個案報告Cerebral Venous Sinus Thrombosis Caused by Hereditary Protein S Deficiency: A Case Report

Cerebral Venous Sinus Thrombosis Caused by Hereditary

Protein S Deficiency: A Case Report
Fang-Ju Yeh1, Chung-Wei Lee2, Sung-Chun Tang3
1
Department of Medical Education, National Taiwan University Hospital, Taipei, Taiwan.
2
Department of Medical Imaging, National Taiwan University Hospital, Taipei, Taiwan.
3
Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.

ABSTRACT
Background: Hereditary thrombophilia account for 10% to 22% of cerebral venous sinus thrombosis
(CVST). Protein S deficiency is one of important diagnostic consideration, but it is difficult to establish
the diagnosis at acute thrombosis. Here, we report a case of CVST related to protein S deficiency who
underwent endovascular thrombectomy (EVT) with favourable outcome.
Case report: A 37-year-old man with a strong family history of deep vein thrombosis experienced headache
with increased intracranial cerebral pressure features, right hemiparesis, aphasia, and apraxia within 7 days.
Brain CT and MR imaging showed CVST involving the superior sagittal sinus and left vein of Trolard,
with venous congestion and parenchymal haemorrhage. Very low protein S function (17.7%) was revealed
during subsequent survey, which suggested protein S deficiency rather than the increased consumption.
Transvenous EVT and heparinization followed by warfarin were administered. The patient was discharged
one month later with independent functional status.
Conclusion: Detailed family history and careful testing interpretation are essential to diagnose protein S
deficiency. Beyond standard anticoagulation, EVT may serve as a salvage therapy for severe or complicated
CVST.

Keywords: Protein S deficiency, cerebral venous sinus thrombosis, endovascular thrombectomy.

INTRODUCTION thromboembolism (VTE), unusual thrombotic site

Cerebral venous sinus thrombosis (CVST) is
a rare disease with a reported annual incidence of
1
3 to 4 cases per one million in adults. Hereditary
thrombophilia are important underlying causes and
account for 10% to 22% of CVST.2, 3 However, the
indication and timing to perform thrombophilia
testing are controversial. Some suggest that it may
be considered in those with unprovoked venous
such as cerebral veins, or are young with strong
family history.4
Protein S deficiency is a congenital
thrombophilia caused by mutations of PROS 1
gene.5 The prevalence of protein S deficiency in the
general population is unknown, while it is found in
10% of patients with thrombosis.2, 6 The common
VTE caused by protein S deficiency includes
deep vein thrombosis (DVT) and pulmonary

Corresponding author: Dr. Sung-Chun Tang, Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan.
E-mail: sctang@ntuh.gov.tw
DOI: 10.6318/FJS.202009_2(3).0007

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 Cerebral Venous Sinus Thrombosis Caused by Hereditary Protein S Deficiency: A Case Report
embolism. CVST is also reported as an uncommon
presentation of protein S deficiency.
As for treatment of CVST, parenteral
7
anticoagulation is currently the first line treatment.
However, in some patients with extensive
thrombosis or refractory to medical treatment,
endovascular thrombectomy (EVT) can be
8
considered. A study demonstrated that EVT
can be a salvage therapy in CVST patients with
intracranial hemorrhage, deep cerebral venous
involvement, coma, or failed medical treatment.9
Here, we report a case with CVST related to
protein S deficiency who received EVT, with
partial recanalization after the procedure and good
clinical improvement.
CASE REPORT
A 37-year-old obese man (body mass index of
2
34.7 kg/m ) suffered from acute-onset headache 7
days prior to the admission. The symptom persisted
in the following days and affected the whole head.
The headache was exaggerated by lying down,
and accompanied with photophobia, phonophobia,
nausea, and vomiting. During the following
days, he could work as usual. Nevertheless, acute
Fig. 1. The patient’s father, uncle, two cousins have DVT history.
250
deterioration of headache and vomiting occurred
along with right hemiparesis and hemi-body
numbness one day before admission. He then
visited the emergency department of our hospital.
He denied prior head trauma, fever, neck stiffness
or other associated symptoms. In addition, his
family history was remarkable of DVT (Figure 1).
Neurological examination revealed right
hemiparesis, right hypoesthesia, anomic aphasia,
ideomotor apraxia, and Gerstmann syndrome
(acalculia, agraphia, finger agnosia, and left-
right disorientation). Brain computed tomography
(CT) without contrast showed a heterogenous
hypodense lesion mixed with multiple patchy
hyperdensities in the left parietal lobe (Figure 2A).
Brain MRI revealed cerebral venous thrombosis
of the superior sagittal sinus (SSS) and left vein
of Trolard, associated with venous congestion
and parenchymal hemorrhage (Figure 2B to D).
His platelet count, PT and aPTT were within
normal limits. The diagnosis of SSS thrombosis
complicated with hemorrhage was made. He was
admitted to the stroke intensive care unit.
Considering the massive thrombosis burden
and concomitant hemorrhage, transvenous EVT
was performed and partial recanalization of
 Cerebral Venous Sinus Thrombosis Caused by Hereditary Protein S Deficiency: A Case Report

Fig. 2. Superior sagittal sinus thrombosis with venous infarction and parenchymal hemorrhage in (A)
non-contrast CT, (B) axial view of T2 FLAIR MRI, (C) axial view of SWI, the arrow implies
thrombosed right vein of Trolard, (D) MRV, (E) angiography, (F) angiography, status post
intravenous thrombectomy, the arrow implies recanalization. Followed image study showed
recanalization of superior sagittal sinus and decrease in size of hemorrhage and edema in (G) MRV,
(H) axial view of T2 FLAIR MRI, (I) axial view of SWI.

