Fisher exact test and
continuous data with a MannWhitney test or Student t test, whichever was appropriate. The primary analysis was the difference in frequency of anemia between cases and controls. Results are given as
percentages with absolute differences and 95% CIs. We used multivariate logistic regression analysis to adjust for potential confounding variables. CVT was used as a dependent variable. Anemia and
hemoglobin concentrations (as a continuous variable) were used as
independent variables in separate models. In each model, we adjusted
for the following potential confounders: age, sex, malignancy, oral
contraceptive use, and pregnancy/puerperium. We stratified the analysis for sex and MCV value. We also performed an analysis in which
we divided subjects into those with normal hemoglobin (reference
category), anemia, or increased hemoglobin. Increased hemoglobin
was defined as >10.2 mmol/L for women or >11.5 mmol/L for men.
In a subgroup analysis, we excluded patients with a history of malignancy. We also did a subgroup analysis in which we excluded cases
with a recent infection or neurosurgical intervention, or who had a

Oral contraceptives*

69.7

21.1

Pregnancy/puerperium*

5.3

1.4

Previous thrombosis

9.2

Malignancy

9.2

3.7

Headache

91.3

Focal neurological deficits

63.3

Papilledema

25.7

Seizures

46.1

Intracranial hemorrhage

48.4

Intracranial nonhemorrhagic
lesion

22.0

Baseline characteristics CVT patients, %

CVT indicates cerebral venous thrombosis.

*Percentage of women.

Coutinho et al Anemia and Cerebral Venous Thrombosis 2737

Table 2. Laboratory Data
Cases
(n=152)

Controls
(n=2916)

Absolute
Difference, % (95% CI)

8.06 (1.4)

8.68 (0.7)

0.63 (0.40 to 0.85)

Anemia

27.0%

6.5%

20.5 (14 to 28)

Microcytic

10.5%

0.7%

9.8 (5.8 to 15.9)

Normocytic

10.5%

5.7%

4.8 (0.7 to 11.0)

Macrocytic

1.4%

0.2%

1.2 (0.2 to 4.8)

Missing MCV

4.6%

0%

Mean hemoglobin,
mmol/L (SD)

Severe anemia

2.6%

0%

2.6 (1.0 to 6.6)

Increased
hemoglobin*

0.7%

0.2%

0.5 (0.8 to 1.8)

CVT did not materially change (adjusted OR, 3.6; 95% CI,
2.25.9). Finally, we divided subjects into those with normal
hemoglobin (reference category), anemia, or increased hemoglobin. This stratification had no effect on the strength of the
association between CVT and anemia (adjusted OR, 4.5; 95%
CI, 2.9 to 7.0). Furthermore, it did suggest that increased
hemoglobin was also associated with CVT (adjusted OR, 9.6;
95% CI, 1.0 to 90.7).

Discussion
In this casecontrol study, we found that CVT was significantly associated with anemia. Accordingly, we found
a linear, inverse association between the risk of CVT and
hemoglobin concentration. Subgroup analysis showed that
the association was stronger in men and in patients with
microcytic anemia.
With a prevalence of 27%, the frequency of anemia
among patients with CVT in our study is higher than has been
reported before. In the International Study on Cerebral Vein
and Dural Sinus Thrombosis (ISCVT), for instance, anemia
was present in 9.2% of patients.11 This discrepancy might be
explained by the fact that the prevalence of anemia was not a
specific research objective in ISCVT, and that measurement

CI indicates confidence interval; and MCV, mean corpuscular volume.

*Defined as >10.2 mmol/L for women or >11.5 mmol/L for men.
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increased in patients with microcytic anemia (adjusted OR,

15.6; 95% CI, 6.7 to 36.2). Exclusion of patients with a recent
infection, neurosurgical intervention, or inflammatory bowel
disease essentially did not change the results (adjusted OR,
3.9; 95% CI, 2.4 to 6.4). When we excluded patients with a
history of malignancy, the association between anemia and

Table 3. Association Between Anemia and Cerebral Venous Thrombosis

Cases

Controls

Anemia

41

1 mmol/L increase in Hb*

10

25.6

Women: anemia

31

Men: increase in Hb*

Women: Increase in Hb*

OR (95% CI)

Unadjusted

Adjusted

27.0

189

6.5%

5.3 (3.67.9)

4.4 (2.86.9)

0.42 (0.350.51)

0.53 (0.420.66)

46

3.3

10.0 (4.621.8)

9.9 (4.123.8)

27.4

143

9.3

3.7 (2.35.8)

3.6 (2.16.0)

0.44 (0.300.65)

0.49 (0.330.74)

