Independent Association Between Lower Level of Social Support and Higher Coagulation Activity Before and After Acute Psychosocial Stress
To investigate the relationship between social support and coagulation parameter reactivity to mental stress in men and to determine if norepinephrine is involved. Lower social support is associated with higher basal coagulation activity and greater norepinephrine stress reactivity, which in turn, is linked with hypercoagulability. However, it is not known if low social support interacts with stress to further increase coagulation reactivity or if norepinephrine affects this association. These findings may be important for determining if low social support influences thrombosis and possible acute coronary events in response to acute stress. We investigated the relationship between social support and coagulation parameter reactivity to mental stress in men and determined if norepinephrine is involved. We measured perceived social support in 63 medication-free nonsmoking men (age (mean +/- standard error of the mean) = 36.7 +/- 1.7 years) who underwent an acute standardized psychosocial stress task combining public speaking and mental arithmetic in front of an audience. We measured plasma D-dimer, fibrinogen, clotting Factor VII activity (FVII:C), and plasma norepinephrine at rest as well as immediately after stress and 20 minutes after stress. Independent of body mass index, mean arterial pressure, and age, lower social support was associated with higher D-dimer and fibrinogen levels at baseline (p < .012) and with greater increases in fibrinogen (beta = -0.36, p = .001; DeltaR(2) = .12), and D-dimer (beta = -0.21, p = .017; DeltaR(2) = .04), but not in FVII:C (p = .83) from baseline to 20 minutes after stress. General linear models revealed significant main effects of social support and stress on fibrinogen, D-dimer, and norepinephrine (p < .035). Controlling for norepinephrine did not change the significance of the reported associations between social support and the coagulation measures D-dimer and fibrinogen. Our results suggest that lower social support is associated with greater coagulation activity before and after acute stress, which was unrelated to norepinephrine reactivity.
Independent Association Between Lower Level of Social Support and Higher
Coagulation Activity Before and After Acute Psychosocial Stress
PETRA H. WIRTZ,PHD, LAURA S. REDWINE,PHD, ULRIKE EHLERT,PHD, AND ROLAND VON KA¨ NEL,MD
Objective: To investigate the relationship between social support and coagulation parameter reactivity to mental stress in men and
to determine if norepinephrine is involved. Lower social support is associated with higher basal coagulation activity and greater
norepinephrine stress reactivity, which in turn, is linked with hypercoagulability. However, it is not known if low social support interacts
with stress to further increase coagulation reactivity or if norepinephrine affects this association. These findings may be important for
determining if low social support influences thrombosis and possible acute coronary events in response to acute stress. We investigated
the relationship between social support and coagulation parameter reactivity to mental stress in men and determined if norepinephrine is
involved. Methods: We measured perceived social support in 63 medication-free nonsmoking men (age (mean ⫾ standard error of the
mean) ⫽ 36.7 ⫾ 1.7 years) who underwent an acute standardized psychosocial stress task combining public speaking and mental
arithmetic in front of an audience. We measured plasma D-dimer, fibrinogen, clotting Factor VII activity (FVII:C), and plasma
norepinephrine at rest as well as immediately after stress and 20 minutes after stress. Results: Independent of body mass index, mean
arterial pressure, and age, lower social support was associated with higher D-dimer and fibrinogen levels at baseline (p ⬍ .012) and with
greater increases in fibrinogen (
⫽⫺0.36, p ⫽ .001; ⌬R
⫽ .12), and D-dimer (
⫽⫺0.21, p ⫽ .017; ⌬R
⫽ .04), but not in FVII:C
(p ⫽ .83) from baseline to 20 minutes after stress. General linear models revealed significant main effects of social support and stress on
fibrinogen, D-dimer, and norepinephrine (p ⬍ .035). Controlling for norepinephrine did not change the significance of the reported
associations between social support and the coagulation measures D-dimer and fibrinogen. Conclusions: Our results suggest that lower
social support is associated with greater coagulation activity before and after acute stress, which was unrelated to norepinephrine
reactivity. Key words: social support, coagulation, clotting factor VII:C, D-dimer, fibrinogen, psychological stress.
CVD ⫽ cardiovascular disease; ACS ⫽ acute coronary syndromes;
BMI ⫽ body mass index; MAP ⫽ mean arterial pressure; BP ⫽
blood pressure; SD ⫽ standard deviation; AUC ⫽ area under the
curve; TSST ⫽ Trier Social Stress Test; FVII:C ⫽ clotting Factor
VII activity; FVIII:C ⫽ clotting Factor VIII activity.
ocial support is a context-specific advocative interpersonal
process centered on the reciprocal exchange of information
on one or more of the following three classes: information
leading the person to believe that he or she (1) is cared for and
loved (2), esteemed and valued (3), and belongs to a network
of communication and mutual obligation (1,2). In the litera-
ture, measures of perceived social support are more commonly
used than measures of received social support (3). Perceived
social support is conceptualized as the subjective appraisal of
the degree of match between the amount and type of support
needed and the amount and type of support available, or the
perception that support would be available if needed (3).
