(Stroke. 1999;30:484-488.)
© 1999 American Heart Association, Inc.
Original Contributions |
Randomized, Placebo-Controlled Trial of Anticoagulant Treatment With Low-Molecular-Weight Heparin for Cerebral Sinus Thrombosis
From Leyenburg Hospital, The Hague (S.F.T.M. d B), and Academic Medical Centre, Amsterdam (J.S), the Netherlands. A complete list of the members of the Cerebral Venous Sinus Thrombosis Study Group appears in the Appendix.
Correspondence to J. Stam, MD, Academic Medical Centre, PO Box 22700, 1100 DE Amsterdam, Netherlands. E-mail J.Stam{at}AMC.UVA.NL
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Background and Purpose—Treatment of cerebral sinus thrombosis with heparin is controversial. We conducted a double-blind, placebo-controlled multicenter trial to examine whether anticoagulant treatment improves outcome in patients with sinus thrombosis.
Methods—Patients were randomized between body weight–adjusted subcutaneous nadroparin (180 anti–factor Xa units/kg per 24 hours) and matching placebo for 3 weeks (double-blind part of trial), followed by 3 months of oral anticoagulants for patients allocated nadroparin (open part). Patients with cerebral hemorrhage caused by sinus thrombosis were also included.
Results—Sixty patients were enrolled, and none were lost to
follow-up. In 1 patient the diagnosis proved wrong after randomization.
After 3 weeks, 6 of 30 patients (20%) in the nadroparin group and 7 of
29 patients (24%) in the placebo group had a poor outcome, defined as
death or Barthel Index score of <15 (risk difference, -4%; 95% CI,
-25 to 17%; NS). After 12 weeks, 4 of 30 patients (13%) in the
nadroparin group and 6 of 29 (21%) in the placebo group had a poor
outcome, defined as death or Oxford Handicap Score of 
3 (risk
difference, -7%; 95% CI, -26% to 12%; NS). There were no new
symptomatic cerebral hemorrhages. One patient in
the nadroparin group had a major gastrointestinal hemorrhage,
and 1 patient in the placebo group died from clinically suspected
pulmonary embolism.
Conclusions—Patients with cerebral sinus thrombosis treated with anticoagulants (low-molecular-weight heparin followed by oral anticoagulation) had a favorable outcome more often than controls, but the difference was not statistically significant. Anticoagulation proved to be safe, even in patients with cerebral hemorrhage.
Key Words: anticoagulants • randomized controlled trials • sinus thrombosis
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Cerebral venous and sinus thrombosis is a rare but alarming disease that usually begins with severe headache. Sinus thrombosis may cause cerebral venous infarcts, which are frequently hemorrhagic and may lead to epilepsy, neurological deficits, or death. Obstruction of the sinuses often causes intracranial hypertension due to impaired drainage of the cerebrospinal fluid, which may cause optic nerve papilledema and impaired vision. On the other hand, sinuses, particularly the lateral sinus, can be occluded without any infarct or intracranial hypertension. In many patients the disease runs a benign course.1 Prothrombotic states, both hereditary and acquired (eg, protein C or S deficiency, factor V Leiden mutation, pregnancy, and puerperium), are regarded as risk factors, but in many cases the cause remains unknown.2
The treatment of sinus thrombosis with heparin is controversial. Heparin may arrest progression of thrombosis and prevent further infarction. It may also cause hemorrhages in infarcted brain tissue, with increased neurological deficits, although well-documented cases are scarce. In the only previous randomized trial,3 unfractionated heparin was compared with placebo in 20 patients. The authors concluded that heparin was a safe and
effective treatment for sinus thrombosis, but the results have been disputed because of the small sample size, the long treatment delay, and questionable outcome criteria.4 5 We conducted a double-blind, placebo-controlled multicenter trial to investigate whether anticoagulant treatment with a therapeutic dose of low-molecular-weight heparin improves outcome in patients with sinus thrombosis.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Patients
All patients with clinically suspected cerebral venous sinus thrombosis confirmed by cerebral angiography or by MRI (including MR angiography) were eligible. Reasons for exclusion were age of <18 years, pregnancy, indications for or contraindications against heparin, conditions with a poor prognosis unrelated to sinus thrombosis, papilledema with impaired vision that required lumbar punctures or cerebrospinal fluid shunting, or recently performed lumbar puncture or surgical procedure. Indications for heparin were leg-vein thrombosis or pulmonary embolism. Contraindications against heparin were bleeding disorders, thrombocytopenia (<100x109/L), hepatic or renal dysfunction, uncontrolled hypertension (diastolic >110 mm Hg), or recent gastrointestinal hemorrhage. Cerebral hemorrhage caused by sinus thrombosis was no reason for exclusion. The study was approved by the ethics committee at each center. Informed consent by the patient or next-of-kin was obtained before inclusion.
