Kudielka B.M., Bellingrath S. & von Känel R. (2008):
Circulating fibrinogen but not D-dimer level is associated with vital exhaustion in school teachers.
Published in: Stress, 11:250-258.
Circulating fibrinogen but not D-dimer level is associated
with vital exhaustion in school teachers
BRIGITTE M. KUDIELKA, SILJA BELLINGRATH, & ROLAND VON KANEL
Meta-analyses have established elevated fibrinogen and D-dimer levels in the circulation as biological risk factors for the
development and progression of coronary artery disease (CAD). Here, we investigated whether vital exhaustion (VE), a
known psychosocial risk factor for CAD, is associated with fibrinogen and D-dimer levels in a sample of apparently healthy
school teachers. The teaching profession has been proposed as a potentially high stressful occupation due to enhanced
psychosocial stress at the workplace.
Plasma fibrinogen and D-dimer levels were measured in 150 middle-aged male and female teachers derived from the first
year of the Trier-Teacher-Stress-Study. Log-transformed levels were analyzed using linear regression. Results yielded a
significant association between VE and fibrinogen (p = 0.02) but not D-dimer controlling for relevant covariates. Further
investigation of possible interaction effects resulted in a significant association between fibrinogen and the interaction term
"VE X gender" (p = 0.05). In a secondary analysis, we reran linear regression models for males and females separately.
Gender-specific results revealed that the association between fibrinogen and VE remained significant in males but not females.
In sum, the present data support the notion that fibrinogen levels are positively related to VE. Elevated fibrinogen might be
one biological pathway by which chronic work stress may impact on teachers' cardiovascular health in the long run.
Keywords: D-dimer, fibrinogen, hemostasis, teacher, Trier-Teacher-Stress-Study, vital exhaustion
Increased circulating levels of fibrinogen, an acute
phase reactant and procoagulant molecule in the
process of hemostasis (Herrick et al. 1999), has been
established as an important and independent risk
factor for cardiovascular morbidity (and mortality),
like coronary artery disease (CAD), atherosclerotic
vascular disease (AVD), myocardial infarction or
(ischemic) stroke (Markovitz and Matthews 1991;
Ernst and Resch 1993; Danesh et al. 1998; Maresca
et al. 1999; Hackam and Anand 2003; Koenig 2003;
Faxon et al. 2004; Fibrinogen Studies Collaboration
2005). The circulating glycoprotein fibrinogen is
synthesized in the liver, acts at the final step in the
coagulation response to vascular and tissue injury and
is transformed by thrombin into fibrin that is the main
component of a thrombus. Besides its role in
thrombosis, other functions of fibrinogen are poten-
tially relevant for onset and progression of cardiovas-
cular syndromes (Hackam and Anand 2003), such as
regulation of cell adhesion, chemotaxis and prolifer-
ation; vasoconstriction at sites of vessel wall injury;
stimulation of platelet aggregation; and determination
of blood viscosity. In the hemostastic process,
enhanced fibrin turnover is indicated by high levels
of D-dimer, which demonstrates activation of both
coagulation (ongoing thrombus formation) and
fibrinolysis (von Kanel 2007). High circulating D-
dimer levels are a marker for a hypercoagulable
state and have been shown to be an independent
predictor of CAD and have proved useful as an early
diagnostic marker for CAD (Lip and Lowe 1995;
Bayes-Genis et al. 2000; Danesh et al. 2001).
In addition to the classical cardiovascular risk
factors for heart diseases (e.g. hypertension, hyper-
cholesterolemia, impaired fasting glucose and dia-
betes, obesity, adverse health behaviors including
smoking and a sedentary lifestyle) (Danesh et al. 1998;
Hackam and Anand 2003; Faxon et al. 2004; Coban
et al. 2005), psychological factors like acute and
chronic stress may also contribute to the development
and progression of heart diseases (Rozanski et al.
