© 1999 American Heart Association, Inc.
Original Contributions |
Coagulation Factors II, V, VII, and X, Prothrombin Gene 20210G
A Transition, and Factor V Leiden in Coronary Artery Disease
High Factor V Clotting Activity Is an Independent Risk Factor for Myocardial Infarction
From the Central Hematology Laboratory, Inselspital, University Hospital Bern, Switzerland (M.R., B.S., I.S., F.D.B., M.F., B.L., W.A.W.); the Department of Hematology and Hemostaseology (H.H.W.), and the Department of Vascular Biology and Thrombosis Research (B.R.B.), University of Vienna, Austria.
Correspondence to Walter A. Wuillemin, MD, PhD, Central Hematology Laboratory, University Hospital, Inselspital, CH-3010 Bern, Switzerland. E-mail wwuillem{at}insel.ch
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Abstract |
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Abstract—Increased levels of hemostatic factors and genetic mutations of proteins involved in coagulation may play a role in the pathogenesis of coronary artery disease. We investigated clotting activity of factors II (FII:C), V (FV:C), VII (FVII:C), and X (FX:C), the prothrombin gene 20210G
A transition, and the factor V Leiden mutation in 200
survivors of myocardial infarction and in 100 healthy controls. FV:C
(P<0.0001) and FVII:C (P<0.0001) were
found to be independent risk factors for myocardial infarction. High
FV:C or high FVII:C combined with smoking or arterial
hypertension increased the relative risk for myocardial infarction up
to 50-fold. One of 177 patients (0.6%) and 4 of 89 controls (4.5%)
had the prothrombin 20210 AG genotype. Eleven of 177 patients
(6.2%) and 6 of 89 controls (6.7%) were heterozygous for the factor V
Leiden mutation. No homozygous carrier for these mutations was found.
Neither the prothrombin gene 20210GA transition (odds ratio [OR],
0.1; 95% confidence interval [CI], 0.01 to 1.1) nor the factor V
Leiden mutation (OR, 1.0; 95% CI, 0.4 to 2.8) were associated with an
increased relative risk for myocardial infarction. In conclusion, our
data indicate that neither the prothrombin gene 20210GA transition
nor the factor V Leiden mutation are risk factors for myocardial
infarction. High FVII:C was confirmed to be an independent risk factor
for myocardial infarction. Moreover, we describe for the first time
that high FV:C is an independent risk factor for myocardial
infarction.
Key Words: coagulation factor V • prothrombin gene • factor V Leiden • myocardial infarction
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Introduction |
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Myocardial infarction and unstable angina pectoris are very common in Western countries. Several studies have clearly shown the pathogenetic role of local thrombotic occlusion in coronary arteries at the site of a ruptured plaque.1 2 3 The fact that high clotting activity of coagulation factor VII (FVII:C) and high plasma levels of fibrinogen are associated with an increased risk for coronary artery disease further corroborates the crucial role of blood coagulation in the pathogenesis of myocardial infarction.4 5 6 7 8 9 The causes of elevated FVII:C and elevated plasma levels of fibrinogen are still a matter of debate. Aside from FVII:C and fibrinogen, other hemostatic factors are under investigation for their possible role as risk factors for coronary artery disease.6 8 10 11
Recently, a novel inherited risk factor for venous thrombosis was
identified.12 A GA transition at nucleotide
20210 in the 3' untranslated region of the prothrombin gene was
associated with a higher prothrombin clotting activity and a 2.7-fold
increased risk for venous thrombosis. Other groups reported similar
findings.13 14 15 16 17 18 19 20 The role of the prothrombin gene 20210A
variant in arterial disease is not established yet. Several
investigators reported a significantly increased prevalence of 1.8% to
12.5% of the prothrombin gene 20210A variant in patients with
arterial disease (coronary artery disease and
cerebrovascular disease) compared with newborns or age-matched
controls,18 21 22 23 24 and a 4.0-fold increased risk for
myocardial infarction in young women with the
variant.25 Others found no increased prevalence of
the prothrombin gene 20210A variant in patients with
arterial disease compared with age- and sex-matched
controls.16 20 26
A single base mutation in which adenine is substituted for guanine at
nucleotide 1691 in the gene coding for coagulation factor V
resulting in the amino acid substitution 506 ArgGln is the cause of
activated protein C (APC) resistance.27 Its
relation to coronary artery disease is still controversial.