Treatment
Treatment consisted of nadroparin in a dose of approximately 180
anti–factor Xa units/kg per 24 hours or matching placebo, administered
by 2 daily subcutaneous injections. Other drugs with effects on
coagulation were not allowed. Graduated compression stockings were
recommended to prevent leg vein thrombosis.6 If a lumbar
puncture was necessary, the trial medication was stopped 24 hours
before and after the procedure. One such interruption was allowed in
each patient. Reasons to stop trial medication were major extracranial
hemorrhage, a symptomatic new intracranial
hemorrhage confirmed by CT scan, the need for repeated lumbar
punctures or surgical intervention, and confirmed leg-vein thrombosis
or pulmonary embolism. After 3 weeks the treatment code was
broken (see below), and patients allocated to nadroparin were to
receive oral anticoagulants for 10 weeks (target: international
normalized ratio between 2.5 and 3.5). Patients on placebo did not
receive follow-up anticoagulant treatment.
Outcome Assessments
The Barthel Index (BI) of activities of daily living (from 1
[totally dependent] to 20 [fully independent]), assessed by the
attending physician at day 21 after randomization when treatment
assignment was still masked, was used to define the primary outcome
measure. Poor outcome was defined as BI of 15 or less, or death.
Secondary outcome measure was the Oxford Handicap Scale (OHS) after 12
weeks (not blinded),7 in which we dichotomized between
death or (partial) dependence (grade 3 to 5) and minor handicap or
better (grade 0 to 2). We also assessed the BI score after 12 weeks.
Safety was examined by recording any new
symptomatic CT-confirmed intracranial hemorrhage,
all extracranial hemorrhages, and confirmed leg vein thrombosis
or pulmonary embolism. Major bleeding complications were
defined as clinically manifest hemorrhages that caused a fall
in hemoglobin of 1.2 mmol/L (2 g/dL) or more; retroperitoneal or
intraocular hemorrhages; and hemorrhages that required
transfusion or surgery. All other bleeding was considered minor.
Sample Size and Statistics
The sample size was based on an expected incidence of 40% poor
outcomes,8 9 10 11 12 and a large expected treatment effect as
suggested by the results of the previous trial.3 To detect
a reduction to 10%, poor outcomes at a 5% level of significance (2
tailed) with a power of 80% a study size of 60 patients is needed. The
primary analysis was according to the `intention to treat'
principle. The numbers of poor outcomes in each trial arm were compared
by calculating the absolute risk reduction and its 95% confidence
interval. Patients with cerebral hemorrhage before treatment
were also analyzed separately in a planned subgroup
analysis. Halfway the study an interim analysis was
performed by the safety committee.
Randomization and Stratification
Participating centers contacted the central study coordination
center if patients met all inclusion and exclusion criteria. Patients
were randomized centrally, by means of a computer generated allocation
schedule. We applied stratified block randomization, with separate
allocation sequences for 3 strata: patients with hemorrhage on
the pretreatment CT scan; patients with chronic (>30 days)
intracranial hypertension (defined as headache, a CSF pressure of more
than 20 cm water, and no other symptoms); all other patients. In view
of the small sample size and the relatively large number of centers, a
very small block size of 2 was used within strata. To minimize overall
imbalance, the probability of the first allocation in each block was
based on the total amount of imbalance in the number of allocated
patients up to that point. In spite of this procedure, an imbalance was
observed after 30 patients had been randomized (21 patients randomized
to placebo), due to a technical error in the computer program. To
correct this, 3 new blocks (1 in each stratum) were defined in the
allocation schedule. The number of allocations in each block was based
on the amount of imbalance plus one, leaving a random component in the
allocation procedure. The block size and the temporary imbalance were
not disclosed to the participating physicians.