1999, 2005; von Kanel et al. 200Ib, 2007; Rosengren
et al. 2004; Strike and Steptoe 2004; Bhattacharyya
and Steptoe 2007; Thrall et al. 2007). A psychological
state that is viewed as a potential consequence of long-
term, chronic stress is vital exhaustion (VE). VE is
characterized by unusual fatigue, loss of mental and
physical energy, increased irritability and a feeling of
demoralization (Kop 1999; Appels 2004). Epidemio-
logical studies accumulated evidence that VE is an
independent risk factor for cardiovascular disease
(Kop 1999; Prescott et al. 2003; Appels 2004). Such
findings led to the hypothesis that elevated fibrinogen
and D-dimer levels might be possible biological
links between VE and the onset and progression of
heart diseases. There is a paucity of data on the
relationship between fibrinogen, and especially D-
dimer and VE in different populations. Van Diest et
al. (2002) observed significantly higher fibrinogen
levels in 29 vitally exhausted men compared to 30
controls, while Kop et al. (1998) could not observe
differences in fibrinogen concentrations in a smaller
sample of 15 men with VE versus 15 otherwise healthy
controls. Also in an exclusively male sample of 231
subjects with and without coronary heart disease
Lahlou-Laforet et al. (2006) found higher fibrinogen
levels in exhausted men than in those who were not
exhausted. In a large scale epidemiological study
comprising 1645 men and 2623 women aged >65
years and at risk for incident cardiovascular disease,
VE as measured by an abridged instrument was
significantly associated with fibrinogen concentrations
in both genders (Kop et al. 2002). Recently, Toker
et al. (2005) investigated fibrinogen levels in 630
women and 933 men with respect to burnout, a
concept closely related to VE. The authors found that,
after controlling for depression, a significant associ-
ation between fibrinogen and burnout emerged in
women but not in men, pointing to the possibility of a
gender-specific association. As regards D-dimer, von
Kanel et al. (2004a) could not find a relationship with
VE in a predominantly male sample of industrial
workers. Though, in other studies D-dimer level was
found to be increased in subjects with panic-like
anxiety (von Kanel et al. 2004b) and in chronically
stressed Alzheimer caregivers compared to controls
(von Kanel et al. 2006).
The present sample is composed of male and female
school teachers. This population was selected since
there appears to be an increased risk of emotional
exhaustion in the teaching profession (Guglielmi and
Tatrow 1998). With this report, we aimed to
contribute to the question whether VE is related to
circulating fibrinogen and D-dimer levels in chroni-
cally stressed but otherwise healthy individuals. Such
an association could help explain the recently reported
increase in the cardiovascular disease risk in individ-
uals suffering from burnout syndrome (Honkonen
et al. 2006; Melamed et al. 2006).
Sample recruitment and study protocol
Teachers of all major school types were approached by
personal visits in local schools and by newspaper
announcements in the region of Trier (Germany) and
Luxembourg. Volunteers with psychiatric disorders,
medicated with corticosteroids or psychotropic drugs, a
history of cancer, artery disease or heart failure, serious
endocrine diseases (including diabetes, polycystic
ovarian syndrome), or pregnant women were not
included. Demographics (gender, age, years of employ-
ment, type of school) and current health status (acute
and chronic diseases, medication intake) were assessed
during a telephone screening in eligible subjects.
After the telephone screening, participants received
questionnaires via postal mail for the psychometric
assessment of VE and depressive symptoms (see
below). After an overnight fast, they were invited to an
early morning laboratory visit (i.e. before school),
which included the assessment of health behaviors
(smoking status, alcohol consumption, physical
activity), anthropometric measures (body-mass-
index BMI, resting blood pressure) and a venous
blood draw for the measurement of fibrinogen, D-
dimer, total cholesterol and glucose levels. At the end
of the laboratory appointment, participants received
saliva sampling materials for ambulatory assessment
of cortisol day profiles (to be reported by Bellingrath
et al. in press). The ethics committees of the State
Medical Association of Rheinland Pfalz and the
University of Trier approved the study protocol. All
participants provided written informed consent and
were paid 50 Euros as an incentive after completion of
VE was measured using a German version of the
9-item short form of the original Maastricht VE
Questionnaire (Appels et al. 1987) as used in previous
studies (Kudielka et al. 2006, 2007). Items ask about
unusual fatigue, a disturbed sleeping pattern, general
malaise, irritability, a loss of mental and physical
energy and feelings of demoralization. Possible
answers are "no", which results in a score of 0,
indeterminate, which is marked as "?" and scored as 1;
and "yes", scored as 2. This answering format gives
rise to a range of a total VE score between 0 and 18.
