From the Service de Neurologie, Hôpital Lariboisière (V.B.,
M.G.B.), and the Service d'Hématologie Biologique, Hôtel
Dieu (J.C., C.B., M.H.H.), Paris, and the Service de Neurologie, Hôpital
de Meaux (A.A.), Meaux, France.
Methods—The 20210A allele of the prothrombin gene was studied
after DNA extraction, polymerase chain reaction amplification, and
HindIII digestion in 35 patients with magnetic resonance
imaging or angiographically confirmed cerebral venous thrombosis (23
women and 12 men, aged 11 to 71 years).
Results—Two patients (5.7%) had the 20210A allele of the
prothrombin gene. Both had other risk factors for thrombosis (use of
oral contraceptives and of intrathecal steroids).
Conclusions—The 20210A allele of the prothrombin gene in
association with other prothrombic factors may increase the risk of
cerebral venous thrombosis, but case-control studies will be necessary
to clarify these associations.
Potential causes and risk factors for CVT were systematically
investigated by clinical examination, neuroimaging, and hematologic
studies including blood cell count, platelets, sedimentation rate,
and coagulation (protein C activity, protein S activity and free
antigen, antithrombin activity, factor V Leiden mutation, lupus
anticoagulant, and anticardiolipin antibodies). The main causes are
summarized in the Table
Prothrombin Gene Polymorphism
Prothrombin Activity
Patient 1 was 50 years old in 1993 when she presented with a
history of seizure-associated headache for 3 days. Her neurological
examination was normal. CT of the brain showed a spontaneously
hyperdense lesion in the left parietal lobe consistent with
hemorrhage. MRI demonstrated occlusion of the superior sagittal
sinus. She was treated with sodium valproate and heparin and then with
warfarin for 3 months. She recovered within a few days. Her medical
history was unremarkable, and at the time of CVT, she had been taking
the same oral contraceptive (ethinyl estradiol 50 µg plus
levonorgestrel 0.5 mg) for 20 years. The patient's mother had
had a history of recurrent episodes of deep vein thrombosis when she
was 50 years old. She had died at 75 and blood samples were not
available for a coagulation work-up. The patient has 1 brother and 1
son, and none had participated in a coagulation study.
Patient 2 was 29 years old in 1994 when he complained of headache,
seizures, and transient left hemiparesis. These symptoms occurred a few
days after an intrathecal injection of steroids for sciatic
neuropathy. CT of the brain was normal. MRI showed
occlusion of both lateral sinuses. He was treated with sodium valproate
and heparin and then with warfarin for 3 months. He recovered within a
few days. There was no family history of thrombosis. Factor II activity
was 1.18 U/mL in patient 1 but could not be measured in patient 2.
Patients without the 20210A polymorphism had factor II activity
levels between 0.87 and 1.20 U/mL.
One of our patients had a family history of venous thrombosis, and in
both, it was the first personal episode of venous thrombosis. Both had
other risk factors for venous thrombosis: 1 had received
intrathecal steroids a few days before the onset of CVT,
and the other was taking oral
contraceptives.3 13 14 15 It has already been
emphasized that in patients with thrombophilia and CVT, there is
usually another cause or risk
factor,4 5 6 7 8 10 13 14 15 16 17 as in our previous series
of 40 CVT patients.4 Six had thrombophilia
(factor V Leiden mutation in 4, protein S deficiency in 1, and protein
C deficiency in 1), and among them, 5 had another risk factor for
venous thrombosis (1 with uveomeningitis, 1 with systemic lupus
erythematosus, 1 with primary antiphospholipid
syndrome, 1 with nephrotic syndrome, and 1 who had received high-dose
intravenous steroids before the onset of CVT). This
suggests that congenital thrombophilia, including prothrombin gene
polymorphism, should be investigated in patients with CVT, whether
a risk factor is detected or not. In our 2 patients the 20210
polymorphism was the only genetic abnormality. By contrast, the
factor V Leiden mutation was present in addition to the 20210A
allele in 40% of the patients reported by Poort et
al8 and in 34% of the patients reported by
Hillarp et al.9 Studies in selected families with
venous thrombosis indicate that the association of these 2 mutations
increase the frequency of venous
thrombosis.8 9 16 17 18
Poort et al8 found that the factor II activity
level was above the highest quartile (>1.15 U/mL) in 87% of the
patients with the prothrombin gene mutation. However, the measurement
of factor II levels in plasma cannot be used as a screening test. It is
not appropriate in patients who are being treated with oral
anticoagulants, since factor II is a vitamin K–dependent protein. In
addition, factor II may be increased in various conditions, such as
during pregnancy or oral contraception. In our series, the factor II
level was similar in patients with (1.18 U/mL) and without (up to 1.20
U/mL) the mutation.
