Cerebral thrombosis

Introduction

Epidemiological studies have shown that oral contraceptives

carry a small but increased risk of venous

thromboembolism (deep vein thrombosis and pulmonary

embolism).[1] Furthermore, women who use oral

contraceptives and carry die factor V Leiden mutation

have a higher risk of venous thromboembolisin than

expected from the mere addition of these risks.[2]

Although the association between oral contraceptives

and venous thromboembolism is generally accepted,

there remains discussion about possible sources of bias

that might influence the magnitude of the risk.

Cerebral venous sinus thrombosis is a relatively

rare disease, often with cerebral infarcts, which may

lead to seizures, other neurological symptoms, or

death. Patients with sinus thrombosis, however, may

recover completely.[3] Oral contraceptives and hereditary

prothrombotic conditions, such as protein C, S,

and antithrombin, deficiency and factor V Leiden

mutation, have been reported as possible causes of cerebral

sinus thrombosis.[4]

We compared a series of patients with cerebral

venous sinus thrombosis from a prospective treatment

trial with population data from the Netherlands to

investigate the risk of oral contraceptive use and

prothrombotic conditions for cerebral sinus thrombosis.

Patients and methods

Cases

Cases were patients with cerebral sinus thrombosis

(newly diagnosed) who participated in a treatment trial

from July 1992 to November 1996 that compared low

molecular weight heparin in a therapeutic dose with

placebo in a randomised double blind design. Patients

younger than 18 years and pregnant women were

excluded. The trial was conducted in neurological

teaching hospitals in different regions in the Netherlands

and the United Kingdom. Cerebral sinus thrombosis

was confirmed by conventional angiography or

magnetic resonance imaging and angiography. For the

present analysis we selected all women aged 18-54

from the Dutch part of the trial population who were

not in the puerperium (within 30 days post partum).

Information on use of oral contraceptives at the

time of the initial symptoms of sinus thrombosis was

obtained from the patient or nearest relative and supplemented

with hospital discharge letters.

Blood samples were collected and analysed in the

participating hospitals. Antithrombin activity and protein

C activity were measured with chromogenic

assays.[5] Protein C antigen, and total and free protein S

were determined by enzyme linked immunosorbent

assay (ELISA) as described elsewhere.[6 7] Values were

defined as abnormal if they were below the 5th centiles

of the values determined in a group of healthy subjects.

Resistance to activated protein C was assessed by the

activated protein C dependent prolongation of the

activated partial thromboplastin time.[8] An activated

protein C ratio below 2.0 or a normalised ratio lower

than 0.80 was considered abnormal. The mutation at

position Arg 506 in factor V was determined with

polymerase chain reaction techniques as described

previously.[9]

Controls

The controls comprised a random sample of 2248

women aged 18-49 years from different regions in the

Netherlands who were interviewed in 1994 about their

current use of contraceptives (continuous health interview

survey of the Central Department of Statistics of

the Netherlands[10]; the methodology of the questionnaire

has been described previously[11]).

Statistics

We calculated odds ratios as approximations of relative

risks on the basis of the crude numbers or the percentage

distribution; confidence intervals, when appropriate,

were calculated by the methods of Woolf or

Robins.[12] When observed odds were compared with

estimated population frequencies we omitted the

calculation of the confidence intervals.

Results

Forty women with cerebral sinus thrombosis who met

the inclusion criteria were studied. The age related use

of oral contraceptives in cases and controls and the

prevalence of hereditary coagulation abnormalities in

the cases are given in the table.

Use of oral contraceptives and prothrombotic disorders in cases

(women with cerebral venous sinus thrombosis aged 18-54 years,

puerperium excluded) and use of oral contraceptives in controls

disorder. In addition, we found that the use of

contraceptives multiplies the risk of hereditary

prothrombotic: conditions.

Sources of bias

Before evaluating the clinical significance of our

findings we must consider potential sources of bias.

Because the cases were obtained in a treatment trial

and the controls were a representative sample of the

population, can the cases really be regarded as

originating from the general population base? As all

major neurological centres in the Netherlands, to

which patients with sinus thrombosis are referred,

participated in the trial the patients in the trial are

representative of all patients with sinus thrombosis in

the Netherlands. As there was no selection as to use of

oral contraceptives or any other characteristic that

might be related to use of contraception, the use of

contraceptives in these patients can be validly

compared with population data.