Allocation Concealment: Masking
Masking was achieved by using prefilled syringes with nadroparin
or an identically appearing placebo solution. The randomization program
allocated a unique number to each patient. This number corresponded to
a package containing study medication. The treatment code was kept by
the trial pharmacist in the coordinating center. After 3 weeks the
treating physician faxed the primary outcome data to the trial center.
Subsequently, the study coordinator obtained the treatment code from
the trial pharmacist, and informed the physician about continuing
anticoagulant therapy.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Between July 1992 and November 1996 sixty patients were recruited from 14 hospitals in the Netherlands and the United Kingdom. We did not collect data on patients who were not eligible. No patients were lost to follow-up (Figure 1
). One patient was
ineligible due to an incorrect diagnosis (arterial cerebral
infarction), discovered 1 day after randomization. There were no
important differences in clinical characteristics at baseline between
the 2 study groups (Table 1).
Thirty-five patients (59%) had an onset within a time period of 10
days between the first symptoms and the time of randomization. In 9
patients there was an acute onset of 
3 days. Twelve patients had
isolated intracranial hypertension. There were no cases of chronic
(>30 days) intracranial hypertension.
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Overall, 29 patients had signs of cerebral hemorrhage on their baseline CT or MRI scans, and 8 patients had nonhemorrhagic infarction. MR imaging or conventional angiography showed involvement of the superior sagittal sinus in 50 cases (88%); in 14 of them the straight sinus was also involved. Overall, the straight sinus was thrombosed in 17 cases (29%).
The most frequent etiologic conditions were puerperium (7 patients,
12%), use of oral contraceptives (35 patients, 59%), and carriership
of hereditary prothrombotic factors (9 patients, 15%; Table 2).
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In 2 patients, 1 in the nadroparin group and 1 in the placebo group, trial medication was stopped and replaced with intravenous unfractionated heparin by the treating physician. In 2 other patients, trial medication was stopped in agreement with the protocol: 1 patient (nadroparin group) had a major gastrointestinal hemorrhage, and 1 (placebo group) needed repeated lumbar punctures. In 2 patients (1 nadroparin, 1 placebo), trial treatment was interrupted for 48 hours for a lumbar puncture.
Outcome
Six of 30 patients (20%) treated with nadroparin and 7/29 control
patients (24%) had a poor outcome (death or BI score of <15) after 3
weeks (risk difference, -4%; 95% CI, -25 to 17; Table 2
). Six patients died, 2 (7%) in
the nadroparin group and 4 (14%) in the placebo group. All deaths
occurred within 2 weeks after inclusion (range, from days 1 to
14).
After 12 weeks, 4 patients (13%) in the nadroparin group and 6
controls (21%) had a poor outcome on the predefined secondary outcome
measure of death or dependence, defined as an OHS score of 3 (risk
difference, -7%; 95% CI, -26 to 12%). Using the same definition as
for the primary outcome (death or BI score <15) 3 patients on
nadroparin (10%) had poor outcomes versus 6 controls (21%) (risk
difference, -11%; 95% CI, -29 to 7%).
A maximal BI score (no limitations in activities of daily living)
was observed in 20 patients (67%) treated with nadroparin and in 21 on
placebo (72%) after 3 weeks (Figure 2).
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After 12 weeks these numbers were 27 (90%) and 23 (79%), respectively. However, many of these patients still had residual symptoms or even minor handicaps. If complete recovery is defined as being entirely without symptoms (OHS grade 1), only 6 patients in the active treatment arm (12%) and 8 of the controls (28%) were cured.
All 6 deaths occurred in the subgroup of 29 patients with hemorrhage on their baseline CT scan, but in none could death be attributed to new or enlarged cerebral hemorrhage. Fifteen patients in this subgroup received nadroparin and 14 placebo, with poor outcome after 3 weeks in 5 (33%) and 6 (43%), respectively (risk difference, -10%; 95% CI, -45% to 26%). Among the 30 patients without hemorrhage, only 2 had a poor outcome after 3 weeks, 1 after nadroparin and 1 after placebo. The patient withdrawn after randomization because of an incorrect diagnosis (allocated placebo) had a good outcome after 3 and 12 weeks.
