Journal of the American College of Cardiology
© 2000 by the American College of Cardiology
Published by Elsevier Science Inc.
Vol. 36, No. 3, 2000
ISSN 0735-1097/00/$20.00
PII S0735-1097(00)00772-5
Prevalence of Factor V Leiden and Prothrombin
Variant G20210A in Patients Age ⬍50 Years
With No Significant Stenoses at Angiography
Three to Four Weeks After Myocardial Infarction
Neil S. Van de Water, PHD,*† John K. French, MB, PHD, FESC,*‡ Mayanna Lund, MB,‡
Thomas A. Hyde, MB,‡ Harvey D. White, MB, DSC, FACC,‡ Peter J. Browett, MB*†
Auckland, New Zealand
We sought to determine the frequencies of factor V Leiden and prothrombin variant
G20210A in patients age ⬍50 years with no significant coronary stenoses three to four weeks
after myocardial infarction (MI).
BACKGROUND Factor V Leiden and prothrombin variant G20210A occur frequently in patients with venous
thromboembolism. However, the contribution of these mutations to the development of MI
requires clarification.
METHODS
The frequencies of factor V Leiden and prothrombin variant G20210A were determined in
41 patients age ⬍50 years who had “normal” or “near normal” coronary arteries (no stenosis
⬎50%) at angiography three to four weeks after MI (the study group) and compared with
those in 114 patients who had at least one angiographic stenosis ⬎50% after MI (the control
group). Patients age ⱖ50 years with, or without, stenoses were also studied.
RESULTS
The frequency of factor V Leiden was 14.6% in patients age ⬍50 years in the study group
compared with 3.6% in patients in the control group (odds ratio [OR] 4.7 [95% confidence
interval (CI) 1.3–17.7], p ⫽ 0.02). The frequency of the prothrombin variant G20210A was
7.3% in the study group compared with 1.8% in the control group (OR 4.4 [95% CI
0.7–27.5], p ⫽ 0.12). One or both mutations were present in 8 of the 41 patients (19.5%) age
⬍50 years in the study group compared with 6 of the 114 patients (5.5%) in the control group
(OR 4.4 [95% CI 1.4 –13.5], p ⫽ 0.01). In all 271 patients (irrespective of age) with normal
arteries, the frequency of factor V Leiden was 11.7% (7/60) compared with 4.3% (9/211) in
patients with at least one ⬎50% stenosis (OR 2.9 [95% CI 1.1– 8.3], p ⫽ 0.04), and the
frequency of prothrombin variant G20210A was 6.7% (4/60) compared with 1.4% (3/211)
(OR 4.9 [95% CI 1.1–22.8], p ⫽ 0.04), respectively.
CONCLUSIONS The frequencies of factor V Leiden and/or prothrombin variant G20210A are increased in
patients age ⬍50 years with normal or near normal coronary arteries after MI. (J Am Coll
Cardiol 2000;36:717–22) © 2000 by the American College of Cardiology
OBJECTIVES
The contribution of genetic and functional alterations in
factors of the coagulation and fibrinolytic pathways (that is,
hemostatic risk factors) to the development of arterial
thrombosis requires clarification. In several studies, fibrinogen levels have been identified as an indicator of risk for
the future development of stroke and myocardial infarction
(MI) (1–5). Inherited abnormalities of plasminogen activator inhibitor-1, von Willebrand factor, factor V and prothrombin have also been implicated in the pathogenesis of
MI (6 –10).
Factor V Leiden, which results in activated protein C
resistance, has been identified as a risk factor for venous
thromboembolism, occurring in 20% to 30% of patients
with this condition (11,12). Factor V Leiden occurs in 4%
to 6% of individuals in most Caucasian populations includFrom the *Department of Molecular Medicine, University of Auckland, †Hematology Department, Auckland Hospital; and ‡Cardiology Department, Green Lane
Hospital, Auckland, New Zealand. This study was supported, in part, by grants from
the Health Research Council of New Zealand and the Auckland Medical Research
Foundation. This study was presented in part at the 71st Scientific Sessions of the
American Heart Association, Dallas, Texas, November 1998.
