Clinical Neurology and Neurosurgery 102 (2000) 33 – 36
www.elsevier.com/locate/clineuro

Case report

Sagittal sinus thrombosis associated with transient free protein S
deficiency after L-asparaginase treatment: case report and review
of the literature
Jae-Hong Lee a,*, Sang-We Kim b, Jong Sung Kim a
a

Department of Neurology, Uni6ersity of Ulsan College of Medicine, Asan Medical Center, 388 -1 Poongnap-dong songpa-gu,
Seoul 138 -736, South Korea
b
Department of Internal Medicine, Uni6ersity of Ulsan, Asan Medical Center, Seoul, South Korea
Received 11 May 1999; received in revised form 15 November 1999; accepted 15 November 1999

Abstract
Cerebral sinus thrombosis associated with acquired free protein S deficiency is very rare. We report the case of an adult patient
with acute lymphoblastic leukemia who presented with repeated transient ischemic attacks followed by a seizure during
consolidation treatment with L-asparaginase. Magnetic resonance of the brain showed a small cortical hemorrhagic infarct.
Superior sagittal sinus thrombosis was demonstrated by cerebral angiogram. A marked decrease of the free form of protein S was
documented. One month later, when the patient was free of symptoms, the follow-up free protein S antigen level was restored to
the normal range. We suggest that the sagittal sinus thrombosis in this patient was caused by acquired, transient free protein S
deficiency. This case also extends the clinical spectrum of cerebral sinus thrombosis to include recurrent transient ischemic attacks
alternating with seizures. © 2000 Elsevier Science B.V. All rights reserved.
Keywords: L-Asparaginase; Acute lymphoblastic leukemia; Blood proteins; Free protein S; Cerebral venous thrombosis; Sagittal sinus

1. Introduction
Acquired or inherited deficiency of natural anticoagulants is a well-known cause of venous thrombosis.
Free protein S serves as a cofactor for activated protein
C, and protein C–S complex exerts its antithrombotic
effect by inactivating activated factor V and VIII, and
by inhibiting plasminogen activator inhibitor [1]. Free
protein S deficiency produces a coagulopathy and may
cause cerebral vessel thrombosis. Cerebral sinus thrombosis (CST) associated with free protein S deficiency,
however, is very rare [2]. Previous cases were mostly
related to hereditary protein S deficiency [3,4]. An
acquired deficiency of the free protein S after L-asparaginase therapy has not yet been reported to be
associated with CST.
* Tel.: +82-2-2224-3446; fax: + 82-2-474-4691.
E-mail address: jhlee@www.amc.seoul.kr (J.-H. Lee)

We report the case of a patient with acute
lymphoblastic leukemia (ALL) who showed an unusual
combination of clinical manifestations of superior sagittal sinus thrombosis during the treatment with L-asparaginase, which was probably due to a
hypercoagulable state caused by free protein S
deficiency.

2. Case report
A 22-year-old man presented in November 1996 with
recurrent episodes of transient left hemiparesis. He had
been well until 19 years of age, when easy fatigability
developed. Complete blood count (CBC) showed a
hemoglobin level of 93 g/l; white blood cell count,
11 100/mm3; and platelet count, 26 000/mm3. Bone marrow was replaced by non-T, non-B cell, L2 morphology
lymphoblasts. Induction therapy consisted of vincristine

0303-8467/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.
PII: S 0 3 0 3 - 8 4 6 7 ( 9 9 ) 0 0 0 7 6 - 1

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J.-H. Lee et al. / Clinical Neurology and Neurosurgery 102 (2000) 33–36

sulfate, prednisone, daunorubicin, and L-asparaginase.
He received 1800 rad cranial irradiation with six doses
of intrathecal methotrexate. Maintenance therapy was
begun with oral methotrexate and 6-mercaptopurine.

Fig. 1. Axial T1- (a) and T2-weighted (b) magnetic resonance images
show an area of high signal intensity in the right frontal lobe,
indicating a hemorrhagic venous infarct.

