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(Stroke. 1996;27:1724-1730.)
© 1996 American Heart Association, Inc.

Articles

Coagulation Studies, Factor V Leiden, and Anticardiolipin Antibodies in 40 Cases of Cerebral Venous Thrombosis

Marie-Anne Deschiens, MD; Jacqueline Conard, PhD; Marie Helene Horellou, MD; Alain Ameri, MD; Maurice Preter, MD; Francois Chedru, MD; Meyer Michel Samama, MD Marie-Germaine Bousser, MD

the Service de Neurologie Hopital Saint-Antoine (M.-A.D., M.P., M.G.B.) and the Service d'Hematologie Biologique, Hotel-Dieu (J.C., M.H.H., M.S.), Paris; and the Service de Neurologie, Hopital de Meaux, Meaux (A.A., F.C.), France.

	Abstract

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Background and Purpose Cerebral venous thrombosis (CVT) is an infrequent condition with a large variety of causes. However, in 20% to 35% of cases, no cause is found. We studied coagulation parameters, including activated protein C resistance associated with factor V gene mutation (factor V Leiden) and anticardiolipin antibodies, in a large series of patients with CVT with or without identified cause or risk factor.

Methods Forty patients (30 women and 10 men) aged 19 to 71 years (mean age, 36.2 years) with CVT diagnosed by angiography and/or MRI were studied 1 to 18 years after thrombosis. No known cause was found in 10 idiopathic cases. Coagulation studies included the following tests: fibrinogen, antithrombin, protein C, protein S, plasminogen, anticardiolipin antibodies, activated protein C resistance, and factor V Leiden.

Results Six cases of thrombophilia (15%) were found: 1 protein C deficiency, 1 protein S deficiency, and 4 activated protein C resistance with heterozygous factor V Leiden mutation (10%). Only 1 case (protein S deficiency) was found in the group of 10 patients with idiopathic CVT. In the other 5, there was another cause or risk factor. Three patients (8%) had increased anticardiolipin antibodies: 1 with systemic lupus and 2 with primary antiphospholipid syndrome; 2 of these 3 patients also had factor V Leiden mutation.

Conclusions Although present in a number of CVT cases, acquired (anticardiolipin) or congenital varieties of thrombophilia (factor V Leiden being the most frequent) are almost invariably associated with other predisposing factors. This suggests that (1) these abnormalities should be looked for in patients with CVT, whether a cause is found or not, and (2) their presence should not deter the search for other potential causes. The detection of such abnormalities has major practical consequences on the long-term management of patients to prevent further thrombotic episodes.

Key Words: coagulation • thrombophilia • cerebral veins • antiphospholipid antibodies • venous thrombosis

	Introduction

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Numerous infective or noninfective conditions can cause CVT or predispose to it.¹ They include all surgical, gyneco-obstetric, and medical causes of leg vein thrombosis, as well as a number of local causes such as head injury, tumors, infusion into the internal jugular vein, and intracranial and regional infections (abscess, otitis, meningitis, etc).¹ Hematologic disorders are infrequent but well-established causes; they include leukemias, thrombocythemias, red blood cell disorders, and congenital or acquired coagulation disorders: AT, PC, and PS deficiencies or lupus anticoagulant.¹ In 1993, Dahlback et al² described a new cause of familial thrombophilia characterized by a poor anticoagulant response to APC that was later related to a mutation in the blood coagulation factor V gene (Arg506Gln), called factor V Leiden.³ This increased resistance to APC (APC-R) seems to be a major risk factor for venous thromboembolism, found in about 15% to 20% of patients.^{4 5}

Despite the continuous description of new causes, the proportion of CVT cases of unknown cause remains high, from 20% to 35% in large recent series.^{1 6 7} The aim of our study was to perform detailed coagulation studies, including aCL antibodies and APC-R related to factor V Leiden in a series of 40 patients with CVT, whatever the etiology.

	Subjects and Methods

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Patients
Patients with CVT were recruited in two different ways. The first group of patients (n=22) came from our series of 110 adult patients recruited between 1975 and 1990.¹ Of these patients, 77 were available for long-term follow-up,⁸ and 40 of them living in the Paris area were contacted by mail. Twenty-two agreed to participate in the study. The second group (18 subjects) corresponded to consecutive patients seen in two neurology departments from 1991 through 1995. All had CVT diagnosed by x-ray angiography and/or MRI with angiography. All gave their fully informed consent to participate in the study.

