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(Stroke. 1996;27:1721-1723.)
© 1996 American Heart Association, Inc.

Articles

Factor V Leiden Mutation in Cerebral Venous Thrombosis

Mathieu Zuber, MD; Pierre Toulon, PhD; Laurence Marnet Jean-Louis Mas, MD

the Service de Neurologie, Centre R. Garcin, Hopital Sainte-Anne (M.Z., J.-L.M.), and Laboratoire d'Hemostase, Hopital Cochin (P.T., L.M.), Paris, France.

	Abstract

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Background and Purpose Resistance to activated protein C is a common inherited risk factor for venous thrombosis, which is due to a mutation in coagulation factor V (factor V Leiden mutation). It is present in approximately 20% of unselected consecutive patients with deep vein thrombosis. The rate of resistance to activated protein C in patients with cerebral venous thrombosis (CVT) is unknown.

Methods We investigated the association of factor V mutation with CVT using a case-control study. Nineteen unselected patients with CVT and 57 healthy control subjects were tested for the point mutation.

Results The mutation was found in a heterozygous form in 4 of the 19 patients with CVT (21%) and in only 1 of the 57 control subjects (2%) (P=.02, Fisher's exact test). The prevalence of the coagulation defect found in our patients with CVT was consistent with that observed in previous studies in patients with deep vein thrombosis. In 3 of the 4 patients positive for the mutation, CVT developed in the presence of an acquired prothrombotic state, including oral contraceptive use in 2 patients and puerperium in the third.

Conclusions Factor V Leiden mutation is a risk factor for CVT and may be the most common inherited coagulation defect associated with this condition.

Key Words: coagulation • genetics • hereditary disease • sinus thrombosis

	Introduction

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A new pathological condition termed activated protein C (APC) resistance has been recently reported to be a common risk factor for venous thromboembolism.^{1 2 3 4 5} The anticoagulant property of APC lies in its capacity to inactivate the activated cofactors Va and VIIIa by limited proteolysis. In APC resistance, the patient's plasma does not exhibit the normal anticoagulant response to the addition of APC, as reflected in a prolongation of the activated partial thromboplastin time (APTT). This coagulation disorder is almost always associated with a single point mutation in one or both alleles of the factor V gene (adenine substituted for guanine at nucleotide 1691, the so-called Leiden mutation) at the site controlling APC cleavage and inactivation of clotting factor V.^{6 7}

APC resistance is the most common inherited factor thus far recognized that predisposes patients to venous thrombosis. It is present in approximately 20% of unselected consecutive patients with deep vein thrombosis and in 3% to 7% of healthy individuals.^{2 3 4 5} Individuals with APC resistance have a 2.7- to 7-fold increased risk of venous thrombosis.^{2 4} A few case reports suggest a possible association of the coagulation defect with ischemic stroke,^{8 9} but APC resistance was not found to be a significant risk factor for stroke or myocardial infarction in case-control studies.^{4 10} Cerebral venous thrombosis (CVT) is a rare condition whose etiology remains unknown in 20% to 35% of cases.¹¹ We investigated the association of factor V mutation with CVT using a case-control study.

	Subjects and Methods

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From 1990 to 1996, 23 patients with CVT were included in the Stroke Registry of Sainte-Anne Hospital (Paris, France). The 23 patients were contacted by mail, and 19 gave informed consent to participate in the present study. The diagnosis of CVT was determined by angiography (n=1), MRI (n=3), or both (n=15). Angiographic findings diagnostic of CVT included, in addition to complete or partial lack of filling of one or several sinuses, occlusion of cerebral veins or indirect signs of venous thrombosis such as delayed emptying and the development of a collateral circulation.¹² MRI studies in 18 patients showed increased signal from the lumen of the affected sinus on at least two planes of section and on both T₁- and T₂-weighted sequences corresponding to an intermediate-stage thrombus.^{13 14} Clinical features included headaches (n=17), focal deficits (n=13), seizures (n=8), disorders of consciousness (n=4), and papilledema (n=4). All patients had brain CT scan, which showed hemorrhagic infarction in 12. Previous personal and family history of thrombosis and recent conditions predisposing to CVT such as pregnancy/puerperium, surgery, oral contraceptive use, and head injury were recorded. All patients underwent a standard etiologic workup including complete blood cell count, erythrocyte sedimentation rate, protein electrophoresis, prothrombin time, APTT, fibrinogen, antinuclear antibodies, and search for regional infection. Antithrombin, protein C, and protein S were measured in all cases with a functional method. Antiphospholipid antibodies were assessed in 16 patients with a standardized enzyme-linked immunosorbent assay.¹⁵ The diagnosis of lupus anticoagulant was assessed according to the recent recommendations of French specialized laboratories¹⁶ With regard to general infective or noninfective causes of CVT, appropriate investigations were performed according to clinical findings.

Each patient was asked to find a healthy control subject according to the following criteria: same age (±5 years), no biological relationship, and no history of cerebrovascular event. Thirty-eight blood donors were randomly recruited as additional control subjects. Overall, each patient was matched with three control subjects of the same age (±5 years) and sex. Three patients and no control subject received oral anticoagulation at the time of the study.

