Neurocrit Care (2012) 16:335–342
DOI 10.1007/s12028-011-9661-1
REVIEW ARTICLE
Duration of Anticoagulation After Cerebral Venous Sinus
Thrombosis
Frances Caprio • Richard A. Bernstein
Published online: 22 December 2011
Ó Springer Science+Business Media, LLC 2011
Abstract Cerebral venous sinus thrombosis (CVST)
often occurs in young patients and is treated with acute and
then long-term oral anticoagulation. It is important to
decide when to discontinue anticoagulation, as lifelong
anticoagulation exposes the patient to considerable cumu-
lative risk. However, a lack of high quality studies makes
choosing a duration of anticoagulation after CVST diffi-
cult. In this article, we review the evidence for different
treatment durations in several common clinical scenarios of
CVST. In addition, when no direct evidence is available,
we discuss and extrapolate from the more comprehensively
studied situation of systemic venous thromboembolic dis-
ease. Recommendations are graded using standard criteria
for the level of evidence.
Keywords Cerebral venous sinus thrombosis

Oral anticoagulation
Duration
Recurrence

Venous thromboembolis
Introduction
Cerebral venous sinus thrombosis (CVST) is an uncommon
condition that presents with a variety of neurologic
symptoms and can lead to severe morbidity and mortality.
With the widespread use of high resolution non-invasive
cerebrovascular imaging and clinical awareness, CVST is
often recognized before major stroke symptoms. Treatment
for CVST in the acute setting involves anticoagulation with
F. Caprio
R. A. Bernstein (&)
Department of Neurology, Stroke Program, Feinberg School
of Medicine of Northwestern University, 710 North Lake Shore
Drive, Abbott Hall 11th Floor, Chicago, IL 60611, USA
e-mail: r-bernstein@northwestern.edu
unfractionated heparin (UFH) or low molecular heparin
(LMWH), even if intracranial hemorrhage is present [1].
UFH or LMWH is generally transitioned to long-term oral
anticoagulation (OAC). The ideal duration of OAC is
unknown due to a lack of prospective randomized trials
studying this question. Because of this, much of these
treatment decisions are currently extrapolated from trials
on systemic venous thromboembolism (VTE). The dura-
tion of anticoagulation may depend on the anticipated risk
of recurrent thrombosis, known and suspected predisposing
factors, and must be weighed against the risk of hemor-
rhagic complications. Our objective is to review the
clinical factors that are important in deciding on the
duration of anticoagulation after CVST, and the evidence
behind this decision, where relevant clinical data we
reviewed are rated based on quality standards established
for evidence-based medicine. Data from adequately pow-
ered randomized trials are ranked as Level of Evidence
(LOE) 1; data from small randomized trials, or case–con-
trol studies, and prospective series with historical control
are ranked as LOE 2; and retrospective case series, chart
reviews, and expert opinion are ranked LOE 3.
Acute Treatment
The pathogenesis of CVST is multi-factorial and incom-
pletely understood. Proposed predisposing factors include
pro-thrombotic conditions (transient or chronic, genetic or
acquired), malignancy, oral contraceptives, pregnancy and
puerperium, infection, and trauma or surgery. However,
15–20% of CVST cases occur in the absence of any of the
above conditions. The diagnosis of CVST is usually con-
firmed by CT or MR venography. Initial treatment with
therapeutic anticoagulation using UFH or LMWH followed
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336 Neurocrit Care (2012) 16:335–342

2 week–10 months when not on AC

by a vitamin K antagonist is beneficial; even in the pres-
ence of ICH (LOE 2) [2–7]. The optimal duration of

Median 10 months, most within

1 year of AC discontinuation

1 year of AC discontinuation
8/9 CVST recurrences within
therapeutic anticoagulation following CVST is unknown.

50% within 1 year of AC

The rationale for initiating anticoagulation after CVST

Time from initial CVST

includes prevention of thrombus propagation and venous

Median 16 months
infarction, facilitation of sinus recanalization, and preven-

discontinuation
tion of pulmonary embolism (PE). Several studies show
early complete or partial recanalization after anticoagulant

Unknown
treatment (LOE 2) [8–10], but found differing relationships
to neurologic outcome. Recanalization is shown to initially
correlate with T1-weighted lesion volume on MRI (thought
to represent reversible edema due to venous congestion),

17/41 Total events on AC

but not the final lesion volume at 12 months [11].

