2097

Accelerated Brain Infarction in Hypertension
Complicated by Hereditary Heterozygous
Protein C Deficiency
Seiji Kazui, MD; Yoshihiro Kuriyama, MD; Toshiyuki Sakata, PhD;
Masahiko Hiroki, MD; Kotaro Miyashita, MD; Tohru Sawada, MD

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Background.: Protein C deficiency leads to reduced inhibition of coagulation and an increased likelihood
of thrombosis. It is widely accepted that the most common syndromes associated with protein C deficiency
are venous thrombosis and pulmonary thromboembolism, whereas arterial thrombosis is rare. Here we
describe two patients with hypertension and hereditary heterozygous protein C deficiency who developed
multiple lacunar infarcts.
Case Descriptions: Patient 1 was a 46-year-old man with a history of hypertension who developed a right
upper quadrantanopia and gradually progressive intellectual and behavioral deterioration. Patient 2 was
a 61-year-old man with history of hypertension and two episodes of right-sided motor weakness who
developed left sixth and seventh cranial-nerve palsies and reduced pinprick sensation in the right
extremities. In both patients, magnetic resonance imaging revealed multiple small lesions in the pons as
well as the bilateral basal ganglia, thalamus, corona radiata, and other subcortical structures, which are
consistent with lacunar infarcts. Protein C activity and antigen levels were reduced to approximately one
half of normal in these two patients, as well as in some of their family members who had no other
serological or coagulation abnormalities. A diagnosis of heterozygous protein C deficiency type 1 was thus
established.
Conclusions: Although it remains uncertain whether protein C deficiency itself increases the risk of
cerebral artery thrombosis, it may predispose a patient to develop multiple brain infarctions in
association with hypertension. (Stroke. 1993;24:2097-2103.)
KEY WORDs * cerebral infarction * hypertension * protein C

P rotein C, a vitamin K-dependent plasma protein
synthesized in the liver, is well known to play
an important role in regulating coagulation.'
Activation of protein C is initiated by complex formation between thrombin and thrombomodulin on endothelial cells.2 Activated protein C, in conjunction with
protein S, is a potent physiological inhibitor of factors
Va and VIIIa3 and potentially is an activator of
fibrinolysis.4 Protein C deficiency thus leads to a loss of
clotting system regulation and a propensity for pathological thrombosis.5 It is widely accepted that the most
common manifestations of this disease are venous
thrombosis and pulmonary thromboembolism6,7; however, arterial thrombosis only rarely complicates protein C deficiency.8
We recently encountered two patients with multiple
brain infarctions associated with hereditary heterozygous protein C deficiency.
Received February 22, 1993; final revision received August 9,
1993; accepted August 9, 1993.
From the Cerebrovascular Division, Department of Medicine
(S.K., Y.K., M.H., K.M., T. Sawada), and the Department of
Clinical Laboratory (T. Sakata), National Cardiovascular Center,
Suita, Osaka, Japan.
Correspondence to Seiji Kazui, MD, Cerebrovascular Division,
Department of Medicine, National Cardiovascular Center, Suita,
Osaka, 565 Japan.

Case Reports
Patient 1
A 46-year-old man, a post office clerk with a history
of hypertension for 20 years, developed a right-sided
visual disturbance 6 months before admission. His colleagues in his office noticed deterioration of his ability
to write and calculate. Members of his family also
became aware that he was indifferent and depressed.
The patient was then admitted to our institute for
evaluation of his medical condition on April 25, 1991.
He had no arrhythmia, cardiac disease, diabetes mellitus, hyperlipidemia, or smoking habit.
On admission, his blood pressure was 156/96 mm Hg.
His pulse was regular at 58 beats per minute. The
results of general physical examination were normal.
The patient was alert but slightly disoriented to time.
On the Mini-Mental State Exam, he scored 23 of 30.
Neurological examinations disclosed a right upper homonymous quadrantanopia and exaggerated deep tendon
reflexes bilaterally. The hematocrit was 41.7%. Serological tests for syphilis, anticardiolipin antibodies, and
lupus anticoagulant were all negative. Magnetic resonance imaging (MRI) studies were carried out using a
1.5-T system (Siemens Corp) with a slice thickness of 4
mm. Axial Ti- and T2-weighted images were obtained
with spin-echo pulse sequences (T1: repetition time, 600
milliseconds; echo time, 17 milliseconds; T2: repetition

