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Venous Thrombotic Recurrence After Cerebral

Venous Thrombosis
A Long-Term Follow-Up Study
Paola Palazzo, MD, PhD*; Pierre Agius, MD*; Pierre Ingrand, MD; Jonathan Ciron, MD;
Matthias Lamy, MD; Aline Berthomet, MD; Paul Cantagrel, MS; Jean-Philippe Neau, MD

Background and Purpose—After cerebral venous thrombosis (CVT), the risk of venous thrombotic events was estimated at
2% to 3% for a new CVT and 3% to 8% for extracranial events. However, because of the paucity of prospective studies,
the clinical course of CVT is still largely unknown. We aimed to prospectively evaluate the rate of thrombosis recurrence
in a cohort of CVT patients with a long-term follow-up and to detect predisposing factors for recurrence.
Methods—Consecutive CVT patients with complete clinical, radiological, biological, and genetic data were systematically
followed up. New venous thrombotic events were detected after hospital readmission and imaging confirmation.
Results—One-hundred eighty-seven patients (mean age 45±18 years, 67% women) with angiographically confirmed CVT
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were included. Cause was found in 73% of patients. Coagulation abnormality and JAK2 gene mutation were detected
in 20% and 9%, respectively. Median follow-up length was 73 months (range 1–247 months). Mean duration of the
oral anticoagulant treatment was 14 months. Mortality rate was 2.5% per year, with 2% in-hospital mortality. During
follow-up, CVT reoccurred in 6 patients, whereas 19 subjects had a symptomatic extracranial venous thrombotic event,
with cumulative venous thrombotic recurrence rates of 3% at 1 year, 8% at 2 years, 12% at 5 years, and 18% at 10
years. A previous venous thrombotic event (hazard ratio, 2.8; P=0.018), presence of cancer or malignant hemopathies
(hazard ratio, 3.2; P=0.039), and unknown CVT causes (hazard ratio, 2.81; P=0.024) were independently associated with
Conclusions—In our cohort of CVT patients followed on average for >6 years, subjects with a previous venous thrombotic
event, cancer/malignant hemopathies, and unknown CVT causes were found to be at higher risk of recurrence. 
(Stroke. 2017;48:321-326. DOI: 10.1161/STROKEAHA.116.015294.)
Key Words: female ◼ mutation ◼ risk ◼ thrombophilia ◼ venous thromboembolism

C erebral venous thrombosis (CVT) is an uncommon dis-

ease that mainly affects subjects younger than 40 years of
age, patients with thrombophilia, and women who are pregnant
polycythemia/thrombocythemia were found to be the only
independent predictors of venous thromboembolism after
CVT.6 These results were not confirmed by other authors who
or receiving hormonal contraceptives. The annual incidence is observed an association between recurrence and a history of
estimated to be 3 to 4 cases per million,1 which increases to previous extracerebral venous thrombotic events,7 whereas in
12 cases per 100 000 deliveries during the peripartum period.2 another study no variable was found to be significantly associ-
Mortality and recurrence rates are lower when compared ated with recurrent VT.4 No study to date has estimated risk of
with arterial stroke, with an estimated annual risk of new VT recurrence with different CVT causes.
venous thrombotic events after a first CVT at 2% to 3% for a We, therefore, aimed to prospectively evaluate the incidence
new CVT and 3% to 8% for extracranial events.3–5 of recurrent cerebral and extracerebral venous thrombotic
However, because of a paucity of prospective studies with events in a cohort of CVT patients and to detect clinical, bio-
long-term follow-up, recurrence of venous thrombosis (VT) logical, and radiological factors associated with VT recurrence.
after CVT is still largely unknown, as are predisposing fac-
tors for recurrence. In fact, mixed results exist on the factors Methods
associated with recurrence risk. In a multicenter observa- A database was established to prospectively follow up a cohort of con-
tional study of 624 adult patients with CVT, male sex and secutive patients with a first episode of angiographically proven CVT