2/8 Total events on AC

Three small randomized trials showed better outcome in

9/23 Events on AC
3/4 Events on AC,
the anticoagulation treatment group versus placebo (com-

AC status during

unknown INR
recurrent VTE
plete recovery 8/10 vs. 1/10 in n = 20, poor outcome in
13% vs. 21% in n = 59, and 0 vs. 3 death/paresis in

Unknown

Unknown

Unknown
n = 57 in the 3 separate studies) (level 2) [3, 4, 12].
Several other observational studies, wherein most patients
received anticoagulation, showed that functional outcome
is generally excellent after CVST with the majority of

14 Retrospective
VTE occurrence
patients gaining full clinical neurologic recovery (LOE 2

5 Prospective
and 3) [5, 6, 9, 13–16].

(% of N)

14.3

4.3

7.1
13

7
Long-Term Anticoagulation
Table 1 Risk of recurrent cerebral venous thrombosis and other VTE after first episode of CVST

All, unknown INR

One major aim of continuing anticoagulation after the acute
CVST recurrence
AC status during

phase of CVST is to prevent recurrence of CVST and

episodes of other systemic VTEs. Recurrent CVST is

Unknown
Unknown
Unknown

Unknown
uncommon, and generally occurs within 1 year of the initial
event (LOE 3) [5, 17]. In a large prospective trial following
All

624 patients who have had CVST, 14 (2.2%) patients had

recurrent CVST and 27 (4.3%) had another arterial or venous
Observed CVST recurrences and VTE occurrences after initial CVST
CVST recurrence

thrombotic event (level 2) [13]. Other studies cite CVST

5 Retrospective
0 Prospective

recurrence rates of 0–11.7% and other thrombotic risk of

(% of N)

4.3–14.3% (LOE 2 and 3) [5, 18–21]. The duration of follow

up, duration from initial CVST, and anticoagulation status
11.7

2.2
1.9
6.5

was different for each study (Table 1).

3

There have been no randomized controlled trials to assess

the effectiveness of various durations of OAC for prevention
(51 = Retrospective)
(91 = Prospective)

of recurrent CVST and other VTE. Since risk stratification

for recurrent VTE after DVT or PE are better documented,
and since recurrence rates of venous thrombotic events are
similar in patients with CVST compared to those with LE
142

624

154

145

DVT [20], clinicians often choose a duration of OAC by

77

54
N

extrapolation from the literature on DVT and systemic VTE.

VENOPORT [18]

Martinelli [21]
Maqueda [19]
Author/Study

Duration of OAC After Systemic VTE

ISCVT [13]

Gosk [20]
Preter [5]