0.44 (0.340.57)

0.54 (0.400.72)

Microcytic anemia

16

10.5

19

0.7

19.4 (9.639.2)

15.6 (6.736.2)

Normocytic anemia

16

10.5

165

5.7

2.2 (1.33.9)

1.9 (1.03.5)

Macrocytic anemia

1.4

0.2

9.8 (1.951.2)

8.9 (0.9385.6)

Anemia

33

25.8

189

6.5

5.0 (3.37.6)

3.9 (2.46.4)

1 mmol/L increase in Hb*

0.44 (0.360.54)

0.59 (0.460.77)

Anemia

30

21.7

179

6.4

4.1 (2.66.3)

3.6 (2.25.9)

1 mmol/L increase in Hb*

0.53 (0.440.65)

0.68 (0.540.85)

Entire study population

Stratification by sex
Men: anemia

Stratification by MCV

Potential residual confounders excluded

Subjects with malignancy excluded

Stratification by decreased, normal, or increased hemoglobin

Anemia
Normal hemoglobin
Increased hemoglobin

41

27.0

189

6.5

5.4 (3.67.9)

4.5 (2.97.0)

110

72.4

2722

93.3

1.0

1.0

0.7

0.2

4.9 (0.5742.7)

9.6 (1.090.7)

Unadjusted and adjusted OR for cases vs controls. In the multivariate model, we adjusted for age, sex, malignancy, oral contraceptive use, and pregnancy/puerperium.
CI indicates confidence interval; Hb, hemoglobin; MCV, mean corpuscular volume; and OR, odds ratio.
*OR for Hb is per 1 mmol/L increase in Hb.
Cases with a recent infection or neurosurgical intervention, or with a history of inflammatory bowel disease were excluded in this subgroup analysis.
Reference category.
Defined as Hb >10.2 mmol/L for women or Hb >11.5 mmol/L for men.

2738StrokeOctober 2015

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of hemoglobin was not mandatory. This may have led to

under-reporting of anemia, especially of milder cases. A large
registry from India where hemoglobin concentrations were
routinely measured and which used a similar definition for
anemia as we did reported anemia in 18.4% of patients.10
We found a stronger association between CVT and anemia
than a previous casecontrol study, despite a similar prevalence of anemia among cases.13 Stolz et al13 reported only a
weak association with severe anemia (OR, 1.1) and no association with mild anemia. This difference is partly explained by
the fact that in their study, the authors calculated separate ORs
for mild and severe anemia, whereas in our main analysis, we
determined the OR of any anemia (mild or severe) versus no
anemia. Using our approach, the unadjusted OR for any anemia in the study by Stolz et al13 would have been 2.8, which
is in the same range as the unadjusted OR in our study (5.3).
It is important to compare the prevalence of anemia in
our control population to other studies that included healthy
subjects. The US National Health and Nutrition Examination
Survey determined the prevalence of anemia in noninstitutionalized civilians.18 The prevalence in men aged 17 to 64
years, comparable with the age range of our control group,
varied between 1.5% and 4.4%. The frequency of anemia
among male controls in our study (3.3%) falls within this estimate. In women of similar ages, the prevalence was 6.8% to
12.2%, which is also comparable with the frequency we found
(9.3%). A population-based study from Germany found a rate
of anemia of 3.2% in men and women aged 45 to 74 years,19
which is even lower than in our study. Therefore, we think
that it is unlikely that an underestimation of the prevalence of
anemia among controls biased our results.
Our data indicate that anemia is a stronger risk factor for
CVT in men than in women. The most likely explanation for
this discrepancy is the difference in absolute incidence of
CVT, which is 2.5 higher in women than in men.1 If anemia adds a similar absolute risk for CVT to the baseline risk
in both sexes, the relative risk associated with anemia will
be higher in the group with a lower absolute baseline incidence (ie, men).20 Another contributing factor could be that
men with CVT more often have an infection or a recent operation as a risk factor, and these conditions are also associated
with anemia.4 Finally, a lower risk of CVT among women
with anemia might be related to the high prevalence of female
patients who used oral contraceptives. Oral contraceptives are
a well-known risk factor for CVT.21 Some studies have found
that these drugs also decrease the risk of anemia, which could
result in a lower prevalence of anemia among women with
CVT.22,23 However, we adjusted for oral contraceptive use in
our analysis, which makes this last explanation less plausible.
Although our study shows an association between anemia and CVT, this finding does not necessarily imply a causal
relationship. Anemia could be an epiphenomenon of another
underlying prothrombotic condition for which we were unable
to adjust. Inflammatory bowel disease, infections, and neurosurgery, for instance, are all established risk factors for both
CVT and anemia.11,24 Because information on these conditions was not available for controls, we could not include
them in the multivariate model. To account for this limitation,
we did a subgroup analysis in which we excluded cases with