Several investigators found a significant association between factor V
Leiden and coronary artery disease,28 29 30 or found
an increased prevalence of APC resistance in stroke
patients,31 whereas other groups reported no association
of APC resistance or factor V Leiden with coronary artery
disease31 32 33 or ischemic
stroke,24 26 32 respectively.
In the present study we investigated in a case control design the possible association of the clotting activity of coagulation factors II, V, VII, and X, the prothrombin 20210A allele, and the factor V Leiden with myocardial infarction.
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Methods |
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Patients, Controls, and Blood Samples
We investigated 200 (174 males, 26 females) survivors of myocardial infarction and 100 (87 males, 13 females) healthy controls. One control of the same sex and the same age (±5 years) was selected for every 2 patients. Patients were selected from the files of the Division of Cardiology of the University Hospital of Bern. Myocardial infarction had occurred at least 2 months before investigation. All patients except 2 had undergone coronary angiography. One-, two-, or three-vessel disease was present in 33.8%, 36.4%, and 26.8%, respectively, whereas 3% had angiographically normal coronary arteries. Patients and controls were considered smokers if they had smoked cigarettes >5 pack years. Arterial hypertension and diabetes mellitus were diagnosed according to the patient's history and medical treatment. Body mass index (BMI) was available from 200 patients and 89 controls. This study was approved by the Ethics Committee of the University of Bern.
Blood was drawn from an antecubital vein with a 19-gauge butterfly needle and was collected into 2 10-mL plastic syringes (Monovette®, Sarstedt) containing 1 mL of 0.106 mol/L trisodium citrate. Plasma was prepared by centrifugation at 1500g twice for 10 minutes at 15°C to 18°C and was stored in polypropylene tubes at -70°C. A sample of 10 mL blood, collected into EDTA (Monovette®, Sarstedt) and stored at -70°C, was available from 177 patients and 89 controls.
Coagulation Assays
Prothrombin time (PT) was performed using
Thromborel®-S (Behringwerke). The clotting
activity of FII (FII:C), FV (FV:C), FVII (FVII:C) or FX (FX:C) was
measured by PT-based assays using the respective deficient substrate
plasmas on a Fibrintimer and expressed as percentage of a normal human
plasma pool (NHP). NHP was prepared from 42 healthy male volunteers and
stored in small aliquots in liquid nitrogen. NHP was used as a standard
for measurement of clotting factors, and was defined to contain 100%
of clotting activity. Fibrinogen was determined according to the method
of Clauss.34
DNA Preparation
Preparation of genomic DNA from EDTA blood was performed using a
commercial kit according to the manufacturer's instructions
(QIAmp® Blood Kit, QIAGEN Inc).
Prothrombin Gene Genotype Analysis
A 345-bp fragment including the 3' untranslated region where the
20210GA transition is located was enzymatically amplified as
described.12 21 PCR-products were subjected to a
restriction digest with HindIII (New England Biolabs) and
then analyzed by polyacrylamide gel
electrophoresis.
Factor V Leiden Genotype Analysis
The G1691A mutation in exon 10 was detected by the loss of a
cleavage site for MnlI. A 286-bp fragment was amplified from
genomic DNA using a commercial primer-mix
(COASET® FV-506, Chromogenix). The PCR
conditions were as follows: 5 µL of purified DNA in 5 µL of
Tris-KCl-MgCl2 buffer (100 mmol/L Tris,
500 mmol/L KCl, 25 mmol/L MgCl2), 10
µL primer-mix, 6.6 µL (1.5 mmol/L of each
nucleotide) dNTP-mix (Boehringer Mannheim), 23 µL
distilled H2O, and 2 U of Taq
polymerase (Life Technologies) overlaid with 50 µL of paraffin oil
was heated in a Perkin Elmer Cetus DNA thermal cycler to 94°C for 5
minutes followed by 30 cycles of 93°C for 60 seconds, 62°C for 30
seconds, and 72°C for 90 seconds followed by a final 10 minutes at
72°C. Aliquots containing 17.5 µL PCR-product and 2 µL
distilled water were digested for 3 hours at 37°C with 0.5 µL
containing 1 U of MnlI (Fermentas Ltd). The fragments
measuring 37-bp, 93-bp, and 156-bp for the 1691G allele, and 130-bp
and 156-bp for the 1691A allele, were separated on 4% agarose gels
and visualized with ethidium bromide.