Manuscript received November 17, 1999; revised manuscript received March 1,
2000, accepted April 13, 2000.
ing New Zealand (13,14). The prothrombin variant
G20210A, a genetic variation in the 3⬘-untranslated region
of the prothrombin gene, is associated with elevated plasma
prothrombin and thrombin levels, thus increasing the risk of
thrombotic events (15). This has a frequency of 1.7% (95%
confidence interval [CI] 1.3–2.2) in populations of northern
European descent (16).
The frequencies of factor V Leiden and the prothrombin
variant G20210A have not been consistently shown to be
increased among patients with previous MI or stroke
(9,10,17). However, increased frequencies of factor V Leiden and prothrombin variant G20210A in younger women
with MI have been shown by one group (18,19).
After MI, the prevalence of “normal” or “near normal”
coronary angiography varies between 1% and 12%, and
various etiological factors have been implicated, including
coronary spasm, coronary embolism and cocaine use (20). In
a previous small series, almost all of the patients without
significant stenoses on coronary angiography after MI were
males aged ⬍50 years and frequent cigarette smokers (20).
Inherited hemostatic risk factors may have more influence
on the development of MI in patients with “normal”
718
Van de Water et al.
Inherited Thrombophilias and MI
JACC Vol. 36, No. 3, 2000
September 2000:717–22
Abbreviations and Acronyms
CI
⫽ confidence interval
MI ⫽ myocardial infarction
OR ⫽ odds ratio
PCR ⫽ polymerase chain reaction
coronary angiograms than in patients with more severe
stenoses before MI in whom there is shear stress-induced
platelet activation.
To determine whether particular inherited hemostatic
risk factors may have contributed to the development of MI
in patients without significant coronary stenoses at angiography three to four weeks after MI, we assessed the
frequencies of factor V Leiden and prothrombin variant
G20210A, particularly in patients age ⬍50 years.
METHODS
Patient population. Patients being followed-up after six
randomized controlled trials of different therapies for acute
MI (21–26) and patients screened for cohort studies (27,28)
were approached to enter this study. Local ethics committee
approval and individual written informed consent were
obtained. Details of angiography performed three to four
weeks after MI (including myocardial score) and clinical
follow-up were as previously described (26,29). All consenting survivors of MI who were age ⬍50 years and had
“normal” or “near normal” coronary angiograms (no coronary stenosis ⬎20% and ⬎50%, respectively) formed the
study group, and patients age ⬍50 years selected at random
from the above studies, with at least one stenosis ⬎50%,
formed the control group. The frequency of mutations/
polymorphism in patients aged ⱖ50 years with, or without,
stenoses ⬎50% after MI was also determined. In this New
Zealand study, 81% of patients were of European origin (of
whom ⬎90% were of northern European origin) (30), 16%
were Polynesian, and 3% were Asian.
Patient samples. Ten milliliters of venous blood was collected into a tube containing sodium citrate. DNA was
prepared by either the proteinase K/phenol or DNAzol
(Life Technologies, Gaithersburg, Maryland) extraction
methods.
Mutational analysis. Single base changes for factor V
Leiden and prothrombin variant G20210A were detected by
polymerase chain reaction (PCR) amplification followed by
restriction enzyme digestion of the PCR product for factor
V Leiden, as previously described by Bertina et al. (12), and
Hind III restriction enzyme cleavage of a 169 bp PCR
product for prothrombin variant 20210A, using a modified
method of Poort et al. (15).
Statistical analysis. Baseline characteristics are expressed
as means ⫾ standard deviations or percentages. Continuous
variables were compared by a one-way analysis of variance.
Chi-square tests or, where appropriate, Fisher exact tests,
were used to compare discrete variables. Odds ratios (OR),
with 95% CIs and p values, were obtained using logistic
regression.
RESULTS
A total of 41 patients age ⬍50 years with “normal” or “near
normal” coronary arteries were identified on coronary angiography at a median of 23 days (interquartile range
19 –27) after MI (study group); 12 of these patients had no
coronary stenosis ⬎20%. The control group consisted of
114 patients age ⬍50 years with at least one stenosis ⬎50%.
Patients age ⱖ50 years with “normal” or “near normal”
coronary angiograms (n ⫽ 19) and patients with at least one
stenosis ⬎50% (n ⫽ 97) after MI were also studied. The
characteristics of these patient groups, which were defined
by age and angiographic coronary disease severity at the time of
angiography, were similar except for smoking (Table 1).