Scores from 0 to 3 indicate "no exhaustion", scores
from 4 to 10 are equivalent to "mild to moderate
exhaustion" and scores from 11 to 14 reflect
"substantial exhaustion", whereas scores > 14 are
consistent with "severe exhaustion". Cronbach's
alpha was 0.87, reflecting good reliability.
Depressive symptoms were assessed by the
German version of the depression subscale of the
Hospital Anxiety and Depression Scale (HADS)
(Herrmann 1997) consisting of seven items. Answers
are coded on a 4-point Likert scale ranging from
0 = not at all to 3 = mostly, giving rise to a range of
a total depression score between 0 and 21. In the
German normative sample (N = 6200) Cronbach's
alpha is 0.81.
With respect to the interrelationship between VE
and depressive symptomatology, we recently showed
in a sample of 822 employees (using the same
questionnaires as in the present study) that both
concepts are significantly interrelated but constitute
distinct psychological constructs (Kudielka et al.
All biological data were determined by a commercial
laboratory (Synlab, Trier, Germany). Venous blood
was collected either into citrate tubes for fibrinogen
and D-dimer or into serum tubes not containing
anticoagulants for total cholesterol and fasting
glucose (Sarstedt, Niimbrecht, Germany). After
blood withdrawal, citrate tubes were instantaneously
stored on ice; all samples were centrifuged immedi-
ately at 4°C for 15 min at 2000g in an adjacent room
and pipetted into aliquots. Within 60 min, aliquots
were transferred to the core lab (Synlab) and
processed immediately. Plasma fibrinogen levels
were determined by a routine clotting assay following
the Clauss method (Clauss 1957). Precision was
between 2.1 and 4.3% (intra assay variability) and
3.7-6.1% (inter assay variability); the upper limit of
detection was 10 g/1. D-dimer levels were analyzed by
an enzyme-linked immuno-fluorescence assay
(VIDAS® D-Dimer Exclusion™). Precision was
between 3.9 and 5.3% (intra assay variability) and
5.8-7.1% (inter assay variability); lower and upper
limits of detection were 0.05 and 10|jig/ml, respect-
ively. Total cholesterol and glucose (hexokinase
method) concentrations were analyzed by a kinetic
enzymatic UV-assay using an autoanalyzer (Olympus
AU 640 + AU 2700, Olympus). For total choles-
terol, precision was between 0.8 and 0.9% (intra
assay variability) and 1.0-2.0% (inter assay varia-
bility); for glucose, precision was between 1.1 and
1.2% (intra assay variability) and 0.8-1.3% (inter
assay variability). Lower and upper limits of detection
for total cholesterol were 25 and 700 mg/dl, respect-
ively and 10 and 800 mg/dl for glucose.
Statistical analyses were performed using SPSS 13.0
for Windows (Chicago, IL, USA). The significance
level was set at£ < 0.05 and all testing was two-tailed.
Data are presented as means ± SD. Body-mass-index
(BMI) was defined as kg/m2; mean arterial blood
pressure (MAP) was ((2 X diastolic blood pressure)
+ systolic blood pressure)/3. Medical data (MAP, total
cholesterol, glucose, fibrinogen and D-dimer levels)
were logarithmically transformed to obtain a normal
distribution. In a first step, univariate analyses were
carried out using Spearman correlation and Student's
t-test. In a second step, linear regression was used to
analyze the association between fibrinogen levels
(dependent variable) and VE (predictor) after adjust-
ment for covariates. D-dimer levels were analyzed
accordingly. We controlled for gender, age, BMI,
seasonality (month of laboratory visit), tobacco
smoking status (yes/no), alcohol consumption (num-
ber of days alcohol was consumed in a typical week),
physical activity (physical exercise per week in hours),
MAP, total serum cholesterol, fasting serum glucose
and depressive symptomatology (HADS-depression
scale) (Folsom et al. 1991). In subsequent linear
regression models, the interaction terms "VE X
gender" and "VE X age" were additionally included
to investigate possible interaction effects. Finally, we
reran linear regression models separately in males and
females for fibrinogen levels. Here, we first controlled
for the full set of covariates. Then we controlled (a) for
the five covariates that rendered significant associ-
ations with fibrinogen level in univariate analysis,
namely age, BMI, smoking status, MAP and total
cholesterol (Table II) and (b) for the five covariates that
showed significant associations with fibrinogen level in
the linear regression analysis in the total sample
(Table III), namely age, BMI, seasonality (trend), total
cholesterol (trend) and fasting serum glucose level to
prevent model overfitting by inclusion of too many
covariates given our sample size of 101 females and 49
males (Babyak 2004). The test power (1 - /3), which
reflects the probability of finding an effect in the data
when the effect actually exists in the "real world", was
calculated using the software GPower3 by Paul et al.