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Stroke Vol 24, No 12 December 1993

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FIG 1. Magnetic resonance images in patient 1 showing numerous areas of low signal intensity on Ti-weighted
spin-echo images (a-d, i-l: repetition time, 600 milliseconds; echo time, 17 milliseconds) and areas of high signal intensity
on T2-weighted spin-echo images (e-h, m-p: repetition time, 2800 milliseconds; echo time, 90 milliseconds) in the pons,
left occipital lobe, corpus callosum, basal ganglia, thalami, coronae radiatae, and other subcortical structures.

time, 2800 milliseconds; echo time, 90 milliseconds).
Ti-weighted images demonstrated numerous areas of
low signal intensity in the pons, left occipital lobe,
corpus callosum, basal ganglia, thalami, coronae radiatae, and other subcortical structures. These lesions were
seen on T2-weighted images as high signal intensity
areas. A neuroradiologist (K.M.), who was unaware of
the clinical status of the patient, counted 50 lacunar
infarcts, in all, on the MRI (Fig 1). Cerebral angiography revealed an occlusion of the left posterior cerebral

artery but no occlusive changes in other extracranial or
intracranial arteries (Fig 2).

Patient 2
This patient was a 61-year-old man, an electrical
engineer, with a history of hypertension for 13 years as
well as two episodes of motor weakness of the right side
approximately 10 years before admission. On January 3,
1992, he suddenly developed vertigo with vomiting and
inability to walk and was admitted to our institute the

Kazui et al Brain Infarction in Protein C Deficiency

2099

FIG 2. Cerebral angiograms of patient 1. Panels A and B show right and left carotid angiograms, respectively, revealing
no occlusive changes. Panel C shows a left vertebral angiogram revealing left posterior cerebral artery occlusion.

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next morning. He was a smoker but had no evidence of
arrhythmia, cardiac disease, diabetes mellitus, or
hyperlipidemia.
On admission, his blood pressure was 176/108
mm Hg. His pulse was 76 beats per minute without
arrhythmia. A general physical examination revealed no
abnormality. The patient was alert and well oriented to
time, space, and person. On the Mini-Mental State
Exam, he scored 30 of 30. Neurological examinations
disclosed left sixth and seventh cranial-nerve palsies
and impaired sensation for pinprick in the right extremities. These findings suggested an infarct on the left side
of the pontine tegmentum. The hematocrit was 43.2%.
Serological tests for syphilis, anticardiolipin antibodies,
and lupus anticoagulant were all negative. MRI studies
demonstrated numerous foci of low signal intensity on
TI-weighted images, which were found to be hyperintense on T2-weighted images in the pons, internal
capsules, basal ganglia, thalami, coronae radiatae, and
other subcortical regions (Fig 3). The gadoliniumdiethylenetriamine pentaacetic acid infusion study dem-

onstrated marked enhancement in the tegmentum of
the left side of the pons. The number of lacunar
infarctions totaled 36. Cerebral angiography revealed
no occlusive changes in extracranial or intracranial
arteries (Fig 4).
Because of the multiple brain infarcts seen in these
two patients, coagulation studies were undertaken for
the two subjects described and their available family
members.

Methods
Coagulation studies were performed approximately 6
months after the onset of stroke for patient 1 and after
1 month for patient 2. The patients were not receiving
anticoagulants.
Venous blood samples were collected in 3.8% sodium
citrate anticoagulant. Each tube was immediately inverted gently several times and then centrifugated at
3000 rpm for 10 minutes at 4°C. The supernatant was

