J Kohler, J Kasper, I Witt and G M von... 1990;21:1077-1080 doi: 10.1161/01.STR.21.7.1077 Ischemic stroke due to protein C deficiency.

Ischemic stroke due to protein C deficiency.
J Kohler, J Kasper, I Witt and G M von Reutern
Stroke. 1990;21:1077-1080
doi: 10.1161/01.STR.21.7.1077
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1077
Case Report
Ischemic Stroke Due to Protein C Deficiency
Jiirgen Kohler, MD, Johannes Kasper, MD,
Irene Witt, MD, and Gerhard-Michael von Reutern, MD
Plasma protein C exerts anticoagulatory effects by inactivating factors V and VIII. Hereditary
protein C deficiency is transmitted as an autosomal dominant disorder. Homozygous individuals usually develop purpura fulminans as newborns; heterozygous protein C-deficient
individuals are at increased risk for venous thrombosis and pulmonary embolism. However,
arterial thrombosis has been only rarely observed. We describe a young patient with
heterozygous protein C deficiency who experienced a severe stroke due to thrombotic occlusion
of the left middle cerebral artery. (Stroke 1990;21:1077-1080)
P
rotein C is a plasmaglycoprotein with a molecular weight of 62 kDa. Its synthesis by the
liver depends on vitamin K. The inactive form
of protein C is converted to the active protein Ca by
thrombin in the presence of Ca2+. Combination of
thrombin with the cofactor thrombomodulin on the
surface of endothelial cells greatly accelerates the
activation rate of protein C.1 Protein Ca acts as an
anticoagulant by inactivating factors Va and VIIIa.
Protein Ca also exerts profibrinolytic properties by
inactivating plasminogen activator inhibitor 1. Protein S, which is also a vitamin K-dependent plasma
protein synthesized by the liver and the endothelium,
enhances the activity of protein Ca.23
Protein C deficiency is inherited as an autosomal
dominant trait with incomplete penetrance. Heterozygous individuals have an increased risk of venous
thrombosis and thromboembolism at a young age.4
Homozygous protein C deficiency is rare and leads to
a purpura fulminans-like syndrome in neonates.
Homozygous individuals usually die within the first
months of life unless treated with replacement of
protein C during the acute phase, followed by lifelong anticoagulation.55 Two types of protein C deficiency are known. Most common is type I, in which
both the absolute concentration of protein C and its
functional activity are reduced. In type II protein C
deficiency the activity is reduced whereas the concentration of protein C is normal.3
We describe a young patient with heterozygous
protein C deficiency. Occlusion of the left middle
cerebral artery led to a severe ischemic stroke.
From the Departments of Neurology (J.K., J.Ka., G-M.v.R.) and
Pediatrics (I.W.), University of Freiburg, Freiburg, Federal Republic of Germany.
Address for correspondence: Dr. Jiirgen Kohler, Department of
Neurology, HansastraBe 9, D-7800 Freiburg, FRG.
Received December 11, 1989; accepted February 28, 1990.
Case Report
After suffering from a headache for several days, a
32-year-old mechanic acutely developed a brachiofacial hemiparesis of his right side and global aphasia. Cranial computed tomography showed an extensive ischemic infarct in the territory of the left middle
cerebral artery (Figure 1). Occlusion of the left
middle cerebral artery at its proximal stem was
demonstrated by transtemporal Doppler sonography
(Figure 2). Duplex scanning of the extracranial
carotid arteries did not show arteriosclerotic lesions
but revealed reduced bloodflowvelocities on the left.
Since the Doppler sonographic data were unequivocal, cerebral angiography was not done.
The patient had been healthy until this event, and
there were no obvious precipitants of thrombosis
(i.e., no trauma, intoxication, or dehydration). His
only apparent risk factor for vascular disease was the
smoking of approximately 15 cigarettes/day. The
patient had neither arterial hypertension nor diabetes. Cardiologic investigations including electrocardiography, Holter electrocardiographic monitoring,
roentgenography of the chest, and two-dimensional
echocardiography did not reveal any abnormality.