Frequency of factor V Leiden. The frequency of factor V
Leiden was 14.6% (6/41) in patients age ⬍50 years with
“normal” or “near normal” angiograms (without hemodynamically significant stenosis) compared with 3.6% (4/114)
in patients with at least one stenosis ⬎50% (OR 4.7 [95%
CI 1.3–17.7], p ⫽ 0.02) (Fig. 1). Of the 12 patients age
Table 1. Patient Characteristics
>50 Years
<50 Years
Age (SD)
Male gender (%)
Hypertension (%)
Smoking (%)*
Diabetes (%)
Prior MI (%)
Family history of coronary disease (%)
Family history of stroke (%)
Cholesterol, mmol/l (SD)
Myocardial score (SD)
Ejection fraction, % (SD)
No Stenosis
(n ⴝ 41)
>1 Stenosis
(n ⴝ 114)
No Stenosis
(n ⴝ 19)
>1 Stenosis
(n ⴝ 97)
All Ages
(n ⴝ 271)
39.1 (6.9)
83
15
54
5
2.2
28
8
5.9 (1.2)
2.6 (2.5)
60.3 (12.3)
43.6 (4.6)
84
25
66
7
5
48
13
6.3 (1.2)
7.5 (2.6)
59.9 (12.3)
58.8 (4.4)
95
11
32
0
11
21
11
6.1 (0.88)
4.7 (2.1)
60.3 (16.0)
59.2 (6.7)
81
29
33
7
4
24
9
6.3 (1.5)
8.6 (2.4)
57.3 (13.0)
50 (10.2)
83
23
50
6.0
5
35
11
6.2 (1.3)
6.9 (3.2)
59.0 (12.8)
*Chi-square ⫽ 25.4; p ⬍ 0.001 (4-way comparison).
MI ⫽ myocardial infarction; SD ⫽ standard deviation.
JACC Vol. 36, No. 3, 2000
September 2000:717–22
Figure 1. Frequencies of factor V Leiden (A) and prothrombin variant
G20210A (B) compared in the study group (patients ⬍50 years with no
stenosis) and the control group (patients ⬍50 years with ⱖ1 stenosis).
⬍50 years with no coronary stenosis ⬎20%, 16.6% (2/12)
had factor V Leiden.
When the frequency of factor V Leiden in all patients
without significant stenoses (irrespective of age) was compared with that in all patients with at least one stenosis
⬎50%, there was an increased frequency (11.7% [8/60] vs.
4.3% [9/211], OR 2.9 [95% CI 1.1– 8.3], p ⫽ 0.04) (Fig. 2).
Interaction of factor V Leiden with other risk factors.
The frequencies and ORs of major cardiovascular risk
factors in the study group compared with the control group
are shown in Table 2. Comparison of the study group
patients with those who had at least one ⬍50% stenosis
after MI revealed no differences in any major cardiovascular
risk factor. When the study group patients were analyzed for
an association between factor V Leiden and other risk
factors, there was a trend towards an increased incidence of
hypertension in the patients with factor V Leiden (OR 5.83
[95% CI 0.95–36], p ⫽ 0.058) (Table 2).
Prothrombin variant G20210A. The frequency of prothrombin variant G20210A was 7.3% (3/41) in patients age
⬍50 years with no significant coronary disease and 1.8%
(2/114) in those with coronary artery stenoses (OR 4.4 [95%
CI 0.7–27.5], p ⫽ 0.12) (Fig. 1). When patients of all ages
with no significant stenosis were considered together, the
frequency of this mutation was 6.7% (4/60) compared with
1.4% (3/211) in patients with coronary artery stenoses (OR
4.9 [95% CI 1.1–22.8], p ⫽ 0.04) (Fig. 2).
Van de Water et al.
Inherited Thrombophilias and MI
719
Figure 2. Frequencies of factor V Leiden (A) and prothrombin variant
G20210A (B) compared in patients of all ages with no stenosis and those
with ⱖ1 stenosis.
Factor V Leiden and prothrombin variant G20210A.
Among patients age ⬍50 years with no significant coronary
stenosis (the study group), the frequency of either or both of
these mutations was 19.5% (8/41) versus 5.5% (6/114) in
the control group (OR 4.4 [CI 1.4 –13.5], p ⫽ 0.01).
