Unusual presentation of more common disease/injury

Early recanalisation of cerebral venous sinus thrombosis in an
unusual case associated with severe protein S deficiency
Rajesh Verma, Tushar B Patil, Neeraj Kumar
Department of Neurology, Chhatrapati Shahuji Maharaj Medical University, Lucknow, Uttar Pradesh, India
Correspondence to Professor Rajesh Verma, drrajeshverma32@yahoo.com

Summary
An inherited or acquired deficiency of protein S leads to a prothrombotic state, with predisposition to venous thrombosis. We describe a
case of cerebral venous sinus thrombosis (CVST) associated with acquired protein S deficiency and recanalisation within 15 days of
anticoagulation. A 38-year-old man presented with recurrent headache, vomiting, altered sensorium and one episode of transient left
hemiparesis. Magnetic resonance venography showed poor flow in the deep cerebral venous sinuses with extensive collateral venous
channel formation, which resolved after 15 days of anticoagulation, along with clinical improvement. Serum protein S activity was found to
be markedly low (16% of biological reference). CVST should be suspected in a patient with acute features of raised intracranial pressure or
focal neurological deficit, and a patient without obvious clinical predisposition for a prothrombotic state should be evaluated for underlying
thrombophilic states like protein S deficiency.

BACKGROUND

INVESTIGATIONS

Protein S is an endogenous vitamin K-dependent anticoagulant, which prevents clotting by acting as a cofactor
for activated protein C in the degradation of clotting
factors Va and VIIa.1 An inherited or acquired deficiency
of protein S leads to a prothrombotic state, with predisposition to thrombosis. It is a cause of cerebral venous
sinus thrombosis (CVST), with only a few sporadic
reports in the literature.2 3 Furthermore, with anticoagulation, recanalisation occurs within 4 months of therapy in
most cases of cerebral venous thrombosis.4 We describe a
case of acquired protein S deficiency-associated CVST
with recanalisation within 15 days of anticoagulation
therapy.

On laboratory investigations, haemoglobin level was 12 g/dl,
total leucocyte count was 8900/cumm with normal differentials. Platelet count was 240 000/cumm. Chest x-ray did not
reveal any abnormality. The patient was negative for HIV
and hepatitis B serology. Cerebrospinal fluid (CSF) examination showed 5 cells/cumm with normal CSF proteins and
sugar levels. CSF ELISA for antibodies against endemic
viruses: Japanese encephalitis, dengue, herpes simplex and
varicella zoster were negative. Considering history of altered
sensorium with transient focal neurodeficit, MRI with MR
angiography of the brain was requested. MRI cranium and
arteriograhy did not reveal any abnormality (figure 1).
However MR venography was showing poor flow in the
deep cerebral venous sinuses with extensive collateral venous
channel formation (figure 2). A diagnosis of CVST was thus
considered and the patient was investigated for a possible
hypercoagulable state. Serum protein S activity was found to
be markedly low (16% of biological reference) (normal range:
77–143%). Other factors that were tested included protein C
activity, homocysetine, lupus anticoagulant, antinuclear
antibody antiphospholipid antibodies, antithrombin III
which were found to be unremarkable.

CASE PRESENTATION
A 38-year-old man presented to our hospital with a
history of headache and vomiting about 2weeks back followed by altered sensorium. He developed weakness of
the left half of the body a few minutes after the onset of
headache. His weakness improved on the next day. He
remained asymptomatic for 4 days after this event, following which he again had an episode of headache,
vomiting and altered sensorium for which he was
brought to our hospital. He was a non-smoker and had
no features suggestive of systemic or haematologic malignancy. He had no history suggestive of thrombotic episodes in any family members. Clinical examination
revealed a young disoriented man. Pulse rate was 84/min,
blood pressure 130/80 mm Hg and respiratory rate was
18/min. Cranial nerve examination was normal. He was
moving all four limbs and maintaining posture but was
not cooperative for a detailed motor system examination.
His deep tendon reflexes were brisk and plantars were
bilateral flexors. Sensory and cerebellar examination
could not be performed.
BMJ Case Reports 2012; doi:10.1136/bcr-2012-006496

TREATMENT
Patient was started on anticoagulation therapy with
low-molecular-weight heparin, enoxaparin 60 mg twice
daily, after withdrawing blood sample for above procoagulant factors estimation. The patient received decongestive
therapy and other supportive measures. Patient’s sensorium improved within 2 days of starting therapy.