Accumulating evidence suggests that social support is asso-
ciated with health outcomes (2). For example, poor social support
prospectively increases the risk of coronary artery disease (CAD)
(3– 6) with a relative risk two- to three-fold and a robust effect
observed even after controlling for conventional (e.g., age, body
mass index (BMI), and high blood pressure (BP)), social, and
behavioral cardiovascular risk factors (4 –7).
Previous research addressed the biological pathways through
which low social support increases cardiovascular risk or, alter-
natively, high social support enhances health. Based on the ef-
fects of social support on physiological processes implicated in
cardiovascular disease, the so-called “social support-reactivity
hypothesis” has been proposed. This view posits that social
support maintains cardiovascular health by reducing psychobio-
logical reactivity to stressors, thereby acting as a “stress buffer-
ing” variable (8,9). Evidence suggests that, in healthy individuals,
social support attenuates psychological and physiological stress
responses as indexed by cardiovascular, autonomic, and hypo-
thalamo-pituitary-adrenal (HPA) responses (8,10 –13). In hyper-
tensive and normotensive middle-aged men, greater levels of
perceived social support were associated with reduced cat-
echolamines reactivity to acute psychosocial stress (14). Notably,
the accumulation of physiological hyperreactivity to stress
throughout a life span that may occur in individuals with low
social support has been proposed to enhance CAD risk (15–18).
Coagulation and fibrinolysis are implicated as stress-reac-
tive physiological systems important in the development of
CAD and acute coronary syndromes (ACS) (19). Patients
whose ACS had been triggered by intense emotions showed
greater platelet activation in response to psychological stress
compared with patients without emotion-triggering ACS (20).
In healthy individuals, acute mental stress activates both the
coagulation and the fibrinolysis components of hemostasis to
result in net hypercoagulability (19,21). Acute psychological
stress-induced increases in several hemostatic parameters,
such as clotting Factor VII activity (FVII:C), clotting Factor
VIII activity (FVIII:C) and FXII:C, thrombin-antithrombin
complex, fibrinogen, von Willebrand Factor, and D-dimer
levels, have been observed (19).
In contrast to stress effects, higher social support may
reduce coagulation activity. Greater social support as assessed
From the Department of Clinical Psychology and Psychotherapy (P.H.W.,
U.E.), University of Zurich, Switzerland; Department of Medicine (L.S.R.),
Cardiology Branch, University of California, San Diego, California; and the
Department of General Internal Medicine (R.v.K.), Bern University Hospital,
Inselspital, and University of Bern, Bern, Switzerland.
Address correspondence and reprint requests to Petra H. Wirtz, Department
of Clinical Psychology and Psychotherapy, University of Zurich, Binzmu¨-
hlestrasse 14, Box 26, CH-8050 Zurich, Switzerland. E-mail: p.wirtz@
Received for publication November 19, 2007; revision received July 3,
Supported by research Grants 56233203 and 56233204 from the University
of Zurich (P.H.W.) and by a research grant from the University of Bern
30 Psychosomatic Medicine 71:30–37 (2009)
Copyright © 2009 by the American Psychosomatic Society
via social integration, social isolation, and social network is
associated with lower amount of fibrinogen (22–27) even
when controlling for cardiovascular risk factors (22,24,26,27).
However, the role of social support as a buffer of acute stress
for hemostasis is not straightforward. In a small sample of 27
healthy middle-aged men, we recently did not find significant
associations between social support as assessed by the Ger-
man Social Support Questionnaire (F-SozU) and stress-in-
duced changes in coagulation parameters (28). However, in
that study, due to the small sample size, we did not control for
age, BMI, and BP. In contrast, a study by Steptoe and co-
workers assessed associations between social support mea-
sures and fibrinogen stress reactivity (27) and found higher
fibrinogen levels in socially isolated participants compared
with nonisolated participants before and after acute mild psy-
chological stress (27).
