Multivessel thromboembolism associated with dysfunction of protein s.

Abstract

Protein S is a vitamin K-dependent coagulation factor that acts as an anticoagulant. Deficiency of protein S increases the risk of thromboembolic events. We report a case of isolated protein S deficiency in a 39-year-old woman suffering arterial occlusion in both lower legs. She underwent a surgical procedure using thrombectomy and balloon angioplasty of her left lower extremity. Later, she had right trans-tibial amputation because of the reperfusion injury. Throughout the evaluation of thromboembolic events, we diagnosed a large thrombus in the right atrium and an asymptomatic pulmonary thromboembolism. The patient was successfully treated with right atrial thrombectomy and systemic anticoagulation. Careful evaluation for protein S levels may be necessary in patients with arterial thromboembolic events, especially young adults.

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Multivessel Th romboembolism Associated with
Dysfunction of Protein S
Eun Jae Ok, M.D., Hye Won Kim, M.D., Sang Dong Kim, M.D.1, Kyoung Soo Park, M.D.,
Yang Soo Kim, M.D., Ha Min Kim, M.D., Seong Hoon Lim, M.D.
Departments of Rehabilitation Medicine, 1Surgery, College of Medicine, Th e Catholic University of Korea, Suwon 442-723, Korea
Protein S is a vitamin K-dependent coagulation factor that acts as an anticoagulant. Deficiency of protein S
increases the risk of thromboembolic events. We report a case of isolated protein S deficiency in a 39-year-old
woman suff ering arterial occlusion in both lower legs. She underwent a surgical procedure using thrombectomy
and balloon angioplasty of her left lower extremity. Later, she had right trans-tibial amputation because of the
reperfusion injury. Th roughout the evaluation of thromboembolic events, we diagnosed a large thrombus in the
right atrium and an asymptomatic pulmonary thromboembolism. Th e patient was successfully treated with right
atrial thrombectomy and systemic anticoagulation. Careful evaluation for protein S levels may be necessary in
patients with arterial thromboembolic events, especially young adults.
Key Words Protein S, Th romboembolism, Trans-tibial amputation
Annals of Rehabilitation Medicine
Case Report
Ann Rehabil Med 2012; 36: 414-417
pISSN: 2234-0645 • eISSN: 2234-0653
http://dx.doi.org/10.5535/arm.2012.36.3.414
vein thrombosis, and pulmonary emboli. The true
prevalence of protein S deficiency is unknown as not
all individuals develop thrombosis. Some studies have
indicated a frequency of 2-8% in patients with deep vein
thrombosis or pulmonary embolism and it is reported
that patients with protein S deficiency have a chance of
developing recurrent thrombosis before age 45.1,2 Among
the patients with thrombosis, exclusive deficiency of
protein S is rare, and only 1 case of multiple arterial
thrombosis associated with decreased protein S activity
(43%) has been reported in the country.3
This case report is an instance of protein S deficiency
diagnosed in the course of elucidating the cause of
occlusions in the lower extremities of the patient,
who had management of below-knee amputation and
incidentally presented right atrial and pulmonary arterial
thrombosis throughout investigations.
Received February 18, 2011; Accepted July 12, 2011
Corresponding author: Seong Hoon Lim
Department of Physical Medicine and Rehabi litation, St. Vincent
Hospital, College of Medi cine, Th e Catholic University of Korea, 93-6, Ji-
dong, Suwon 442-723, Korea
Tel: +82-31-249-7650, Fax: +82-31-251-4481, E-mail: seonghoon@
catholic.ac.kr
This is an open-access article distributed under the terms of the
Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/3.0) which permits unrestricted
noncommercial use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Copyright © 2012 by Korean Academy of Rehabilitation Medicine
INTRODUCTION
Various genetic risk factors are known to be responsible
for recurrent venous and arterial thromboembolisms.
Among the risk factors, protein S is a plasma protein that
functions as a cofactor for the anticoagulant activity of
protein C. Defi ciency of protein S may result in recurrent
episodes of coagulopathy, including superficial, deep