Pregnant women were excluded from the trial, and

women in the puerperium or with a recent miscarriage

were excluded from the analysis but not from the controls.

Therefore oral contraceptive use in the controls

might be slightly underestimated. The estimated

percentage of premenopausal women who were pregnant

or in the puerperium in the Netherlands was 5%

in 1994,[10] which is too small to affect our results.

As sinus thrombosis is a rare condition the chance

that women with this disease were present in the control

group is fairly small. According to the British registrar

general the average mortality during the period

1952-61 from sinus thrombosis was 0.4/[10.sup.6]/year.[16] If

we assume a mortality of 10%, the incidence would be

4/[10.sup.6]/year.

Diagnostic suspicion and referral bias might occur

if doctors were more likely to diagnose sinus thrombosis

in women taking oral contraceptives. Women taking

contraceptives might be under better medical supervision,

and contraceptive use is known to increase the

risk of venous thromboembolism. This type of bias has

been suggested for deep vein thrombosis.[17] For sinus

thrombosis this bias seems unlikely. Sinus thrombosis

is a rare and alarming disease, often with severe

neurological symptoms.[3] It seems reasonable to

assume that all patients with sinus thrombosis are

referred to a hospital, irrespective of oral contraceptive

use. Misdiagnosis in our patients is unlikely because

conventional angiography or magnetic resonance

imaging, which are regarded as reliable diagnostic procedures

for sinus thrombosis,[18] were used in all cases.

Known risk factors

In various case series oral contraceptive use alone[19] or

superimposed on a hereditary prothrombotic disorder

has been suggested as an aetiological factor for sinus

thrombosis. A recent Italian case-control study in

patients with sinus thrombosis found an odds ratio for

oral contraceptive use of 4.2, after exclusion of

pregnant and puerperal women. The presence of the

factor V Leiden mutation in itself increased the risk for

sinus thrombosis about ninefold.[20 21]

Other probable risk factors for sinus thrombosis

are pregnancy and puerperium.[3] In our treatment trial

seven women in the puerperium were included. Many

other risk factors for sinus thrombosis have been

reported in retrospective series, including the known

risk factors for deep vein thrombosis, but a significant

association with sinus thrombosis has not been

demonstrated. The influence of smoking--if any--is

unknown.

There is ample evidence that oral contraception

predisposes to venous thromboembolism,[1 17] especially

when the factor V Leiden mutation is present.[2] The risk

of leg vein thrombosis in women with the mutation

who use oral contraceptives compared with women

without the mutation who do not, increases more than

30-fold.[2] The tentative analysis of the interaction

between oral contraceptive use and hereditary

prothrombotic conditions in our study points in the

same direction.

Recently, a biological explanation of the increased

risk for venous thrombosis in oral contraceptives users

was reported.[22] In this study the effects of activated

protein C on thrombin generation in the plasma of

women using oral contraceptives were compared with

the response in women not using oral contraceptives

and in women heterozygotic or homozygotic for the

factor V Leiden mutation. Oral contraceptives induced

a degree of activated protein C resistance comparable

with the resistance caused by a factor V Leiden mutation.

In women heterozygotic for factor V Leiden

mutation who used contraceptives the activated

protein C resistance was as high as that among women

homozygotic for the mutation.[22] These results fit with

the epidemiological data, including those from our

series of patients with cerebral venous thrombosis, and

are an additional argument against objections that the

epidemiological findings are merely explained by prescription

bias or other sources of confounding.

That sinus thrombosis is predominantly a disease

of women was already clear from recent retrospective

series.[23] A comparison with sex distribution in larger

series in the past, which showed no or a much less

marked predominance of women in sinus thrombosis,[24]

suggests a shift in the epidemiology and aetiology

of the disease in recent years. Possibly the widespread

use of oral contraceptives has caused this increasing

relative number of women with sinus thrombosis.