Catecholamines play a role in stress-induced hemostatic
changes because catecholamine infusion elicited hypercoagu-
lability in healthy persons (29). In addition, we recently found
associations between epinephrine and FVIII:C and between
norepinephrine and fibrinogen under resting conditions, inde-
pendent of age, BMI, and mean arterial pressure (MAP) in
middle-aged hypertensive and normotensive men (30). More-
over, in the same study, stress-induced changes in D-dimer were
predicted by norepinephrine stress change (30). In another study,
we found that the stress-induced increase in norepinephrine sig-
nificantly correlated with thrombin formation (31). However, it is
unknown whether lower social support is associated with greater
catecholamine stress reactivity, which in turn could induce hy-
percoagulability. More specifically, the role of norepinephrine in
stress-induced D-dimer changes in those with low social support
has not previously been examined.
The aim of this study was to extend previous research
investigating whether perceived social support is associated
with several coagulation parameter levels at rest and through-
out a potent acute psychosocial stressor in a sizeable group of
medication-free nonsmoking men. We hypothesized that
lower social support is associated with higher baseline
levels and greater increases in response to stress in the
coagulation measures fibrinogen and FVII:C, and the hy-
percoagulability marker D-dimer. Moreover, we examined
whether such associations were moderated or mediated by
The study is part of a project studying the biological response in general
and coagulation activation in particular to acute psychosocial stress in men as
previously described (32,33). Whereas our previous report addressed the
acute stress-induced increases of the coagulation parameters D-dimer and
fibrinogen in relationship to age (33), in the present study, we specifically
examined the relationship of social support to acute stress-induced coagula-
tion changes. In the present study, we also tested whether the relationship
between social support and coagulation activation to stress would be modu-
lated by norepinephrine.
The Ethics Committee of the State of Zurich, Switzerland, formally
approved the research protocol. Of the original 66 subjects, three persons had
to be excluded because of incomplete blood samples for coagulation param-
eters. The final study sample consisted of 63 subjects who provided their
written informed consent. The study was conducted between April 2004 and
August 2005. We intentionally recruited nonsmoking men between the ages
of 20 and 65 years who were in excellent physical and mental health
confirmed by an extensive health questionnaire (34) and telephone interview.
Specific exclusion criteria were obtained by the subjects’ self-report and were
as follows: regular strenuous exercise; alcohol and illicit drug abuse; any heart
disease, varicosis or thrombotic diseases; elevated blood sugar and diabetes;
elevated cholesterol, liver, and renal diseases; chronic obstructive pulmonary
disease; allergies and atopic diathesis, rheumatic diseases; and current infec-
tious diseases. In addition, participants were included only if they reported
taking no prescribed and/or over-the-counter medication, either regularly or
occasionally, and if their BP was in the normotensive or moderately hyper-
tensive range (systolic BP ⬍160 mm Hg and diastolic BP ⬍100 mm Hg).
When the personal or medication history was not conclusive, the subject’s
primary care physician was contacted for verification.
Assessment of Social Support
The first part of the Berlin Social Support Scale consists of 17 items
assessing perceived social support (PSS), support seeking (SS), and need for
support (35). Previous literature on social support and cardiovascular disease
as well as our own previous findings of greater catecholamine stress reactivity
with increasing PSS led us to use the 8-item PSS subscale composed of the
two subscales “emotional support” and “instrumental support” in the present
study (3,14). Using a 4-point rating scale ranging from 1 (completely wrong)
to 4 (completely right), we asked the participants whether they agree with
certain statements on their perception of social support (e.g., “there are people
who help me if I need help”; “there are people cheering me up when I am
sad”). The PSS renders scores between 1 (minimum score) and 4 (maximum
score). Higher scores mean higher PSS. Cronbach’s
(n ⫽ 437) is 0.83 for
the PSS subscale (35).
Subjects were tested between 2 PM and 4 PM. They abstained from
physical exercise, alcohol, and caffeinated beverages for at least 24 hours
before testing. We used the Trier Social Stress Test (TSST) combining a
5-minute preparation phase followed by a 5-minute mock job interview, and
5-minute mental arithmetic task in front of an audience (36). The TSST
evokes reliable physiological responses across different biological systems,
including coagulation factors also investigated in the present study (37).
During recovery, the subjects remained seated in a quiet room for 40 minutes.
Blood for coagulation and norepinephrine measures was obtained imme-
diately before stress, immediately after stress, and 20 minutes after stress. BP
was measured immediately before and 40 minutes after stress by sphygmo-
manometry (Omron 773, Omron Healthcare Europe B.V., Hoofddorp, Neth-
erlands) and MAP was calculated by the formula (2/3 ⫻ mean diastolic BP) ⫹
(1/3 mean systolic BP).