OUTCOME AND FOLLOW-UP
A repeat MR venography was performed 15 days later,
which revealed recanalisation in the form of striking
improvement in flow with a marked decrease in collaterals
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Figure 1 MRI, T2 fluid-attenuated inversion-recovery image
revealed normal study.
(figure 3). The patient was shifted on oral anticoagulation
with warfarin and discharged. He was asymptomatic on
further follow-up. Serum protein S estimation was repeated
8 weeks after the initial presentation and it was found to be
persistently low (18%), further confirming the protein S
deficiency.

DISCUSSION
This young patient had come to us with recurrent headache, vomiting, altered sensorium and a transient hemiparesis episode, which led us to consider possibility of

Figure 2 Magnetic resonance venography showed poor flow in
deep venous sinuses with the presence of collaterals.
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Figure 3 MR venogram on repeat study demonstrated
recanalisation of deep venous sinuses with disappearance of
collaterals.
either a cerebrovacular episode or viral encephalitis. Viral
encephalitis was refuted by a normal CSF examination.
Further, in view of a normal MRI and MR ateriography,
we considered the diagnosis of CVST, which was confirmed by poor flow and extensive collaterals in MR venography. The rich collaterals and absence of an obvious
occlusive thrombus suggests a recurrent, chronic thrombotic process in cerebral venous sinuses. Thus, transient
focal neurodeficit is an unusual presentation of CVST and
the diagnosis can be made in such cases only with a high
index of suspicion for CVST.
Protein S (named in reference to its isolation and characterisation in Seattle in 1979) is a vitamin K-dependent protein
synthesised in the liver, vascular endothelium and megakaryocytes. It helps in cleaving activated clotting factors Va and
VIIa on vascular endothelium by acting in association with
protein C. Protein S deficiency can be inherited or acquired.
Bertina classified protein S deficiency into three clinical subtypes based on laboratory findings. Type I refers to deficiency
of both free and total protein S as well as decreased protein S
activity; type II shows normal plasma values, but decreased
protein S activity; and type III shows decreased free protein
S levels and activity, but normal total protein S levels.5 Of 71
protein S-deficient members from 12 Dutch pedigrees, 74%,
72% and 38% of the individuals sustained deep vein thrombosis (DVT), superficial thrombophlebitis and pulmonary
emboli, respectively.6 However, CVST has been described in
only a few case reports. Acquired protein S deficiency secondary to HIV and pregnancy leading to CVST has been
described in a previous case report. As per our knowledge,
ours is the first case report of an idiopathic, acquired protein
S deficiency causing CVST. Few case reports have also implicated protein S deficiency in recurrent ischaemic strokes in
the young.7–9 Similarly, progressive intracranial occlusive
disease has been reported in association with protein S deficiency.10 However, current data do not support an
BMJ Case Reports 2012; doi:10.1136/bcr-2012-006496

association between hereditary protein S deficiency and an
increased risk of arterial thrombosis.11 The recommended
therapy for CVST is anticoagulation with heparin followed
by oral anticoagulation, which should be continued indefinitely for patients with underlying thrombophilia.12 Despite
similar treatment as that for DVT, CVST management poses
a unique management issue, with respect to discontinuation
of anticoagulation. Because DVT in the limbs is precipitated
by immobilisation, it is assumed that after a sufficient period
of anticoagulation and achieving mobility, anticoagulation
can be discontinued, which cannot be the case with CVST.
Hence, assessment of recanalisation is important in CVST. A
study showed that most of the recanalisation occurs during
initial 4 months of anticoagulation therapy.4 Another study
demonstrated a recanalisation rate of 60% at 4 weeks after
CVST.13 Recanalisation of CVST has been described as early
as 24 h in a previous case report.14 Recanalisation is affected
most importantly by endogenous fibrinolysis. Recanalisation
in CVST can have potential therapeutic implications in
framing future guidelines of therapy, particularly with regard
to discontinuation of anticoagulation. Thus, the scarcity of
data regarding recanalisation in CVST and its implications in
outcome of patients mandates a major study addressing
these issues.

Learning points
▸ Cerebral venous sinus thrombosis (CVST) should be
suspected in a patient with acute features of raised
intracranial pressure or focal neurological deficit.
▸ A transient ischaemic attack-like presentation is also
possible in CVST, and in such cases if work-up for an
arterial stroke is negative, then a venography should be
considered.
▸ Patients of CVST should be evaluated for underlying
thrombophilic states like protein S deficiency in the
absence of well-defined causes/risk factors.
▸ The early institution of anticoagulants in cerebral
venous thrombosis is helpful in achieving early
recanalisation in CVST.

Competing interests None.
Patient consent Obtained.

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Reports 2012;10.1136/bcr-2012-006496, Published XXX
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