ICD-9-CM診斷代碼：446.6
ICD-10-CM診斷代碼：M31.19
疾病簡介
先天性血栓性血小板減少性紫斑症（cTTP），也稱為Upshaw-Schulman綜合徵，是一種極為罕見的血栓微血管病變，由一種由雙等位基因ADAMTS13突變引起的罕見血栓性疾病，ADAMTS13將止血糖蛋白和UL-VWF多聚體裂解為較小的靜止狀態，嚴重時可導致致命的缺血性器官衰竭。
發生率
免疫性血栓性血小板減少性紫斑症(TTP)和cTTP的發生率估計為每年每百萬人2至6人；cTTP 佔國際登記處所有TTP案件的2%至10%，盛行率約為百萬分之一。
病因學
ADAMTS13會經歷各種類型的糖基化作為翻譯後修飾，不完全的糖基化會導致該酶的分泌中斷、酶活性降低或循環清除。根據ADAMTS13胰蛋白酶勝肽的質譜分析，至少有6個血小板反應蛋白1型重複(TSP)結構域被O-岩藻糖二糖修飾。當HEK293 T-REx細胞中O-岩藻糖基轉移酶2（一種將岩藻糖轉移到TSP結構域中的絲氨酸的酶）的基因表現被siRNA中斷時，ADAMTS13的分泌會受到顯著抑制。其他研究團隊也發現N連接聚醣調節ADAMTS13分泌和VWF裂解活性。在TSP1、接頭TSP4-TSP5和TSP8中鑑定出C-甘露糖基化位點，這些位點在含TSP的蛋白質的分泌中也發揮著重要作用。總之，ADAMTS13突變會導致結構異常或有時破壞翻譯後修飾，導致ADAMTS13活性嚴重受損。
ADAMTS13基因發現3類主要的致病突變：移碼突變、錯義突變和無義突變，其中錯義突變占主導地位(約一半)。
遺傳模式
體染色體隱性。
ADAMTS13位於染色體9q34上，由29個外顯子組成，包含1427個胺基酸，全世界已通報了200多種不同的致病突變，這些突變以體染色體隱性方式從父母遺傳給兄弟姊妹，甚至一種致病突變也會使ADAMTS13活性降低20-50%。
ADAMTS13突變分佈在所有ADAMTS13基因中，沒有累積的基因熱點，顯示各種致病突變以不同方式損害ADAMTS13活性。歐洲是c.4143_4144dupA (p.E1382Rfs*6)和p.R1060W為常見突變點位，日本的是p.R193W和p.C908Y，台灣的則不清楚。
臨床表徵
三分之二的患者在出生當天出現嚴重的新生兒黃疸並伴有血小板減少症，將近一半的兒童期患者為近親通婚所生之小孩。懷孕也是女性 cTTP 患者急性發作的誘因，母親（cTTP 患者）和嬰兒都面臨致命血栓形成的風險。
觀察到兩個表現高峰：兒童期和成年期，最常見的診斷提示是血小板減少症。兒童期發病的 cTTP 最常見的誘因是感染，懷孕是成人發病 cTTP 最常見的誘發因素，大部分的患者診斷表現為 MAHA(微小血管內溶血性貧血，microangiopathic hemolytic anemia)。
大人另外還有常見的臨床症狀有:嗜睡、頭痛和腹痛等症狀，所有患者均患有兩種以上的神經精神症狀，即頭痛、注意力不集中和抑鬱。其他症狀包括先兆性頭痛（推測為偏頭痛）、視力改變、健忘、疲勞、神經病變、構音障礙、視力喪失、癲癇發作、短暫性無力、跌倒和吞嚥困難，部分患者隨著年齡的增長而患有中風及腎臟衰竭。
診斷方式
cTTP 根據以下標準診斷：存在不明病因的嚴重血小板減少症和 Coombs 陰性溶血性貧血、健康個體的 ADAMTS13活性嚴重耗竭低於 10%、缺乏抗ADAMTS13抗體（抗 ADAMTS13 IgG 自身抗體或抗 ADAMTS13 抑製劑），以及純合或複合雜合模式存在雙等位基因ADAMTS13突變。