(2007) which can be downloaded from http://www.
Table I. Demographic and medical data of 150 teachers studied (mean ± SD).
Age in years (range)
Years of employment
Type of school (A/)
Primary/elementary school ("Grundschule")
Basic-level secondary school ("Hauptschule")
Secondary school ("Realschule") Grammar
school ("Gymnasium") Comprehensive
school ("Gesamtschule") Vocational school
("Berufsbildende Schule") Not further
Smoking yes/no (A?)
Mean arterial blood pressure (MAP; mmHg)
Total serum cholesterol (mg/dl)
Fasting serum glucose (mg/dl)
Plasma fibrinogen (g/1)
Plasma D-dimer (|j,g/ml) (N— 149)
HADS-depression score (range)
VE score (range)
45.5 ± 9.9 (23-63)
18.2 ± 11.2
25.2 ± 4.4
97.2 ± 13.0
208.3 ± 40.3
95.2 ± 11.8
3.9 ± 0.7
0.27 ± 0.2
4.6 ±3.9 (0-19)
8.6 ± 5.5 (0-18)
Normal range*: < 200
Normal range*: 74-106
Normal range*: 1.80-3.50
Normal range*: 0.00-0.50
Normal range as provided by the laboratory (Synlab, Trier, Germany).
Data were complete in N= 150 apparently healthy
employed teachers, except for one missing data point
for D-dimer levels. Demographics, medical data and
questionnaire scores of the 101 women and 49 men
are shown in Table I.
First, we tested bivariate associations between
fibrinogen level and VE score as well as traditional
risk factors and covariates using Student's r-test and
Spearman correlation. Results are shown in Table II.
Linear regression with the dependent variable
fibrinogen level and the VE score as predictor revealed
a significant association (p = 0.02) after controlling
for covariates, explaining 3% of the observed variance
by VE score. R 2 for the full model was 0.29. Results of
the full linear regression model are shown in Table III.
Subsequent linear regression models additionally
including the interaction terms VE X gender or
VE X age revealed a significant relationship for VE X
gender (p = 0.05; see Table III) but not for VE X age
(p > 0.59). In a final step, we computed separate
linear regression models for males and females. In the
female subsample, the association between the VE
score and fibrinogen level was not significant when
controlling for the full set of covariates (p > 0.3), as
well as for the models with reduced sets of covariates
(both p > 0.6). In the male subsample, however, the
association between the VE score and fibrinogen level
rendered significance controlling for the reduced sets
of covariates (both Std.fi > 0.38 both t > 3.2 both
Table II. Bivariate associations between plasma fibrinogen level and traditional risk factors or covariates.
Plasma fibrinogen (g/1)
VE score < 10:
2.9 ± 0.6
3.3 ± 0.8
3.1 ± 0.8
2.8 ± 0.6
3.2 ± 1.0
3.0 ± 0.7
£(148) = 3.54, p = 0.001
VE score > 10:
£(148) = 2.78, p = 0.006
£(148) = -0.99,p> 0.3
Seasonality (month of lab visit)
Alcohol consumption (days consumed alcohol in typical week)
Physical activity (physical exercise per week in hours)
Mean arterial blood pressure (MAP; mmHg)
Total serum cholesterol (mg/dl)
Fasting serum glucose (mg/dl)
r= 0.26, p = 0.002
r = 0.33, p = 0.001
r = 0.17, p = 0.03
r = 0.24, p = 0.003
r = 0.24, p = 0.003
Statistics are based on log-transformed levels for fibrinogen, MAP, total serum cholesterol and fasting serum glucose levels.