The consequences of detecting the prothrombin gene polymorphism may
be important for the treatment and follow-up of patients with CVT,
although the optimal duration of anticoagulation in patients with a
first episode of venous thrombosis presently remains unknown. As in
other thrombophilias, it seems reasonable to avoid the use of oral
contraceptives, to eventually start preventive treatment in
prothrombotic situations (surgery, pregnancy, etc), and to study other
family members, since the mutation is transmitted as an autosomal
dominant trait.10
These results suggest that the 20210A allele of the prothrombin
gene in association with other prothrombic factors may increase the
risk of CVT. However, case-control studies will be necessary to allow
more precise determination of the causal relationship and the size of
the clinical risk.
Correspondence to Pr Marie Germaine Bousser, Hôpital Lariboisière, Service de Neurologie, 2 rue Ambroise Paré, 75010 Paris, France.
Received February 19, 1998;
revision received April 7, 1998;
accepted April 7, 1998.
2.
Einhaüpl KM, Masuhr F. Cerebral venous and sinus
thrombosis: an update. Eur J Neurol. 1994;1:109–126.
3.
Bousser MG, Russell RR. Cerebral Venous
Thrombosis. London, England: Saunders; 1997.
4.
Deschiens MA, Conard J, Horellou MH, Ameri A, Preter
M, Chedru F, Samama MM, Bousser MG. Coagulation studies, factor V
Leiden, and anticardiolipin antibodies in 40 cases with cerebral venous
thrombosis. Stroke. 1996;27:1724–1730.
5.
Zuber M, Toulon P, Marnet L, Mas JL. Factor V Leiden
mutation in cerebral venous thrombosis. Stroke. 1996;27:1721–1723.
6.
Brey RL, Coull BM. Cerebral venous thrombosis: role of
activated protein C resistance and factor V gene mutation.
Stroke. 1996;27:1719–1720.
7.
Martinelli I, Landi G, Maerati G, Cella R, Tosetto A,
Mannucci PM. Factor V gene mutation is a risk factor for cerebral
venous thrombosis. Thromb Haemost. 1996;75:393–394.[Medline]
[Order article via Infotrieve]
8.
Poort SR, Rosendaal FR, Reitsma PH, Bertina R. A
common genetic variation in the 3'-untranslated region of the
prothrombin gene is associated with elevated plasma prothrombin levels
and increase in venous thrombosis. Blood. 1996;88:3698–3703.
9.
Hillarp A, Zöller B, Svensson PJ, Dahlbäck
B. The 20210 A allele of the prothrombin gene is a common risk
factor among Swedish outpatients with verified deep venous thrombosis.
Thromb Haemost. 1997;78:990–992.[Medline]
[Order article via Infotrieve]
10.
Bloem BR, van Putten MJAM, v d Mer FJR, van Hilten JJ,
Bertina RM. Superior sagittal sinus thrombosis ina patient heterozygous
for the novel 20210A allele of the prothrombin gene. Thromb
Haemost. 1998;79:235. Letter.[Medline]
[Order article via Infotrieve]
11.
Bentolila S, Ripoll L, Drouet L, Mazoyer E, Woimant F.
Thrombophilia due to 20210 G
12.
Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH,
Hay CRM. The prothrombin gene 20210A variant: prevalence in a UK
anticoagulant clinic population. Br J Haematol. 1997;98:353–355.[Medline]
[Order article via Infotrieve]
13.
Lane DA, Mannucci PM, Bauer KA, Bertina RM,
Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK,
Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia: part
I. Thromb Haemost. 1996;76:651–662.[Medline]
[Order article via Infotrieve]
14.
Lane DA, Mannucci PM, Bauer KA, Bertina RM,
Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK,
Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia: part
II. Thromb Haemost. 1996;76:824–834.[Medline]
[Order article via Infotrieve]
15.
Wilder-Smith E, Kothbauer-Margreiter I, Lämmle B,
Sturzenegger M, Ozdoba C, Hauser S. Dural puncture and
activated protein C resistance: risk factors for cerebral
venous sinus thrombosis. J Neurol Neurosurg Psychiatry. 1997;63:351–356.
16.
Miletich JP, Prescott SM, White R, Majerus PW, Bovill
EG. Inherited predisposition to thrombosis. Cell. 1993;72:477–480.[Medline]
[Order article via Infotrieve]
17.
De Stefano V, Finazzi G, Mannuci PM. Inherited
thrombophilia: pathogenesis, clinical syndromes and management.
Blood. 1996;87:3531–3544.
18.
Conard J, Mabileau-Brouzes C, Horellou MH, Elalamy I,
Samama MM. Multigenic thrombophilia: genetic anomaly of factor II and
mutation of factor V Leiden: study in a French family. Presse
Méd. 1997;26:951–953.
© 1998 American Heart Association, Inc.
Original Contributions
Frequency of the 20210 G
A Mutation in the 3'-Untranslated Region of the Prothrombin Gene in 35 Cases of Cerebral Venous Thrombosis
Abstract
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Background and Purpose—A novel
sequence variation in the 3'-untranslated region of the prothrombin
(factor II) gene (nucleotide 20210 GA) has been recently
described as a risk factor for deep vein thrombosis and
pulmonary embolism. It is found in 
1% to 4% of healthy
subjects. We studied the frequency of this factor II variant in
patients with cerebral venous thrombosis.