any of these conditions. Although attenuated, the association

between CVT and anemia remained clinically relevant and
statistically significant in this analysis. Nevertheless, we cannot exclude the possibility that other residual confounders had
an effect on the analysis.
If a causal relation exists between anemia and CVT, it is
interesting to speculate about the pathogenesis. Anemia, especially when caused by iron deficiency, can sometimes lead to
thrombocytosis, which is a risk factor for venous thrombosis.25,26 This mechanism would be in line with the fact that we
observed a stronger association between CVT and microcytic
anemia because iron deficiency is the most important cause
of microcytic anemia. Unfortunately, thrombocytes were not
measured in the MEGA study, and thus we could not examine whether the presence of thrombocytosis modified the
association between anemia and CVT. Iron deficiency has
also been associated with an increased concentration of factor VIII, which is also a risk factor for thrombosis.27 On the
contrary, if either of these hypotheses were correct, anemia
should probably also increase the risk of venous thromboembolism (deep-vein thrombosis of the leg and pulmonary
embolism). Although there is some evidence supporting an
association between venous thromboembolism and anemia,28
anemia is generally not considered to be a risk factor for this
condition.29,30
It is uncertain if the results of our study can be extrapolated to pediatric CVT. Children with CVT have other risk factors than adults, with an over-representation of infections and
dehydration.31 A previous study indicated that there may also
be an association between iron deficiency anemia and CVT in
children, but this study included only 6 patients with CVT.32
Our data also suggest that increased hemoglobin is associated
with CVT. Causes of increased hemoglobin include dehydration and polycythemia vera, both of which have been reported
in patients with CVT.31,33 However, the degree of uncertainty
of this observation is high because there was only 1 case with
increased hemoglobin, and a larger sample size is required to
confirm this finding.
Several limitations of our study warrant comment. First,
although all cases were enrolled in a prospective study, the
association between anemia and CVT was not a predefined
research question. As a result, hemoglobin concentrations
were missing in a small proportion (3%) of cases. Also,
laboratory data that would have been helpful in determining
the cause of anemia, such as ferritin, folic acid, and vitamin
B12, were not available. However, we were able to categorize anemia according to MCV values, which provides a crude
indication of the underlying cause. Second, cases and controls were not recruited in the same time period. The MEGA
study recruited control individuals between 1999 and 2004,
whereas the CVT cases were collected from 2006 to 2014.
If the prevalence of anemia increased in those years, it could
have biased the results. However, it seems unlikely that the
extent of such a change in prevalence in such a short time
period could be large enough to fully explain our findings. In
fact, there is evidence that the prevalence of anemia among
healthy women has decreased in the past decades.34 Third, it
would have been interesting to examine whether the association between anemia and CVT was influenced by the presence

Coutinho et al Anemia and Cerebral Venous Thrombosis 2739

of thrombophilia. Unfortunately, this analysis was not possible because routine testing for thrombophilia was not done in
cases. Finally, we were unable to calculate an adjusted OR for
severe anemia because none of the controls had severe anemia.
The fact that 4 of the 152 cases had severe anemia, compared
with zero of the 3000 controls, indicates an association, but
severe anemia may have been under-represented in controls.
Severe anemia often leads to symptoms, and this may lead
to reluctance to participate in a medical research study as a
control subject. Still, even if severe anemia is a risk factor for
CVT, our data suggest that it is not a common risk factor.
In summary, we found that anemia is associated with the
occurrence of CVT. Anemia is a risk factor for both sexes, but
the association was stronger in men than in women.

Sources of Funding
Downloaded from http://stroke.ahajournals.org/ by guest on November 15, 2016

Dr Coutinho was supported by The Netherlands Organisation for

Scientific Research, grant number 021.001.045 and the Dutch
Thrombosis Society, grant number 2012-2.

Disclosures
Dr Coutinho received a lecturing fee from Boehringer Ingelheim,
which was donated to the Stichting Klinische Neurologie, a local
foundation that supports research in the field of neurological disorders. The other authors report no conflicts.

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Association Between Anemia and Cerebral Venous Thrombosis: CaseControl Study

Jonathan M. Coutinho, Susanna M. Zuurbier, Aafke E. Gaartman, Arienne A. Dikstaal, Jan
Stam, Saskia Middeldorp and Suzanne C. Cannegieter
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Stroke. 2015;46:2735-2740; originally published online August 13, 2015;

doi: 10.1161/STROKEAHA.115.009843
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