There was also no evidence of an immunologic
disease. Routine blood parameters and the hemostasiologic tests prothrombin and partial thromboplastin
times, albumin, fibrinogen, factor VIII, and antithrombin III concentrations, platelet count, platelet
aggregation, and bleeding time were normal. Protein
C activity of the patient's plasma was measured in the
Department of Internal Medicine using the Protein
C Reagent Test (Behringwerke AG, Marburg, FRG);
normal protein C activity was assumed to be in the
range 60-160% of that in pooled normal plasma. The
absolute concentration of protein C antigen was not
determined. The patient's protein C functional activity was only 36% and 33% in two consecutive evaluations 5 days apart. The functional activity of anti
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1078
Stroke
Vol 21, No 7, July 1990
of the protein C-deficient sisters were found to be
heterozygous for protein C deficiency also. None of
these protein C-deficient relatives had suffered from
thromboembolic disease. Protein S concentration
was measured by the Electroimmunodiffusion Protein S Test (Boehringer) and was in the normal range
in all relatives investigated.
FIGURE 1. Cranial computed tomogram of 32-year-old man
4 weeks after event shows large hypodense area in temporoparietalpart of left hemisphere consistent with ischemic stroke
in middle cerebral artery territory. Bar indicates 5 cm; left side
of body appears on right side of figure.
thrombin III and the concentrations of antiphospholipid antibodies and protein S were not measured at
that time.
We treated the patient initially with 10% dextran
until the diagnosis of a hypercoagulopathy due to
protein C deficiency became probable; at that time
long-term anticoagulation with 25,000 units/day heparin and 3 mg/day phenprocoumon was started.
When adequate anticoagulation was achieved with
phenprocoumon as shown by the prothrombin time,
heparin was discontinued. There were no complications, particularly no coumarin necrosis.
The patient's hemiparesis improved during the
following months, but his aphasia remained severe.
One year after his stroke, the patient suffered two
epileptic seizures, one beginning focally in the left
hemisphere. He was thereafter treated with carbamazepine.
On reexamination 15 months after the stroke, the
patient's left middle cerebral artery was recanalized
according to Doppler sonographic criteria.
The family history was positive for thromboembolic disease; that is, the patient's father had died of
pulmonary thromboembolism at age 49 years, and his
paternal grandmother had died of ischemic stroke at
age 64 years. Protein C activity was measured in
plasma samples from several family members in the
Department of Pediatrics with Thromboquant Protein C (Boehringer, Mannheim, FRG). The patient's
mother and three of his siblings had normal protein
C activity, whereas four of his sisters showed protein
C deficiency (Figure 3). Furthermore, some children
Discussion
Cerebrovascular events in young and middle-aged
persons can become a diagnostic problem since
numerous disorders may lead to a stroke. In some
cases, the cause remains unclear.7-9 Protein C deficiency has been known for some time to be a major
risk factor for venous thrombosis. Its prevalence
seems to be 6-8% in patients <40 years old with a
history of venous thrombosis.4 Thrombosis of the
cerebral veins, however, seems to be rare in heterozygous patients.10 There have been a few reports on
cerebral hemorrhagic infarction caused by sinus
thrombosis in homozygous protein C-deficient infants.11 However, a well-documented case of thrombosis of the cerebral arteries due to heterozygous
protein C deficiency has not been reported yet.
Dusser and coworkers12 described two children who
had suffered from cerebral arterial thrombosis associated with a protein C deficiency that, however, was
only temporary and probably not inherited. Smith
and Ens13 discussed that protein C deficiency may
cause amaurosis fugax. Israels and Seshia14 described
a 17-month-old girl with protein C deficiency who
presented with an acute hemiparesis; the computed
tomogram was normal in this patient. KemkesMatthes15 examined a heterozygous protein Cdeficient man who experienced the occlusion of a
carotid artery 4 weeks after surgery for a nasal liquor
fistula.
In our patient, occlusion of the left middle cerebral
artery led to ischemic infarction with the clinical
symptoms of right hemiparesis and persisting global
aphasia. Embolic infarction from a cardiac source or
arterioarterial embolism due to preexisting carotid
artery sclerosis could largely be excluded as could
immunologic diseases. The patient's protein C activity was significantly decreased in two tests before
anticoagulation was started. Prior to his stroke, the
patient had not experienced thromboembolic complications, but his father had died of pulmonary thromboembolism during middle age. The family study
proved heterozygous protein C deficiency. Hypercoagulopathy due to inherited heterozygous protein C
deficiency apparently caused the thrombosis of this
patient's left middle cerebral artery. During anticoagulation therapy with phenprocoumon the occlusion
was recanalized.