Patients who have had a first time DVT are recommended

to complete at least a 3 month period of therapeutic

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Neurocrit Care (2012) 16:335–342
OAC [22]. It has been shown that shortening the duration
of anticoagulation treatment from 3 months to 4 weeks,
and from 6 months to 6 weeks, doubles the rate of recur-
rent DVT in 1–2 years following the initial thrombosis
(level 1) [23–25].
The decision to continue anticoagulation after 3 months
of treatment for systemic VTE is dependent upon whether
the initial VTE was provoked or spontaneous. Transient
provoking risk factors include recent surgery, hospitaliza-
tion, plaster cast immobilization (all within 1 month); and
minor risk factors include estrogen therapy, pregnancy,
prolonged travel; or the occurrence of a major risk factors
that occurred within 3 months of the thrombosis. The
presence of one of the above risk factors will usually
promote extension of anticoagulation for 3–6 months.
For VTE attributable to a transient risk factor, thera-
peutic anticoagulation for 3 months is recommended over
shorter periods. If the VTE is unprovoked, the risk–benefit
ratio for long-term anticoagulation must be considered
before continuing anticoagulation beyond the 3 months. In
a patient with initial VTE that is unprovoked and is either a
proximal DVT or PE, with no significant risk factors for
bleeding and reliable anticoagulation monitoring, life-long
anticoagulation is recommended [22]. Studies comparing
anticoagulation for 3 months versus 6 or 12 months overall
showed very low recurrence of VTE during anticoagulation
treatment but markedly increased rate of recurrent throm-
bosis after anticoagulation was stopped (LOE I) [26–29].
Indefinite anticoagulation results in a 90% relative risk of
reduction for recurrent VTE [30–33]; on-treatment analysis
discloses a 95% relative risk reduction. (LOE I)
The benefit of long-term treatment is partially offset by
the increased risk of hemorrhage, and the loss of protection
against recurrent VTE once anticoagulation is discontin-
ued. However, long-term anticoagulation was associated
with about double the risk of major bleeding, with absolute
rate of 1–2% per year (LOE I) [30–35]. Conventional
versus low-intensity long-term anticoagulation showed no
difference in major bleeding, with no fatal or intracranial
hemorrhage in either group (LOE I) [36]. Risk factors for
bleeding include increasing age (particularly >75), prior
gastrointestinal bleeding, chronic renal or hepatic insuffi-
ciency, active cancer, concurrent use of antiplatelet agents,
higher doses of anticoagulant, and length of treatment
[37, 38]. Of note, there is inadequate data to assess risk of
major (particularly intracranial) hemorrhage in CVST
patients receiving long-term anticoagulation for prevention
of recurrent VTE.
Overall, patients with VTE thought to be provoked by a
reversible risk factor have rates of recurrent VTE of 2% at
1 year and 6% at 5 years, after completing 3 months of
therapeutic anticoagulation. In patients with VTE that is
idiopathic or unprovoked, the rate of recurrent VTE is 10%
337
Table 2 Recommendations for duration of OAC after VTE
Risk factor for VTE Duration of treatment
with goal INR 2–3
Transient risk factor 3 months
Unprovoked Indefinite
Unprovoked + isolated distal DVT, 3 months
increased bleeding risk, or patient
preference
Active malignancy Indefinite
Active malignancy + high bleeding Consider discontinuation at
risk, isolated distal DVT, or 3 months or when cancer
additional transient risk factor becomes inactive
at 1 year and 30% at 5 years. This data suggests that
patients with idiopathic or unprovoked VTE will benefit
from long-term anticoagulation, particularly if the risk for
bleeding on anticoagulation is low. Long-term anticoagu-
lation is recommended after a second episode of VTE [22],
since the risk of another recurrence is about 1.5 times
higher than after a first VTE event.
These recommendations are summarized in Table 2.
Specific Risk Factors for CVST and Recommendations
for Duration of OAC
Similarly to the situation with systemic VTE, the context in
which CVST occurred influences decisions on the duration
of OAC. In this section we discuss data behind the duration
of OAC when it is associated with specific risk factors. In
some cases, the only extant data comes from the systemic
VTE literature. The estimated prevalence of these risk
factors in patients with CVST is shown in Table 3.
Cancer
Cancer was identified as a risk factor in 7.4% of CVST
cases in a large observational study [13], including
malignancy in the CNS, outside the CNS, and hematologic
malignancies. Recurrence rates are not well established in
patients with cancer and there are currently no guidelines
for duration of anticoagulation for patients who develop
CVST with underlying malignancy.
Malignancy was identified as a risk factor in approxi-
mately 20% of patients with systemic VTE, and conversely
patients with cancer are 6 times more likely to develop
VTE than those patients without [39, 40]. Patients with
malignant brain tumors, adenocarcinomas, and hemato-
logic disorders are at particular high risk [41]. In patients