Adverse Events
New symptomatic cerebral hemorrhages did not
occur. One patient on nadroparin had a major gastrointestinal
hemorrhage. Four patients in each treatment group had a minor
extracranial hemorrhage. Skin hemorrhages at the
injection site were recorded 5 times in the nadroparin group and
once in the placebo group. There were no confirmed thromboembolic
complications, but 1 patient on placebo died suddenly from (suspected)
pulmonary embolism.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Patients with sinus thrombosis treated with nadroparin followed by oral anticoagulants had better outcomes than control patients, but the large treatment effect suggested previously could not be confirmed. Although none of the differences we found were statistically significant, there is a trend for all predefined outcomes in favor of anticoagulation that would be clinically important if confirmed. Anticoagulation appeared safe, even in patients with cerebral hemorrhage caused by sinus thrombosis.
The only other published randomized trial was set up to include 60 patients, but recruiting was stopped after 20 patients.3 There was a statistically nonsignificant reduction of mortality in the patients treated with heparin (0/10 deaths in the heparin group versus 3/10 in the placebo group). The interpretation of this trial is complicated by the use of a grading system that counted patients in the placebo group with mild sequelae as poor outcomes4 and by the long delay before the treatment was started (means of 33 and 25 days for the heparin and placebo groups, respectively).5
The delay between onset of symptoms and treatment in our study (mean, 10.6) is much shorter. A higher clinical awareness of sinus thrombosis, combined with the possibility of noninvasive confirmation by MRI, may have led to inclusion of less-severe cases. On the other hand, the proportion of patients in coma was similar in both studies, and we included more patients with some degree of hemorrhage (49% versus 25%). Therefore, we do not believe the difference between our results and those from the previous trial can be explained by important differences in patient characteristics.
We used subcutaneous low-molecular-weight heparin in a therapeutic dose instead of intravenous unfractionated heparin. No data are available that allow direct comparison of low-molecular-weight heparins versus unfractionated heparin in the treatment of cerebral sinus thrombosis. Randomized trials in patients with leg vein thrombosis or pulmonary embolism show that low-molecular-weight heparins, nadroparin included, are as effective as unfractionated heparin and cause fewer hemorrhagic complications.13 14 15 An additional advantage is that low-molecular-weight heparin can be given in fixed doses, only adjusted for body weight, without laboratory monitoring.
There were no new symptomatic cerebral hemorrhages in our study, which is remarkable in a condition characterized by a high rate of venous hemorrhagic infarcts. There were no confirmed thromboembolic complications, but 1 patient in the placebo group died from a clinically suspected pulmonary embolus. Pulmonary embolism associated with sinus thrombosis, caused by embolization from the cerebral sinuses or from concurrent leg-vein thrombosis, has been reported.8 The prevention of pulmonary embolism is probably an important benefit of anticoagulant treatment in patients with sinus thrombosis.
Some minor problems occurred during the course of the trial. There were 2 protocol violations, but on-treatment analysis (data not shown) does not alter the conclusion. The diagnosis was found to be wrong after inclusion in 1 case, although state-of-the-art diagnostic procedures were used in all patients. The diagnosis of sinus thrombosis with angiography or MRI can sometimes be difficult, but in the large majority of patients the diagnosis can be made reliably with these techniques.16 17
Although the study was double-blind during the first 3 weeks, side effects of the treatment might have caused unblinding in some cases. More hemorrhages at the injection site were reported in the nadroparin group, which may have influenced the judgment of outcome. The open design after 3 weeks may have introduced bias in the 3-month assessment.
The small size of the trial implies that moderate effects in favor of treatment (if present) could not be reliably confirmed or refuted. The sample size was based on the large treatment benefit suggested before3 and on the large proportion of patients with poor outcomes in published case series at the time of the start of the study.8 9 10 11 12 The present series and other recent series show that patients with cerebral sinus thrombosis have a better outcome in terms of mortality or handicap than was previously reported. Recruitment was limited, as we anticipated, by the rarity of the condition. Nevertheless, the trial was 3 times larger than the only other randomized trial.
If we combine the results of both trials in a meta-analysis, the summary risk difference is a mortality reduction of 14.3% with heparin treatment (95% CI, -36 to 6%; random effects model of Der Simonian and Laird18 ). The outcome "death or dependence" occurred in 4 of 40 of the anticoagulated patients (10%) and in 9 of 39 controls (23.1%), which gives a combined risk difference of -15.5% (95% CI, -37 to 6). Thus, a meta-analysis of both trials shows a modest but clinically important (but not statistically significant) benefit of any heparin treatment for sinus thrombosis. Approximately 300 patients would have to be recruited in a new trial to reliably confirm the treatment effect estimated in the meta-analysis. It seems unlikely that such a trial will be realized in the near future.