All patients and control subjects were tested for the factor V Leiden mutation. Venous blood was collected into evacuated tubes containing 0.129 mol/L trisodium citrate 1:9 (Venoject VT-050SCB, Terumo-Europe). Leukocytes were isolated within 48 hours and stored frozen until DNA extraction. The detection of the transition G to A at nucleotide 1691 of the factor V gene was performed as previously described.¹⁷ Briefly, the method comprises amplification of the factor V gene exon 10 with a modified nucleotide, permitting the introduction of a cleavage site for the restriction endonuclease HindIII in the fragment bearing the mutation. Evaluation of the poor anticoagulant response to APC in patients with factor V Leiden mutation was performed with an APTT-based assay (Coaset APC resistance, Chromogenix). Results were expressed as the (APTT+APC)/(APTT-APC) ratio.²

Fisher's exact test was used to compare the prevalence of factor V mutation in patients and control subjects.

	Results

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The factor V Leiden mutation was found in a heterozygous form in 4 of the 19 patients (21%) and in 1 of the 57 control subjects (2%) (P=.02, Fisher's exact test). No patient with the mutation reported a family history of thrombosis. The main characteristics of patients with and without factor V mutation are summarized in the Table. The (APTT+APC)/(APTT-APC) ratios were 1.60, 1.63, 1.64, and 1.94 in the 4 patients with the mutation (normal laboratory value, >2.0) and 1.96 in the control subject with the mutation. None of the 5 subjects received oral anticoagulation at the time of the functional assay. Coagulation studies were otherwise normal, except for the presence of a lupus anticoagulant in 1 patient negative for factor V mutation.

View this table: [in this window] [in a new window]   Table 1. Main Characteristics of 19 Patients With Cerebral Venous Thrombosis, According to Presence or Absence of Factor V Leiden Mutation

In 3 of the 4 mutation carriers, CVT developed in the presence of an acquired prothrombotic state, including oral contraceptive use in 2 patients and puerperium in the third. The fourth patient, a 70-year-old man, had an inaugural CVT involving the superior sagittal and the right lateral sinuses. Two months later, while he was still on anticoagulants, he had an ischemic stroke in the middle cerebral artery territory due to occlusion of the internal carotid artery. This patient had a poor general state, but extensive investigations failed to demonstrate an underlying neoplasm or a nonmalignant systemic disease. A prothrombotic state was found in 10 of the 15 patients without the mutation for factor V (Table).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The present study showed that patients with CVT had a significantly higher prevalence of factor V Leiden mutation in a heterozygous form (21%) than did the control subjects (2%) (P=.02, Fisher's exact test). These results are similar to those recently reported by Martinelli et al,¹⁸ who found the point mutation in 5 of 25 CVT patients (20%) compared with 2 of 75 control subjects (2.7%). Both studies strongly suggest that the factor V Leiden mutation is a risk factor for CVT. The prevalence of the coagulation defect found in CVT patients is consistent with that observed in patients with deep vein thrombosis. In these patients, the prevalence of factor V mutation ranged from 12% to 20%, a rate significantly higher than in the general population (3% to 6%).^{4 5}

Factor V Leiden mutation is inherited as an autosomal dominant trait.² Homozygous individuals can be expected with a prevalence of approximately 2 per 10 000 births, and most of them will experience at least one thrombotic event in their lifetime.⁵ By contrast, most heterozygous individuals do not have clinical thrombotic complications, which suggests that clinical thrombosis results from the unfortunate convergence of an inherited predisposition to thrombosis with an acquired thrombogenic stimulus.^{19 20} In the Leiden Thrombophilia Study,²¹ the combined effect of oral contraceptive use and heterozygous carriage of the factor V mutation was responsible for a 30-fold increase of the risk of deep vein thrombosis in women with both factors compared with those with none, corresponding to a multiplicative effect of the separate relative risks. In our study, 3 women heterozygous for factor V had an associated prothrombotic state, including oral contraceptive use in 2 patients and puerperium in the third. An underlying prothrombotic disease was also suspected (but not proved) in the fourth patient, who had a poor general state and recurrent thromboses. Since resistance to APC may be associated with other more obvious conditions predisposing to thrombosis, the coagulation defect should be considered in CVT regardless of the results of other etiologic investigations. In the 19 CVT patients included in the present study, no other inherited coagulation defects, including antithrombin, protein C, and protein S deficiencies, were detected. Factor V Leiden mutation may be the most common inherited coagulation defect associated with CVT.

Screening for resistance to APC may be performed with the use of a functional assay (inadequate prolongation of the APTT after addition of APC).^{2 3} However, because there may be an overlap between the range of the functional assay values from heterozygous patients and healthy control subjects without the mutation,²² inconclusive values should lead to the performance of molecular genetic analysis.

Whether the risks of long-term warfarin anticoagulation outweigh the risks of recurrent thromboembolism in individuals who have had only one episode of thrombosis has not been established. In patients not treated with lifelong oral anticoagulation, short-term anticoagulant prophylaxis should be considered during times of high risk, such as pregnancy, immobilization, or the postoperative period.

	Acknowledgments

 
We are grateful to Martine Alhenc-Gelas (Laboratoire d'Hemostase, Hopital Broussais, Paris, France), who performed the molecular genetic analysis.

	Footnotes

 
Reprint requests to Pr M. Zuber, Service de Neurologie, Centre R. Garcin, Hopital Sainte-Anne, 1 rue Cabanis, 75674 Paris Cedex 14, France.

Received March 4, 1996; revision received May 21, 1996; accepted May 24, 1996.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zuber, M. Articles by Mas, J.-L. Search for Related Content PubMed PubMed Citation Articles by Zuber, M. Articles by Mas, J.-L.