It could be argued that an ischemic stroke by itself
could lower the protein C concentration by way of
increased consumption and that our patient was
falsely assumed to have an inherited protein C deficiency. However, this hypothesis would not explain
his consistently low protein C activity some days after
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Kohler et al Stroke and Protein C Deficiency
1079
R
kHz
MCA
50 mm
FIGURE
-5
-3
-3
- 1
0
+ 1
+2
ICA
2.
Transtemporal
Doppler sonograms of 32-yearold man 1 day after stroke indicate occlusion of the left (L)
middle cerebral artery (MCA).
Intracranial carotid arteries
(top) were examined with pulsed
Doppler sonography
(fo—2
MHz), and extracranial carotid
arteries (bottom) were examined
with continuous-wave Doppler
sonography (fo=4 MHz). Positive Doppler shift corresponds to
blood flow toward probe. There
was little side-to-side difference
in signals of internal and common carotid arteries (ICA and
CCA). Signals of anterior cerebral artery (ACA) could be easily
found on both sides, whereas
there was no signal from left
MCA. R, right.
-5
L,
3
2
1
0
1
2
CCA
to = 4 MHz
0.5s
III
79
42
103
33
Protein C
normal
Male
Female
•
o
de
deficient
Propositus
L
Died from thromboembolism
TE
FIGURE 3. Pedigree of 32-year-old man with heterozygous
protein C deficiency who suffered severe ischemic stroke due to
thrombotic occlusion of left middle cerebral artery. Numerals
beneath each symbol indicate protein C activity in percent
(normal range 60-160%).
the event. Moreover, protein C concentrations do not
differ significantly between patients suffering from
acute stroke and healthy controls.16
It remains unclear, however, why persons with
heterozygous protein C deficiency do not present
more often with arterial thromboembolic events.
Smoking may have imposed an additional risk in our
patient, but other still-unknown factors might also
have contributed.
We conclude that protein C deficiency may cause
cerebral artery thrombosis and ischemic cerebral
infarction. Therefore, protein C activity should be
evaluated in young persons presenting with ischemic
stroke of unobvious cause.
References
1. De Fouw NJ, van Hinsbergh VWM, De Jong YF, Haverkate F,
Bertina RM: The interaction of activated protein C and
thrombin with the plasminogen activator inhibitor released
from human endothelial cells. Thromb Haemost 1987;
57:176-182
2. Clouse LH, Comp PC: The regulation of hemostasis: The
protein C system. NEnglJMed 1986;314:1298-1304
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3. Strickland DK, Kessler CM: Biochemical and functional properties of protein C and protein S. Clin Chim Ada 1987;
170:1-24
4. Broekmans AW, Conard J: Hereditary protein C deficiency, in
Bertina RM (ed): Protein C and Related Proteins. Edinburgh/
London/Melbourne/New York, Churchill Livingstone, 1988,
pp 160-181
5. Horrellou MH, Conard J, Bertina RM, Samama M: Congenital protein C deficiency and thrombotic disease in nine
French families. Br Med J 1984;289:1285-1287
6. Marlar RA, Montgomery RR, Madden RM: Homozygous
protein C deficiency, in Bertina RM (ed): Protein C and
Related Proteins. Edinburgh/London/Melbourne/New York,
Churchill Livingstone, Inc, 1988, pp 182-195
7. Bogousslavsky J, Regli F: Ischemic stroke in adults younger
than 30 years of age. Cause and prognosis. Arch Neurol
1987;44:479-482
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10. Pabinger I: Clinical relevance of protein C. Blut 1986;53:63-75
11. Tarras S, Gadia C, Meister L, Roldan E, Gregorios JB:
Homozygous protein C deficiency in a newborn. Arch Neurol
1988;45:214-216
12. Dusser A, Boyer-Neumann C, Wolf M: Temporary protein C
deficiency associated with cerebral arterial thrombosis in
childhood. J Pediatr 1988;13:849-851
13. Smith DB, Ens GE: Protein C deficiency: A cause of amaurosis fugax? / Neurol Neurosurg Psychiatry 1987;5:361-362
14. Israels SJ, Seshia SS: Childhood stroke associated with protein
C or S deficiency. / Pediatr 1987;lll:562-564
15. Kemkes-Matthes B: Heterozygous protein C deficiency type I.
Blut 1989;58:201-206
16. D'Angelo A, Landi G, D'Angelo SV, Orazio EN, Boccardi E,
Candelise L, Mannucci PM: Protein C in acute stroke. Stroke
1988;19:579-583
KEY WORDS
protein C
• arterial occlusive disease • cerebral ischemia •
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