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CASE REPORT
A previously healthy 39-year old woman presented to
the emergency department with 4 days of painful swelling
and discoloration of her right lower leg, and gangrenous
change of her right toe tips (Fig. 1). The patient had no
history of hypertension, diabetes, dyslipidemia, trauma
or illicit use of drugs, including oral contraceptives, but
had used tobacco for 10 years.
Th e patient had been suff ering from pain and swelling
in her right lower leg for 4 days and on arrival in the
hospital, initial physical examination showed a gangre-
nous change of her entire foot and toes below the right
metatarsals, and her calf appeared to be pale with pain,
paresthesia and cold sensation. Laboratory investigation
showed a platelet count of 37,000/mm3. Due to suspicion
of arterial thrombosis, computed tomography (CT) of
ar teries of the lower extremities was conducted and it
demonstrated diffuse vascular occlusion by thrombus
in the right infra-renal aorta through the popliteal ar-
tery and also left superficial femoral artery (Fig. 2). The
patient underwent emergency thrombectomy, and
im mediate infusion of 50,000 IU of urokinase in both
lower legs through a catheter and balloon angioplasty
of the left superfi cial femoral artery. Following the ope-
ration, reperfusion injury developed that advanced
erythematous edema and necrosis which necessitated
below-knee amputation. The patient transferred to the
Department of Rehabilitation Medicine and began stump
care for its maturation and had started a comprehensive
rehabilitation program with a patellar-tendon bearing
below-knee prosthesis (PTBS). She was prescribed an
oral anticoagulant (warfarin) to prevent recurrences of
arterial thrombosis through maintaining an International
normalized ratio (INR) of 2-3.
Detailed laboratory investigations were done to identify
the cause of multiple arterial thromboses. Th e aCL (anti-
cardiolipin antibody), aPA (anti-phospholipid antibody),
antithrombin III, platelet aggregation test, VDRL (vene-
real disease research laboratory microflocculation),
LA (lupus anticoagulant), ANCA (antineutrophil cyto-
plasmic antibody), serum complement C3/C4 level,
homocysteine (11.04 μmol/L), bone marrow biopsy,
chromosome test and coagulation factor V, VIII, IX and
XI were in normal ranges and did not appear to be the
reason for thrombosis. Serum C protein showed an anti-
gen level of 51.70% (normal: 72-160%) and activity of 63%
(normal: 70-130%), which were lightly decreased at the
initial exam, but a followup showed normal activity of
89%. Otherwise, protein S demonstrated a total level of
57.40% (normal: 60-150%), and activity of 0.2% (normal:
73.7-146.3%) which were the only remarkably decreased
factors throughout the followup laboratory investigations.
Thereupon, authors diagnosed the cause of multiple
arterial thromboses as decreased protein S activity.
Considering possibilities of multiple thrombosis
in other organs, transthoracic and transesophageal
Fig. 1. On the day of arrival in the hospital, pedal gangrenous
change and ischemia had progressed to the distal third of the
right leg and whole foot.
Fig. 2. Lower extremity 3D CT showed occlusions in right
superficial femoral, popliteal arteries and total occlusion
below the knee.

