ARTICLE IN PRESS

Early Identification of Protein S K196E Mutation in a Patient
With Cerebral Venous Thrombosis: A Case Report
D2X XKyohei Fujita, D3XMD,
X * D4X XKazutaka Sonoda, MD,
D5X X † D6X XToshiyuki Miyata, PhD,
D7X X *
D8X XMasafumi Ihara, MD,
D9X X PhD,‡ D10X XKazunori Toyoda, MD,
D1X X PhD,* and
D12X XMasatoshi Koga, MD,
D13X X PhD*
Background: Mutation of protein S K196E (PS K196E) is a genetic risk factor for
venous thromboembolism; however, there are few reports on cerebral venous
thrombosis (CVT) with this mutation. We report a case of CVT
D14X X
that was diagnosed
as having PDS
15X X K196E mutation at the initial thrombotic event. Methods: A 54-year-old
man suddenly developed generalized seizures after headache and nausea. Brain
magnetic resonance imaging showed cerebral edema, and angiography revealed D16X X
D17XCVT.
X
Blood examination revealed that protein S activity was low (44%) despite normal free protein S antigen levels (81%). Sequence analysis revealed a heterozygous
PS K196E mutation. We treated him with warfarin with the international normalized ratio maintained at 2.0-D3.0.
18X X
After 1D19X Xmonth, he was discharged without any neurological sequelae. Results: Early identification of the causes of thrombophilia is
important for the long-term management of CVTD.20X X However, detection of PDS
21X X K196E
mutation is difficult because its only feature is a moderate decrease in the activity of
protein S, which is influenced by environmental factors. Conclusions: The possibility
of PDS
2X X K196E mutation should be considered if other causes of CVT
D23X X
are ruled out
and if protein S activity is decreased.
Key Words: Cerebral venous thrombosis—pDrotein
24X X
S activity—pDrotein
25X X
S K196E
mutation—gDenetic
26X X
analysis
© 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.

Case Report
A 54-year-old man with a history of hypertension, dyslipidemia, and hyperuricemia experienced progressive
headache and nausea. He had never taken routine
From the *Department of Cerebrovascular Medicine, National
Cerebral and Cardiovascular Center, Suita, Osaka, Japan; †Division
of Stroke Care Unit, National Cerebral and Cardiovascular Center,
Suita, Osaka, Japan; and ‡Department of Neurology, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
Received May 5, 2018; revision received August 29, 2018; accepted
September 24, 2018.
Financial Disclosure: This study was supported by research grants
from the Japan Society for the Promotion of Science, Grant-in-Aid for
Scientific Research (C): 16K09834 (T.M.), and the Takeda Scientific
Foundation (T.M., K.T.).
Address correspondence to K. Fujita, MD, Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center,
5-7-1 Fujishiro-dai, Suita, Osaka 565-8565, Japan. E-mails:
fujinuro@ncvc.go.jp, k.sonoda@ncvc.go.jp, miyata@ncvc.go.jp,
ihara@ncvc.go.jp, toyoda@ncvc.go.jp, koga@ncvc.go.jp.
1052-3057/$ - see front matter
© 2018 National Stroke Association. Published by Elsevier Inc. All
rights reserved.
https://doi.org/10.1016/j.jstrokecerebrovasdis.2018.09.040

medication and had no history of thrombotic events. His
father had developed ischemic stroke at 70 years of age.
Seven days after symptom onset, he suddenly developed
generalized seizures and visited our emergency room. On
arrival, he was clear and showed weakness in his right
arm.
Emergent brain magnetic resonance imaging showed
vasogenic edema in the left frontal lobe (Fig 1, A-C) and
prominent cortical veins on T2*-weighted images (Fig 1, D).
Cerebral angiography showed cerebral venous thrombosis (CVT) in superior sagittal sinus and left transverse
sinus (Fig 1, E, F). Heparin, glycerin, and oral levetiracetam were started for this patient.
On blood examination, protein S (PS) activity was low
(44%) despite a normal free PS antigen level (81%). Hereditary PS deficiency was suspected because the possible
causes of CVT including infection, connective tissue disease, cancer, trauma, and other thrombophilia were
excluded. After written informed consent was obtained
from the patient, sequence analysis was performed, which
revealed a heterozygous protein S K196E (PS K196E)
mutation. Heparin was switched to warfarin with the

Journal of Stroke and Cerebrovascular Diseases, Vol. &&, No. && (&&), 2018: && &&

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ARTICLE IN PRESS
K. FUJITA ET AL.

2

FigureD1X 1X . Brain magnetic resonance imaging shows a hyperintense area in the left frontal lobe on diffusion-weighted imaging (A) and fluid-attenuated inversion
recovery imaging (B). This area shows isointensity on the apparent diffusion coefficient map (C). T2*-weighted image shows hypointense lesions, suggesting
prominent cortical veins, in the bilateral cerebral hemispheres (D). Cerebral angiography shows occlusion in the superior sagittal sinus and the left transverse
sinus (E and F).

international normalized ratio maintained at 2.0-3.0. After
1D27X X month, the patient was discharged without any neurological sequelae.

Discussion
PS K196E mutation is a genetic risk factor for venous
thromboembolism specific to the Japanese populationsD128X X
2-4
with an odds ratio ranging 3.74D
D29X X
30X X
-8.56.D
31X X It is estimated that
approximately 1D32X X in every 55 Japanese persons is heterozygous for this mutation.D53X X however, there are few reports on
CVT with PS K196E mutation. In the only reported case of
CVT with PS K196E mutation, the mutation was detected
6
after recurrent thrombotic events.
D34X X
D35X X
Earlier identification of the causes of thrombophilia
can be beneficial for long-term management of CVT.D36X7,X D37X8X
However, the detection of PS K196E mutation is difficult because the only feature of this mutation is the
moderate decrease in PS activity, which is influenced
by environmental factors.D38X9X Thus, genetic analysis is
useful for early definite diagnosis. On the other hand,
it should be noted that genetic analysis is not always
feasible at all hospitalsD39X X and ethical considerations are
necessary. Thus, as in the present patient, if there are
no other abnormalities causing CVT and the PS activity is decreased, the possibility of the PS K196E mutation should be considered, especially in Japanese
populations.

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