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 Previous Article | Table of Contents
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 704-705
CORRESPONDENCE
The Prothrombin G20210A Mutation and Factor V Leiden Mutation in
Patients With Cerebrovascular Disease
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LETTER |
To the Editor:
Genetic variants leading to a persistent hypercoagulable state may
predispose to thrombotic events. A recently discovered G to A mutation
at position 1691 of the factor V gene (factor V Leiden mutation),
occurring in 3% to 5% of the normal Caucasian population, has emerged
as a major genetic risk factor of venous thrombosis.1 The
role of this mutation for arterial vascular events, in particular
cerebrovascular disease, is still under discussion.2-6
Another recently described mutation (G to A at position 20210 in the
3 -untranslated region of the prothrombin gene) has been associated
with a threefold increased risk of venous thrombosis in heterozygous
carriers of the mutation.7 The mutation is as frequent as
1% to 2% in the population and also seems to represent an important
genetic risk factor of venous thrombosis. Currently, the role of the
prothrombin variation for arterial vascular disease is unclear. In a
recent study, 5.1% heterozygous carriers of the mutation
among young women with myocardial infarction were found, compared with
1.6% heterozygous carriers among a control population.8
The age-adjusted odds-ratio for MI was 4.0 and was particularly high in
the presence of other vascular risk factors, eg, smoking. In another
recent study, the G20210A prothrombin mutation was found in 5.1% of 98 patients with coronary heart disease as compared with 1.96% among
healthy newborns.9 On the other hand, three studies did not
find a significantly increased prevalence of the mutation in patients
with cerebrovascular disease.10-12 Only in one of these
studies were cerebrovascular risk factors detailed,10 and
only one study also analyzed the presence of the factor V Leiden
mutation in age- and sex-matched control subjects.12 Furthermore, patients were highly selected in one of these
studies,11 with 30 of 125 patients suffering from arterial
dissection as the cause of cerebral infarction. Another study found no
increased prevalence of the prothrombin G20210A mutation in patients
with cerebrovascular disease13; however, a synergistic role
of the prothrombin mutation and the factor V Leiden mutation in the
development of thrombosis was observed. To date, no study has evaluated
the effect of the factor V Leiden mutation and the G20210A prothrombin
mutation in patients with cerebrovascular disease and age- and
sex-matched control subjects under particular consideration of other
vascular risk factors in patients with and without the prothrombin
G20210A mutation.
We investigated the prevalence of the factor V Leiden mutation and the
G20210A prothrombin mutation in 96 patients with transient ischemic
attacks (TIA) or minor strokes (MS; 58 men and 38 women; age
[x ± s], 64.4 ± 13.1 years; range, 28 to 91 years) and in 96 age- (±10 years) and sex-matched control subjects free of clinically manifest vascular disease. Furthermore, we compared history, clinical data, and the prevalence of risk factors for stroke between patients with and without the G20210A prothrombin mutation. All patients underwent cranial computerized tomography, duplex sonography of carotid
and vertebral arteries, and a thorough cardiac investigation (including
electrocardiography, transthoracic echocardiography, as well as
transesophageal echocardiography in selected cases). In addition, all
patients were evaluated with respect to the generally accepted risk
factors for stroke and any coexisting diseases, in particular
coronary heart disease, peripheral arterial disease, and venous
thrombosis. Concerning the presumed etiology of stroke, each
patient was assigned to one of the following four
groups14: lacunar (n = 23; 24.0%); atherothrombotic
(n = 33; 34.4%); cardioembolic (n = 24; 25.0%); or undetermined
(n = 16; 16.6%). The prevalence of the 20210 AG genotype was equal
in patients and in control subjects, with 5 of 96 subjects in each
group (patients: 4 men and 1 woman; mean age, 64 years; control
subjects: 3 men and 2 women; mean age, 63 years; odds ratio [OR],
1.0; 95% confidence interval [CI], 0.52 to 1.91). The prevalence of
the factor V Leiden mutation was 8 of 96 in the patient group (5 men and 3 women; mean age, 60 years) and 5 of 96 in the
control group (3 men and 2 women; mean age, 60 years; OR,
1.65; 95% CI, 0.92 to 2.98). One patient (53-year-old man) and none of
the control subjects was homozygous for the factor V Leiden mutation.
One patient (67-year-old man) and none of the control subjects carried
both mutations. This patient had experienced recurrent cerebrovascular
events (starting at the age of 60 years) and one myocardial infarction (at the age of 65 years) but had no history of venous thrombosis. Coronary artery disease had become manifest at the age of 45 years (angina pectoris). However, this patient also had multiple other vascular risk factors (hypertension, hypercholesterolemia, overweight, and cigarette smoking).
Patients exhibiting the prothrombin wild-type genotype and patients
carrying the G20210A prothrombin mutation were not different with
regard to current age, age at the time of the first cerebrovascular event, or age at the time of the first vascular event
(cerebral/cardiac/peripheral arterial system or venous). Recurrent
cerebrovascular events were reported by 1 of 5 carriers of the 20210 GA
genotype and by 4 of 91 carriers of the wild-type (not significant
[NS]). The prevalence of ischemic cardiac disease was 3 of 5 in carriers of the GA genotype and 28 of 91 in carriers of the GG
genotype (NS). The prevalence of peripheral arterial disease was 1 of 5 in carriers of the GA genotype and 8 of 91 in carriers of the GG
genotype (NS). Two of five patients with the GA genotype and 13 of 91 patients with the GG genotype reported a history of deep-vein
thrombosis (with and without pulmonary embolism; NS). Carotid artery
disease was present in 1 of 5 of the GA patients and in 11 of 91 of the
GG patients. The etiology of the cerebrovascular event in the 5 carriers of the GA genotype was classified as lacunar (n = 1),
atherothrombotic (n = 3), and cardioembolic (n = 1). This
distribution was not significantly different from that in the patients
carrying the wild-type.
Comparing the risk factors for stroke, no significant differences were
found between the two groups with respect to cardiac disease,
hypertension, diabetes mellitus, hypercholesterolemia, hyperfibrinogenemia, alcohol abuse (history), cigarette smoking (recent), history of other drug abuse, and oral contraceptive use.
In conclusion, our data do not suggest a role for the G20210A mutation
as a relevant risk factor for TIA/MS in an unselected group of
patients. We did not find evidence for an effect of the factor V Leiden
mutation or an increased combined occurrence of both mutations in
patients with TIA/MS. In comparison with carriers of the wild-type, the
carriers of the 20210 GA genotype did not show distinct clinical
features or a distinct risk factor profile. The question whether the
G20210A prothrombin mutation, alone or in combination with other
vascular risk factors, increases the risk of cerebrovascular disease
in specific populations (as it could be shown for myocardial
infarction8) remains to be answered in further
studies.
Wolfgang Lalouschek
Susanne Aull
Wolfgang Series
Karl Zeiler
University Clinic for
Neurology
Christine Mannhalter
Department of Laboratory
Medicine
Molecular Biology Division
University Vienna Medical
School
Vienna, Austria
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