Table III. Linear regression analyses in the total study sample (N
— 150) with the dependent variable plasma fibrinogen level, the
predictor VE score and covariates.
with the dependent variable D-dimer level and VE
score as predictor revealed no significant association
for VE score (p > 0.40) after controlling for covari-
ates. In the full regression model, only gender
(£ = 0.03), age (£ = 0.02) and BMI (£ = 0.01)
reached significance. Inclusion of interaction terms
did not reveal any significant interaction effects (both
£ > 0.65). Finally, post-hoc analyses of the test power
(1 — /3) showed that the probability of revealing a
significant association between the VE score and D-
dimer level in the full linear regression was >99%
given big or medium sized effects of interest (effect
sizes /2 = 0.35 and /2 = 0.15 according to Cohen's
criteria) but 41% for small effect sizes (/2 = 0.02),
respectively. This shows that the given /3-error was
satisfactorily low for medium to big but not small
effect sizes. A sensitivity power analysis showed that an
effect size off = 0.09 (or/ = 0.05) could have been
detected if the /3-error was fixed to 95% (or 80%).
A secondary regression model additionally included the interaction
term VE X gender; only significant results are shown; statistics are
based on log-transformed levels for plasma fibrinogen level, MAP,
total serum cholesterol and fasting serum glucose level.
p < 0.003) and approached significance for the full
set of covariates (Std./3 = 0.29, t > 1.7, £ = 0.10).
Figure 1 illustrates the bivariate correlation between
the VE score and fibrinogen level separately in females
(r = ns) and males (r = 0.45, p = 0.001).
For D-dimer level, significant bivariate associations
emerged for age (r=0.27, p< 0.001), BMI
(r=0.30, p< 0.001), MAP (r=0.17, p < 0.05)
and fasting serum glucose (r = 0.20, p < 0.02). No
significant differences in D-dimer level emerged
between males and females, neither between smokers
and non-smokers nor between subjects with a VE
score < 10 and > 10 (all p > 0.28). Linear regression
This study further elucidated whether heightened
circulating fibrinogen and D-dimer levels might be
plausible biological links between chronic stress and
CAD. We assessed chronic stress in terms of VE in 150
male and female school teachers since the teaching
profession has been proposed as a potentially highly
stressful occupation (Guglielmi and Tatrow 1998). In
sum, we confirmed findings of a modest association
between VE score and the level of the procoagulant
molecule fibrinogen but not D-dimer. These findings
are consistent with earlier reports from predominantly
male samples (Kop et al. 2002; van Diest et al. 2002;
von Kanel et al. 2004a; Lahlou-Laforet et al. 2006).
We also showed that the association between the VE
score and fibrinogen level was retained independently
of a set of traditional cardiovascular risk factors. In
accordance with Toker et al. (2005) who strongly
Figure 1. Scatterplots illustrating the association between plasma fibrinogen levels (g/1) and VE score separately in females (N — 101) and
males (N — 49); statistics are based on log-transformed fibrinogen levels.
argued for the control for depression, our set of
control variables also included depressive symptoma-
tology as an important psychosocial risk factor of
CAD (Rozanski et al. 1999; von Kanel et al. 200la;
Rosengren et al. 2004; Strike and Steptoe 2004;
Bhattacharyya and Steptoe 2007). In contrast to these
previous studies, our sample of potentially stressed
school teachers was composed of males (N = 49) as
well as females (N = 101). This meets the claim by
Vorster (1999) to also include women in studies on
fibrinogen and health because women have largely
been neglected in earlier studies.
Interestingly, we found a significant interaction
between the VE score and gender for the association
between the VE score and fibrinogen level.
A secondary analysis stratified by gender revealed
that the association was significant in the male but not
in the female subsample. Earlier studies on a
relationship between fibrinogen levels and burnout
(Toker et al. 2005) and job conditions in terms of
Karasek's job-demand-control model (Tsutsumi et al.
