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54
Fibrinogen and Factor VII in the Prediction
of Coronary Risk
Results From the PROCAM Study in Healthy Men
Jurgen Heinrich, Leopold Balleisen, Helmut Schulte, Gerd Assmann, Jurgen van de Loo
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Abstract Coronary thrombosis is regarded as the final
occlusive event in the progress of coronary heart disease
(CHD). Disturbances of the hemostatic system may favor this
process and thus may indicate increased risk of myocardial
infarction. Coagulation and lipid factors were measured in
2116 healthy male participants of the Prospective Cardiovascular Miinster (PROCAM) study. After 6 years of follow-up,
82 coronary events (9 sudden cardiac deaths and 14 fatal and
59 nonfatal myocardial infarctions) were observed. The mean
plasma fibrinogen levels of the event and nonevent groups
differed by 0.25 g/L (2.88 [SD, 0.68] versus 2.63 [SD, 0.63] g/L,
respectively; P=.OO1). The incidence of coronary events in the
upper tertile of the plasma fibrinogen distribution was 2.4-fold
higher than in the lower tertile. By multiple logistic function
analysis, plasma fibrinogen was found to be an independent
risk indicator for CHD (P<.05). Individuals in the high serum
low-density lipoprotein (LDL) cholesterol tertile who also
showed high plasma fibrinogen concentrations had a 6.1-fold
increase in coronary risk. Unexpectedly, individuals with low
plasma fibrinogen had a low incidence of coronary events even
when serum LDL cholesterol was high. The mean factor VIIc
activities in the event and nonevent groups did not differ
significantly (112.3% [SD, 19.9] versus 108.4% [SD, 21.6];
P=.O9). There was, however, a trend toward higher factor VIIc
values when only fatal events were taken into account. Thus,
higher levels of plasma fibrinogen markedly increased the
predictive power of high serum LDL cholesterol. Low plasma
fibrinogen is associated with low coronary risk even when LDL
is raised. (Arterioscler Thromb. 1994;14:54-59.)
Key Words • myocardial infarction • coronary heart
disease • fibrinogen • factor VII • LDL cholesterol •
smoking • prospective study
M
diovascular risk factors and were then kept under observation
to record mortality, subsequent MI, and stroke.11 The examination at onset included each patient's history, physical examination, electrocardiogram (ECG) at rest, and a laboratory
blood analysis.
The study began in 1979. Two years later the determination
of plasma fibrinogen and factor VIIc was included, and 10 581
individuals (7540 men and 3041 women) were recruited (Table
1). As expected, relevant numbers of MI or coronary heart
disease (CHD) death occurred only in men aged 40 years and
over. The analysis described below was therefore confined to
the 2116 male participants between 40 and 65 years of age
without a prior history of MI or stroke who had completed
their 6-year follow-up.
Diagnostic criteria and the definition of the end points have
been published in detail.13 Two end points were considered:
definite nonfatal MI and definite coronary death including
sudden cardiac death and fatal MI. Sudden cardiac death was
diagnosed if a subject was observed to have died within 1 hour
from onset of symptoms. Fatal MI was diagnosed when a death
certificate or hospital record described the cause of death
accordingly or when an autopsy finding of acute MI was
available. Definite nonfatal MI was diagnosed if one or more
of the following conditions were fulfilled: (1) diagnostic ECG
at the time of event; (2) ischemic cardiac pain plus diagnostic
enzymes; (3) ischemic cardiac pain plus equivocal enzymes
and equivocal ECG; or (4) an ECG that was diagnostic for MI
while a previous one was not.
The blinded members of the Critical Event Committee (see
"Appendix") verified diagnoses and causes of death of all
event cases.
ost cases of acute myocardial infarction (MI)
and cardiac death appear to be associated
with the occurrence of occlusive coronary
thrombi.1-3 One reason favoring or even precipitating
thrombus formation might be a thrombogenic state in
the patient's blood. Long-term epidemiological studies 4 1 0 in healthy persons report increased levels of
plasma fibrinogen and factor VIIc in those individuals
who develop a coronary event. This might suggest an
increase in coagulation activity. To evaluate the possible role of the hemostatic system, plasma fibrinogen
and factor VIIc were measured in the Prospective
Cardiovascular Miinster (PROCAM) study. 1112 Since
that time, plasma fibrinogen and factor VIIc have been
determined in more than 10 000 persons who had not
suffered from MI or stroke at the time of entry. The
results from 2116 men who completed an observation
period of 6 years are reported here.