The coagulation study was performed in 1995, from 1 to 18 years after CVT in 28 patients and within the first year in 12 patients (5 of these during the first 3 months). Twenty-one subjects had no treatment at the time of the study. Three were taking heparin and 11 were taking oral anticoagulants, either for acute treatment of the CVT or because of an underlying prothrombotic condition such as paroxysmal nocturnal hemoglobinuria or Behcet's disease. Five subjects were treated with aspirin for an underlying condition requiring antiplatelet therapy. These treatments were not discontinued during the study.

Coagulation Studies
Blood samples were drawn in the hematology laboratory using Vacutainer tubes containing 0.129 mol/L sodium citrate as anticoagulant for hemostatic parameters and EDTA for blood cell count. Citrated blood was centrifuged at 4000g for 15 minutes twice and was used rapidly or frozen in aliquots at -30°C.

Determination of APC-R was performed on frozen plasma using the APTT-based assay originally described by Dahlback et al² : the prolongation of the APTT in the presence of APC was measured with the Coatest APC resistance kit (Chromogenix) on a KC 10 instrument (Amelung). This test was used for screening; normal values for the APC-R ratio, determined with the method used in the laboratory, are higher than 2.2, and all ratios between 2.2 and 2.5 are considered borderline. In patients treated with oral anticoagulants, a modified APC-R assay, first carried out in our laboratory, was performed⁹ : the plasma to be tested was diluted 1:5 in factor V–deficient plasma (Diagnostica Stago) before the APTT-based assay. The presence of the mutant factor V gene (factor V Leiden) was determined after DNA extraction, polymerase chain reaction, and Mnl I restriction as described by Bertina et al.³ Genetic analysis was performed for all patients but four, who had APC-R ratios of 2.4, 2.6, 2.8, and 2.8.

APTT determination was performed using two different reagents (Automated APTT Organon Teknika and Silimat bioMerieux) together with kaolin clotting time to detect lupus anticoagulant. aCL antibodies were determined by ELISA methods (BMD).

Antithrombin, plasminogen, and PC activity were measured with a chromogenic assay (antithrombin and plasminogen with Du Pont reagents and ACA SX instrument [Du Pont] and Berichrom PC on Chromotimer [Behring]). PS was determined by a functional and an ELISA method (Staclot and Asserachrom Protein S, Stago). Precipitation by polyethylene glycol was performed to assay free PS. In addition, in patients treated with oral anticoagulants, factor II and X antigen were measured by electroimmunoassay.

Prothrombin time and thrombin time were determined by standard methods and fibrinogen according to the method of Clauss.¹⁰

Blood cell count was performed on a Coulter STKS.

	Results

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Baseline characteristics of the patients are summarized in Table 1: 30 women and 10 men, aged 19 to 71 years (mean age, 36.2 years) were studied. Nearly half of them (19/40) presented with isolated intracranial hypertension, whereas the others had focal signs (deficits, seizures, or both). Potential causes were local in 3 patients, general inflammatory diseases such as Behcet's disease or systemic lupus in 7, postpartum in 8, treatment with estro-progestogens for contraception in 11 (in the absence of other cause in 6), and a variety of other conditions in 6. There was more than one possible cause for some patients. No cause or risk factor was found in 10 subjects (25%).

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of 40 Patients With CVT

There were no significant differences between the present 40 patients and the initial cohort of 77 for any studied variable (age, sex, mode of onset, focal signs, coma, intracranial hypertension, seizures, site of occlusion, presence of a brain lesion at neuroimaging, and number of idiopathic cases).

Hematocrit level was normal in all subjects, as was platelet count, except in one patient with thrombocytopenia (65 g/L) associated with nocturnal paroxysmal hemoglobinuria. Prothrombin time and APTT were normal in patients without anticoagulant treatment, and no lupus anticoagulant was evidenced. There was no hypofibrinogenemia or dysfibrinogenemia. Other results are given in Table 2.

View this table: [in this window] [in a new window]   Table 2. Risk Factors and Biological Results in Patients With CVT

Six cases of congenital thrombophilia (15%) were found: 1 PC deficiency (patient 25), 1 PS deficiency (patient 34), and 4 heterozygous factor V Leiden (patients 21, 22, 28, and 30). Three patients had increased aCL antibodies, 1 with systemic lupus (patient 21) and 2 with a primary aPL syndrome (patients 8 and 22); 2 of these had also factor V Leiden mutation. There was no antithrombin or plasminogen deficiency. Cases with thrombophilia and/or aCL antibodies are briefly summarized. Treatment and outcome are not detailed because all patients received heparin followed by oral anticoagulants and made an uneventful recovery.