儘管所有 cTTP 患者都表現出隨著時間的推移ADAMTS13活性嚴重下降，但在沒有 TTP 觸發因素的情況下，他們的血小板計數、乳酸脫氫酶 （LDH） 和其他 TTP 癥狀可能表現出正常範圍。我們認為，更多潛在的 cTTP 患者在兒童時期未被診斷或誤診為免疫介導的 TTP（iTTP）、新生兒的 ABO/Rh 血型不合或妊娠期的溶血升高肝酶和低血小板 （HELLP） 綜合征。因此，臨床醫生必須認識到，cTTP不能通過臨床表現來診斷，例如如果沒有ADAMTS13試驗，臨床癥狀的五聯征在臨床實踐中不再使用。至於抗ADAMTS13抗體（IgG自身抗體或抗ADAMTS13抑製劑），我們有時會遇到難以診斷為cTTP或iTTP的病例，這些病例的檢出限為陰性或臨界限。在這些情況下，只有在監測患者的ADAMTS13活動並分析父母的ADAMTS13活動後才能診斷出患者，因為始終可以看到輕度至中度的ADAMTS13活動減少 （20-50%）。
治療方式
在急性期，1 或 2 個單位的血漿輸注可迅速完全改善 cTTP 患者的血小板計數和 LDH 水準。血小板計數可在正常範圍內維持兩週，而血漿輸注後2.5-3.5天ADAMTS13活性恢復到基線。最近的國際血栓形成和止血學會 (International Society of Thrombosis and Hemostasis， ISTH)TTP 建議每一至三週輸注血漿(10-15 mL/kg)治療 cTTP，作為維持治療，對有症狀的患者每日輸注血漿，直至症狀消退且血小板計數恢復正常。如前所述，同樣，在過去二十年中，日本每兩週進行240-480 mL 的預防性血漿輸注。迄今為止，FFP的最佳開始時間和劑量/隔仍有待討論。當我們調查預防性血漿輸注的問題時，大多數患者及其家人抱怨過敏反應，例如輸注期間的蕁麻疹，在最壞的情況下，血漿衍生蛋白引起的危及生命的過敏反應。血漿製品可以傳播來自每個獻血者的病原體，三名患者通過輸注血漿感染了丙型肝炎病毒。
預後
損害患者生活品質的 cTTP 的長期生存率和併發症仍未闡明。1998 年日本 cTTP 佇列的累積數據揭示了總生存率、死因和長期死亡率。截至 2022 年 6 月，68 名患者中有 10 名在隨訪期內死亡。研究統計，10 年總生存率為91.1%，許多死亡患者出現終末期腎功能衰竭，需要腎臟替代治療並猝死。心肌梗死、心力衰竭和心律失常已被描述為猝死的原因。多達四分之一的血液透析患者死於心源性猝死，這可能是由於血液透析與室性心律失常和動態心電圖變化有關。進行性腎功能損害 cTTP 患者腎活檢的組織病理學結果顯示，與非 cTTP 病例相比，慢性腎小球硬化變化和更多的 C4d 沉積，表明 C4d 免疫染色為 cTTP 患者補體介導的腎小球損傷提供了證據。
Reference
1.Sakai, K., Hamada, E., Kokame, K., & Matsumoto, M. (2023). Congenital thrombotic thrombocytopenic purpura: genetics and emerging therapies. Annals of Blood, 8.
2.Alwan, F., Vendramin, C., Liesner, R., Clark, A., Lester, W.,
Dutt, T., ... & Scully, M. (2019). Characterization and treatment of congenital thrombotic thrombocytopenic purpura. Blood, The Journal of the American Society of Hematology, 133(15), 1644-1651.