Venous blood was drawn through an indwelling forearm catheter into
polypropylene tubes containing 3.8% sodium citrate and centrifuged at 2000
g for 20 minutes at 4°C. The obtained plasma sample was immediately
aliquoted in polypropylene tubes and frozen at ⫺80°C. All analyses of
coagulation factors used the BCS Coagulation Analyzer (Dade Behring,
Liederbach, Germany). Determination of FVII:C used standard coagulometric
methods, factor-deficient standard human plasma, and reagents (Dade Be-
hring); plasma fibrinogen was determined using a modified Clauss method
(Multifibren U, Dade Behring). Plasma D-dimer was measured by means of
an enzyme-linked immunosorbent assay (Asserachrom Stago, Asnie`res,
France). Inter- and intra-assay coefficients of variation were ⬍10% for all
Blood samples for measurement of plasma norepinephrine were drawn
into ethylenediaminetetraacetic acid-coated monovettes (Sarstedt, Numbre-
cht, Germany), and immediately centrifuged for 10 minutes at 2000 g; plasma
was stored at ⫺80°C until analysis. Plasma norepinephrine was determined by
means of high-performance liquid chromatography and electrochemical de-
SOCIAL SUPPORT, COAGULATION ACTIVITY, AND STRESS
31Psychosomatic Medicine 71:30–37 (2009)
tection after liquid-liquid extraction (38,39). The limit of detection was 10
pg/ml. Inter- and intra-assay variance was ⬍5%. To reduce error variance
caused by imprecision of the intra-assay, all samples from one subject were
analyzed in the same run.
Data were analyzed using SPSS (version 13.0) statistical software package
(SPSS Inc., Chicago IL). All tests were two-tailed with level of significance
of p ⱕ .05 and level of statistical trends of p ⱕ .10. Using the trapezoid
formula, we calculated areas under the total response curves, expressed as area
under the measured time points with respect to ground for all coagulation
measures and norepinephrine (40). Before statistical analyses, all data were tested
for normality using the Kolmogorov-Smirnov test. Coagulation values and co-
agulation areas under the curve (AUCs) were logarithmically transformed to
achieve normal distributions. For clarity, we provide untransformed data.
To assess the associations between social support and coagulation activity
at baseline and after stress, we first calculated linear regression analyses with
the respective coagulation measure as the dependent variable and social
support score as a continuous independent variable. We used coagulation
baseline measures as the dependent variables to assess associations between
social support and coagulation activity at rest. We employed AUC measures
of the coagulation parameters to assess the associations between social
support and stress-induced coagulation changes. In light of previously re-
ported associations between BMI, MAP, and age with coagulation parameters
at rest and in response to stress (30,33,41), we controlled for BMI, MAP, and
age. We entered these parameters as predictors in all analyses. All indepen-
dent variables were simultaneously forced into the regression equations. The
optimal total sample size to predict stress reactivity in coagulation parameters
was n ⫽ 59 for detecting a medium-to-large effect size of f
⫽ 0.25 in
multiple regression analyses with a power of 0.80 using four predictors.
Second, we further tested regression results by performing general linear
models with repeated measures for each coagulation parameter as the depen-
dent variable and with social support as the continuous independent variable.
In these analyses, we again controlled for BMI, MAP, and age. For illustrative
purposes, we categorized the study group based on their social support scores
into four groups of subjects with increasing levels of social support termed as
follows: lowest (2.75–3.38, n ⫽ 11), lower (3.50 –3.63, n ⫽ 16), higher
(3.75–3.88, n ⫽ 25), and highest social support scores (4 – 4, n ⫽ 11).
To test for associations between social support and norepinephrine stress
reactivity, we used general linear modeling with norepinephrine levels as
repeated dependent factor and levels of social support as the continuous
independent factor, at the same time controlling for age, BMI, and MAP. To
assess whether associations between social support and coagulation activity at
baseline and after stress are related to norepinephrine levels, we again calcu-
lated regression analyses. As dependent variables, we entered those coagula-
tion measures that were significantly associated with social support in the
linear model. As independent variables, we simultaneously entered social
support and norepinephrine to test for a mediation effect of norepinephrine.
To test for a moderating effect of norepinephrine, we simultaneously entered
social support, norepinephrine, as well as their interaction term (social sup-
port ⫻ norepinephrine) as independent variables. We always controlled for
age, BMI, and MAP. Interaction terms were computed on Z-transformed data
rendering means of 0 and standard deviations (SD) of 1. All regression
analyses including interaction terms were performed on Z-transformed data.
We calculated Pearson’s product-moment correlations to assess the associa-
tions between social support, age, BMI, and MAP.