Patient 25 was 34 years old in 1986 when she complained of headache, seizures, and left-sided sensory symptoms in a context of uveomeningitis. No other signs of Behcet's disease¹¹ or sarcoidosis were present. Angiography and MRI showed right LS thrombosis. The patient has been well since then. While receiving oral anticoagulants, PC activity was 24%, antigen was 33%, and factors II and X antigen were 56% and 52%, respectively. These tests were repeated 2 months later, and PC activity was 17%. Her 16-year-old son was tested; results were normal. No other family member was available for study.

This patient, highly suspected of having congenital PC deficiency, suffered from CVT during an episode of uveomeningitis of unknown etiology.

Patient 34 was 34 years old in 1984 when she presented with transient visual obfuscations and severe papilledema. Angiography disclosed SSS and right LS thrombosis. No cause was found at that time, but 11 years later, protein S deficiency was found with levels of PS activity and total and free antigen of 25, 30, and 40, respectively. All other coagulation parameters were normal. No other cause of CVT was found. No recurrent thrombosis occurred. The patient has seven brothers and sisters, and there is no family history of thrombosis. PS could not be measured in other family members.

This patient was thought to have an "idiopathic" CVT until PS deficiency was detected 11 years later.

Patient 21 had a systemic lupus known since 1976 and was 25 years old in 1988. Three days after cesarean section, she experienced severe headache, focal and generalized seizures, and left hemiplegia. CT scan showed a right frontal hemorrhagic infarct. Angiography and MRI disclosed SSS and left LS thrombosis. She has been well since then but had one spontaneous abortion at 6 weeks pregnancy in 1994.

Coagulation study performed 7 years after CVT showed a moderately prolonged APTT (patients, 41 seconds; controls, 32 seconds; patients+controls, 37 seconds) without evident lupus anticoagulant. aCL antibody levels were very high, above 100 GPL U/mL. The APC-R ratio was 1.21, and heterozygous factor V Leiden was detected.

One maternal aunt had a history of deep vein thrombosis, and a cousin had had pulmonary embolism at 28 years of age while receiving an estro-progestogen for contraception.

This patient with systemic lupus, aCL antibodies, and factor V Leiden suffered CVT during postpartum.

Patient 22 had a history of recurrent deep vein thrombosis, two spontaneous abortions, and thrombocytopenia. She was considered as having a primary aPL syndrome, although no lupus anticoagulant was detected at any of the numerous coagulation studies, but aCL IgG antibodies were moderately elevated (18 GPL U, normal values <5). She was 30 years old in May 1994 when, 10 days after discontinuation of oral anticoagulants, she experienced acute headache, dysphasia, and right-sided weakness with MRI signs of SSS and right LS thrombosis. An abnormal APC-R was found with the modified test applicable to patients on oral anticoagulants (ratio=1.48), and mutant factor V was detected. No family history of thrombosis was known, but the family was not informative (the patient was a single child, as was her mother).

This patient with CVT has borderline aCL levels and APC-R with factor V Leiden associated with a primary aPL syndrome.

Patient 28 was 50 years old in 1978 when he presented with headache and papilledema with angiographic evidence of SSS and right LS thrombosis. A nephrotic syndrome was discovered.¹¹ He has been well since then, and there is no family history of venous thrombosis. Coagulation studies were performed 17 years later, and the only abnormality was a heterozygous factor V Leiden. This patient with factor V Leiden suffered CVT in association with a nephrotic syndrome.

Patient 30 was 34 years old in May 1994 when he suffered acute myelitis for which he received 5 infusions of 1 g methylprednisolone. The day after the last bolus, he experienced grand mal seizures with left hemiplegia. Brain CT scan showed a right rolandic hemorrhagic infarct. MRI disclosed SSS thrombosis. Three months later, after a 3-day interruption of oral anticoagulants, he suffered deep vein thrombosis and pulmonary embolism, from which he recovered. Family inquiry disclosed a history of superficial vein thrombosis in the mother and deep vein thrombosis in a maternal cousin. Coagulation studies in the patient (while he was taking oral anticoagulants) lead to the detection of factor V Leiden in the patient and in his mother.

This patient experienced CVT 1 day after high doses of intravenous methylprednisolone, given for a cervical myelitis of unknown etiology. He has a familial APC-R with heterozygous factor V Leiden.