SSS to torcula was achieved (Figure 2E& F).
Continuous heparinization followed by warfarin
were administered. Hypercoagulability survey,
including DRVVT, anti-β 2 glycoprotein, anti-
phospholipid body, antithrombin III, protein C,
and protein S were done and very low protein S
function (17.7%) was revealed (normal range:
64-159%). Focal-onset aware seizure with right
limbs twitching and aphasia developed, and he
was treated with lacosamide. The patient was
discharged one month later and the aforementioned
neurological deficits were significantly improved
with independent functional status. The follow-
up magnetic resonance venography after 2 months
showed patent SSS.
Moreover, his father was evaluated for the
familial tendency of venous thromboembolism.
Very low protein S function (13.7%) was disclosed.
Therefore, the diagnosis of hereditary protein S
deficiency was made.
DISCUSSION
In our reported case, a newly-developed
persistent headache in a 37-year-old man, followed
by acute-onset right hemiparesis, aphasia and
apraxia, prompted urgent work-up. Cortical
hemorrhage and unproportional perifocal cerebral
edema raise the suspicion of CVST. The MR
venography confirmed the acute thrombosis of
SSS. EVT was done due to extensive thrombotic
burden and hemorrahge, with good clinical
outcome.
CVST can be classified as provoked or
unprovoked. In our patient, there was no obvious
provocative factor for CVST beyond obesity. In
addition, the strong family history of VTE implied
a hereditary cause. The hypercoagulability survey

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 Cerebral Venous Sinus Thrombosis Caused by Hereditary Protein S Deficiency: A Case Report
showed a very low level of protein S function
(17%). Nevertheless, the interpretation of protein S
assay at acute thrombosis is challenging, because
there is no universal diagnostic criteria and some
potential confounding factors may contribute to
the low protein S level. Theoretically, the level of
protein S is of wide variability because 60% of
protein S bind to complement 4b-binding protein
(C4b-BP), which acts as an acute phase protein.10
Therefore, low protein S level could be found in
the setting of inflammation, hormonal change,
acute thrombosis event including DIC, liver and
renal disease, and vitamin K antagonist usage.11
In our hospital, function rather the free
protein antigen of protein S is measured, which
represented the degree of prolongation of a
prothrombin time-based clotting assay. 12 The
reference range of protein S function and free
protein S antigen are quite similar. Due to the
remarkably low value of this patient, it is hard to
be explained by consumption of protein S during
acute thrombosis alone. Reviewing the previous
literatures, there were another 3 case reports
of protein S deficiency related CVST. Serum
protein S activity of the 3 cases was 25%, 16%,
2, 13, 14
43% respectively. Although genetic testing
of PROS was not performed, we evaluated his
father when he did not have ongoing thrombotic
event and the low level of protein S function was
confirmed in his father.
As for treatment, beyond anticoagulation,
EVT can be considered in patients with CVST.
Partial recanalization and a good clinical recovery
in our patient suggested that EVT is feasible and
effective in protein S deficiency related CVST,
even when parenchymal hemorrhage was present.
Although complete recanalization may not be
achievable due to the multiple thrombosed cortical
veins, venous congestion could still be relieved
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if the downstream sinus can be recanalized. 9
A review including 235 patients with CVST
reported the complete resolution of CVST was
69%.15 Successful endovascular recanalization of
massive CVST in a patient with tuberous sclerosis
and protein S deficiency has been reported. 14
Importantly, the previous report from our hospital
included three cases of CVST related to protein S
deficiency who received EVT and all had excellent
functional outcomes (3-month mRS ≤1).9
In summary, detailed family history and
careful testing interpretation are essential to the
evaluation of CVST. Besides, EVT is a feasible
and effective treatment modality for patient with
CVST related to protein S deficiency.
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 Cerebral Venous Sinus Thrombosis Caused by Hereditary Protein S Deficiency: A Case Report

遺傳性S蛋白缺乏症引起腦靜脈竇栓塞：
一病例報告

葉芳如 1、李崇維 2、湯頌君 3

台大醫院 1教學部、 2影像醫學部、 3神經部暨腦中風中心

摘　要
背景：腦靜脈竇栓塞的原因中，遺傳性凝血異常佔了10-22%，S蛋白缺乏症是其中一個重要的鑑別
診斷。但在急性栓塞期，要建立此診斷並不容易。本文報告一個S蛋白缺乏症引起腦靜脈竇栓塞的
個案，其在接受藥物及血管內血栓移除治療後達到良好的預後。
病例報告：一位具有明顯深層靜脈栓塞家族史的37歲男性，到院前7天產生具顱內壓增加性質的急
性頭痛，右側肢體無力，失語症及失用症。腦部電腦斷層及核磁共振顯示為上矢狀竇及左側上吻合
靜脈的腦靜脈竇栓塞，並有靜脈鬱血及腦出血之情形。凝血功能檢查發現病人具有非常低數值的S
蛋白(17.7%)，難以單用其在急性中風時期被消耗掉來解釋。病人到院後接受經靜脈血栓移除術，
肝素與口服抗凝血藥物，於一個月後出院，出院時為良好的功能狀態。
結論：詳盡的家族史及仔細的實驗室數據判讀對於診斷S蛋白缺乏症甚為重要。而除了抗凝血藥物
的標準治療，血管內血栓移除治療對於嚴重或具併發症的腦靜脈竇栓塞，可作為有效的救援性治
療。

關鍵詞：S蛋白缺乏症、腦靜脈竇栓塞、血管內血栓移除治療

通訊作者：湯頌君醫師　台大醫院神經部暨腦中風中心
E-mail: sctang@ntuh.gov.tw

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