Social support scores of our 63 study participants ranged
between 2.75 and 4 (mean ⫾ SD ⫽ 3.66 ⫾ 0.32). The mean
age was 37 ⫾ 13.7 years, the mean BMI was 24.8 ⫾ 3.04, and
MAP was 94.7 ⫾ 10.62 mm Hg. Age, MAP, and BMI were
intercorrelated (p ⬍ .001) but they did not correlate with
social support (p ⬎ .21).
Relationship Between Social Support and Coagulation
Activity at Rest and in Response to Stress
Social Support and Coagulation Activity at Rest
D-Dimer at Rest
Lower social support scores were significantly associated
with higher D-dimer levels at rest (
⫽⫺0.22, p ⫽ .012;
⫽ .05) independent of MAP (p ⫽ .11), BMI (
p ⬍ .001; ⌬R
⫽ .15), and age (
⫽ 0.51, p ⬍ .001; ⌬R
0.17) with the total model explaining 60% of the variance in
D-dimer resting levels.
Fibrinogen at Rest
Higher fibrinogen at rest was significantly associated with
lower social support (
⫽⫺0.35, p ⬍ .001; ⌬R
independent of MAP (p ⫽ .90), BMI (
⫽ 0.42, p ⬍ .001;
⫽ .12), and age (
⫽ 0.33, p ⫽ .004; ⌬R
⫽ .08) with
the total model explaining 52% of the variance in fibrinogen
FVII:C at Rest
Social support was not significantly associated with FVII:C
at rest (p ⫽ .96).
Social Support and Coagulation Levels Between Rest
and 20 Minutes After Stress
Lower social support was associated with higher D-dimer
⫽⫺0.21, p ⫽ .017; ⌬R
⫽ 0.04) independent of
MAP (p ⫽ .07), BMI (
⫽ 0.42, p ⬍ .001; ⌬R
⫽ .13), and
⫽ 0.56, p ⬍ .001; ⌬R
⫽ .21). The whole model
explained 59% of the variance in D-dimer AUC.
Independent of MAP (p ⫽ .95), BMI (
⫽ 0.38, p ⫽ .001;
⫽ .10), and age (
⫽ 0.34, p ⫽ .005; ⌬R
⫽ .08), lower
social support was associated with higher fibrinogen AUC
⫽⫺0.36, p ⫽ .001; ⌬R
⫽ 0.12). The whole model
explained 48% of the observed variance in fibrinogen AUC.
There were no associations between social support and
AUC of FVII:C (p ⫽ .83).
General Linear Models
Across all subjects, the TSST elicited significant increases
in D-dimer (p ⫽ .009, f ⫽ 0.34), fibrinogen (p ⫽ .012, f ⫽
0.32), and FVII:C (p ⫽ .046, f ⫽ 0.32) from baseline to
immediately after stress at the same time controlling for age,
BMI, and MAP. To validate the results from the above re-
gression analyses, we applied general linear models with
repeated measures of coagulation factors as dependent vari-
ables and social support as a continuous independent variable.
After controlling for BMI, MAP, and age, there were signif-
icant main effects for social support for repeated D-dimer and
fibrinogen levels (D-dimer: F(1,58) ⫽ 6.0, p ⫽ .018, f ⫽ 0.31,
P. H. WIRTZ et al.
32 Psychosomatic Medicine 71:30–37 (2009)
Figure 1A; fibrinogen: F(1,58) ⫽ 13.8, p ⬍ .001, f ⫽ 0.47,
Figure 1B) whereas there were no significant interactions
between stress and social support (p ⬎ .58). Neither main
effects nor interaction effects were observed in terms of re-
peated measurements of FVII:C (p ⬎ .24).
For illustrative purposes, Figure 1 (panels A and B) shows
coagulation responses to the TSST in four groups of subjects
with increasing levels of social support (lowest: 2.75–3.38,
n ⫽ 11; lower: 3.50 –3.63, n ⫽ 16; higher: 3.75–3.88, n ⫽ 25),
and highest social support scores (4 – 4, n ⫽ 11) based on
quartiles (note that subject numbers differ in the four groups
because individual PSS values were not balanced above and
below the particular cut-off values).
Norepinephrine, Social Support,
and Coagulation Parameters
Social Support and Norepinephrine Stress Reactivity
The TSST stimulated significant increases in norepineph-
rine levels (F(1/61) ⫽ 94.9, p ⬍ .001). General linear mod-
eling with norepinephrine as repeated dependent variable and
social support as continuous independent variable revealed
that higher social support was associated with lower norepi-
nephrine levels before and after stress (main effect: F(1/57) ⫽
4.65, p ⫽ .035, f ⫽ 0.27, Figure 2), at the same time control-
ling for age, BMI, and MAP. There was no interaction be-
tween social support and stress (p ⫽ .33).