Based on our results and previous randomized data, we conclude that anticoagulant treatment with heparin is probably safe and beneficial for patients with sinus thrombosis, even those with intracranial hemorrhages.
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Acknowledgments |
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We thank Mrs L. Nieweg for her secretarial assistance and pharmacists A. Vyth and S.E. Greuell for management of the trial medication and allocation list.
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Appendix 1 |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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Sinus Thrombosis Study Group
Trial Coordination and Writing: S.F.T.M. de Bruijn, J. Stam.
Steering Committee: H.R. Büller, J. van Gijn, P.J. Koudstaal, A.W.A. Lensing, J. Stam, M. Vermeulen.
Advice on Study Protocol and Antithrombotic Treatment: A.W.A. Lensing.
Statistical Analysis, Computer Allocation: P.M. Bossuyt, J.G.P. Tijssen.
Safety Monitoring Committee: E. Briët, A. Algra, G.J.E. Rinkel.
Investigators: S.F.T.M. de Bruijn, J. Stam (Academic Medical Centre, Amsterdam), L.J. Kappelle, J. van Gijn (Academic Hospital, Utrecht), D.W.J. Dippel, P.J. Koudstaal, (Dijkzigt Academic Hospital, Rotterdam), J.J. van Hilten, R.A.C. Roos (Academic Hospital, Leiden), J.J. van der Sande, H.L. Hamburger (Slotervaart Ziekenhuis, Amsterdam), J.L.A. Eekhof (Diaconessenhuis, Leiden), C.L. Franke (de Wever Ziekenhuis, Heerlen), J. Lodder (Academic Hospital, Maastricht), C.C. Tijssen (St. Elisabeth ziekenhuis, Tilburg), F.W. Bertelsman, J.C. Koetsier (Academic Hospital, Free University, Amsterdam), P. Sandercock (Western General Hospital, Edinburgh), P. Humphrey (The Walton Centre, Liverpool), G.N. Mallo (Flevoziekenhuis, Almere), P. Verlooy, H.K. van Walbeek (Onze Lieve Vrouwen Gasthuis, Amsterdam), J.W. Snoek (Martini ziekenhuis, Groningen).
Sponsor: Study medication and partial financial support were provided by Sanofi-Winthrop (Dutch division).
Received August 5, 1998; revision received November 2, 1998; accepted December 7, 1998.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionAppendix 1References |
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R. L. Sacco, R. Adams, G. Albers, M. J. Alberts, O. Benavente, K. Furie, L. B. Goldstein, P. Gorelick, J. Halperin, R. Harbaugh, et al. Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline. Stroke, February 1, 2006; 37(2): 577 - 617. [Abstract] [Full Text] [PDF]
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G. Guyatt, D. Gutterman, M. H. Baumann, D. Addrizzo-Harris, E. M. Hylek, B. Phillips, G. Raskob, S. Z. Lewis, and H. Schunemann Grading Strength of Recommendations and Quality of Evidence in Clinical Guidelines: Report From an American College of Chest Physicians Task Force Chest, January 1, 2006; 129(1): 174 - 181. [Abstract] [Full Text] [PDF]
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P. Canhao, J. M. Ferro, A. G. Lindgren, M.-G. Bousser, J. Stam, F. Barinagarrementeria, and for the ISCVT Investigators Causes and Predictors of Death in Cerebral Venous Thrombosis Stroke, August 1, 2005; 36(8): 1720 - 1725. [Abstract] [Full Text] [PDF]
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C. Rottger, K. Madlener, M. Heil, T. Gerriets, M. Walberer, T. Wessels, G. Bachmann, M. Kaps, and E. Stolz Is Heparin Treatment the Optimal Management for Cerebral Venous Thrombosis?: Effect of Abciximab, Recombinant Tissue Plasminogen Activator, and Enoxaparin in Experimentally Induced Superior Sagittal Sinus Thrombosis Stroke, April 1, 2005; 36(4): 841 - 846. [Abstract] [Full Text] [PDF]
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G. W. Albers, P. Amarenco, J. D. Easton, R. L. Sacco, and P. Teal Antithrombotic and Thrombolytic Therapy for Ischemic Stroke: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 483S - 512S. [Abstract] [Full Text] [PDF]