Methods
Study Design
In the PROCAM study, apparently healthy employees of
Westphalian companies were examined deliberately for carReceived April 2, 1993; revision accepted September 27, 1993.
From the Institute of Clinical Chemistry and Laboratory Medicine (J.H., G.A.); the Department of Internal Medicine (LB.,
J. van de L.); and the Institute of Arteriosclerosis Research (H.S.,
G.A.), University of Munster, Miinster, FRG.
Correspondence to Dr J. Heinrich, Institute of Clinical Chemistry and Laboratory Medicine, A. Schweitzer-Str 33, 48149 Miinster, FRG.
Blood Sample Collection
Blood samples for the coagulation tests were collected in
1/10 of 3.13% trisodium citrate from 7 to 9 AM in a fasting
Heinrich et al
TABLE 1. Overall PROCAM Study Population and the
Selection Process of the Subset Studied
No. of persons Invtted to participate
33 000
No. of persons screened (total PROCAM
population*)
20 060
No. of persons with complete data records
19698
No. of persons with plasma flbrlnogen and
factor Vile measurements!
10 581
Male
7540
40-65
4548
Hemostasis, Llpids, and Coronary Risk
55
TABLE 2. Population Characteristics and Incidences of
CHD and Other Events
No. of patients studied
2116
Observation period, m
72
Mean age, y
48.9 (SD, 6.2)
Age range at entry, y
Annual Incidence
40-65
rate
No. of CHD events
0.65%
82
Sudden cardiac deaths
9
Complete follow-up records
4084
Fatal infarctions
6-Y follow-up completed
2116
Nonfatal infarctions
59
Deaths from causes other than CHD
61
PROCAM indicates the Prospective Cardiovascular Munster
study.
•Recruitment period from 1979 through 1985.
tFibrinogen and factor Vile were measured in all persons
entering the study between 1981 and 1985.
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state. Within 60 minutes plasma was separated by centrifugation of blood samples at room temperature for 15 minutes at
2500g. Serum for clinical chemistry was prepared from blood
samples without additives by centrifugation for 10 minutes at
3000g. Serum and plasma, transferred in aliquots into plastic
tubes, were kept in liquid nitrogen until they were stored in the
laboratory at -70°C.
Fibrinogen
Clottable plasma fibrinogen was determined according to
Gauss 14 by using thrombin and control plasma from Behringwerke, Marburg, FRG, and a plasma pool.
Factor Vile
Plasma factor VIIc was determined by a one-step assay13
using thromboplastin (Thromborel), factor VH-deficient
plasma, and control plasma from Behringwerke and a plasma
pool.
Total, HDL, and LDL Cholesterol and Trigtycerides
Triglycerides and total and high-density lipoprotein cholesterol (HDL-C) were measured in serum by using en2ymatic
assays and (for the latter) a precipitation method from Boehringer Mannheim, FRG, on a Hitachi 737 autoanalyzer. Lowdensity lipoprotein cholesterol (LDL-C) was calculated by the
Friedewald formula.
Statistics
An explorative analysis of data was performed. Continuous
variables were compared by t test (triglycerides after logarithmic transformation), and discrete parameters were compared
by the x2 t e s t - 1° a " analyses, except where age was included
as an independent variable in the multiple logistic regression,
results are age adjusted using regressions derived from the
entry data. For additional description of the relation between
a specific variable and the probability of suffering a cardiovascular event, the numbers in tertiles of the variable are given. In
addition, a multiple logistic analysis was performed; variables
included were age, body mass index, systolic blood pressure,
cholesterol, HDL-C, triglycerides, uric acid, fasting blood
glucose, diabetes mellitus, angina pectoris, smoking, and a
family history of MI. The level of significance was fixed at
P<.05. The statistical analysis was done with the software
packages SPSS" and SAS.
14
Other diseases of the circulatory system
Malignant neoplasms
8
27
Accidents and violence
15
Other diseases
11
Nonfatal strokes
11
No events In 6 y
1962
CHD indicates coronary heart disease.
