Case Report

An Embolic Stroke in a Patient With PROC p.Lys193del
Kana Ueki, MD,* Kuniyuki Nakamura, MD, PhD,* Yoshinobu Wakisaka, MD, PhD,*
Shinichi Wada, MD, PhD,* Yoji Yoshikawa, MD, PhD,* Shinya Matsumoto, PhD,†
Taeko Hotta,† Dongchong Kang, MD, PhD,†,‡ Takanari Kitazono, MD, PhD,* and
Tetsuro Ago, MD, PhD*

We report a 58-year-old woman who suddenly developed brain infarction with
weakness of the left lower extremity and left perioral dysesthesia during postoperative tamoxifen therapy for breast cancer and prednisolone therapy for rheumatoid
arthritis. Diffusion-weighted images detected multiple areas of hyperintensity in
the posterior circulation system of the brain. Despite extensive examinations, we
could not identify any embolic sources except hypoplasia of the right vertebral
artery. We found decreased activity of protein C against its antigen level (activity:
59% versus antigen: 122%) with enhanced activity of coagulation factor VIII (178%)
and von Willebrand factor (285%). DNA sequencing identified trinucleotide deletion of the PROC gene leading to 1 amino acid deletion at Lys-193 (p.Lys193del).
We speculate that the PROC gene polymorphism may have participated in tamoxifen- and prednisolone- associated hypercoagulable state, leading to development of
an embolic stroke in this patient.
Key Words: Embolic stroke—hypercoagulable state—protein C p.Lys193del—
tamoxifen—hypoplastic vertebral artery
© 2019 Elsevier Inc. All rights reserved.

Introduction
A hypercoagulable state is found in approximately
3%-21% in patients with ischemic stroke.1 There is a racial
difference in the cause of a hypercoagulable state. Factor
V Leiden, which is the most common genetic polymorphism causing coagulation abnormality in Western

From the *Department of Medicine and Clinical Science, Graduate
School of Medical Sciences, Kyushu University, Fukuoka, Japan;
†Clinical Chemistry and Laboratory Medicine, Kyushu University
Hospital, Fukuoka, Japan; and ‡Department of Clinical Chemistry
and Laboratory Medicine, Graduate School of Medical Sciences,
Kyushu University, Fukuoka, Japan.
Received October 3, 2019; revision received November 19, 2019;
accepted December 9, 2019.
Address correspondence to Kana Ueki, Tetsuro Ago, Department of
Medicine and Clinical Science, Graduate School of Medical Sciences,
Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582,
Japan. E-mail: kana1028@intmed2.med.kyushu-u.ac.jp.
1052-3057/$ - see front matter
© 2019 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.104597

people, has not been reported in East Asian and African
populations.2,3 Instead, deficiency of protein C or S is
often reported in East Asian populations.3 The protein C
gene (PROC) p.Lys193del polymorphism, where the
amino acid lysine at 193 of protein C is genetically
deleted, has been thought to associate with a hypercoagulable state and is frequently found in East Asia.3,4 We
report a patient with PROC p.Lys193del who developed
an embolic stroke during therapeutic use of tamoxifen for
breast cancer and methylprednisolone for rheumatoid
arthritis.

Case Report
A 58-year-old woman was admitted to our hospital
because of sudden onset with weakness of the left lower
extremity and left perioral dysesthesia. She had been
receiving tamoxifen (20 mg/day) for postoperative breast
cancer and methylprednisolone (4 mg/day) for rheumatoid arthritis. On admission, her blood pressure was 112/
74 mm Hg on administration of an antihypertensive

Journal of Stroke and Cerebrovascular Diseases, Vol. 29, No. 5 (May), 2020: 104597

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(olmesartan, 10 mg/day), heart rate was 71 beats/min
and regular, and body temperature was 36.08C. She had
neither a family history of cardiovascular disease including stroke nor a past history of miscarriage. Diffusionweighted images (DWI) in magnetic resonance imaging
showed multiple areas of hyperintensity in the posterior
circulation system, such as the right thalamus, right hippocampus, left midbrain, and left cerebellar hemisphere.
The hyperintense areas on DWI were observed as hypointensity on apparent diffusion coefficient images (Fig 1A).
These findings suggested the possibility of embolic stroke.
Magnetic resonance angiography showed stenosis of the
right posterior cerebral artery and hypoplasia of the right
vertebral artery (Fig 1B). The diameter of the right vertebral artery was 2.0 mm at the V2 segment and 1.4 mm at
the narrowest point on magnetic resonance angiography.
We confirmed the diameter of the hypoplastic right vertebral artery (2.1 mm versus 5.0 mm on the left side) on a
carotid ultrasound. We could not identify other possible
embolic sources on carotid ultrasound and transthoracic
and transesophageal echocardiogram. Atrial fibrillation
was not detected on Holter monitor electrocardiogram.
Laboratory data were almost normal, except for high levels of serum creatinine (1.03 mg/dl), triglycerides (258
mg/dl), C-reactive protein (.26 mg/dl), antinuclear antibody (£ 320), rheumatoid factor (34 IU/ml), and anticyclic citrullinated peptide antibody (372.8 U/ml).