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P. Monagle, A. Chan, P. Massicotte, E. Chalmers, and A. D. Michelson Antithrombotic Therapy in Children*: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 645S - 687S. [Abstract] [Full Text] [PDF]
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J. M. Ferro, P. Canhao, J. Stam, M.-G. Bousser, F. Barinagarrementeria, and for the ISCVT Investigators Prognosis of Cerebral Vein and Dural Sinus Thrombosis: Results of the International Study on Cerebral Vein and Dural Sinus Thrombosis (ISCVT) Stroke, March 1, 2004; 35(3): 664 - 670. [Abstract] [Full Text] [PDF]
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P. H. Lalive, P. de Moerloose, K. Lovblad, F. P. Sarasin, B. Mermillod, and R. Sztajzel Is measurement of D-dimer useful in the diagnosis of cerebral venous thrombosis? Neurology, October 28, 2003; 61(8): 1057 - 1060. [Abstract] [Full Text] [PDF]
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S. Cakmak, L. Derex, M. Berruyer, N. Nighoghossian, F. Philippeau, P. Adeleine, M. Hermier, J.C. Froment, and P. Trouillas Cerebral venous thrombosis: Clinical outcome and systematic screening of prothrombotic factors Neurology, April 8, 2003; 60(7): 1175 - 1178. [Abstract] [Full Text] [PDF]
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R W Baumgartner, A Studer, M Arnold, and D Georgiadis Recanalisation of cerebral venous thrombosis J. Neurol. Neurosurg. Psychiatry, April 1, 2003; 74(4): 459 - 461. [Abstract] [Full Text] [PDF]
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L. R. Caplan Resolved: Heparin May Be Useful in Selected Patients With Brain Ischemia Stroke, January 1, 2003; 34(1): 230 - 231. [Full Text] [PDF]
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A. Kao, D. Dlugos, J. V. Hunter, P. Mamula, and O. Thorarensen Anticoagulation Therapy in Cerebral Sinovenous Thrombosis and Ulcerative Colitis in Children J Child Neurol, July 1, 2002; 17(7): 479 - 482. [Abstract] [PDF]
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M. Wasay, R. Bakshi, S. Kojan, G. Bobustuc, N. Dubey, D.H. Unwin, P. Gates, and R. Gerraty Nonrandomized Comparison of Local Urokinase Thrombolysis Versus Systemic Heparin Anticoagulation for Superior Sagittal Sinus Thrombosis Editorial Comment Stroke, October 1, 2001; 32(10): 2310 - 2317. [Abstract] [Full Text] [PDF]
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G. deVeber, M. Andrew, C. Adams, B. Bjornson, F. Booth, D. J. Buckley, C. S. Camfield, M. David, P. Humphreys, P. Langevin, et al. Cerebral Sinovenous Thrombosis in Children N. Engl. J. Med., August 9, 2001; 345(6): 417 - 423. [Abstract] [Full Text] [PDF]
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M. Marietta, M. Bertesi, L. Simoni, I. Castelli, C. Cappi, and G. Torelli Cerebral Vein Thrombosis and Lupus Anticoagulant Antibodies Clinical and Applied Thrombosis/Hemostasis, July 1, 2001; 7(3): 238 - 238. [PDF]
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K. W Muir MEDICAL MANAGEMENT OF STROKE J. Neurol. Neurosurg. Psychiatry, April 1, 2001; 70(90001): 12i - 16. [Full Text]
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S F T M de Bruijn, R J de Haan, and J Stam Clinical features and prognostic factors of cerebral venous sinus thrombosis in a prospective series of 59 patients J. Neurol. Neurosurg. Psychiatry, January 1, 2001; 70(1): 105 - 108. [Abstract] [Full Text] [PDF]
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H. C. Diener, E. B. Ringelstein, R. von Kummer, H. D. Langohr, H. Bewermeyer, H. Landgraf, M. Hennerici, D. Welzel, M. Grave, J. Brom, et al. Treatment of Acute Ischemic Stroke With the Low-Molecular-Weight Heparin Certoparin : Results of the TOPAS Trial Stroke, January 1, 2001; 32(1): 22 - 29. [Abstract] [Full Text] [PDF]
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M. E. Andrew, P. Monagle, G. deVeber, and A. K.C. Chan Thromboembolic Disease and Antithrombotic Therapy in Newborns Hematology, January 1, 2001; 2001(1): 358 - 374. [Abstract] [Full Text] [PDF]
