[Presentation of Case]
This 50-year-old woman had been previously healthy except for chronic HBV infection. She started to develop a gradual onset of dull headache in the morning on 28 March, 2013. The pain was generalized with a pain score less than 5 (pain score, from 0 to 10, with 10 indicating the most severe pain). The symptom worsened in the evening on 30 March, 2013, but she did not seek medical attention. She woke up in the next morning with persistent headache. Otherwise, she denied fever, neck stiffness, photophobia, photophobia, aura, rhinorrhea, tearing, nasal stuffiness, nausea or vomiting. However, she developed a sudden onset of weakness of the right upper limb at 10:00 AM while she was washing cutlery. She also noted weakness of the right lower limb later at 3:00 PM. As a result, she was admitted to the emergency department at this hospital. She was a housewife without smoking, alcohol ingestion, or use of illicit drugs. She lived in Da-An District of Taipei with family members, whom were not noted to have similar symptoms. She had no sick contacts, recent travel, or taking hormone replacement.
On examination, She was afebrile and the blood pressure was 170/90 mmHg, the pulse was 91 beats per minute, and the respiratory rate was 20 breaths per minute. The oxygen saturation was 97% while she was breathing ambient air. The sclera was anicteric and the conjunctiva was pink. The neck was supple and the Brudzinski sign was negative. There were no carotid bruits. Neither neck lymphadenopathy nor jugular vein engorgement was noted. The lungs were clear, and the heart sounds were normal. The abdomen was soft without tenderness. There was no abnormal pigmentation on the skin and there was no limbs or trunk edema, either.
On neurologic examination, the patient was alert and oriented. There was right central-type facial palsy. The light touch and pinprick sensations were decreased on the right face, right limbs and right trunk. Motor function was graded at 2/4 (R/L) throughout, with normal tone. The deep-tendon reflexes were +++/++ (R/L) throughout, and the plantar responses were flexor bilaterally. The remainder of the neurological examination was normal.
A diagnosis of acute stroke was made, for which computed tomography (CT) of the brain without administration of contrast material was performed (Figure 1). No intracerebral hemorrhage (ICH) or masses were detected. Two episodes of seizures occurred during her stay at the emergency department, with the second episode lasting for several minutes. A second brain CT revealed ICH and subarachnoid hemorrhage (SAH) (Figure 2). A diagnosis of cerebral venous thrombosis was made by consulting a neurologist. CT venography was performed to confirm the presence of superior sagittal sinus thrombosis (Figure 4).
She was admitted to the stroke center. The symptoms did not improve with continuous infusion of heparin. On the contrary, NIHSS (National Institute of Health Stroke Scale, which is composed of 11 items, each of which scores a specific ability between a 0-normal and 4-impairment, with the maximum possible score of 42 and the minimum score of 0) worsened from 8 to 16 points. As a result, she received radiologic intervention on 1 April, 2013. She underwent thrombolysis, balloon angioplasty with thrombectomy and continuous infusion of heparin locally. Follow-up CT venography (CTV) revealed regression of the superior sagittal sinus thrombosis (Figure 5). The neurological symptoms improved smoothly to NIHSS 5 after the procedure. The follow-up brain CTV three days later also revealed better perfusion of superior sagittal sinus. She was transferred to the general ward to continue treatment with enoxaparin and warfarin. She was discharged with warfarin on 13 April, 2013.
The laboratory data during the hospital stay revealed erythrocytosis (Table 1). The etiology of erythrocytosis was further investigated while she was followed at the outpatient clinic. Tests for JAK2 V617F, serum EPO levels and abdominal sonography were performed. The abdominal sonography revealed a huge tumor in the right lobe of the liver (Figure 6). The triphasic abdominal CT showed the features consistent with hepatocellular carcinoma (HCC) (Figure 7). Extended right lobectomy was performed and the pathology proved HCC (Figure 8). Erythrocytosis resolved with the surgery (Figure 9). Hepatic cavernous hemangioma was also incidentally found by the pathology.
Other investigations for thrombophilia revealed protein S deficiency and increased factor VIII activity, which persisted even after lobectomy of the liver. She continued to receive warfarin for thrombophilia and minimal neurologic sequelae was noted.