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echo cardiograms were conducted, which surprisingly
showed a 3.33×1.22 cm sized mass. Magnetic resonance
imaging (MRI) of the heart and coronary angiographic
CT revealed thrombus in the right atrium and inferior
vena cava (IVC) and thromboembolism involving both
segmental and subsegmental branches of the pulmonary
artery (Fig. 3). Th e patient underwent surgery to remove
the right atrial thrombus with pathologic confirmation.
After the operation, she continued taking oral warfarin to
prevent recurrent thromboembolism and also aggressive
rehabilitation with her prosthesis.
DISCUSSION
Acute arterial occlusions in lower limbs are typically
the result of atrial fibrillation, myocardial infarction,
thrombus and embolus formed in valvular heart dise-
ases, decreased perfusion of peripheral arteries, and
other hypercoagulable states. When arterial occlusion
occurs, pathognomonic 5P’s signs (which stand for pain,
polar, pulseless, paresthesia and paralysis) appear, just
like the patient in this case showed at initial physical
examination. It is a principle of management to conduct
amputation if ischemic necrosis already developed.
The patient also presented right atrial thrombus in
her heart. The most common underlying pathologic
predisposition to atrial thrombus is atrial dilatation,
decreased cardiac output, intracardiac catheter inser-
tion, peripheral deep vein thromboembolism and
other generalized conditions such as a malignant tu-
mor, amyloidosis and nephritic syndrome.4 Right atrial
thrombus is a rare condition commonly related to pul-
monary embolism, which can be life threatening, and
therefore requires an accurate diagnosis and immediate
management. In this case report, the size of the atrial
thrombus was relatively large and accompanied pul-
monary thromboembolism, which means the thrombus
was a secondary product. It has been reported that sur-
gical treatment is more beneficial for the patient than
single anticoagulation therapy, as in this case.5
Formation of multiple thromboses in arteries and
organs means that a patient is in a hypercoagulable
state. Few publications exist regarding arterial occlusion
and protein C or S defi ciencies. Protein S is a vitamin K
dependent glycoprotein which acts as a cofactor for protein
C and phospholipids to inactivate factors Va and VIIIa.
The prevalence of protein S deficiency in the general
popu lation is unknown but is 0.03-0.13% in Caucasians6;
however, in patients with venous thrombosis, a frequency
of 5% has been reported for S deficiency.2 As of yet,
nothing has been reported regarding prevalence in South
Korea. Protein S defi ciency may be caused by congenital
or secondary etiologies. Secondary deficiency can be
caused by pregnancy, oral contraceptives, disseminated
intravascular coagulation (DIC), liver failure, type 1
diabetes mellitus, nephritic syndrome, malignant tu-
mors or autoimmune diseases, including lupus erythe-
matosus.7 These conditions contribute to venous (of
lo wer limbs, commonly) thromboembolism and less to
pulmonary embolism. Arterial thrombosis associated
with protein S defi ciency is uncommon, and Broekmans
and Conrad showed frequency of arterial thrombosis as
0.1% of that of venous thrombosis.8,9 In this case report,
the patient had no specifi c disease or condition that in-
curred by protein S deficiency, and other laboratory
findings were clear, except the activity of protein S
showed a marked decline to an almost inactivate state of
0.2% normal value.
In plasma, protein S has two circulating forms: 60%
exists as a covalent complex with the β-chain of the
Fig. 3. (A) Heart MRI showed a
calcified thrombi in apex of the
right ventricle (arrow) and in IVC
(arrowhead), near the atriocaval
junction. (B) Coronary artery CT
showed low density thromboses
in proximal left inferior pulmonary
artery.

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com plement component C4b binding protein, while
the remaining 40% unbound protein. This free protein
S functions in plasma as a cofactor to activate protein
C2.9 Although total protein S levels remained in the
normal range, decreased free protein S levels results
in a hypercoagulable state. There are 3 types of protein
deficiency: type I characterized by low total and free
protein S antigen level; type II characterized by selective
reduction in activity of protein S levels, and type III
exhibits normal total protein S levels with decreased free
protein S and decreased activity.10 Th e patient in the case
report showed a nearly normal level of total protein S of
57.40% (normal: 60-150%), but activity of protein S was
selectively decreased to 0.2% of normal, which suggests
the possibility of type II or type III defi ciency. We could
not clearly define the type of deficiency because the
selec tive free protein S level was not examined.
There are few instances of arterial thromboses asso-
ciated with protein S defi ciency in the thoracic aorta, the
mesenteric, cerebral and renal arterial vascular beds,3
with a decreased activity of 43%. No cases of multiple
thromboembolisms in both arteries of lower limbs, heart
and pulmonary arteries have been reported, but did
occur in this case.
In summary, this case report suggests that young patients
who present with thromboses and demonstrate no risk
factors such as trauma, surgery, immobilization, obesity,
smoking, hypertension, oral contraceptives, tumor, and
stroke should be evaluated for hypercoagulable states,
including protein C or protein S deficiency. Although
protein S deficiency has a low prevalence, its systemic
relapsing thromboses can be fatal. It is required to exa-
mine protein S levels when diagnosing thrombosis.
Overall, we present a case of protein S deficiency with
remarkably decreased activity, which resulted in multiple
thromboembolisms and below-knee amputation.
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