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G. W. Albers, P. Amarenco, J. D. Easton, R. L. Sacco, and P. Teal Antithrombotic and Thrombolytic Therapy for Ischemic Stroke Chest, January 1, 2001; 119 (2009): 300S - 320S. [Full Text] [PDF]
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A RABINSTEIN, R J DAVENPORT, and M S DENNIS Neurological emergencies: acute stroke J. Neurol. Neurosurg. Psychiatry, December 1, 2000; 69(6): 836 - 837. [Full Text]
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H T S BENAMER and I BONE Cerebral venous thrombosis: anticoagulants or thrombolyic therapy? J. Neurol. Neurosurg. Psychiatry, October 1, 2000; 69(4): 427 - 430. [Full Text] [PDF]
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C. Barnes, D. Deidun, K. Hynes, and P. Monagle Alopecia and dalteparin: a previously unreported association Blood, August 15, 2000; 96(4): 1618 - 1619. [Full Text] [PDF]
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P. M. W. Bath, R. Iddenden, and F. J. Bath Low-Molecular-Weight Heparins and Heparinoids in Acute Ischemic Stroke : A Meta-Analysis of Randomized Controlled Trials Stroke, July 1, 2000; 31(7): 1770 - 1778. [Abstract] [Full Text] [PDF]
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M B LEWIS Cerebral venous sinus thrombosis: heparin or nothing? Postgrad. Med. J., July 1, 2000; 76(897): 453c - 453. [Full Text]
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M. Verstraete, C. R. M. Prentice, M. Samama, and R. Verhaeghe A European View on the North American Fifth Consensus on Antithrombotic Therapy Chest, June 1, 2000; 117(6): 1755 - 1770. [Abstract] [Full Text] [PDF]
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D. J. Lanska and R. J. Kryscio Risk Factors for Peripartum and Postpartum Stroke and Intracranial Venous Thrombosis Stroke, June 1, 2000; 31(6): 1274 - 1282. [Abstract] [Full Text] [PDF]
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S. F. T. M. de Bruijn, M. Budde, S. Teunisse, R. J. de Haan, and J. Stam Long-term outcome of cognition and functional health after cerebral venous sinus thrombosis Neurology, April 25, 2000; 54(8): 1687 - 1689. [Abstract] [Full Text] [PDF]
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J. J. Raizer and L. M. DeAngelis Cerebral sinus thrombosis diagnosed by MRI and MR venography in cancer patients Neurology, March 28, 2000; 54(6): 1222 - 1226. [Abstract] [Full Text] [PDF]
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R. Davenport and M. Dennis Neurological emergencies: acute stroke J. Neurol. Neurosurg. Psychiatry, March 1, 2000; 68(3): 277 - 288. [Abstract] [Full Text] [PDF]
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B. J. Murray, R. Llinas, L. R. Caplan, T. Scammell, and A. Pascual-Leone Cerebral deep venous thrombosis presenting as acute micrographia and hypophonia Neurology, February 8, 2000; 54(3): 751 - 751. [Abstract] [Full Text] [PDF]
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H. Allroggen and R. J Abbott Cerebral venous sinus thrombosis Postgrad. Med. J., January 1, 2000; 76(891): 12 - 15. [Abstract] [Full Text]
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V. Biousse, A. Ameri, and M.-G. Bousser Isolated intracranial hypertension as the only sign of cerebral venous thrombosis Neurology, October 22, 1999; 53(7): 1537 - 1537. [Abstract] [Full Text]
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M. B. Lewis and M.-G. Bousser Cerebral Venous Thrombosis: Nothing, Heparin, or Local Thrombolysis? • Response Stroke, August 1, 1999; 30(8): 1729 - 1729. [Full Text] [PDF]
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M.-G. Bousser Cerebral Venous Thrombosis : Nothing, Heparin, or Local Thrombolysis? Stroke, March 1, 1999; 30(3): 481 - 483. [Full Text] [PDF]
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