K. UEKI ET AL.

Coagulation blood tests were almost normal (prothrombin time-international normalized ratio: .99, activated partial thromboplastin time: 25.4 seconds, and D-dimer level:
.6 mg/ml). A cerebrospinal fluid examination was within
normal limits. Therefore, we diagnosed the patient with
embolic stroke.
We initiated continuous intravenous infusion of heparin sodium (10,000 U/day) and edaravone (60 mg/day)
after admission. However, on the fifth hospital day, she
had recurrent embolic stroke with mild neurological deterioration, which was accompanied by the appearance of
new small areas of hyperintensity in the left cerebellar
hemisphere and the left vermis cerebelli and by enlargement of lesions in the right thalamus on DWI (Fig 1C). We
increased the dose of heparin to 12,500 U/day and discontinued tamoxifen. During the course, we found decreased
activity of protein C against its antigen level (activity: 59%
versus antigen: 122%) with enhanced activity of coagulation factor VIII (FVIII) (178%) and von Willebrand factor
(vWF) (285%). These findings suggested type II protein C
deficiency. The antigen (92%) and activity (77%) of protein
S were normal. We therefore conducted DNA sequencing
for the PROC gene using genomic DNA extracted from
white blood cells. We found a heterozygous trinucleotide
deletion leading to 1 amino acid deletion at Lys 193
(p.Lys193del) (Fig 2). After identifying the polymorphism
of PROC, we administered warfarin and maintained the

Figure 1. (A) Diffusion-weighted images (DWIs) in magnetic resonance imaging (top panels) on admission show multiple areas of hyperintensity in the posterior circulation system, such as the right thalamus, right hippocampus, left midbrain, and left cerebellar hemisphere. The hyperintense areas on DWIs are shown
as hypointensity in apparent diffusion coefficient (ADC) images (bottom panels). (B) Magnetic resonance angiography on admission shows stenosis (arrowhead)
of the right posterior cerebral artery and hypoplasia of the right vertebral artery (arrow). The diameter of the right vertebral artery is 2.0 mm at the V2 segment
and 1.4 mm at the narrowest point. (C) DWIs (top panels) on the fifth hospital day show new hyperintense areas in the left cerebellar hemisphere and left vermis
cerebelli, and enlargement of lesions of the right thalamus and right corona radiata. ADC images on the fifth hospital day are shown in the bottom panels. “R”
indicates right.

ISCHEMIC STROKE AND PROC P.LYS193DEL

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Figure 2. DNA sequencing for the PROC gene (top, reference sequence; middle, patient; and bottom, normal control) shows the trinucleotide AAG deletion.
This led to deletion of the amino acid lysine (Lys) at 193 (p.Lys193del) accompanied by a frame shift.

target prothrombin time-international normalized ratio
within 2.0-3.0. She was discharged on the 22nd hospital
day with mild perioral dysesthesia as a sequela.

Discussion
We report a middle-aged woman who developed
embolic stroke during therapeutic use of tamoxifen and
methylprednisolone. We identified the PROC p.Lys193del
and speculate that the polymorphism may underlie the
tamoxifen- and prednisolone- associated hypercoagulable
states. To the best of our knowledge, this is the first case
report of ischemic stroke associated with the PROC
p.Lys193del.
PROC p.Lys193del was originally identified as a nonfrequent mutation that may cause a hypercoagulable
state.5 However, a recent report showed that PROC
p.Lys193del was present in 2.4% of Chinese healthy people and was as high as 6.8% in Chinese patients with
venous thromboembolism.4 Furthermore, another report
showed that PROC p.Lys193del was present in 1.3% of
Japanese healthy people.3 Therefore, PROC p.Lys193del
may be a common polymorphism at least, in the East
Asian population.
The deletion of lysine at 193 does not appear to affect
the structural stability of protein C.5 Blood antigen levels
of protein C in patients with PROC p.Lys193del are often
normal. However, protein C activity is decreased by 50%
in case of a heterozygote, which is a characteristic finding
of type II protein C deficiency.4,5 Because some compensatory mechanisms may increase the production of protein
C antigen to maintain its overall activity, as was found in
the present case, the PROC p.Lys193del polymorphism
may often be difficult to identify. We also found abnormally elevated activity of FVIII and vWF, despite the mild
decrease in protein C activity (approximately 60%) in the
present case. FVIII, as well as factor V, are coagulation factors that are inactivated by activated protein C/protein S.
Additionally, FVIII and vWF form a complex and stabilize
each other. Therefore, abnormally elevated activity of
FVIII and vWF implied an impaired anticoagulation system mediated by protein C/protein S. Measurement of

FVIII and vWF may be helpful for detecting protein C/
protein S abnormalities.
There have been some reports indicating that tamoxifen
can induce a hypercoagulable state leading to thromboembolism. Tamoxifen may antagonize thrombomodulin
and suppress activation of protein C.6,7 Additionally,
tamoxifen inactivates tissue factor pathway inhibitor and
activates the extrinsic coagulation cascade, thereby leading to production of thrombin. Because tamoxifen alone
may not always cause thromboembolism, genetic polymorphisms predisposing to hypercoagulable states, such
as deficiency of protein C or S, may underlie development
of thromboembolism during use of tamoxifen. Prednisolone can also induce thromboembolism in complex mechanisms, including increased production of vWF and
stabilization of FVIII.8 We should note that genetic polymorphisms predisposing to hypercoagulable state, such
as protein C deficiency, may underlie the thromboembolism induced by these medications.
The fact that the patient repeated posterior circulation
stroke suggested the presence of embolic sources in the
subclavian or vertebral arteries. We could not find any
abnormalities in these arteries except hypoplasia of the
right vertebral artery. Because there have been reports
suggesting that congenital hypoplasia of the vertebral
artery can cause posterior circulation stroke,9,10 there
remains the possibility that the hypoplastic vertebral
artery might have caused the embolic source due to
hypercoagulable states in the present case.

Conclusions
This is the first report of embolic stroke patient with the
PROC p.Lys193del polymorphism. The polymorphism
may be a common one leading to a hypercoagulable state,
particularly in East Asians, and can underlie medicationassociated thromboembolism, including ischemic stroke,
as shown in this patient.
Acknowledgments: We thank Ellen Knapp, PhD, from
Edanz Group (www.edanzediting.com/ac) for editing a draft
of this manuscript.

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