then placed in plastic tubes and stored frozen at -80°C
until used.
Routine coagulation tests, including prothrombin
time, activated partial thromboplastin time, and fibrinogen assay were performed according to standard procedures. Fibrin degradation products were measured by
the latex coagulation method using LPIA FDP
(Teikokuzoki-seiyaku, Tokyo, Japan). Activities of antithrombin III, plasminogen, a2-plasmin inhibitor, and
factor X were evaluated by the chromogenic substrate
method; all kits were obtained from Kabi Vitrum AB
(Stockholm, Sweden). Cl-inhibitor activity was measured by the chromogenic substrate method (Behringwerke, Marburg, FRG). Plasma prekallikrein was measured with the chromogenic substrate S-2302 from Kabi
Vitrum AB. Activities of a2-macroglobulin, cv-antitrypsin, and plasminogen were assayed by the turbidimetric
immunoassay using the corresponding antiserum supplied by Behringwerke. Protein induced by vitamin K
absence-LI (PIVKA-II) was measured with the
PIVKAL test (Teikokuzoki-seiyaku). Protein C antigen
was measured by electroimmunoassay with the protein
C test (Teijin, Tokyo, Japan). Protein C amidolytic
activity was determined by a thrombin-activated assay
with chromogenic substrate S-2236 (Kabi Vitrum AB),
and protein C anticoagulant activity was measured
using commercially available kits from Diagnostica
Stago (Asnieres-Sur-Seine, France). Free protein S was
quantitated by electroimmunoassay using the protein S
test (Teijin). Protein S activity was measured according
to the method described by Suzuki and Nishioka.9 C4b
binding protein antigen was measured by a turbidimetric immunoassay using antiserum supplied by Diagnostica Stago.

Results
An isolated decrease of protein C activity was found
in both patients and in some of their family members.

2100

Stroke Vol 24, No 12 December 1993

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FIG 3. Magnetic resonance images in patient 2 demonstrating numerous foci of low signal intensity on Ti-weighted
spin-echo images (a-d, i-I: repetition time, 600 milliseconds; echo time, 17 milliseconds), which are hyperintense on
T2-weighted spin-echo images (e-h, m-p: repetition time, 2700 milliseconds; echo time, 90 milliseconds), in the pons,
internal capsules, basal ganglia, thalami, coronae radiatae, and other subcortical structures.

Patient 1 and His Family
In patient 1, the results of coagulation studies were all
within normal range except for protein C levels (Tables
1 and 2). Protein C amidolytic and anticoagulant activities were found to be 52% and 54%, respectively, and
the protein C antigen level was also reduced to 54%.
Thus, a diagnosis of heterozygous protein C deficiency
type 1 was established in this patient. The mother and
two sons of the propositus, who were asymptomatic, also
had protein C concentration of approximately one half

of the normal range; however, his brother and sister had
normal protein C levels (Table 2).

Patient 2 and His Family
A diagnosis of heterozygous protein C deficiency type
1 was also established in patient 2, because protein C
amidolytic and anticoagulation activities were reduced
to 43% and 50%, respectively, and the protein C antigen
level was at 57%, while the results of other coagulation
studies were all within normal range (Tables 1 and 2).

Kazui et al Brain Infarction in Protein C Deficiency

2101

FIG 4. Cerebral angiograms of patient 2. Panels A, B, and C show right carotid, left carotid, and right vertebral
angiograms, respectively, revealing no significant stenosis.

The sister of the propositus, who was asymptomatic,
also had protein C levels at approximately one half of
the normal range; however, his son had a normal
protein C concentration (Table 2).

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Discussion
There have been several case reports of arterial
ischemic stroke associated with protein C deficiency.10-19 In the majority of these patients, computed
tomographic and/or MRI studies revealed large lesions
encroaching on the cerebral cortices."11"3"14,16-19 Angiography or duplex carotid or transcranial Doppler ultrasonography showed that major cerebral vessels were
involved, including the internal carotid,1216,17 middle
cerebral,"13'6"1 9posterior cerebral," and anterior cerebral" arteries. Some authors'2"7 have described thrombotic occlusion of the internal carotid artery in association with protein C deficiency, while others13"9 have
noted recanalization of the middle cerebral artery,
which suggested an embolic mechanism.20'21