Key Words: cerebral veins • venous thrombosis • thrombophilia
Introduction
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Numerous causes and
predisposing conditions have been associated with cerebral venous
thrombosis (CVT). They include all surgical, obstetric, and medical
causes of deep vein thrombosis as well as a number of local or regional
causes, either infective or noninfective. Despite the continuous
description of new causes, the proportion of cases of unknown etiology
remains high, from 20% to 35%.1 2 3 Congenital
coagulation disorders, such as protein C, protein S, and antithrombin
deficiencies, have been reported in patients with
CVT.3 More recently, resistance to
activated protein C has been identified as a possible new cause
of CVT.4 5 6 7 Poort et al8
have described a novel sequence variation in the 3'-untranslated region
of the prothrombin (factor II) gene (nucleotide 20210
GA), which is associated with an increased risk of deep vein
thrombosis and pulmonary embolism.8 9
Only 1 case with CVT associated with a 20210A genotype of the
prothrombin gene has been reported.10 The aim of
our study was to determine the frequency of this factor II
polymorphism in a series of 35 patients with CVT and to assess any
associated cause or risk factor for CVT.
Subjects and Methods
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Subjects
Thirty-five patients (23 women and 12 men) aged 11 to 71 years
(mean±SD, 35.6±13.1 years) who were seen from 1989 to 1997 in 2
neurology departments were studied. CVT was diagnosed by MRI, MR, x-ray
angiography, or some combination thereof. Thirty of these patients had
already participated in a previously published
study.4 All gave their fully informed consent to
participate in the current study. 
.
View this table:
[in a new window]
Table 1. Etiologies of Cerebral Venous Thrombosis in 35 Patients Tested
for the 20210A Factor II Polymorphism
The coagulation study was performed in 1997, from 2 weeks to 8
years after CVT. Blood was collected into tubes containing 0.129 mol/L
sodium citrate (1:9, vol/vol). After centrifugation at
2000g for 20 minutes, cells were frozen at -30°C. The
20210A allele of the prothrombin gene was studied after DNA
extraction, polymerase chain reaction amplification, and
HindIII digestion, as described by Poort et
al.8
Prothrombin activity was measured in citrated plasma by using a
chronometric method with rabbit thromboplastin and factor II–deficient
plasma (Neoplastine, Diagnostica Stago). This test could
not be performed in 11 patients who were receiving oral anticoagulants
at the time of blood sampling but was possible in 18 patients (no
samples were available for the other 6).
Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
Two patients (5.7%) had the 20210 A allele of the prothrombin
gene. None was in the "idiopathic" group of 10 patients. Both had
other risk factors for thrombosis (use of oral contraceptives and of
intrathecal steroids, respectively; see the Table
).
Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
In this series of 35 patients with CVT, 2 (5.7%) had the 20210
GA mutation in the 3'-untranslated region of the prothrombin gene.
Prothrombin is the precursor of serine protease thrombin, a key enzyme
in the processes of hemostasis and thrombosis, that exhibits
procoagulant, anticoagulant, and antifibrinolytic activities.
Prothrombin is encoded by a 21-kb-long gene localized on chromosome 11,
position 11p11-q12. The prothrombin gene is organized into 14 exons,
separated by 13 introns with the 5'-upstream translated region and the
3'-untranslated region, which may play regulatory roles in gene
expression.8 9 Poort et al8
recently examined the prothrombin gene as a candidate gene for venous
thrombosis and found a GA transition at nucleotide
position 20210 in the 3'-untranslated region of the prothrombin gene in
18% of selected Dutch patients with a personal and family history of
venous thrombosis, in 6.2% of unselected consecutive patients with a
first episode of deep vein thrombosis, and in 2.3% of healthy control
subjects. More recently, Hillarp et al9 published
similar results. They found the 20210A factor II polymorphism in
7.1% of 99 Swedish patients with deep venous thrombosis and in 1.8%
of 282 healthy controls. Bentolila et al11 found
this polymorphism in 3.7% of 134 young, healthy French control
subjects. Cumming et al12 found the 20210A
allele in 5.5% of 219 patients with deep venous thrombosis or
pulmonary embolism and in 1.2% of 164 healthy controls. The
frequency found in the present series of CVT (5.7%) is thus in
accord with the series of deep vein
thrombosis,8 9 10 11 12 suggesting that this prothrombin
polymorphism may be another risk factor for CVT.
Footnotes
Reviews of this manuscript were directed by Mark L. Dyken, MD.
References
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References
1.
Ameri A, Bousser MG. Cerebral venous thrombosis.
Neurol Clin. 1992;10:87–111.[Medline]
[Order article via Infotrieve]A prothrombin polymorphism and
cerebral ischemia in the young. Stroke. 1997;28:1846–1847.
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