Results
The 2116 subjects were observed for 72 months. Their
mean age at entry was 48.9 (SD, 6.2; range, 40 through
65) years. In this group 82 coronary events were observed (9 sudden cardiac deaths and 14 fatal and 59
nonfatal Mis), which corresponds to an annual incidence rate of 0.65% (Table 2). Causes other than CHD
accounted for 61 deaths (8 from other diseases of the
circulatory system, 27 from malignant neoplasms, 15
from accidents or violence, and 11 from other diseases).
Additionally, 11 nonfatal strokes were observed. A total
of 1962 subjects did not experience a stroke or MI
during the 6 years after examination.
Table 3, which compares the event and nonevent
groups, shows significantly higher levels of fibrinogen,
total cholesterol, LDL-C, triglycerides, and systolic
blood pressure in men who suffered a coronary event.
Their HDL-C was significantly lower. The mean fibrinogen concentration was 0.25 g/L higher in the event
group than in the healthy, asymptomatic population
(F=.001). Factor VIIc activity did not differ significantly
(112.3% [SD, 19.9] versus 108.4% [SD, 21.6], respectively; P=.09). However, when only fatal events were
considered, this difference was more pronounced
(117.0% [SD, 11.7] versus 108.4% [SD, 21.6], respectively; P=.O6). The number of coronary events in tertiles of variables is shown in Table 4. It confirms the
information of Table 3 except for the body mass index.
Body mass index, diastolic blood pressure, and factor
VIIc were associated with an approximately 1.5-fold
higher number of events when comparing the lower with
the upper tertile.
In the event group, 45.1% of the individuals were
active cigarette smokers compared with 27.8% in the
nonevent group. A total of 1089 nonsmokers had low or
medium fibrinogen levels (<2.77 g/L); only 29 (2.7%) of
56
Arteriosclerosis and Thrombosis Vol 14, No 1 January 1994
TABLE 3. Age-Adjusted Mean Values of Coagulation, LJpId, and Other Variables In the
Groups With and Without Coronary Events
Variable
No Event
(n=1962)
Fibrinogen, g/L
2.63 (0.63)
Event
(n=82)
P
.001
2.88 (0.68)
Factor Vile, %
108.4 (21.6)
112.3 (19.9)
.086
Cholesterol, mg/dL
225.0 (40.6)
251.6 (48.1)
<.001
HDL-C, mg/dL
45.6 (11.6)
40.2 (10.9)
<.001
LDL-C, mg/dL
148.5 (35.6)
175.0 (38.3)
<.0O1
Triglycerides, mg/dL*
136.4
163.4
.003
Systolic BP, mm Hg
132.5 (18.3)
137.9 (21.5)
.03
Dlastollc BP, mm Hg
87.2 (11.0)
89.8 (12.3)
.06
BMI, kg/m 2
26.1 (3.0)
26.4 (3.0)
.44
HDL-C indicates high-density lipoprotein cholesterol; LDL-C, low-density llpoprotein cholesterol;
BP, blood pressure; and BMI, body mass index. Numbers in parentheses are standard deviations.
*Geometric mean.
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them suffered a coronary event. In contrast, 24 (7.9%)
of 304 smokers with fibrinogen levels >2.77 g/L belonged to the event group (Table 5).
To elucidate the interdependence of different variables to an increased coronary risk, the multiple logistic
function (MLF) was applied. The standardized coefficient of logistic regression for fibrinogen was .00465 ±
.00134 (P<.001). Applying the MLF analysis, this coefficient remained greater than zero (.00352±.00140,
P=.O2) after taking into account age, systolic blood
pressure, smoking, diabetes mellitus, angina pectoris,
and family history of MI. Allowing in addition for total
cholesterol and HDL-C, significance was still reached
(.00299±.00147, P=.O5). The distribution of coronary
events among quintiles of the estimated risk by MLF
resulted in only 26.9 CHD cases/1000 in 6 years in the
three lowest quintiles, taking into account the following
factors: age, systolic blood pressure, total cholesterol,
HDL-C, diabetes mellitus, angina pectoris, smoking, a
family history of MI, and fibrinogen (Fig 1). Thus, in
60% of all participants only 13% of all events occurred.
However, not taking into account fibrinogen, 59% of all
TABLE 4.
events were found in the highest quintile of the MLF.
The addition of fibrinogen resulted in 129.6 events/1000
in 6 years, ie, 65% of all cases.