Conclusion

We conclude that the major risk factors for deep vein

thrombosis and cerebral venous sinus thrombosis in

women are the same. As the absolute risk for sinus

thrombosis in premenopausal women is low, with an

estimated incidence of 4/[10.sup.6]/year, our findings should

not be used to advise against oral contraceptive use in

all women. In women who have a history of venous

thrombotic disease, including sinus thrombosis, however,

advice against use of oral contraceptives should

be considered, especially in women with a hereditary

prothrombotic disorder

The Cerebral Venous Sinus Thrombosis Study Group

comprised S F T M de Bruijn, J Stam, A W A Lensing, J G P

Tijssen, P M Bossuyt, LJ Kappelle, J Van Gijn, D W J Dippel,

PJ Koudstaal, JJ Van Hilten, R A C Roos, J L A Eekhof, JJ Van

der Sande, H L Hamburger, J Lodder, C C Tijssen, F W Bertelsman,

J C Koetsier, P Sandercock, P Humphrey, G N Mallo,

P Verlooy, H K Van Walbeek, J W Snoek, and C L Franke.

We thank M Budde for help in collecting patient data and blood

samples; C Hooykaas, H van der Heide, and G C G Verweij for

kindly providing control data; and M Vermeulen, H R Buller,

and W A van Gool for their useful comments.

Contributors: SFTMdeB, JS, and JPV formulated the

research hypothesis, designed the study, analysed the data, and

wrote the paper MMWK analysed the data on prothrombotic

disorders and helped to write the paper SFTMdeB collected

and checked all data on use of contraceptives and prothombotic

disorders, assisted by M Budde. SFTMdeB, JS, and JPV are

guarantors for the paper.

Funding: The treatment trial was partly funded by Sanofi

Winthrop.

Conflict of interest: None.

[1] World Health Organization Collaborative Study of Cardiovascular 24

Disease and Steroid Hormone Contraception Venous thromboembolic:

disease and combined oral contraceptives: results of international multicentre

case-control study. Lancet 1995;346:1575-82.

[2] Vandenbroucke JP, Koster T, Briet F, Reitsma PH, Bertina RM, Rosendaal

FR. Increased risk of venous thrombosis in oral-contraceptive users who

are carriers of factor V Leiden mutation. Lancet 1994;344:1453-7.

[3] Bousser M, Chiras J, Bories J, Castaigne P. Cerebral venous thrombosis: a

review of 38 cases. Stroke 1985;16:199-213.

[4] Deschiens MA, Conard J, Horellou MH, Ameri A, Preter M, Chedru F,

et al. Coagulation studies, factor V Leiden, and anticardiolipin antibodies

in 40 cases of cerebral venous thrombosis. Stroke 1996;27:1724-30.

[5] Peters M, Breederveld C, Kahle LH, ten Cate JW. Rapid microanalysis of

coagulation parameters by automated chromogenic substrate methods,

application in neonatal patients. Thromb Res 1982;28:773-81.

[6] Boyer C, Rothschild C, Wolf M, Amiral J, Meyer D, Larrieru M. A new

method of estimation of protein C by ELISA. Thromb Res 1984;36:579-89.

[7] Deutz-Terlouw PP, Ballering L, Wijngaarden vA, Bertina RM. Two

ELISAs for measurement of protein S, and their use in the laboratory

diagnosis of protein S deficiency. Clin Chim Acta 1989; 186:321.

[8] Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a

previously unrecognized mechanism characterized by poor anticoagulant

response to activated protein C. Proc Natl Acad Sci USA

1993;90:1004-8.

[9] Voorberg J, Roelse J, Koopman R. Association of idiopathic venous

thromboembolism. with single point mutation at Arg 506 of factor V.

Lancet 1994;343:1535-6.

[10] CBS; Nederlands Instituut voor onderzoek van de Eerstelijnsgezondheidszorg;

Inspectie voor de Gezondheidszorg. Enkele vormen van

gehoortenregeling. In: Centraal Bureau voor de Statistiek.

Statistisch jaarboek 1996. The Hague: SDU, 1996:502.

[11] Statistics Netherlands. Netherlands health interview survey 1981-1995. The

Hague: SDU, 1996.

[12] Rothman KJ. Modern epidemiology. Boston: Little, Brown, 1986.

[13] Ridker PM, Miletich JP, Hennekkens CH, Buring JE. Ethnic distribution of

factor V Leiden m 4047 men and women. Implications for venous

thromboembolism screening. JAMA 1997;277:1305-7.

[14] Hach-Wunderle v Scharrer I. Pravalenz des hereditaren Mangels an

Antithrombin III, Protein C und Protein S. Deutschen Medischen

Wochenschrift 1993;118:187-90.

[15] Tait RC, Walker ID, Reitsma PH, Islam SI, McCall F, Poort SR, et al.