Among the 3 patients with increased aCL levels, 2 (patients 21 and 22) have already been described above because they have mutant factor V. The third (patient 8), a 23-year-old woman, was taking oral contraceptives and presented in March 1994 with headache and papilledema with MRI signs of SSS and right LS thrombosis. Increased aCL levels were found twice (40 and 24 GPL U). All other test results were normal. Her father had suffered recurrent deep vein thrombosis and pulmonary embolism at 37 years of age and later; all his coagulation test results were normal. This young woman suffered CVT while taking oral contraceptives and was found to have increased aCL antibodies.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this series of 40 patients with CVT, PC and PS deficiencies were each found in 1 patient, APC-R with factor V Leiden in 4, and aCL antibodies in 3. There was no antithrombin deficiency, but 1 such case was found in our initial cohort of 110 patients.¹ No plasminogen deficiency or hypofibrinogenemia or dysfibrinogenemia was detected. No similar systematic coagulation study including APC-R has so far been performed in CVT, but a number of studies have been devoted to some of the coagulation parameters.^{6 12 13 14}

PS deficiency has been reported in isolated cases of CVT,^{15 16 17 18} in 2 of 46 patients in a Mexican series,¹⁴ and in 3 of 40 patients from Saudi Arabia⁶ ; in 1 of these 3 patients, the low PS level was transitory, and no information was given concerning the methods used for assays. It is important to confirm PS deficiency long enough after the CVT because acquired deficiencies may be present during the acute phase of thrombosis, possibly related to excessive binding to C4b binding protein¹⁹ or because patients are pregnant or taking contraceptive pills.^{20 21} CVT has also been associated with deficiencies in PC^{22 23 24 25 26} and antithrombin,^{27 28} and 2 cases were mentioned in the series from Saudi Arabia.⁶ Thus, about 30 cases of CVT have now been reported in association with these three varieties of thrombophilia. CVT is equally rare in large series of congenital antithrombin,²⁹ PC,³⁰ or PS¹⁵ deficiencies with thrombosis, representing less than 5% of all venous thromboses. In the present series, no other cause or associated condition was present in the patient with PS deficiency, but in the patient with PC deficiency, CVT occurred in a context of uveomeningitis of unknown etiology, thus suggesting that CVT was the consequence of the conjunction of an acute event and a congenital predisposition.

APC-R is a newly described variety of familial thrombophilia² caused by a mutation in the gene coding for factor V.³ A case of CVT associated with factor V Leiden and oral contraceptive intake has been reported recently.³⁰ In the present series of 40 patients with CVT, we found 4 cases (10%) of APC-R with heterozygous factor V Leiden. In a previous study, this abnormality was found in 4% of 50 healthy subjects and in 17% of 175 patients with history of venous thrombosis or pulmonary embolism.⁵ Thus, the frequency of factor V Leiden in the present series of CVT (10%) is intermediate between that of normal subjects and that of patients with history of leg vein thrombosis. It is slightly less than in another series of CVT, in which 5 of 25 patients (20%) had the factor V mutation.³¹ An important observation in the present series is that none of the 4 cases with factor V Leiden was found in the group of idiopathic CVT patients. All had associated risk factors or potential causes: 1 had systemic lupus and suffered CVT during postpartum, 1 had a primary aPL syndrome, 1 had a nephrotic syndrome, and 1 had a cervical myelitis of unknown etiology and suffered CVT 1 day after high doses of intravenous methylprednisolone. Furthermore, in only 1 of these patients was there a personal history of deep vein thrombosis, and in another 1 a family history was present. This strongly suggests that either the presence of factor V Leiden is coincidental or that other circumstantial risk factors (such as pregnancy or oral contraceptives) are crucial in the occurrence of CVT in these subjects.^{31 32} This stresses the importance of looking for APC-R in all patients with CVT, whatever the cause, and even in the absence of personal or family history of venous thrombosis. This equally applies to congenital deficiencies in antithrombin, PC, and PS, which can be associated with factor V Leiden.^{33 34 35}

aCL antibodies were found in 3 of our patients, isolated in 1 and in association with other conditions in 2 (systemic lupus and factor V Leiden in 1, factor V Leiden in the other). Beside systemic lupus, CVT occasionally has been reported with aCL, but other predisposing factors were also frequently present: pregnancy,³⁶ nephrotic syndrome,³⁶ or postpartum.¹⁸ This suggests that factors other than aCL alone are important to induce CVT.