討論
血栓好發症 (Thrombophilia)
除了診斷出腦部靜脈栓塞並加以治療之外，還要找出引發血栓的原因。除了後天性的原因，對於下列情況應考慮進行遺傳性血栓疾病的鑑定：
1. 在40歲以前發生靜脈血栓 2. 反覆發生靜脈血栓或靜脈血栓性血管炎 3. 在特異部位(如腸系膜靜脈或腦靜脈)發生血栓 4. 使用warfarin之初，反而發生血栓性皮膚潰爛 5. 在妊娠初期發生血栓 6. 有家族其他成員曾發生血栓者 7. 無明顯誘發原因者。此病例在上矢狀竇發生栓塞，因此要做遺傳性血栓疾病的鑑定。
根據流行病學統計，在東方人發生的遺傳性血栓疾病以C蛋白缺乏(Protein C deficiency)、S蛋白缺乏(Protein S deficiency)和Anti-thrombin III 缺乏(Anti-thrombin III deficiency)為多。Table 2為急性期仍在使用heparin continuous infusion 時的數據，發現病人的S蛋白和Anti-thrombin III下降，在血栓產生的急性期，Anti-thrombin III 常會下降到正常的 30%，在病發後兩個月再追蹤Anti-thrombin III，其值已達到115.7%，所以Anti-thrombin III 缺乏可被排除；急性血栓產生時S蛋白也會被消耗而低下，但後續追蹤仍發現S蛋白數值仍偏低( Table 3)，雖然是在病人服用warfarin 的情況下檢查的，但因為warfarin 會同時抑制S蛋白和C蛋白，所以看S蛋白和C蛋白的比值仍可以幫助診斷S蛋白或C蛋白缺乏。我們發現病人的S蛋白和C蛋白的比值小於0.6，仍強烈懷疑病人有S蛋白缺乏。不過家族史中，並沒有血栓好發的情形，因此讓我們懷疑病人會不會是後天性S蛋白缺乏？後天性S蛋白缺乏的原因包含懷孕、使用口服避孕藥、腎病症候群、肝疾病、惡性腫瘤以及DIC。病人並沒有懷孕也沒有使用口服避孕藥，尿液分析尿蛋白僅一價，肝臟相關GOT、GPT、INR 正常(Table 1)，臨床並沒有DIC的症狀和徵候，所以剩下惡性腫瘤的部分是我們要再去釐清的。
抗磷脂質抗體症候群(Antiphospholipid antibody syndrome)也是臨床上必須排除造成血栓好發症的原因，病人過去的婦產科病史是G2P1AA1，沒有自然流產或不孕，而Table 4的結果讓我們可以排除抗磷脂質抗體症候群。
接著討論後天性血栓好發的原因；根據問診，病人並沒有immobilization或服用口服避孕藥。實驗室檢查發現Hb> 16.5，已經符合absolute erythrocytosis 的診斷，病人在住院中的血氧飽和度為 97%，hypoxic erythrocytosis可以被排除。這時候我們再去檢查JAK2 V617F mutation，因為primary polycythemia 中最多是polycythemia vera，而polycythemia vera當中有95%其JAK2 V617F mutation為陽性 (Figure 10)，病人的JAK2 V617F mutation為陰性，因此真性紅血球增多的機會很低；這時候只剩下normoxic erythrocytosis 是最有可能的。Normoxic erythrocytosis 主要是腫瘤不受hypoxemia刺激，即分泌過多的erythropoietin (EPO)：renal cell carcinoma、hepatocellular carcinoma、cerebellar hemangioblastoma、pheochromocytoma、uterine fibroids 是最常見分泌 EPO的腫瘤。因此接著安排腹部超音波，發現肝臟右葉有腫瘤，進一步的腹部三相電腦斷層懷疑為肝細胞癌。在擴大右葉切除之後追蹤紅血球，發現紅血球增多有改善。
回到S蛋白缺乏的議題，病人的S蛋白缺乏是否為肝細胞癌造成的呢？Table 5 是在開完刀後兩個月檢查的，發現S蛋白和C蛋白的比值仍小於0.6，病人的S蛋白缺乏很可能是先天性的。
後續在血液科門診還檢查了第八凝血因子，發現病人有第八凝血因子活性增加( increased factor VIII activity)的情況。第八凝血因子活性增加是血栓形成的獨立危險因子，當其數值是正常的兩倍以上時，形成血栓的機會是正常人的十一倍；第八凝血因子活性增加分成暫時和永久兩大類；因為第八凝血因子也是一個急性蛋白(acute phase reactant)，在inflammatory bowel disease、cancer 和post-thrombosis都會暫時性增加；永久性第八凝血因子活性增加是發現有一群人第八凝血因子活性持續偏高，但目前還無法找到造成這個表現的基因變化。臨床上要分辨暫時或永久性的第八凝血因子活性增加是很困難的。病人的第八凝血因子活性增加和肝細胞癌有無關聯呢？我們看Table 6，發現術後追蹤第八凝血因子活性仍高，即使術後病理下已達到 margin free且術後腹部超音波無肝腫瘤，所以病人很可能是先天第八凝血因子活性較高的病例。
腦部靜脈栓塞 (Cerebral venous thrombosis)
腦部靜脈栓塞發生率並不高，每年每十萬人小於1.5，新生兒及幼童較成年人常發生，女性是男性的三倍，主要是因為女性獨有的危險因子：懷孕、周產期以及使用口服避孕藥；平均發生年齡是39歲。臨床表現最常見(>90 %)是頭痛，可以是唯一症狀也可以在其他症狀表現前數日到數週發生，頭痛的位置和栓塞的位置通常沒有關聯；另外還有腦壓上升致噁心嘔吐、意識不清甚至昏迷，局部神經學症狀、抽筋甚至癲癇重積症(status epilepticus)，腦部靜脈栓塞比其他類型的中風更容易發生抽筋。危險因子見Figure 11。
診斷的黃金標準是Brain MRI 加上 MR venography (MRV)。若做Brain CT，會發現1/3的病人為正常，CT上看不出任何異常，有1/3會出現 direct signs，例如 Empty delta sign、Cord sign (Figure 3)。Cord sign 指的是大腦皮質上因為靜脈栓塞顯出hyperdensity 變化，這反映靜脈栓塞如同大腦實質出血。Indirect signs 比direct signs更常出現，例如ICH、brain edema。以CT venography做診斷的正確率相當高(90-100%)，可以取代MR venography。
治療主要以抗凝血劑為主，不論是EFNS (European Federation of Neurological Societies、ACCP (American College of Chest Physicians) 或是AHA/ASA(American Heart Association/American Stroke Association) 的治療guideline大同小異：急性期以LMWH 或heparin 治療，若症狀惡化，則做endovascular thrombolysis，接著再使用三至六個月的warfarin，INR 目標為正常的2到3倍。
在使用抗凝血劑治療後預後相當好，有80%的病人可以達到complete recovery 或是只有輕微的神經學缺陷。
Table 1.