with systemic VTE and underlying malignancy, the risk of
recurrent VTE is 3 times higher than in those patients
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338
Table 3 Risk factors for CVST [1, 9]
Condition
Prothrombotic condition (AT III deficiency, protein C/S deficiency, APL Ab, ACL Ab,
PT gene mutation, FVL, hyperhomocysteine)
Pregnancy and puerperium
OCP use
Drugs (androgen, danazol, lithium, vit A, IVIG, ecstasy)
Cancer-related (local compression, hypercoagulable state, anti-neoplastic agents)
Infection (parameningeal: ear, sinus, mouth, face, neck)
Mechanical precipitants (epidural blood patch, spontaneous intracranial hypotension, lumbar puncture)
Other hematologic disorders (PNH, iron deficiency anemia, nephritic syndrome, PV, TCP)
Systemic disease (SLE, Behcet, IBD, thyroid disease, sarcoid)
None identified
without malignancy. Patients with cancer and DVT are
recommended to receive long-term anticoagulation,
including LMWH for the first 3–6 months followed by
VKA or LMWH indefinitely or until the cancer resolves
(level 1) [22]. By analogy, we suggest following the same
treatment strategy in the setting of CVST and cancer.
Pro-Thrombotic States
Testing for thrombophilias after any thrombotic event is
controversial. In general, testing if recommended for all
patients after CVST without another obvious cause and
longer duration anticoagulation is recommended after
CVST depending on severity of the thrombophilic condi-
tion. There is evidence to support both checking and not
checking for thrombophilias after systemic VTE, differing
from the approach to patients with CVST. Current rec-
ommendations for VTE state that the presence of a
thrombophilia is not a major factor in determining length of
treatment.
Prothrombotic States and Systemic VTE
Screening for thrombophilia after systemic VTE and
duration of anticoagulation in the presence of thrombo-
philia is controversial. Though some recommendations for
duration of anticoagulation after CVST are based on
studies that show high recurrence of VTE after initial
systemic VTE, there are other studies that suggest testing
for thrombophilia after initial systemic VTE is not clini-
cally useful.
After initial systemic VTE, thrombophilia does not
appear to be a clinically important risk factor for recurrent
VTE, and testing for thrombophilia is not used as a major
factor when determining duration of treatment [22, 38].
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Neurocrit Care (2012) 16:335–342
Prevalence (%)
34
21 (of female patients)
54.3 (of female patients)
7.5
7.4
12.3
4.5
12
7.2
12.5
Some prospective studies have shown that the presence of
thromobophilic conditions is not a major risk factor for
recurrence [22, 30, 31, 37, 42–51]. It is argued that the
presence of thrombophilias does not lead to change in
duration of anticoagulation and is cost-ineffective (LOE 2
and 3) [52–54]. Other studies suggest that multiple pro-
thrombotic defects do lead to high rates of recurrent VTE
(LOE 3) [55–57]. The thrombotic risk is shown to be
higher in patients with protein C, protein S, and anti-
thrombin III deficiencies than in those with factor V
Leiden, PT gene mutation, and high factor VIII [58], sug-
gesting that perhaps screening for thrombophilias may
have higher yield in family members with more severe
thrombophilic defects (LOE 3).
Pro-Thrombotic States and CVST
Thrombophilic state was identified in 34.1% of the 624
patient in the ISCVT study [9], and in 21% of 182 patients
in a more recent study [59]. Epidemiologic studies have
shown a higher prevalence of protein C, protein S, and
antithrombin III deficiencies, antiphospholipid and anti-
cardiolipin antibodies, factor V Leiden, and prothrombin
gene mutation among patients after CVST compared to
control patients [13, 60–63]. Hyperhomocysteinemia has
not been clearly associated with increased risk of CVST
[1].
Small studies have shown a higher rate of VTE recur-
rence in CVST patients with a thrombophilia than in those
without thrombophilia (LOE 2 and 3) [19, 21]. Larger trials
studying the recurrence rates of VTE in patients with dif-
ferent thrombophilias, specifically after CVST, are lacking.
In VTE patients with antithrombin III, protein C, or protein
S deficiency, the rate of recurrence is 19% at 2 years, 40%
at 5 years, and 55% at 10 years (level 3) [58]. Along with
homozygous prothrombin G20210A, homozygous factor V
Neurocrit Care (2012) 16:335–342
Leiden, antiphospholipid syndrome, and combined throm-
bophilias are considered severe [1, 64]. Patients with these
prothrombotic conditions are recommended to receive
indefinite anticoagulation (LOE 3) [1, 64].
In VTE patients with more common hereditary throm-
bophilias such as heterozygous factor V Leiden,
heterozygous prothrombin G20210A and elevated factor
VIII, the recurrence rate of VTE is 7% at 2 years, 11% at
5 years, and 25% at 10 years [58]. These thrombophilias
are considered mild [1]. The EFNS recommends contin-
uing anticoagulation for 6–12 months in patients with
CVST and a mild thrombophilia [64]. Hyperhomocystein-
emia is not significantly associated with high risk of VTE
recurrence [13].
Antiphospholipid antibody syndrome (APS) is an
acquired thrombophilia associated with lupus anticoagu-