1999; Kittel et al. 2002) already raised the idea of
gender-specific associations. However, findings are
not uniform. Toker et al. (2005) found a significant
association between burnout and fibrinogen levels in
women but not in men (after controlling for
depression). In the SHEEP study, Tsutsumi et al.
(1999) concluded that the relation between adverse
job characteristics and plasma fibrinogen concen-
trations might be more relevant in female workers.
Using multiple logistic regression, they found that
men in the job strain group had an increased risk of
falling into the increased plasma fibrinogen concen-
tration group while in women, low self-reported
control, high demand and job strain were significantly
associated with increased plasma fibrinogen concen-
trations. More in line with the present results, Kittel
et al. (2002) found a significant association between
higher levels of job strain and plasma fibrinogen in
males but not in females in the BELSTRESS study.
Only after stratification for educational level, was
there a positive association observed between psycho-
logical job demands or job strain and plasma
fibrinogen levels in males (in the lowest educational
level) and job strain and plasma fibrinogen in females
(in the middle educational level). Notably, the
educational level as well as socioeconomic status was
relatively high and homogeneous in our sample of
school teachers. Finally, our finding of a significant
association between fibrinogen and VE in men but not
women could partially explain recent observations
by Honkonen et al. (2006). In a representative
nationwide population health survey, they examined
the relationship between burnout and physical illness
in Finland and found that burnout is associated with
musculoskeletal diseases among women and with
cardiovascular diseases among men. Our results could
point to one potential biological pathway underlying
their findings. One might speculate that such gender
differences might be related to differences in the
importance of life roles in men and women (Cinamon
and Rich 2002). For example, in the Stockholm
Female Coronary Risk Study (Orth-Gomer 2007), it
was found that marital stress and stressful conditions
in family life were stronger predictors of heart disease
in women than stress at work, though work stress had
also been established as an important risk factor for
cardiovascular disease in women as well as in men.
Our findings are in line with reports on biological
links between VE and CAD focusing on other
parameters of the hemostasis process. For example,
several studies report on positive associations between
VE and plasminogen activator inhibitor 1 (PAI-1)
(Raikkonen et al. 1996; Kop et al. 1998; van Diest
et al. 2002; von Kanel et al. 2004a; Lahlou-Laforet
et al. 2006). Elevated PAI-1 levels under chronic stress
point to a reduced fibrinolytic capacity, which may
facilitate atherothrombotic conditions. Since we did
not observe a relationship between VE and D-dimer
levels, which concurs with a finding by von Kanel et al.
(2004a), it might be speculated that unchanged D-
Dimer levels indicate that VE does not necessarily
result in enhanced fibrin turnover. From this, one
could further hypothesize that VE is associated with
the increase in an individual clotting factor (i.e.
fibrinogen), yet this increase might not be sufficient to
lead to overall coagulation activation as reflected by
the lack of an association between VE and D-dimer
We acknowledge that the clinical relevance of the
3% of the variance in fibrinogen accounted for by VE
remains somewhat unclear. As suggested by
Kop (1999), the impact of exhaustion on fibrinogen
might have been greater if participants had been more
exhausted. While 94 of our subjects scored between 0
and 10 in the VE questionnaire, indicating no to
moderate exhaustion, 56 subjects scored above 11,
indicating substantial to severe exhaustion; no subject
was on sick leave or had clinical treatment due to
exhaustion. It is noteworthy, however, that the VE
score correlated with fibrinogen level at least as highly
as some of the cardiovascular risk factors like MAP,
total serum cholesterol and even age (Table II). Only
BMI showed a somewhat higher univariate association
with fibrinogen levels. In accordance, in multiple
regression analysis we found a higher beta weight for
BMI compared to the contribution of the VE score,
although comparable beta weights emerged for age
and fasting serum glucose levels. A clinical signifi-
cance of our findings might be assumed based on
earlier reports from the PROCAM study and two
meta-analyses published by Danesh and coworkers. In