Received September 2, 2016; final revision received November 3, 2016; accepted November 10, 2016.
From the Department of Neurology, Poitiers University Hospital and University of Poitiers, France (P.P., P.A., J.C., M.L., A.B., P.C., J.-P.N.); Department
of Neurology, S. Giovanni Calibita-Fatebenefratelli Hospital, Rome, Italy (P.P.); and Clinical Investigation Center INSERM CIC-P 802, Poitiers University
Hospital, France (P.I.).
*Drs Palazzo and Agius contributed equally.
Correspondence to Paola Palazzo, MD, PhD, Department of Neurology, Poitiers University Hospital, 2 rue de la Milétrie, 86021 Poitiers, France. E-mail
paola.palazzo@chu-poitiers.fr; ppalazzo@hotmail.it
© 2016 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.116.015294

322  Stroke  February 2017

admitted to primary (n=3) and comprehensive (n=1) stroke centers puncture was performed in 99 patients: 20 patients had >5
in the French Poitou-Charentes region (1.8 million inhabitants, mean cells and 47 had >45 mg/dL protein. Demographic, clinical,
age 42 years, 48% <40-year old, 51% women) from January 2005 to
December 2014. The study was approved by the local ethics commit-
and imaging features are shown in Table 1.
tee, and all enrolled subjects signed informed consent forms. Clinical CVT cause was found in 73% of subjects (Table 2). Genetic
diagnosis of CVT was confirmed by brain computed tomography or acquired thrombophilia was detected in 20% of subjects,
(CT) with CT venography, magnetic resonance imaging combined mainly represented by factor V or II mutation. JAK2 gene
with magnetic resonance venography, conventional angiography, or
analysis was assessed in 120 patients, and a mutation was
multimodal imaging. Complete clinical, radiological, biological, and
genetic data were collected, including demographic data, symptoms detected in 9% (n=11) of them. A pharmacological cause was
and signs from onset to diagnosis, Glasgow Coma Scale and National observed in 47% of patients, mainly (91%) represented by
Institutes of Health Stroke Scale scores in the acute phase, thrombus hormonal contraceptives or replacement therapy and less fre-
localization, and presence of parenchymal lesions. Thrombophilic quently by chemotherapy.
screening was assessed in all the study subjects, including factor V
Leiden, G20210A mutations, lupus anticoagulant, and anticardiolipin In the acute phase, 185 (99%) patients were anticoagulated
antibodies. However, proteins C and S and antithrombin III were with intravenous heparin (94%) or subcutaneous low-molec-
not systematically assessed before anticoagulation was started and ular–weight heparin (6%) in therapeutic dosages followed by
not controlled after treatment interruption; therefore, they were not oral vitamin K antagonists with a target international normal-
analyzed in this study. Patients underwent lumbar puncture unless
contraindicated. The JAK2 V617F mutation analysis was systemati-
ized ratio of 2:3.8 One patient was treated with local endovascu-
cally assessed in all subjects included from 2008 using a real-time lar thrombolysis, and 1 underwent mechanical thrombectomy.
polymerase chain reaction method. Jugular vein stenting was performed in 2 patients, and 1 had
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Follow-up visits were performed at 6 months, including neuro- optic nerve fenestration. Additional treatment included anti-
imaging follow-up, at 12 months, and yearly thereafter at outpa- epileptic medication (59 patients [32%]), mannitol (13 [7%]),
tient evaluation that included neurological examination. If in-person
evaluation was impossible, alternative methods included a telephone and acetazolamide (22 [12%]).
interview of the patient or an interview with a relative or general Mean and median follow-up lengths were 80 (SD 60)
practitioner. Subjects known to be hospitalized for any reason during and 73 months (range 1–247 months), respectively. Patients
follow-up underwent direct inpatient neurological evaluation. received oral anticoagulant treatment for 14 months on aver-