lant, anticardiolipin antibody, and anti-ß2-glycoprotein
antibody, and a history of venous or arterial thrombosis,
which requires laboratory diagnosis by testing on 2 or more
occasions, at least 12 weeks apart [65, 66]. Patients with
the diagnosis of APS have an increased risk for recurrent
thrombosis. Recurrent VTE occurs in 29% of patients with
APS versus 14% in those without, over 4 years (LOE 2)
[67]. Based on the high risk of recurrent VTE in the
presence of APS, current recommendations are for indefi-
nite OAC after initial VTE, including CVST [1, 22].
Oral Contraceptives and CVST
The use of oral contraceptives (OCP) has been shown in
multiple studies to be associated with higher risk of
developing CVST, particularly in the presence of a
hereditary prothrombotic defect such as prothrombin gene
mutation or factor V Leiden [60, 62, 68]. Estrogen-con-
taining OCPs are considered a minor risk factor for
recurrent VTE. Progestin-only OCPs are generally thought
to carry a relatively small or no increased risk for VTE
[69, 70]. VTE that occurs within 1 month of OCP use
usually is treated with 3 months of anticoagulation. Current
treatment practices favor cessation of OCPs in the setting
of CVST, which may reduce the risk of recurrent throm-
bosis. Prolonged OAC after a single episode of CVST is
likely unwarranted (LOE 3) [71].
Pregnancy and Puerperium
Pregnancy induces several pro-thrombotic changes in the
coagulation system that persists into the post-natal period,
leading to an increased risk of VTE [72]. The highest risk
period for CVST includes the third trimester and the first
4 weeks postpartum [73]. A pro-thrombotic state may be
339
Table 4 Risk factors for CVST and suggested treatment duration
Risk factor for CVST Suggested treatment duration
Malignancy Indefinite or until malignancy
resolves, LMWH for initial
3–6 months
Transient thrombophilic state* 3 months
Mild thrombophilia** 3–6 months
Severe thrombophilia*** 6–12 months
Oral contraceptives 3 months
Pregnancy/puerperium LMWH for remainder of
pregnancy + at least
6 weeks post-partum, total
6 months
* Dehydration, drugs, infection, trauma, surgical precipitants
** Heterozygous PT gene mutation, heterozygous factor V Leiden,
high levels of factor VIII
*** Homozygous PT gene mutation, homozygous factor V Leiden,
protein C/protein S/AT III deficiency, combined thrombophilias, an-
tiphospholipid syndrome
worsened in the puerperium due to intravascular volume
depletion, trauma, infection, and instrumentation [74].
About 2% of pregnancy-related strokes are attributable to
CVST, which carries an estimated incidence of 1 per
2,500–10,000 deliveries [73, 75–77]. The current recom-
mendation for treatment of CVST during pregnancy is
application of the same anticoagulation scheme directed at
treating systemic venous thrombosis: LMWH for the
remainder of the pregnancy and for at least 6 weeks post-
partum for total minimum 6 months of therapeutic
anticoagulation (LOE 2 and 3) [1, 22, 78].
Women with history of VTE are at risk for recurrent
thrombotic events during future pregnancies [79]. Outcome
studies following women after CVST showed low risk of
complications in future pregnancies, though a high pro-
portion of spontaneous abortion was noted [5, 13, 18, 80–
82]. CVST is not thought to be a contraindication for future
pregnancies, and the role of prophylactic LMWH during
future pregnancy and puerperium is likely beneficial but
not yet definitively determined [1].
Conclusion
Risk factors associated with CVST and their suggested
treatment duration is listed in table 4.
Duration of anticoagulation after cerebral venous
thrombosis needs to be individualized based on risk factors
for recurrent thrombosis, taking into consideration pro-
thrombotic predispositions. For patients with CVST pro-
voked by a transient risk factor, anticoagulation is
recommended for 36 months. For patients with CVST that
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340
is idiopathic or due to a mild thrombophilia, anticoagula-
tion may be considered for 612 months. For patients with
CVST due to a severe thrombophilia or combined throm-
bophilias, and for patients with recurrent CVST, indefinite
anticoagulation is recommended. In patients with CVST
setting of malignancy, anticoagulation (with LMWH) is
recommended for at least 36 months or until the malig-
nancy resolves. In setting of pregnancy and puerperal
CVST, anticoagulation (with LMWH) is recommended for
the remainder of the pregnancy and for at least 6 weeks
postpartum for a total of 6 months of therapy. Due to
similarities in the risk of recurrent thrombosis after initial
CVST compared to initial systemic VTE, some recom-
mendations are based on evidence gathered from VTE
patients. Large randomized prospective trials are needed to
more accurately assess the effectiveness of different treat-
ment durations in different clinical situations after CVST.
Increased risk of hemorrhage with prolonged anticoagula-
tion and patient preference and compliance must also be
considered. Novel anticoagulants may improve the risk–
benefit ratio and decrease challenges faced with prolonged
usage of oral vitamin K antagonists.
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