Three-dimensional analysis of event rate, fibrinogen,
and LDL-C, with the latter two depicted in their
tertiles, revealed a 6.1-fold higher coronary risk for
individuals with high LDL-C and high fibrinogen compared with those with high LDL-C but low fibrinogen
(103.1 versus 16.9 events/1000 in 6 years, respectively;
Fig 2). Individuals with high fibrinogen values had a
more than twofold risk even if LDL-C was low (48.4
versus 19.0 events, respectively). However, low fibrinogen was still associated with a lower event rate even if
the LDL values were high.
Discussion
Several prospective studies 49 report an association of
plasma fibrinogen with the risk of cardiovascular disease. Differences between the annual incidence rates in
these studies are mainly dependent on the age at entry.
This could account for minor differences in the results.
The sample studied here had a comparatively low mean
Number of Coronary Events by Tertlles of Coagulation and LJpId and Other Variables
No. of Events In Tertlles
Variable
Rbrinogen, g/L
Factor Vile, %
TertJIe Cutting
Points
Low
Middle
High
2.36 and 2.77
17
25
40
99and115
23
26
33
207 and 242
15
20
47
HDL-C, mg/dL
39 and 49
46
20
16
LDL-C, mg/dL
132 and 163
13
17
50
Triglycerides, mg/dL
106 and 169
20
24
38
Systolic BP, mm Hg
123 and 138
21
23
38
Diastolic BP, mm Hg
81 and 91
23
24
35
24.7 and 27.0
24
25
33
Cholesterol, mg/dL
BMI, kg/m 2
HDL-C indicates high-density llpoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; BP, blood
pressure; and BMI, body mass Index.
Heinrich et al Hemostasis, Lipids, and Coronary Risk
57
TABLE 5. Absolute and Relative Numbers of Smokers and Nonsmokers Distributed by Coronary Events and Tertiles
of Fibrinogen Level
Fibrinogen
Smoker
Nonsmoker
Low
Without event
With event
Individuals with event, %
High
Low
484
357
90
182
280
11
18
16
6
7
24
6.3
3.7
1.9
Middle
Middle
High
576
3.6
4.3
7.9
Cutting points for tertiles of fibrinogen level were 2.36 and 2.77 g/L
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age at entry of 48.9 years and a low annual incidence
rate of 0.65%, whereas the corresponding figures for the
Northwick Park Heart (NPH) study were 52.4 years and
0.8%, respectively.7
The distribution of events to tertiles of plasma fibrinogen was similar in the NPH and PROCAM studies; the
odds ratio of incidences in the lower and upper tertiles
was 2.4 in our study. In the NPH study the odds ratio
was 3.2 for ischemic heart disease events within 5 years
of entry and 2.1 for events in the whole observation
period, respectively.7
In a recent meta-analysis of six prospective studies by
Ernst and Resch10 surveying more than 90 000 personyears, plasma fibrinogen was confirmed as an independent risk factor for CHD. However, the studies surveyed differed in design. Most did not take HDL-C and
family history of CHD into account. The latter variables
have an important effect on the risk of MI and may also
be related to plasma fibrinogen. In particular, factors
affecting fibrinogen (eg, smoking and body weight) also
alter HDL-C values.11 Moreover, fibrinogen concentrations may have a strong genetic component, identified
by Humphries et al16 by using restriction fragment
length polymorphism markers of the fibrinogen locus. In
the PROCAM study the independent association of
fibrinogen with the risk of CHD was demonstrated even
after the addition of HDL-C and family history of CHD
to the risk factors in the MLF analysis.
In the 21-year follow-up of the Gothenburg study,5
plasma fibrinogen was found to be an independent risk
factor for stroke but not for CHD if smoking was
included in the multivariate analysis. This is not confirmed by our findings; even after addition of smoking to
the MLF, plasma fibrinogen remained significant.
The simultaneous consideration of event rate, serum
LDL-C, and plasma fibrinogen confirmed the independent risk association of the two plasma factors (see the
MLF analysis). High fibrinogen added markedly to the
predictive power of high LDL. Unexpectedly, however,
low fibrinogen appeared to counterbalance the clear-cut
risk association of high LDL-C. This latter observation
is so far unexplained and needs further analysis.