Modified APC Resistance
Resistance to APC was assayed using a commercial
activated partial thromboplastin time-based APC resistance
assay (COATEST® APC(TM) Resistance V, Chromogenix)
on a Fibrintimer (Behringwerke). The patient plasma was diluted with 4
volumes of factor V-deficient plasma according to the manufacturer's
recommendation. Response to APC was expressed as the APC sensitivity
ratio (ie, the quotient of the clotting time in the presence of APC
divided by the clotting time obtained in the absence of APC). Factor V
R506Q was diagnosed according to our APC sensitivity ratio in-house
cutoffs (normal 
2.2, heterozygous >1.3 and 
1.9, and homozygous
1.15).
Statistics
Medians or proportions were calculated for patients and controls
for cardiovascular risk factors. The significance of
any difference in medians was tested using the Mann-Whitney U-test
(MWU), and the significance of any difference in proportions was tested
using 
2 statistics. All probability values are
2-tailed and probability values below 0.05 were considered
statistically significant. Statistical analysis was done using
SigmaStat, version 1.0 (Jandell). Odds ratios (ORs) were calculated as
a measure of relative risk in the standard unmatched fashion.
Confidence intervals (CI) were calculated at the 95% level. ORs (and
their 95% CI) were used to describe the association between
coronary artery disease and prothrombin gene 20210GA
transition, factor V Leiden mutation, FII:C, FV:C, FVII:C, and FX:C,
respectively. To adjust for the effects of other coronary risk
factors, we used logistic regression. Adjustments were made for the
dichotomized risk factors sex, smoking status (yes/no),
arterial hypertension (yes/no), diabetes mellitus (yes/no),
and for age, cholesterol, and fibrinogen. Inclusion of BMI
did not affect the results. Since BMI was not available for all
controls, we excluded this variable from the final
analysis. Logistic regression analysis was carried out
with the SAS statistical package, release 6.12 (SAS Institute).
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Results |
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Patients and Controls
We investigated 200 survivors of myocardial infarction and 100 healthy controls. Table 1
shows
cardiovascular risk factors for patients and controls.
The prevalence of arterial hypertension, diabetes mellitus,
and smoking status (including former smokers) was significantly higher
in patients than in controls. Median values of total
cholesterol and fibrinogen were significantly higher in the
patient group compared with the control group.
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Factor II
We found no significant difference (P=0.977) between
FII:C of the nonanticoagulated patients (n=129) and the control group
(Table 2). High FII:C showed no
association with myocardial infarction (Table 3). Three of the controls with the
prothrombin gene 20210 GA genotype were in the highest FII:C
quartile (>102%) and 1 in the second lowest (90% to 94%),
respectively. The patient with the prothrombin gene 20210GA
transition was anticoagulated and his FII:C value was therefore not
analyzed.
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Factor V
We found significantly elevated FV:C levels among the 200 patients
compared with the controls (Table 2
). Analysis of the
relative risk for myocardial infarction associated with FV:C levels
revealed that subjects in the highest quartile (>109%) had a 3.3-fold
(95% CI, 1.8 to 6.6) increased risk compared with those in the first
quartile (96%) (Table 3). This association was present in
both the nonsmoking and the smoking subgroups (Table 4) and remained significant after
correction for lipid and nonlipid risk factors (Table 3).