Follow-up data recorded included: disability (modified Rankin
Scale), death, recurrent symptomatic CVT (new symptoms with age. Mortality rate was 2.5% per year with 2% in-hospital
new thrombosis on repeated neuroimaging), and other symptomatic mortality and 17% overall mortality, mainly related to can-
venous thrombotic events. cer or hematologic malignancies. Discharge modified Rankin
Primary outcome was cerebral or extracranial VT recurrence. All Scale score was 0 to 1 in 74% of patients, whereas 8% of them
the new venous thrombotic events were detected after readmission
had a slight residual disability (modified Rankin Scale score
to regional hospitals and received imaging confirmation. In case of
multiple recurrences, only the first one was included in the time-to- of 2) and 16% moderate to severe disability (modified Rankin
event analysis. Scale score of 3–5).
Clinically suspected deep vein thrombosis (DVT) was confirmed by During follow-up, 30 new venous thrombotic events
duplex ultrasonography, CT, or magnetic resonance imaging venog- occurred in 25 CVT patients. CVT reoccurred in 6 patients,
raphy. Symptomatic pulmonary embolism (PE) was confirmed by
contrast-enhanced CT or ventilation–perfusion lung scan interpreted whereas 19 subjects had new extracranial venous thrombotic
as high probability for PE. Symptomatic portal vein thrombosis was events, represented by DVT (12 patients), PE (5 patients),
confirmed by contrast-enhanced CT or duplex ultrasonography. A and portal vein thrombosis (2 patients). A single new event
recurrent CVT was distinguished from the original thrombosis by occurred in 23 patients, whereas 1 patient experienced CVT
comparing serial imaging. To be classified as a recurrent CVT, new
or recurrent symptoms had to develop with new filling defects in the
followed by PE, and 1 had 5 episodes of DVT. The first recur-
follow-up study not present in the first images or in an interval study rent event was included in the analysis.
showing thrombus resolution. The cumulative venous thrombotic recurrence rate was
3±1% at 1 year, 8±2% at 2 years, 12±3% at 5 years, and
Statistical Analyses 18±4% at 10 years. Recurrence rate is represented in Figure.
The Kaplan–Meier product-limit method was used to calculate cumu- In patients with a new CVT, mean recurrence delay was 28.5
lative recurrence rates and SE. Cox proportional hazards models were months (SD 19.7).
used for univariate and multivariate prognostic analyses. All variables In 1 of the 6 patients with a recurrent CVT and 1 of the
with a P value <0.2 at univariate analysis were entered in the multi-
variate analysis. The final model was obtained after applying a back- 19 patients with a new extracranial venous thrombotic event
ward elimination procedure; all variables with a P value <0.05 were (PE), mortality was directly attributable to the recurrence.
retained. All analyses were performed with SAS release 9.3 software. In univariate analysis, recurrence was associated with older
age, a previous venous thrombotic event, absence of hormonal
Results agents, presence of cancer or malignant hemopathy, and
One-hundred ninety-four patients with confirmed CVT were unknown causes (Table 3). In addition, patients who discon-
enrolled in our prospective observational study. Seven (3.6%) tinued estrogens after CVT displayed decreased recurrence
patients were lost to follow-up after discharge and excluded rates compared with subjects who had not taken hormonal
from the study. Of the remaining 187 patients (mean age 45±18 treatment (P=0.0036).
years, 67% women, 97% white), 98% had an admission Glasgow No association was found between the duration of antico-
Coma Scale score between 9 and 15, and 2% were comatose agulation treatment and the recurrence risk in the overall study
(Glasgow Coma Scale score of <9). Sixty-two patients (33%) population (P=0.70) or the subgroup of patients with CVT of
presented with isolated intracranial hypertension. Lumbar undetermined cause (P=0.30).
Palazzo et al   Venous Thrombotic Recurrence After CVT    323