The results of the present study suggest that some tests are particularly important to perform in patients with CVT, whatever the etiology (Table 3). The timing and modalities of these investigations are open to debate, since many of them can be transiently modified by a number of factors, including antithrombotic treatments, pregnancy,³⁷ estro-progestogen intake,³⁸ or acute thrombotic events. We suggest that these investigations be performed twice: as soon as the diagnosis of CVT is established, just before starting heparin treatment, and then 6 months later when the majority of patients have discontinued anticoagulation therapy. If the initial investigations without treatment have not been performed, it is still possible to detect PC and PS deficiencies during heparin therapy (outside pregnancy and at an interval from contraceptive pill intake) and antithrombin deficiency, lupus anticoagulant, increase in aCL antibodies, and even APC-R during oral anticoagulant treatment.⁹ This requires a modified technique using a plasma deficient in factor V.⁹ Results should be confirmed by the molecular detection of factor V Leiden mutation, which can be performed at any time and allows the differentiation of homozygous and heterozygous forms. Whether to use the original Dahlback's test, the modified APC-R test, or the molecular assay is a matter of debate. We favor the modified test for screening because it is less expensive and more readily available than the molecular test, and more specific for factor V Leiden than Dahlback's test.³⁹

View this table: [in this window] [in a new window]   Table 3. Important Coagulation Tests to be Performed in Patients With CVT

The consequences of the detection of an aPL syndrome and of thrombophilic disorders are important in the treatment of patients with CVT, both acutely and on a long-term basis. Heparin is the acute-phase treatment of choice.^{1 7} Treatment is usually switched to oral anticoagulants after a few days, but it should not be stopped before an international normalized ratio of between 2 and 3 during 2 consecutive days is obtained, to avoid recurrences. The usual duration of oral anticoagulant treatment in CVT is between 3 and 6 months when there is no prothrombotic underlying disease. In some conditions, such as systemic lupus⁴⁰ or Behcet's disease,⁴¹ long-term anticoagulation is warranted. This approach seems reasonable in patients with primary aPL syndrome but is more debatable in patients with an isolated increase in aCL, since the long-term prognosis after a single thrombotic episode is unknown. We favor prolonged anticoagulation when increased aCL antibodies are associated with another thrombotic factor such as APC-R.

In congenital thrombophilia, the duration of anticoagulation should also be discussed on a case-by-case basis. In antithrombin deficiency, which seems to carry the highest risk of recurrence, prolonged anticoagulation may be proposed, particularly in idiopathic CVT cases. It is more debatable in other varieties of congenital thrombophilia (isolated PC or PS deficiency or APC-R). In these conditions, it is important, however, to avoid the use of oral contraceptives containing estro-progestogens and to start a preventive treatment with low doses of heparin in prothrombotic situations, such as bed rest or pregnancy. The discovery of a thrombophilic state also has important consequences for the family, since these abnormalities are transmitted as autosomal dominant traits.

In conclusion, congenital thrombophilia was found in 6 of 40 patients with CVT (15%): PC deficiency in 1, PS deficiency in 1, and APC-R with factor V Leiden in 4 (10%). Only one of these abnormalities (PS deficiency) was found in the group of 10 patients with idiopathic CVT; in the other 5 patients, there was another associated cause or risk factor. This indicates that congenital thrombophilia should be looked for in patients with CVT, whether a cause is detected or not. However, it should be kept in mind that the occurrence of factor V Leiden is frequent in the general population and that its imputability as a cause of CVT is always difficult to establish. Thus, its presence should not deter the search for other potential causes. The detection of thrombophilia in CVT patients has a major bearing on long-term management to prevent further venous thrombotic episodes. Finally, given the frequency of CVT with no detectable cause (25%),¹ it is very likely that other varieties of thrombophilia will be identified. This stresses the need for the long-term follow-up of such patients to allow the performance of new tests as soon as they become available.

	Selected Abbreviations and Acronyms

 

aCL = anticardiolipin APC = activated protein C APC-R = activated protein C resistance aPL = antiphospholipid APTT = activated partial thromboplastin time CVT = cerebral venous thrombosis ELISA = enzyme-linked immunosorbent assay LS = lateral sinus PC = protein C PS = protein S SSS = superior sagittal sinus

	Footnotes

 
Reprint requests to Pr M.G. Bousser, Neurology Department, Hopital Saint-Antoine 184, rue du Faubourg Saint-Antoine, 75571, Paris Cedex 12, France.

Review of this manuscript was directed by Mark L. Dyken, MD.

Received May 13, 1996; revision received June 26, 1996; accepted June 27, 1996.

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