WBC |
RBC |
Hb |
MCV |
Hct |
PLT |
Blast |
Pro/Mye |
5.7k/uL |
7M/uL |
17.7g/dL |
76.9fL |
54% |
99k/uL |
0% |
0/0% |
Meta |
Band |
Seg |
Eos |
Baso |
Mono |
Lym/Aty |
Plasma |
0% |
0% |
81% |
0.4% |
0.2% |
3.3% |
14.6/0% |
0% |
UN |
Cre |
Na |
K |
AST |
ALT |
14mg/dL |
7mg/dL |
133mM/L |
3.8mM/L |
17U/L |
17U/L |
PT |
INR |
PTT |
Fibri. |
D-D |
FDP |
12.3sec |
1.16 |
29.0sec |
277mg/dL |
2.6ug/mL |
9.7ug/mL |
Table 2. (on continuous infusion of heparin)
Protein C: Fun (normal>79%) |
97.5% |
Protein S: Fun (normal 59-118%) |
21.8% |
Anti-thrombin III: Fun (normal>83%) |
66.5% |
Table 3.
|
Protein S:Fun
(59-118%) |
Protein C: Fun
(>79%) |
S/C ratio |
急性期第三天
(under heparin) |
21.8 |
97.5 |
0.22 |
腦部靜脈栓塞兩個月後
(under warfarin INR 1.53) |
19.9 |
76.9 |
0.258 |
Table 4.
DRVVT |
APA IgG
(<15) |
ACA IgM
(<9.8) |
ACA IgG(<13.3) |
Anti-B2-GP1(<10) |
negative |
1.525U/ml |
3.543U/ml |
3.963U/ml |
0.58U/ml |
Table 5.
|
Protein S:Fun
(59-118) |
Protein C: Fun
(>79%) |
S/C ratio |
做擴大肝右葉切除(extended right lobectomy)後兩個月
(INR 2.33) |
16.2 |
51.8 |
0.31 |
Table 6.
|
Factor VIII (normal 48-179%) |
做擴大肝右葉切除(extended right lobectomy) 前 |
249.1 |
術後兩個月 |
280.8 |
術後三個月
(腹部超音波追蹤無肝腫瘤) |
305 |
術後四個月 |
264.9 |
Figure 1.至Figure 11.點此下載
Figure 1. First CT of the brain without administration of contrast material
Figure 2. Second CT of the brain without administration of contrast material revealing bilateral frontal ICH and SAH
Figure 3.First CT of the brain without administration of contrast material revealing Cord sign (circled)
Figure 4.CT venography showing that the superior sagittal sinus was not enhanced, which suggests the presence of superior sagittal sinus thrombosis
Figure 5. Improvement of superior sagittal sinus enhancement after intervention (circled)
Figure 6. A hepatic tumor in the right lobe by abdominal sonography
Figure 7. Triphasic CT revealing a right hepatic tumor with early enhancement and early washout after administration of contrast material
Figure 8. Pathology showing hepatocellular carcinoma
Figure 9. Resolution of erythrocytosis with surgery
Figure 10.
Figure 11.
參考文獻
- Wintrobe's Clinical Hematology 12e
- The revised World Health Organization diagnostic criteria for polycythemia vera, essential thrombocytosis, and primary myelofibrosis: An alternative proposal. Blood 2008; 112:231-239
- Somatic Mutations of Calreticulin in Myeloproliferative Neoplasms. NEJM 2013; 369: 2379
- Acquired protein S deficiency. J Clin Invest. 1988;81(5):1445
- Hereditary protein S deficiency: clinical manifestations. Ann Intern Med. 1987;106(5):677.
- 台大內科學講義第五版”血栓好發症”
- Uptodate：Etiology,clinical features, and diagnosis of cerebral venous thrombosis,Treatment and prognosis of cerebral venous thrombosis
| 
Case Discussion
繼續教育考題