Table 1.  Demographic, Clinical, Biological, and Radiological Table 1.  Continued
Characteristics of the Study Cohort
 Any parenchymal lesion 78 (42)
Age at first CVT, mean (SD), y 45 (18)
Ischemic lesions 72 (39)
Female sex 126 (67)   
Hemorrhagic lesions 60 (32)
BMI, mean (SD) 25 (7)   
Edema 56 (30)
Current smoking 54 (29) Laboratory exams
Diabetes mellitus 7 (4)  Hemoglobin, g/dL, mean, (SD) 13.4 (2)
Previous stroke 4 (2)  Platelets, giga/L, mean, (SD) 266 (109)
CAD 7 (4) Thrombophilia testing
Dyslipidemia 28 (15)  Factor V mutation‡ 14 (8)
Arterial hypertension 42 (22)  Factor II mutation§ 18 (11)
Hyperhomocysteinemia* 26 (28)  JAK2 mutation‖ 11 (9)
Previous VTE 24 (13)  Anti-β2-GP1 antibodies 1 (0.6)
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Family history of VTE 38 (20)  Anticardiolipin antibodies 4 (2)

History of miscarriages† 19 (15) Data are expressed as n(%) unless specified. BMI indicates body mass index;
CAD, coronary artery disease; CVT, cerebral venous thrombosis; GCS, Glasgow
Clinical presentation Coma Scale; NIHSS, National Institutes of Health Stroke Scale; and VTE, venous
 Asymptomatic 3 (2) thrombotic events.
*Homocysteine was tested in 94 subjects (50%); percentage was calculated
 Altered mental status 17 (9) in this subgroup.
 Headache 167 (89) †Percentage calculated in the female subgroup.
‡Evaluated in 173 subjects (93%); percentage was calculated in this subgroup.
 Focal deficits 66 (35) §Evaluated in 167 subjects (89%); percentage was calculated in this subgroup.
 Intracranial hypertension 102 (55) ‖Evaluated in 120 subjects (64%); percentage was calculated in this subgroup.

 Seizures 55 (29)
When all potential risk variables with P value <0.2 at uni-
 GCS score, mean (SD) 14.6 (0.3) variate analysis were entered into multivariate model, a previ-
 NIHSS score, mean (SD) 3.5 (0.5) ous venous thrombotic event (hazard ratio [HR], 2.8; P=0.018),
presence of cancer or malignant hemopathy (HR, 3.2; P=0.039),
 Clinical onset delay
and unknown CVT cause (HR, 2.81; P=0.024) were indepen-
≤7 d
   111 (59) dently associated with any first VT recurrence (Table 3).
7–21 d 45 (24)
Table 2.  Cerebral Venous Thrombosis Causes in the Study
≥21 d
   31 (17) Population
 Occluded sinus number, mean (SD) 2.4 (2.4)
Cryptogenic 51 (27)
 Site of thrombosis
Recent trauma 9 (5)
  Superior sagittal sinus 94 (50)
CNS infection 29 (16)
  Inferior sagittal sinus 12 (6) Chronic inflammatory disease 9 (5)
  Right lateral sinus 87 (46) Cancer 10 (5)
  Left lateral sinus 81 (43) Malignant hemopathies 19 (10)
Straight sinus 28 (15) Thrombophilic abnormalities 37 (20)
Cortical veins 16 (9) Recent/ongoing chemotherapy 8 (4)
  Vein of Galen 13 (7) OC* 72 (57)
  Internal cerebral veins 10 (5) HRT* 7 (6)
Cavernous sinus 3 (2) Pregnancy* 3 (2)
Torcular Herophili 28 (15) Postpartum* 1 (1)
  Left jugular vein 26 (14) Data are expressed as n (%). Forty-seven (25%) patients had >1 known risk
factor for cerebral venous thrombosis. CNS indicates central nervous system;
  Right jugular vein 27 (14) HRT, hormone replacement therapy; and OC, oral contraceptives.
(Continued ) *Percentage calculated in the female subgroup.
324  Stroke  February 2017

Table 3.  Association of Baseline Characteristics and

Potential Risk Factor for Recurrent VTE at Univariate and
Multivariate Analyses
Variables HR 95% CI P Value
Univariate analysis
 Age, 1-y increment 1.03 (1.00–1.05) 0.026
 Sex, female vs male 1.31 (0.53–2.96) 0.535
 Previous VTE 3.50 (1.44–8.14) 0.0036
 Thrombophilia 0.86 (0.31–2.04) 0.75
 Infection 1.04 (0.30–2.73) 0.95
 Cancer+hemopathies 2.30 (0.76–5.72) 0.099
 Pregnancy+postpartum (n=126) 4.40 (0.69–16.0) 0.052
 OC+HRT (n=126) 0.25 (0.09–0.67) 0.0070
 Unknown cause 2.37 (1.05–5.22) 0.032
Multivariate analysis
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Figure. Kaplan–Meier curve of venous thrombosis ­recurrence  Previous VTE 2.82 (1.14–6.46) 0.018
rate.  Cancer+hemopathies 3.24 (0.98–9.57) 0.039
 Unknown cause 2.81 (1.15–7.04) 0.024
Discussion CI indicates confidence interval; HR, hazard ratio; HRT, hormone replacement
Our study showed that cumulative risk of recurrent VT contin- therapy; OC, oral contraceptive; and VTE, venous thrombotic events.
ues to increase over time. We also detected factors associated
with VT recurrence in subjects who were diagnostically evalu-
ated and treated for the initial CVT. during a median follow-up period of 16 months (mean=18.6,
Early recurrence rates in our study are comparable with the SD=11.1).3 Ruling out subjects lost to follow-up immediately
results of other studies.3–5,7,9–11 Details on the studies that eval- after discharge (n=80), cerebral and extracerebral venous
uated venous thrombotic events recurrence in CVT patients thrombotic recurrence rates were 2.6% and 3.4%, respectively.
are displayed in Table 4.
Similarly, Gosk-Bierska et al4 found a 2.2% annual sinus
In the ISCVT study (International Study on Cerebral Vein
and Dural Sinus Thrombosis), a large prospective multi- thrombosis recurrence rate and a 2.8% annual extracerebral
national observational study conducted on 624 adult cases thrombosis (ie, DVT or PE) recurrence rate during a mean
of CVT, a 2.2% overall CVT recurrence rate and 3% extra- follow-up period of 36±47 months (range 0–262 months) after
cranial venous thrombotic recurrence rate were observed a CVT, with a median time to recurrence of 10 months.