It is of further interest to consider the CHD frequency in nonsmokers and smokers in relation to fibrinogen (Table 5). A smoker with a high fibrinogen level
had a fourfold elevated risk of CHD compared with a
nonsmoker with low fibrinogen. This accords with other
reports.1718
The precise pathophysiological relation of fibrinogen
and risk of CHD is currently unknown. Increased fibrinogen concentrations could adversely affect plasma viscosity and platelet aggregability. On the other hand, atherosclerosis could secondarily cause increases of fibrinogen as
an acute-phase protein. In support of the latter hypothesis
are observations of higher leukocyte counts in the event
groups of other studies919-20 and significantly higher levels
of C-reactive protein in angina pectoris patients who
develop a coronary event within 2 years.21
In 1987, preliminary follow-up data from the coagulation part of the PROCAM study22 showed that the
CHD-incidences in 6 years/1000
160
129-6
140
120
Fra 1. Bar graph showing coronary Incidences
according to quintiles of estimated risk by multiple
logistic function (MLF) analysis. A, Independent
variables are age, systolic blood pressure, total
and high-density llpoprotein cholesterol, diabetes
mellitus, angina pectoris, smoking, and a family
history of myocardial infarction. B, Same as A plus
fibrinogen. CHD indicates coronary heart disease.
100
80
60
40
20
4,9 4,9
o•
II
III
IV
Quintiles of estimated risk by MLF
58
Arteriosclerosis and Thrombosis
Vol 14, No 1 January 1994
CHD-incidenoes in 6 years/1000
FIG 2. Three-dimensional bar graph showing
number of coronary heart disease (CHD) incidences/1000 in 6 years broken down by fibrinogen and
low-density lipoprotein (LDL) cholesterol (n=1983;
80 events). The numbers in parentheses are the
number of CHD events per number of individuals in
the specified subgroup. Fibrinogen: low, <2.36
g/L; middle, 2.36-2.77 g/L; high, >2.77 g/L; LDL
cholesterol: low, <132 mg/dL; middle, 132-163
mg/dL; high, >163 mg/dL.
low
low
middle
high
LDL c h o l e s t e r o l
(tertile)
fibrinogen (tertile)
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mean factor VIIc activity in the coronary event group
(n=15) was 10% higher compared with the group
without an event (n = 1659; P=.O7). This trend toward
higher factor VIIc activity for all CHD events was
confirmed in the present study as well as having been
shown after 5 years of observation in the NPH study
(117.4% in event versus 107.0% in nonevent cases;
/><.OO1).7 When only fatal events were taken into
account, the difference was more pronounced in both
studies: 123.9% (SD, 27.7) versus 107.0% (SD, 25.1),
P<.001, in the NPH study and 117.0% (SD, 11.7) versus
108.4% (SD, 21.6), P=.O6, in the PROCAM study.
To evaluate possible differences of methodology, a
laboratory comparison has been performed23 that includes the factor VII assays of the NPH, Atherosclerosis
Risk in Communities,24 and PROCAM studies. Plasma
samples enriched with activated factor VII (factor Vila)
expressed a proportionately greater factor VIIc in the
NPH assay using mixed human and bovine thromboplastin than in the Munster pure human system. It could
also be shown that the converse held in samples that
were relatively deficient in factor Vila. These differences in test results may be important if part of the clear
association of the risk of CHD with factor VII activity,
as found in the NPH study, is due to the presence of
increased circulating levels of factor Vila.
Based on our results, fibrinogen should be considered
as a powerful independent risk factor of CHD and
should be taken into account in CHD risk algorithms. In
other words, the individual prediction of coronary risk
may be markedly improved by applying risk scores that
include plasma fibrinogen.
Acknowledgments
This study was supported by Bundesministerium fur Forschung und Technologies Ministerium fur Wissenschaft und
Forschung NRW; Deutsche Forschungsgemeinschaft; and
Landesversicherungsanstalten Westfalen und Rheinprovinz.
The excellent technical cooperation of M. Kase, J. Bailey, and
C. Sandau is gratefully acknowledged.
Appendix
Members of the Critical Event Committee included K.
Kochsiek, MD, Wurzburg; B.E. Strauer, MD, Dusseldorf; U.
Gleichmann, MD, Bad Oeynhausen; and R. Uebis, MD,
Aachen, FRG.
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Fibrinogen and factor VII in the prediction of coronary risk. Results from the PROCAM
study in healthy men.
J Heinrich, L Balleisen, H Schulte, G Assmann and J van de Loo
Arterioscler Thromb Vasc Biol. 1994;14:54-59
doi: 10.1161/01.ATV.14.1.54
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272
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Copyright © 1994 American Heart Association, Inc. All rights reserved.
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