He had a relapse in November 1995 and his bone
marrow was replaced by L1 lymphoblasts. The second
re-induction was done with uneventful remission, followed by alternating courses of consolidation therapy.
Courses one, three, five, and seven of consolidation
chemotherapy consisted of daunorubicin, vincristine,
prednisone, and L-asparaginase. Courses two, four, six,
and eight consisted of VP-16 and Ara-C. He received
the seventh consolidation therapy in October 1996 with
a 2-week course of vincristine, prednisone, daunorubicin, and L-asparaginase. Three days after the last
sixth dose of L-asparaginase (18 000 U), he was admitted to the Medical Oncology Service due to abrupt
onset of headache, nausea, and paresthesia in the left
extremities, followed by paralysis in the same extremities. It resolved in 5–10 min. During the attack, the
consciousness was not impaired at all. The same
episode recurred twice during hospitalization. Neurologic consultation was obtained. General physical examination including funduscopic examination was
normal. Neurologic examination at the time of paralysis revealed the patient to be alert and coherent. A mild
left central facial palsy was noted. He showed a left
hemiparesis with the arm Gr I and the leg Gr IV. There
was a plantar extensor response on the left. The remainder of neurologic examination was normal. The
focal neurologic deficits resolved in 20 min. A computed tomography of the head was unrevealing. He was
started on intravenous heparin under the impression of
recurrent transient ischemic attacks (TIAs). Admission
laboratory studies included CBC, electrolytes, electrocardiogram, and chest roentgenogram; all were normal.
On hospital day 2, he developed a simple partial motor
seizure in the left extremities, followed by a loss of
consciousness for several minutes. Postictal paralysis in
the left extremities was noted. Shortly afterward, an
electroencephalogram was performed and was unremarkable. Phenytoin was placed and he had no recurrent seizures after that. A brain magnetic resonance
imaging showed a focal high signal intensity lesion in
the right frontal area on a T1- and T2-weighted image,
suggesting an infarct with some hemorrhage (Fig. 1).
The cerebral angiogram revealed superior sagittal sinus
thrombosis with a marked impairment of venous return
on the right side (Fig. 2). Intravenous heparin was
maintained for 1 week, and then he was switched to
warfarin. Follow-up magnetic resonance venogram
showed recanalization of the superior sagittal sinus
(Fig. 3).
The antithrombin III activity, the protein C level,
and the total protein S antigen concentration were
within normal limits. Other coagulation studies including fibrinogen, D-dimer, and antiphospholipid antibody
were all normal. The free protein S antigen level on day
3, however, was 30% (normal, 70–140%). He was discharged symptom-free on hospital day 22. L-Asparagi-

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35

3. Discussion

Fig. 2. Venous phase angiography demonstrates nonopacification of
the entire superior sagittal sinus. There are prominent cortical veins
draining to patent basal sinuses.

Fig. 3. Follow-up magnetic resonance venogram shows recanalization
of the superior sagittal sinus.

nase was withdrawn from the consolidation regimen.
Follow-up free protein S level 1 month after the stroke
onset was 70%. At 2 years, he continued to be well.