Table 4.  Summary of Studies That Evaluated VTE Recurrence in CVT Patients
Year of Median/
Author Publication Country Study Design Setting Subjects, n Mean FU Definition of Recurrence
Preter et al 9
1996 France Retrospective Tertiary center 77 6.5 y Interview or questionnaire
Ferro et al10
Tertiary centers and community
2002 Portugal Mixed 126 1.8 y Clinical visit or interview
Gosk-Bierska et al4 2006 United States Retrospective Tertiary center 154 3y Clinical visit
Miranda et al 6
Tertiary centers and community
2010 Multinational Prospective 624 1.2 y Clinical visit
Martinelli et al5 2010 Italy Prospective Tertiary center 145 6y Clinical visit or interview
Dentali et al 7
Tertiary centers and community Clinical visit or interview or
2012 Multinational Retrospective 706 3.3 y
hospitals questionnaire and hospital records
Hiltunen et al11
2016 Finland Retrospective Tertiary center 161 3.2 y Questionnaire

Tertiary center and community

Present study 2016 France Prospective 187 6.7 y Clinical visit or interview
Palazzo et al   Venous Thrombotic Recurrence After CVT    325

An annual CVT recurrence rate of 1.8% was observed by 95% CI, 1.25–5.83; P<0.011) has previously been observed
Preter et al9 in 77 patients with CVT during a median follow- by Dentali et al,7 while the association with cancer was found
up period of 63 months, mainly (89%) occurred within the only in the univariate analysis.
first 12 months, whereas in the VENOPORT study (Cerebral On the contrary, in the ISCVT, male sex (HR, 2.6; 95% CI,
Venous Thrombosis Portuguese Collaborative Study Group), 1.4–5.1; P=0.004) and polycythemia/thrombocythemia (HR,
a 1.6% overall CVT recurrent thrombosis rate was reported in 4.4; 95% CI, 1.6–12.7; P=0.005) were the only independent
126 CVT patients with a mean follow-up length of 1.8 years.10 predictors of venous thromboembolism after CVT.6
Similarly, Martinelli et al5 found an event rate of 2.03 per Similarly, in the study conducted by Martinelli et al,5 male
100 patient-years in a population of 145 patients with a first CVT patients had a 7- to 8-fold increased risk of recurrence
episode of CVT followed up for 6 years after discontinuation compared with female patients, while severe thrombophilia
of anticoagulant therapy. was associated with an increased risk of DVT or PE (HR,
In a large, retrospective cohort study, an overall recurrence 4.71; 95% CI, 1.34–16.5), but not with CVT recurrence.
incidence of 23.6 events per 1000 patient-years (95% confi- However, these findings may not be applicable to the general
dence interval [CI], 17.8–28.7) was observed during a median CVT population because patients with malignancies or in
follow-up period of 40 months (range 6–297 months).7 need of permanent anticoagulation were not included in this
Recently, in a retrospective single-center study conducted study. Differences in the inclusion criteria might be the reason
on 161 CVT patients with a median follow-up period of 39 of the discrepancy between our results and those of the Italian
months (interquartile range 14–95 months), Hiltunen et al11 group because we did not find any correlation between sex and
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observed a 1.1% annual venous thromboembolic recurrence recurrence risk.