Norepinephrine and Associations Between Social
Support and Coagulation Parameters
Table 1 depicts regression results for associations between
norepinephrine, social support, and coagulation parameters at
rest and in response to stress.
Regression analyses after controlling for BMI, MAP, and
age revealed that resting norepinephrine levels were not sig-
nificantly related to any of the coagulation parameters (p ⬎
.60), and was determined to not be a significant factor in the
associations between social support and resting levels of D-
dimer and fibrinogen (Table 1). This suggests that resting
norepinephrine levels do not mediate the observed associa-
tions between social support and resting levels of D-dimer and
fibrinogen. Additionally, entering baseline norepinephrine,
levels, social support, plus the norepinephrine-by-social sup-
Figure 1. Prothrombotic factor levels in four groups of subjects with lowest
(2.75–3.38, n ⫽ 11), lower (3.50 –3.63, n ⫽ 16), higher (3.75–3.88, n ⫽ 25),
and highest social support (SS) scores (4 –4, n ⫽ 11). (A, B). Values are
mean ⫾ standard error of the mean. Stress reactivity of D-dimer (A) and
fibrinogen (B) across all 63 subjects. We applied general linear models with
repeated measures of coagulation factors as dependent variables and social
support as continuous independent variable at the same time controlling for
body mass index, mean arterial pressure, and age in all analyses. The main
effect of social support was significant in terms of D-dimer F(1,58) ⫽ 6.0,
p ⫽ .018, f ⫽ 0.31, (A) and fibrinogen (F(1,58) ⫽ 13.8, p ⬍ .001, f ⫽ 0.47,
B). The figure shows these data for illustrative purposes by four categories of
SS scores. TSST ⫽ Trier Social Stress Test.
Figure 2. Norepinephrine levels in four groups of subjects with lowest
(2.75–3.38, n ⫽ 11), lower (3.50 –3.63, n ⫽ 16), higher (3.75–3.88, n ⫽ 25),
and highest social support (SS) scores (4 – 4, n ⫽ 11). Values are mean ⫾
standard error of the mean. Stress reactivity of norepinephrine across all 63
subjects. We applied general linear models with repeated measures of nor-
epinephrine as dependent variables and social support as continuous indepen-
dent variable at the same time controlling for body mass index, mean arterial
pressure, and age. Higher social support was associated with lower norepi-
nephrine levels before and after stress (main effect: F(1,57) ⫽ 4.65, p ⫽ .035,
f ⫽ 0.27). Figure 2 shows these data for illustrative purposes by four
categories of SS scores. TSST ⫽ Trier Social Stress Test.
SOCIAL SUPPORT, COAGULATION ACTIVITY, AND STRESS
33Psychosomatic Medicine 71:30–37 (2009)
port interaction into the regression equation revealed that
resting norepinephrine levels did not moderate the relation-
ship between social support and both D-dimer and fibrin-
ogen (p’s ⬎ .69).
To determine if norepinephrine secretion mediates between
social support and stress reactivity of coagulation parameters
D-dimer and fibrinogen, regression analyses were recalculated
with norepinephrine AUC entered as an independent variable
(Table 1). To test for a moderation effect of norepinephrine,
its interaction with social support was additionally entered as
an independent variable. Controlling for norepinephrine AUC
did not significantly affect the observed associations between
social support and AUC of D-dimer and fibrinogen. Thus,
neither norepinephrine AUC alone nor its interaction with
social support were significantly associated with any of the
coagulation parameter AUCs (p ⬎ .50). In sum, norepineph-
rine does not seem to be a mediator or a moderator of social
support effects on coagulation activity.
Notably, results of the PSS subscales “instrumental sup-
port” and “emotional support” were similar to the combined
PSS scale in all analyses (data not shown).
Research suggested that poor social support is associated
with health risks (2), such as CAD (3– 6). The mechanisms
involved are not known, although overactivation of hemosta-
sis might be one contributing factor. The main objective of the
present study was to investigate whether social support is
associated with elevated coagulation factor levels at rest and
throughout an acute stress process. The coagulation factors
fibrinogen and D-dimer were examined at baseline, represent-
ing resting activity, and also for the AUC (i.e., immediately
before stress, immediately after stress, and 20 minutes after
stress), representing the total stress-response course. The re-
sults of our study suggest that low social support is associated
with increased fibrinogen and D-dimer levels at rest, and that
acute stress and low social support are independently associ-
ated with an increased AUC. This may indicate that individuals
with reduced social support run an even higher atherothrom-
botic risk during acute stress. Specifically, effects sizes of
stress-induced coagulation increases suggest clinical impor-
tance. A prothrombotic state of the blood promotes athero-
sclerosis development and, after rupture of an atherosclerotic
plaque, thrombotic occlusion of a coronary artery leading to
an ACS (42,43).