The interaction of factor V Leiden or prothrombin
variant G20210A with major cardiovascular risk factors was
considered. Within the study group, no major cardiovascular risk factors were more prevalent in patients with either
mutation than in those without mutations although there
was a trend towards an increased incidence of hypertension
Table 2. Interaction of Factor V Leiden With Other
Risk Factors
OR (95% CI)
p Value
Patients ⬍50 years with no stenosis with, and without, factor V Leiden
Diabetes
5.8 (0.32–106.4)
0.23
Smoking
0.92 (0.21–4.1)
0.91
Hypertension
5.8 (0.95–36.0)
0.058
Total cholesterol ⬎5.5 mmol/l
1.1 (0.27–4.4)
0.119
Two or more risk factors
1.33 (0.33–0.55)
0.69
Patients ⬍50 years without stenoses vs. controls
Diabetes
0.67 (0.15–3.0)
Smoking
1.1 (0.57–2.2)
Hypertension
0.48 (0.19–1.2)
Total cholesterol ⬎5.5 mmol/l
0.52 (0.25–1.1)
CI ⫽ confidence interval; OR ⫽ odds ratio.
0.60
0.75
0.12
0.082
720
Van de Water et al.
Inherited Thrombophilias and MI
in patients with factor V Leiden or prothrombin variant
G20210A (OR 4.13, p ⫽ 0.12).
DISCUSSION
Factor V Leiden is more common in individuals with
venous thromboembolism, emphasizing the important role
of activated protein C resistance in venous thrombosis (11).
An increased frequency of factor V Leiden has not previously been reported in studies of unselected patients surviving acute MI (31) and has not been found to be associated
with the severity of coronary artery disease (32).
In this study we postulated that in circumstances of
“normal” or “near normal” coronary arteries (little or no
coronary stenosis) and, thus, relatively low shear stress, an
increased procoagulant tendency mediated by factor V
Leiden or prothrombin variant G20210A may contribute to
the development of MI, perhaps in conjunction with other
factors, particularly smoking. This study was designed to
examine the hypothesis that there may be an increased
frequency of factor V Leiden among individuals age ⬍50
years with no angiographic stenosis three to four weeks after
MI (compared with patients ⬍50 years with ⱖ1 stenosis
⬎50%), and it was found that the OR for the increased
frequency of factor V Leiden in these patients was 4.7
(14.6% vs. 3.6%, p ⫽ 0.02). There was a trend towards an
increase in the frequency of prothrombin variant G20210A
(from 1.8% to 7.3%, p ⫽ 0.12). The frequency of either or
both of these inherited thrombophilias was 19.5% (8/41) in
the study group compared with 5.5% in the control group
(OR 4.4 [CI 1.4 –13.5], p ⫽ 0.01).
In a study of 22 young patients with MI and normal
coronary arteries, there was a trend towards an increased
incidence of factor V Leiden compared with young patients
with angiographic coronary artery disease after MI or
age-matched controls (9.1% vs. 3.8%, p ⫽ NS) (33). A
preliminary report of an enlarged cohort from the same
group documented a 14% frequency of factor V Leiden in
patients age ⬍50 years with “normal” coronary arteries (34),
which is similar to our frequency of 14.6%.
Two other studies have identified an increased frequency
of factor V Leiden in selected subgroups of survivors of MI
(18,35). The reported frequency of factor V Leiden was
9.5% in female survivors of first MI age 18 to 44 years from
western Washington state compared with 4.1% in agematched controls without MI (OR 2.4 [95% CI 1.0 –5.9]),
and the OR for factor V Leiden was higher when combined
with at least one other risk factor (18). Smoking was the
main risk factor interacting with factor V Leiden and
leading to increased risk although an interaction with
treated hypertension was not reported separately (18). Neither factor V Leiden nor prothrombin variant G20210A has
been shown to be independently increased in patients age
⬍70 with first MI although these mutations were increased
in frequency in conjunction with one of the major cardiovascular risk factors (smoking, hypertension, dyslipidemia
JACC Vol. 36, No. 3, 2000
September 2000:717–22
and diabetes) or obesity (35). However, these studies did not
examine factor V Leiden with respect to the severity of
angiographic coronary artery disease.