rate (5 DVT, 2 PE, and 3 superficial vein thrombosis) with In the study by Gosk-Bierska et al,4 no variable was found
a 0.1% annual CVT recurrence rate. Authors stated that low to be significantly associated with recurrent VT, whereas
incidence of recurrence could be explained by the frequent Hiltunen et al11 did not specifically address this issue.
use of antithrombotic agents in this study population because To our knowledge, this is the first time that cryptogenic
39% of patients received permanent anticoagulation and 25% CVT was found to be associated with the risk of recurrence.
received aspirin. The prospective design and long-term follow-up of our study
Similarly to other studies, in our population, new venous might explain this difference. Our cryptogenic CVT rate
thrombotic events mainly (52%) occurred in the first 24 is similar to that reported in other studies; however, a wide
months. range of idiopathic thrombosis rates, from 9% to 44%, has
In our cohort of CVT patients with long-term follow-up, been reported.3–5,7,11 In our opinion, unknown causes may limit
subjects with a previous venous thrombotic event, presence of secondary prevention measures in this subgroup of patients,
cancer or malignant hemopathies, and unknown CVT causes leading to an increase in the risk of recurrence. This finding
were found to be at higher risk of recurrence in the multivari- underscores the need for further research to better identify
ate analysis. both congenital and acquired VT risk factors to develop more
The increased risk of both cerebral and extracerebral specific treatment strategies.
venous thrombotic recurrence in CVT patients with a history Another finding of our study is that women receiving hor-
of previous extracerebral venous thrombotic events (HR, 2.70; monal agents such as oral contraceptives or replacement therapy

Cerebral/Extracerebral VTE Thrombophilia

Annual Recurrence Rate Testing Reported New Cerebral/Extracerebral VTE Factors Associated With VTE Recurrence
1.8%/* Not specified 9 CVT* NA

NA Incomplete 2 CVT2 DVT1 PE NA

2.2%/2.8% Complete 23 VTE occurred in 20 subjects: 10 CVT, 8 DVT, and 5 PE No associated factors
1.5%4.1% overall VTE annual 38 VTE occurred in 36 subjects: 14 CVT, 16 DVT, 4 PE, 3 upper Male sex; polycythemia/
recurrence rate limb DVT, and 1 mesenteric venous thrombosis thrombocythemia
0.53%/1.05% Complete 15 VTE occurred in 15 subjects: 5 CVT, 8 DVT, and 2 PE Male sex; severe thrombophilia
2.4% overall VTE annual
Incomplete 77 VTE occurred in 75 subjects: 31 CVT and 46 extracerebral VTE Previous extracerebral VTE; cancer†
recurrence rate
9 VTE occurred in 9 subjects: 1 CVT, 5 DVT, 2 PE, and 3
0.1%/1.1% Not specified NA
Superficial vein thrombosis
Previous VTE; cancer, malignant
30 VTE occurred in 25 subjects: 6 CVT, 16 DVT, 6 PE, and 2 Portal
0.5%/1.7% Incomplete hemopathies, or JAK2 mutation;
vein thrombosis
unknown CVT causes
CVT indicates cerebral venous thrombosis; DVT, deep vein thrombosis; FU, follow-up; PE, pulmonary embolism; NA, not assessed; and VTE, venous thrombotic events.
*Not known the exact number/incidence of new extracerebral VTE (11 arterial or venous extracerebral events).
†Association found only in the univariate analysis.
326  Stroke  February 2017

at the time of their first CVT event had lower recurrence risk Acknowledgments
compared with women who had not taken estrogens. These data We are grateful to Pr Andrei V. Alexandrov for his precious comments
suggest that subjects whose CVT is favored by hormonal agents and suggestions.
are at lower risk of new venous thrombotic events after estro-
gen discontinuation compared with CVT patients with other Disclosures
risk factors or whose CVT cause was not detected. Similar data None.
were obtained in a study conducted on patients with a first event
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Venous Thrombotic Recurrence After Cerebral Venous Thrombosis: A Long-Term
Follow-Up Study
Paola Palazzo, Pierre Agius, Pierre Ingrand, Jonathan Ciron, Matthias Lamy, Aline Berthomet,
Paul Cantagrel and Jean-Philippe Neau
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Stroke. 2017;48:321-326; originally published online December 15, 2016;

doi: 10.1161/STROKEAHA.116.015294
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