In ALL, induction therapy with L-asparaginase
sometimes causes venous thrombosis [5]. L-Asparaginase hydrolyzes asparagine to aspartic acid, depleting
asparagine and inhibiting protein synthesis. This inhibition is thought to be the basis of its antineoplastic
effect, but it also leads to the depletion of other plasma
proteins involved in coagulation and fibrinolysis [6].
Plasminogen and antithrombin III production can be
interfered, tipping the equilibrium in favor of coagulation and producing deep vein thrombosis or CST.
Protein S deficiency, particularly a free, active form, is
also reported to be associated with CST [4]. Free
protein S enhances the inactivation of factors Va and
VIIIa by serving as a cofactor for activated protein C,
and protein C–S complex inhibits the clotting cascade.
A decrease in free protein S concentration may lead to
overactivity of the coagulation system and promote
thrombosis. Since free protein S, not the bound form,
functions in the activation of protein C, it is necessary
to estimate the free as well as the total immunoreactive
protein S levels to evaluate a suspected hypercoagulable
state [7].
A few instances of venous infarction due to CST
have been identified in patients with protein C deficiency and antithrombin III deficiency [8,9]. Inherited
protein S deficiency has also rarely been described [3,4].
Acquired free protein S deficiency has been previously
reported in association with nephrotic syndrome [10],
ulcerative colitis [11], multiple myeloma [12], and some
infection [13]. Occasional occurrences of CST related to
the treatment of ALL were known to be mostly due to
high incidence of disseminated intravascular coagulation during remission induction of ALL [14]. To our
knowledge, this is the first reported case of CST associated with acquired free protein S deficiency and L-asparaginase treatment. The evolution of free protein S
level in our patient, initially low and then, after withdrawal of L-asparaginase, back to normal at follow up
measurement, defines the association. Why there was a
selective free protein S deficiency after L-asparaginase
treatment, however, is unknown.
The possibility of sagittal sinus occlusion due to
leukemic cell infiltration cannot be completely excluded, since a lumbar puncture was not performed in
the course of intravenous heparin therapy. Even with
intrathecal methotrexate and total brain irradiation,
there may be some remaining nests of lymphoblasts
around cerebral venous sinuses. Given that the patient
may be immunosuppressed, some opportunistic infection could also be among other possibilities of cerebral
sinus thrombosis. However, the dramatic disappearance
of recurring symptoms after the use of heparin, recanalization of the sagittal sinus after a short period of time,
and his good clinical course make those possibilities less
likely.

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J.-H. Lee et al. / Clinical Neurology and Neurosurgery 102 (2000) 33–36

CST is frequently asymptomatic in patients with
ALL. When symptomatic, it usually presents abruptly
with seizures. Focal neurologic signs may result when
cerebral infarction occurs. Focal signs are heterogeneous depending on the mode of onset, their nature,
and their possible association with altered consciousness. Acute cases may simulate an arterial stroke. They
can be even more misleading when presenting like a
TIA, as in our patient. Bousser et al. [15] reported in
their review of 38 cases of CST that only one or two
patients had a TIA with episodes of paresthesia and/or
dysphasia lasting from 15 min to 1 h. It is unique that
our patient exhibited both TIAs and a seizure at the
same time as manifestations of CST. One can argue
that a TIA, in fact, was a manifestation of a seizure,
which developed later on. However, given the fact that
during attacks, his consciousness was not impaired at
all and there was no tonic or clonic movement of the
involved extremities other than pure paralysis, it was
most likely to be a TIA, not a seizure. The pathomechanism of these deficit (TIA) and excitation (seizure)
phenomena in the same patient remains speculative.
One possibility would be hemodynamic instability of
the cerebral venous system in the setting of sagittal
sinus thrombosis. As the thrombus obstructs the cerebral venous flow and the resultant venous hypertension
develops, collateral vessels proliferate around the occluded sagittal sinus, serving as the alternative channel,
as demonstrated in our patient. If the thrombus in the
sinus cavity is unstable, and occlusion and recanalization of the sinus alternate, the venous hypertension
would fluctuate, and the resultant edema and venous
infarct could change in size and severity accordingly. In
that situation, one minute it may serve as a destructive
lesion causing a neurologic deficit and the next, it may
act as an irritative lesion giving rise to a seizure. The
transient, capricious nature of the focal cerebral signs
shown in our patient might be explained on this hemodynamic basis.
This case extends the clinical spectrum of CST and
the implication of free protein S deficiency. The presence of alternate TIA and seizure during a short period
of time should alert the clinician to the possibility of
CST. Patients with stroke complication caused by L-as-

.

paraginase should be tested for both the free and total
protein S and other anticoagulant deficiencies.
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