Prevalence of protein C deficiency in the healthy population. Thromb Haemost

1995;73:87-93.

[16] Kalbag RM, Woolf AL. Cerebral venous thrombosis London: Oxford

University Press, 1967.

[17] Realini JP, Goldzielier JW. Oral contraceptives and cardiovascular disease:

a critique of the epidemiologic studies. Am J Obstet Gynecol 1985;152:

729-98.

[18] Dormont D, Anxionnat C, Evrard S, Louaille C, Chiras J, Marsault C. MRI

in cerebral venous thrombosis. J Neuroradiol 1994;21:81-99.

[19] Buchanan LTCDS, Brazinsky MAJJH. Dural sinus and cerebral venous

thrombosis Incidence in young women receiving oral contraceptives. Arch

Neurol 1970;22:440-4.

[20] Martinelli I, Landi G, Merati G, Cella R, Tosetto A, Mannucci PM. Factor

V gene mutation is a risk factor for cerebral venous thrombosis. Thromb

Haemost 1996;75:393-4.

[21] Martinelli I, Rosendaal FR, Vandenbroucke JP, Mannucci PM. Oral

contraceptives are a risk factor for cerebral vein thrombosis [letter].

Thromb Haemost 1996;76:477-8.

[22] Rosing J, Tans G, Nicolaes GA, Thomassen MC, van Oerle F, van der

Ploeg PM, et al. Oral contraceptives and venous thrombosis: different

sensitivities to activated protein C in women using second- and third

generation oral contraceptives. Br J Haematol 1997;97:233-8.

[23] Zuber M, Toulon P, Marnet L, Mas J. Factor V Leiden mutation in cerebral

venous thrombosis. Stroke 1996;27:1721-3.

[24] Krayenbuhl HA. Cerebral venous and sinus thrombosis. Clin Neurosurg

1966;14:1-24.

(Accepted 11 November 1997)

RELATED ARTICLE: Key messages

* The use of oral contraceptives is associated with

an increased risk of cerebral venous sinus

thrombosis

* This risk of cerebral venous sinus thrombosis in

women who use oral contraceptives is larger if

there is an additional hereditary prothombotic

factor (protein Q S, or antithrombin deficiency,

factor V Leiden mutation)

* The association between oral contraceptives,

thrombophilia, and deep vein thrombosis is

also valid for cerebral sinus thrombosis

* Women do not need to stop using oral

contraceptives as die absolute risk of cerebral

sinus thrombosis is very small

RELATED ARTICLE: Fifty years ago The new NHS: The press and the profession

Speaking at die opening of the East Glamorgan County Hospital

on Saturday, Mr. Aneurin Bevan, the Minister of Health gave this

advice to doctors: "Do not allow your minds to be inflamed or

your judgment to be distorted by slogans which are addressed to

your emotions and not to your intelligence." This sound piece of

advice is perhaps hardly necessary for members of a profession

used to making a differential diagnosis. The doctor uses the

methods of science, and the politician the technique of the

hustings. At this moment the medical profession is being

subjected to abuse, misrepresentation, and malicious innuendo

from the highly emotional press which supports Mr. Bevan. This

campaign was started by the Tribune, of which Mr. Bevan was a

director and editor until he took office in the present

Government in 1945. The Tribune suggested that "the BMA may

still try to fight the battle of the Tory Party against the

development of a socialist service," and it went on to state:

"Politically, the Minister's firmness has been most important. If he

had been weak in face of this reactionary profession ... it would

have increased doubts as to the intention to carry out a socialist

programme."

(Editorial, 24 January 1948, p 155. See also editorial by Gordon

Macpherson, 3 January 1998, p 6.)

Department of

Neurology,

Academic Medical

Centre, PO Box

22700, 1100 DE

Amsterdam,

Netherlands

SFTM de Bruijn,

senior registrar in

neurology

J Stam,

professor of neurology

Department of

Vascular Medicine,

Academic Medical

Centre, Amsterdam

M M W Koopman,

Internist

Department of

Clinical

Epidemiology,

University hospital,

Postbus 9600,2300

RC Leiden,

Netherlands

J P Vandenbroucke,

professor of clinical

epidemiology

Correspondence to:

Professor Stam

j.stam@amc.uva.nl

BMJ 1998;316:589-92

COPYRIGHT 1998 British Medical Association
COPYRIGHT 2000 Gale Group