Even though FVII:C was responsive to the TSST, we did
not find a significant association between social support and
FVII:C both at baseline and throughout the stress period.
Clotting factor FVII belongs to the extrinsic system of blood
coagulation, whereas fibrinogen is the precursor of fibrin
further down in the coagulation cascade after intrinsic and
extrinsic coagulation pathways have merged (21). Therefore,
it could be that social support is more strongly related to
factors involved in the intrinsic pathway of blood coagulation,
which reasoning we did, however, not address in the present
study. After clot formation, the fibrinolysis system degrades
fibrin, whereby fibrin degradation products such as D-dimer
are formed. Because it indicates activation of the entire coag-
ulation system (i.e., the step of fibrin formation) and also the
fibrinolysis system (i.e., the step of fibrin dissolution), D-
dimer is termed a hypercoagulability marker (44). Hyperco-
agulability markers are more sensitive to change than are
individual hemostatic factors (45), providing one explanation
for why D-dimer emerged as a significant correlate of social
support whereas FVII:C did not. Our findings correspond to
previous studies that social support scores were negatively
associated with resting fibrinogen levels (19,21) now extend-
ing these findings to D-dimer. These may be important find-
ings in relationship to health. Elevated fibrinogen levels are
associated with cardiovascular disease risk (46), and are re-
lated to both atherogenesis and thrombogenesis. For each SD
increase in fibrinogen above the mean, it was suggested that
there is an 84% increase in the 5-year risk of ischemic heart
disease (47). In addition, increased D-dimer levels are asso-
ciated with greater risk of myocardial infarction (48), cere-
brovascular events (49), and peripheral arterial disease (50).
Acute mental stress activates both the coagulation and the
fibrinolysis components of hemostasis to result in net hyper-
coagulability (19,21). Increased social support has been sug-
gested to act as a buffer to attenuate physiological stress
responses, as indexed by cardiovascular, autonomic, and HPA
TABLE 1. Hierarchical Regression Analyses for Associations
Between Social Support and Coagulation Parameters Controlling for
D-dimer at baseline
Age 0.50 4.89 ⬍.001 .17
BMI 0.47 4.63 ⬍.001 .15
MAP ⫺0.16 ⫺1.61 .11 .02
NEPI at baseline 0.02 0.20 .84 .00
SS ⫺0.22 ⫺2.47 .017 .04
Fibrinogen at baseline
Age 0.33 2.89 .005 .07
BMI 0.41 3.69 .001 .12
MAP 0.01 0.10 .92 .00
NEPI at baseline 0.05 0.54 .60 .00
SS ⫺0.33 ⫺3.45 .001 .10
Age 0.55 5.31 ⬍.001 .20
BMI 0.42 4.12 ⬍.001 .12
MAP ⫺0.19 ⫺1.88 .07 .03
NEPI AUC 0.03 0.36 .72 .00
SS ⫺0.20 ⫺2.29 .026 .04
Age 0.33 2.78 .007 .07
BMI 0.37 3.22 .002 .09
MAP 0.00 0.02 .98 .00
NEPI AUC 0.07 0.68 .50 .00
SS ⫺0.34 ⫺3.42 .001 .11
BMI ⫽ body mass index; MAP ⫽ mean arterial blood pressure; NEPI ⫽
norepinephrine; AUC ⫽ area under the curve; SS ⫽ social support score.
P. H. WIRTZ et al.
34 Psychosomatic Medicine 71:30–37 (2009)
responses (8,10 –13). However, our present findings did not
suggest an interaction between social support and stress for
hemostatic measures, but social support and stress are inde-
pendent factors and therefore may be additive. Higher social
support predicted lower D-dimer and fibrinogen AUC from
baseline to 20 minutes after the stress task. These findings
support a previous study showing that higher fibrinogen levels
were found in socially isolated participants both before and
after a color-word and a mirror-tracing task (27). The present
study extends those results to include D-dimer, which is
involved with both coagulation and fibrinolysis. Furthermore,
an interpersonal stressor, the TSST, was used in the present
research, which expands the range of psychological stress
that is found to generate such hemostatic responses. Cat-
echolamines play a role in stress-induced hemostatic changes
(30), but their role in social support-related changes in coag-
ulation parameters is unclear. To examine if norepinephrine
mediates or moderates the association between social support
and hemostatic changes at rest and in response to stress,
fibrinogen and D-dimer were measured at baseline and
throughout the stress task (baseline through 20 minutes post
task). Resting norepinephrine levels and the interaction of
norepinephrine baseline levels with social support did not
predict levels of D-dimer and fibrinogen, suggesting that
norepinephrine is not associated with hemostatic reactions to
stress in relationship to social support.