our study, fibrinogen levels differed by 0.4 g/1 between
subjects with no to moderate VE score versus subjects
with substantial to severe VE score (Table II). In the
PROCAM study, the predictive power of hemostatic
variables was assessed for coronary risk in healthy
men. At 6-year follow-up, the mean plasma fibrinogen
level of the coronary event group (82 events in 2116
screened participants) exceeded that of the non-event
groups by 0.25 g/1 (Heinrich et al. 1994); at the 8-year
follow-up, the difference was 0.32 g/1 between the
non-event and event group (130 events in 2781
screened participants) (Assmann et al. 1996). Danesh
et al. (1998) conducted a meta-analysis of published
data from 18 studies, involving approximately 4000
cases of CAD and found a relative risk of 1.8 (95%
confidence interval CI 1.6-2.0) per 1 g/1 increase in
plasma fibrinogen. More recently, the Fibrinogen
Studies Collaboration (2005) conducted another large
and comprehensive meta-analysis, which comprised
6944 first non-fatal myocardial infarction or stroke
events and 13,210 deaths; cause-specific mortality
information was available among 1,54,211 partici-
pants derived from 31 different studies. Interestingly,
there was no evidence of a threshold within the range
of usual fibrinogen levels studied at any age. The age-
and sex-adjusted hazard ratio per 1 g/1 increase in
usual fibrinogen levels was 2.42 (95% CI 2.24-2.60)
for CAD, 2.06 (95% CI, 1.83-2.33) for stroke, 2.76
(95% CI, 2.28-3.35) for other vascular mortality and
2.03 (95% CI, 1.90-2.18) for non-vascular mortality.
An important limitation of our study is its cross-
sectional design, which does not allow for any causal
inferences. Furthermore, although our study sample is
larger than some earlier reports on VE and fibrinogen
levels (Kop et al. 1998; van Diest et al. 2002), our
sample size was limited, especially with respect to men.
However, it can be regarded as a strength that our study
sample comprised a significant number of women
(Vorster 1999). Furthermore, we did not include any
clinical cases of exhaustion, but recruited working
teachers with a homogeneous level of educational and
socioeconomic status, which in turn can also be
regarded as a strength. Unfortunately, we did not assess
poor dental status which has previously been shown to
be associated with increased fibrinogen levels (Beck
et al. 1998). Furthermore, periodontitis was suggested
as another risk factor for coronary heart disease.
Finally, analyses of the test power confirmed that the
probability of revealing an association between D-
dimer levels and VE score was very high (1 — /3 > 99%
for medium and big effects). The sensitivity analysis
underlined that at least an effect with an effect size of
/2 = 0.09 (medium to low) could have been discovered
within the present sample giving a test power of 95%.
In clinical terms, our data may suggest that a
reduction in chronic stress by psychological interven-
tion might be suitable to reduce coronary risk by
decreasing fibrinogen levels. Recently, Claesson et al.
(2006) conducted a stress management program
designed specifically for women with CAD to test
whether an improvement in psychosocial well-being is
associated with an improvement in biochemical
indicators of cardiovascular risk. This controlled
study randomized 80 women to a 1-year cognitive-
behavioral stress reduction program and 86 women to
usual care. Although the program was successful in
reducing self-rated stress behavior and VE, the
changes in psychosocial variables were not associated
with changes in any of the biological risk indicators,
including fibrinogen, PAI-1 and other hemostatic
factors. This challenges the proposition that the
relationship between psychological well-being and
biological cardiovascular risk indicators is a direct
In summary, studying a sample of 150 male and
female school teachers, we found that higher levels of
VE were independently associated with higher
circulating levels of fibrinogen but not with D-dimer
levels. In gender-specific analysis, this effect remained
significant in men but not women. From this, our
findings corroborate the hypothesis that altered
hemostasis might be one possible biological pathway
by which chronic psychological stress might negatively
impact on teachers' cardiovascular health in the
This study was supported by Emmy Noether research
grant KU 1401/4-1 and KU 1401/4-2 of the German
Research Foundation (DFG) awarded to Brigitte
M. Kudielka. BMK and SB are members of the
International Research Training Group IRTG funded
by the DFG (GRH 1389/1).
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