Smokers with FV:C levels in the highest quartile had a 10.5-fold (95%
CI, 4.1 to 26.5) increased risk for myocardial infarction compared with
nonsmokers in the lowest quartile. Furthermore, FV:C levels in the
highest quartile were associated with an OR of 3.7 (95% CI, 1.6 to
8.4) and 2.1 (95% CI, 0.3 to 13.8) among subjects without
arterial hypertension and among those with hypertension,
respectively. Arterial hypertension combined with FV:C
levels in the highest quartile was associated with a 27.6-fold (95%
CI, 7.2 to 104.6) increased risk for myocardial infarction compared
with the absence of arterial hypertension and FV:C levels
in the lowest quartile (Table 4).
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Factor VII
FVII:C levels among the 133 nonanticoagulated patients were
significantly elevated when compared with the 100 controls (Table 2). Subjects with FVII:C levels in the highest quartile
(>110%) were found to have a 5.2-fold (95% CI, 2.4 to 11.2)
increased risk for myocardial infarction compared with those in the
first quartile (93%) (Table 3). This association was
unchanged when analyzed separately among nonsmokers and smokers
(data not shown) and remained significant after correction for lipid
and nonlipid vascular risk factors (Table 3). Smokers with
FVII:C levels in the highest quartile had a 29.4-fold (95% CI, 8.8 to
98.1) increased risk for myocardial infarction in comparison to
nonsmokers with FVII:C in the lowest quartile. Moreover, FVII:C levels
in the highest quartile in the absence or in the presence of
arterial hypertension, respectively, were associated with a
5.6-fold (95% CI, 2.2 to 14.3) and a 2.9-fold (95% CI, 0.4 to 22.9)
increased risk for myocardial infarction (data not shown). High FVII:C
levels combined with hypertension were associated with a 48.6-fold
(95% CI, 9.6 to 244.7) increased risk for myocardial infarction
compared with low FVII:C in the absence of arterial
hypertension (data not shown).
Factor X
Levels of FX:C were significantly higher (P=0.0054) in
nonanticoagulated patients (n=129) compared with those of the control
group (Table 2). Patients with FX:C levels in the highest
quartile (>109%) had a 2.2-fold (95% CI, 1.03 to 4.52) increased
risk for myocardial infarction compared with those who had FX:C levels
in the lowest quartile (90%) (Table 3). However, this
association was not significant after adjustment for possible
confounders (Table 3).
Prothrombin Gene 20210GA Transition
One of 177 patients (0.6%; 95% CI, 0% to 1.6%) and 4 of 89
controls (4.5%; 95% CI, 0.2% to 8.8%) had the prothrombin 20210 AG
genotype; no subject was homozygous (AA genotype). The
AG genotype was not associated with an increased risk for
myocardial infarction as shown in Table 5
(OR, 0.1; 95% CI, 0.01 to 1.1).
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Factor V Leiden Mutation and Modified APC Resistance
A low APC sensitivity ratio (>1.3 and 1.9) corresponding to the
factor V R506Q mutation was found in 12 of 200 patients (6%;
95% CI, 2.7% to 9.3%) and in 6 of 100 controls (6%; 95% CI, 1.3%
to 10.7%). Out of the 177 patients and the 89 controls from whom DNA
was available, the factor V Leiden mutation was detected in 11 patients
(6.2%; 95% CI, 2.7% to 9.8%) and 6 controls (6.7%; 95% CI, 1.5%
to 12%), respectively. All 11 patients and 6 controls with the
factor V R506Q had APC sensitivity ratios <1.9, whereas 166
patients and 83 controls with normal factor V genotype
had APC sensitivity ratios 2.2. No homozygous carrier for the factor
V Leiden mutation was found. As shown in Table 5, the factor V
Leiden mutation was not associated with an increased risk for
myocardial infarction, either when assessed indirectly using the
modified APC resistance assay (OR, 1.0; 95% CI, 0.4 to 2.8) or when
assessed by factor V genotyping (OR, 0.9; 95% CI, 0.3 to 2.6).
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Discussion |
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In the present study, we investigated the association of the FII:C, FV:C, FVII:C, and FX:C levels, of the prothrombin gene 20210G
A transition, and of the factor V Leiden mutation with
myocardial infarction.