Future studies are needed to examine additional pathways
that may mediate social support and health, besides the sym-
pathetic reactivity hypothesis, antistress hormones, inflamma-
tory responses, and sympatho-vagal balance may play roles as
alternative mediators. For example, oxytocin was found to
have potential antistress effects and when combined with
social support, there was a reduced cortisol response along
with increased calmness and decreased anxiety during the
TSST (13). In turn, cortisol changes during stress are associ-
ated with total fibrin formation (51), suggesting a potential
alternate pathway in which social support may buffer stress-
induced hemostatic activity and ultimately health.
Social networks were associated with reduced inflamma-
tory marker interleukin-6 responses in male Framingham
Heart Study participants (52), and reactivity in interleukin-6
and D-dimer to stress were positively correlated (51). Addi-
tionally, in patients with coronary heart disease (CHD), ele-
vated social support is associated with greater probability of
sympatho-vagal balance (i.e., reduced heart rate, MAP, car-
diac index, and increased high frequency heart rate variability)
during recovery from mental stress (53). In contrast, social iso-
lation was associated with decreased heart rate variability (54)
suggesting a reduction in parasympathetic or vagal tone. In
women with CHD, we previously observed elevated levels of
fibrinogen in association with reduced vagal cardiac control (55).
There are also hypotheses about social relationships sug-
gesting that they exhibit main effects on health but do not
necessarily interact with stress (56). Lack of social support
due to social isolation had a hazard ratio (HR) of 1.75 for
mortality in patients with heart failure (57). Compared with
heart failure patients reporting a high social network, hospital
readmission was more frequent among those who had mod-
erate social networks (HR ⫽ 1.87; 95% Confidence Interval
(CI) ⫽ 1.06 –3.29; p ⬍ .05) and low social networks (HR ⫽
1.98; 95% CI ⫽ 1.07–3.68; p ⬍ .05) (58). Similarly, loneli-
ness was significantly associated with elevated systolic BP,
but not so with differences in autonomic or endocrine reactivity
to stress (59). Comparisons of persons reporting more types of
contacts (parents, children, family members, and friends) with
those reporting fewer types yielded age- and gender-adjusted
HRs of 0.73 (95% CI ⫽ 0.64 – 0.82) for mortality and HRs of
0.75 (95% CI ⫽ 0.61– 0.91) for CHD (60).
In summary, social support is associated with various fac-
tors that might also affect hemostasis and that warrant an
investigation as potential pathways linking social support and
hemostasis and ultimately health. Alternatively, social rela-
tionships may function as a main effect on health. As is often
the case, both hypotheses are likely true depending on the
situation and factors being measured.
Our study has several strengths, which include recruitment
of a sizable group of apparently healthy and unmedicated
subjects across a range of perceived social support levels in a
natural unselected setting. However, the study has also its
limitations. First, its cross-sectional nature does not allow us
to interpret the direction of the social support-coagulation-
stress link, although we feel it is unlikely that coagulation
influences social support. Second, our findings were obtained
in a sample of apparently healthy men with BP in the normo-
tensive and mildly hypertensive range and may not be gener-
alized to individuals with more severe hypertension and
women. Third, we restricted our analyses to three coagulation
parameters. Fourth, the significance of low scores on PSS
remains to be elucidated and future studies should include
assessments of a person’s social network.
In conclusion, social support seems to be important for coag-
ulation parameter levels, such as fibrinogen and D-dimer, which
may affect thrombosis and atherosclerotic disease. Lower social
support was associated with higher baseline levels of fibrinogen
and D-dimer. In addition, lower social support was independently
related to an increase of these hemostatic factors throughout the
stress response period. Stress-related alterations in hemostasis
might act as a potential trigger for the onset of ACS (19).
Although social support did not seem to affect the magnitude of
the coagulation parameter responses to stress, low social support
may have added risk because of its association with greater
overall coagulation parameter levels. Furthermore, social support
does not seem to drive stress-associated changes in norepineph-
rine. Therefore, future studies are needed to examine the mech-
anisms that are involved in the relationship between social sup-
port and hemostasis factors in order to develop interventions that
can reduce hemostatic risk factors of CHD related to low levels
of social support.
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