The reasons why patients with normal or near normal
coronary arteries have clinical events are unclear, as subclinical thrombosis often occurs at sites of plaque fissuring or
rupture (36,37), but differences in various hemostatic risk
factors may be a contributory factor.
In contrast with earlier reports (20,35), we did not find an
increased frequency of smoking in young patients with
normal coronary arteries compared with those with angiographic stenoses although all patients age ⬍50 years were
more likely than older patients to have been smokers at the
time of MI.
Prothrombin, the precursor of thrombin, potentiates
coagulation, and prothrombin variant G20210A leads to
elevated levels of prothrombin, thereby increasing the risk of
venous thrombosis (15). We found a trend towards an
increased frequency (7.3%) of prothrombin variant
G20210A in young patients without angiographic coronary
stenoses compared with 1.8% in patients with ⱖ1 coronary
stenoses and the general population. Furthermore, one or
both of these inherited thrombophilias occurred in 19.5% of
young patients with no hemodynamically significant stenoses after MI.
The U.S. Physicians’ Health Study reported no association between factor V Leiden and MI (9). This study
predominantly included individuals with a lower frequency
of major risk factors for MI than in other studies (17). The
U.S. Physicians’ Health Study also reported a lack of
association between prothrombin variant G20210A and MI
but did report a higher frequency (3.9%) of prothrombin
variant G20210A although ethnicity was not reported (17).
This frequency is higher than the figure of 1.7% (95% CI
1.3–2.2) derived from several published papers in the
analyses of Rosendaal and colleagues (16) of 2,756 individuals of northern European descent.
Study limitations. A limitation of coronary angiography is
that it is a “lumenogram,” which does not consistently
demonstrate the increase in vessel diameter occurring in the
early stages of atherosclerosis (38). In this study we categorized patients as having “normal” or “near normal” coronary
arteriograms according to the absence of stenoses ⬎50% at
three to four weeks after MI, and it must be noted that
angiographically “normal” coronary arteries are found in 1%
to 12% of all patients after MI (20). Angioscopy and
intracoronary ultrasound are more sensitive methods of
demonstrating the early stages of coronary atherosclerosis
and, particularly, plaque rupture.
To recruit our prespecified group of patients aged ⬍50
years with no coronary angiographic stenosis ⬎50%, we
obtained samples for the study group from all consenting
patients from our series (21–28), and patients in the control
group were randomly selected from these series. Unappreciated selection bias could have occurred although, as
in-hospital coronary angiography was performed in only
JACC Vol. 36, No. 3, 2000
September 2000:717–22
10% of patients after MI in Auckland, New Zealand in
1993 (39), consecutive patients undergoing angiography
would have been highly selected.
Another potential limitation of this work was the reliability of the estimate of the frequencies of factor V Leiden
and prothrombin variant G20210A due to the relatively
small number of patients with angiographically “normal”
coronary arteries. While both our prespecified subgroup of
patients age ⬍50 and all patients (irrespective of age) with
“normal” coronary angiograms after MI had higher frequencies of factor V Leiden (14.6% and 11.7%) and prothrombin
variant G20210A (7.3% and 6.7%), respectively, this observation needs to be confirmed prospectively in a larger
patient cohort. However, the frequency estimates of factor
V Leiden and prothrombin variant G20210A reported here
in the control group of post-MI patients with ⬎50%
angiographic coronary stenosis (3.6% and 1.8%, respectively) are consistent with those derived from populations of
predominantly northern European descent (4% to 6% and
1.7% [95% CI 1.3–2.2], respectively) (15,16).
Conclusions. We conclude that the frequencies of factor V
Leiden or prothrombin variant G20210A are increased in
patients age ⬍50 years who suffer MI but have no significant coronary stenoses at angiography. Whether such patients with inherited thrombophilias should receive specific
therapies is unknown.
Acknowledgments
We gratefully acknowledge the assistance of Loretta Bush
and Alison Randall in obtaining blood samples, Stephanie
Kaye and Janine Lander for technical assistance, Drs. Toby
Whitlock and Samuel Manda for statistical advice and Edie
Scadden for secretarial support.
Reprint requests and correspondence: Dr. John French, Cardiology Department, Green Lane Hospital, Private Bag 92 189,
Auckland 1030, New Zealand. E-mail: [email protected].
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