In the present series, patient 1 had posterior cerebral
artery occlusion that caused cortico-subcortical infarction in the occipital lobe, which was classified as atherothrombotic according to the system of the National
Institute of Neurological Disorders and Stroke.22 However, the vast majority of the patient's infarcts were
small and were located in the basal ganglia, internal
capsule, thalamus, corona radiata, centrum semiovale,
and pons. These lesions could thus be regarded as
lacunar infarcts.22-24
It is well known that lacunar infarcts most often result
from the occlusion of small arteries (usually less than
200 gm in diameter) by lipohyalinosis, which is a
hypertensive cerebral vasculopathy.2S Our two patients
also had a history of hypertension for more than 10
years. Thus, it is unclear whether protein C deficiency
itself was the sole cause of infarction in our patients.
Their most characteristic MRI findings were multiple
lacunar infarcts. It is known that hypertension can cause
white matter lesions without stroke symptoms in the

TABLE 1. Coagulation Tests in Patients 1 and 2
Patient 1
Prothrombin time, %
International ratio
Activated partial thromboplastin time, s
Fibrinogen, mg/dL
Antithrombin Ill activity, %
Plasminogen activity, %
a2-Plasmin inhibitor activity, %
Fibrin degradation products, rg/mL
Cl-inhibitor activity, %

a2-Macroglobulin, mg/dL
ca-Antitrypsin, mg/dL
Plasma prekallikrein, %
Factor X, %
Protein induced by vitamin K absence-l1, gg/mL

91
1.08
30
280
101.7
100.2
94.1
9
106.9

167
209
81.3
83.2
<1

Patient 2
91
1.06
35
301
85.7
98.6
93.6
8
98
125
162
75.5

85.3
<1

Normal Range
79-116
0.19-1.14
24-40
150-340

80-120
70-120
70-110
<10
78-120
130-350
150-260
70-120
70-120
<1

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Stroke Vol 24, No 12 December 1993
TABLE 2. Protein C Levels and Other Coagulation Parameters in Patients 1 and 2 and Their
Family Members
Protein C*

Activity

Patient 1 and relatives
Patient 1
Mother
Sister

Sex

Age, y

M
F
F
M

46
78
43
48
15
18

Antigen
54
49
83
85
52
33

Brother
M
Son 1
Son 2
M
Patient 2 and relatives
M
Patient 2
62
57
F
62
68
Sister
32
M
100
Son
62-125
Normal range (n=27)
*Values show percentages of normal plasma levels.

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elderly.26 However, our patients had small, round, and
circumscribed lesions in the basal ganglia and other
subcortical regions without any confluent lesions. To
avoid overdiagnosis, we defined lacunar infarcts as small
subcortical or pontine lesions of decreased intensity on
Ti-weighted images and hyperintensity on T2-weighted
images, according to the recommendation of Shimada et
al.27 Fisher23 performed a detailed pathological study of
lacunar infarcts in a series of 1042 consecutive autopsies. In 114 cases, he found 376 lacunar infarcts, with an
average of approximately 3 per brain and a maximum of
15 lacunes in a single patient. Ishii et a128 studied 30
necropsy cases of vascular dementia with lacunar infarcts and found that the number of lacunes varied from
6 to 24 per patient. In comparison with these studies, far
more lacunes were observed in our patients, since 50
were noted in patient 1 and 36 in patient 2. Miletich et
a129 have stated that heterozygous protein C deficiency
is not necessarily an important risk factor for thrombosis. In addition, Wong and coauthors30 have reported
that the distribution of thrombomodulin varies among
the different regions of the human brain, with significantly less thrombomodulin in the putamen, pons, and
mesencephalon than in the neocortex. The thrombinthrombomodulin complex activates protein C approximately 20 000 times more rapidly than thrombin alone.31
Therefore, we suggest that protein C deficiency may
have accelerated the development of lacunar infarcts in
the deep structures of brain in our patients in association with long-standing hypertension. Coagulation studies should be performed in patients with a large number
of lacunes, even when they are hypertensive. Our two
case reports may help to illuminate the multifactorial
pathogenesis of brain infarction. It is to be hoped that a
prospective study will be undertaken to investigate the
relation between heterozygous protein C deficiency and
brain infarction.
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Amidolytic

Clotting

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54
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Protein S*
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C4 Binding
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