Our main finding was a strong and independent association between high
FV:C levels and myocardial infarction. FV:C levels were significantly
elevated in patients compared with controls (Table 2). Subjects
with FV:C in the highest quartile (>109%) had a 3-fold increased risk
for myocardial infarction (Table 3). This association remained
significant after adjustment for possible confounders (Table 3).
High FV:C levels combined with smoking or arterial
hypertension increased the risk for myocardial infarction up to 27-fold
(Table 4). To the best of our knowledge, this is the first
report showing FV:C to be an independent risk factor for myocardial
infarction.
Furthermore, we confirmed that elevated FVII:C levels are an
independent risk factor for myocardial infarction (Table 3),
which is in agreement with data from the Northwick Park Heart
Study4 and the third Glasgow MONICA Survey II
study.9 Moreover, we found up to 50-fold increased
relative risk for myocardial infarction for high FVII:C levels in
combination with smoking or arterial hypertension (data not
shown). However, as discussed by others,35 on the basis of
this case-control study, we cannot rule out the possibility that
elevated FVII:C or FV:C levels are consequence of, rather than the
cause of, coronary artery disease.
FX:C levels were significantly elevated in patients compared with
controls (Table 2). Patients with FX:C levels in the highest
quartile (>109%) had a 2-fold increased risk for myocardial
infarction (Table 3). This association was not significant,
however, after adjustment for lipid and nonlipid vascular risk factors
(Table 3).
The prothrombin gene 20210GA transition has been described as an
independent risk factor for venous thrombosis.12 Carriers
of the mutation tend to have higher prothrombin levels than
noncarriers.12 16 17 19 Moreover, high prothrombin
clotting activity, also in the absence of the 20210GA transition,
are associated with an increased risk for venous
thrombosis.12 Our data show that the prevalence of the
prothrombin gene 20210GA transition is not increased in patients
with myocardial infarction (0.6%) compared with healthy controls
(4.5%) (Table 5). This result is in agreement with other
reports16 20 indicating that the prothrombin 20210GA
transition should not be considered a risk factor for myocardial
infarction in the general population. The prevalence of the prothrombin
20210 GA genotype among our Swiss healthy controls (4.5%) is
rather high compared with that in other European countries such as
Sweden (1.8%),14 England (0.7% to
2.6%),13 15 19 Netherlands (1.2% to
2.3%),12 23 Austria (2%),21 Spain
(1.4%),20 and Italy (4%).16 We found that
the FII:C levels were similar among patients and controls and were not
associated with myocardial infarction (Table 2).
Factor V Leiden is known to be a common risk factor for venous
thrombosis but it is still debated whether this mutation is associated
with arterial thromboembolism. Our data show no association
between factor V Leiden and myocardial infarction (Table 5).
This is in agreement with several other studies, indicating that factor
V Leiden is not a risk factor for coronary artery
disease31 32 36 or ischemic cerebrovascular
disease.32 However, a recent report showed a relatively
high prevalence of the factor V Leiden mutation in young female smokers
who had suffered from myocardial infarction.30
In conclusion, our findings indicate that neither the factor V R506Q
mutation nor the prothrombin gene 20210GA transition are associated
with myocardial infarction. We show for the first time that high FV:C
is an independent risk factor for myocardial infarction, and confirm
that high levels of FVII:C are an independent risk factor.
Neither FII:C nor FX:C were found to be independent risk factors for
myocardial infarction. Our data suggest that combinations of high
coagulation factors (FV:C or FVII:C) and clinical
cardiovascular risk factors (smoking,
arterial hypertension) may result in more than additive
risk for myocardial infarction. Further studies are needed to define
the role of FV:C levels in coronary artery disease.
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Acknowledgments |
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This study was supported by a grant from the Swiss National Foundation for Scientific Research (3200-047016.96), and by a grant from the Department of Clinical Research, University Hospital, Inselspital, Bern, Switzerland.
Received May 25, 1998; accepted September 25, 1998.
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