Diagnose
cTTP is diagnosed using the following criteria: the presence of severe thrombocytopenia and Coombs-negative hemolytic anemia of unknown etiology, severe depletion of ADAMTS13 activity below 10% of healthy individuals, absence of anti-ADAMTS13 antibodies (anti-ADAMTS13 IgG autoantibodies or anti-ADAMTS13 inhibitors), and presence of biallelic ADAMTS13 mutations in homozygous or compound heterozygous mode. ADAMTS13 activity is measured mainly by two different assays: a fluorescence resonance energy transfer (FRET) assay using FRETS-VWF73 as a substrate and a chromogenic ADAMTS13 activity ELISA using a murine monoclonal antibody that specifically recognizes Y1605 of the VWF cleavage site. Notably, the FRET-VWF73 assay sometimes fails to determine the ADMATS13 activity in patients with hyperbilirubinemia [>100 µmol/L (5.85 mg/dL)] because high levels of bilirubin interfere with fluorescence evolution by acting as a quencher at an emission wavelength of 450 nm. Although all cTTP patients show severely decreased ADAMTS13 activity over time, they may show a normal range of platelet counts, lactate dehydrogenase (LDH), and other TTP symptoms in the absence of TTP triggers. We believe that more potential cTTP patients are left undiagnosed or misdiagnosed with immune-mediated TTP (iTTP) in childhood, ABO/Rh-incompatibility in newborns, or Hemolysis Elevated Liver enzymes and Low Platelets (HELLP) syndrome in pregnancy. Therefore, clinicians must recognize that cTTP cannot be diagnosed by clinical presentation, such as the pentad of clinical symptoms no longer used in clinical practice without the ADAMTS13 test. As for anti-ADAMTS13 antibodies (IgG autoantibodies or anti-ADAMTS13 inhibitors), we sometimes encounter cases difficult to diagnose as either cTTP or iTTP, which show a negative or borderline detection limit. In these cases, patients can only be diagnosed after monitoring their ADAMTS13 activity and analyzing ADAMTS13 activity in their parents because a mild to moderate depletion of ADAMTS13 activity is consistently seen (20–50%).
Treatment
One or two units of plasma infusion quickly achieve complete improvement in platelet counts and LDH levels among cTTP patients in the acute phase. Platelet counts can be maintained within the normal range for 2 weeks, whereas ADAMTS13 activity returns to baseline 2.5–3.5 days after plasma infusion. The recent International Society of Thrombosis and Hemostasis (ISTH) TTP guidelines recommend treating cTTP with plasma infusion (10 to 15 mL/kg) every 1 to 3 weeks as maintenance therapy and daily plasma infusion for symptomatic patients until the symptoms resolve and platelet counts normalize, as previously described. Similarly, 240–480 mL of prophylactic plasma infusion every 2 weeks has been performed over the past two decades in Japan. To date, the optimal starting timing of FFP and dosage/intervals remains open to discussion. When we investigated the issues for prophylactic plasma infusion, most patients and their families complained about allergic reactions, such as urticaria during infusion, and in the worst case, life-threatening anaphylaxis induced by plasma-derived protein. Plasma products can transmit pathogenic organisms from each blood donor, and three patients are infected with hepatitis C virus via infused plasma
Prognosis
The accumulated data in the Japanese cTTP cohort from 1998 revealed the overall survival, cause of death, and long-term mortality. As of June 2022, 10 of the 68 patients died within the follow-up periods. Figure 4 shows that the 10-year overall survival rate was 91.1%, and the median age at death, except for one suicide case, was 44 (IQR: 41–52). Many patients who died experienced end-stage renal failure, requiring renal replacement therapy and suffered from sudden death. Myocardial infarction, heart failure, and arrhythmia have been described as the causes of sudden death. The causes of death in our cTTP cohort are summarized in Table 1. Previous studies have revealed that increased VWF antigen levels lead to high mortality risk in dialysis patients without cTTP . In addition, dialysis patients with high VWF antigen levels and low ADAMTS13 activity have a 2.2-fold higher mortality rate than those with low VWF antigen levels and high ADAMTS13 activity. Up to one-fourth of hemodialysis patients died of sudden cardiac death, which might have resulted from the fact that hemodialysis is associated with both ventricular arrhythmia and dynamic electrocardiographic changes. Histopathological findings of renal biopsy from cTTP patients with progressive renal impairment revealed chronic glomerular sclerotic changes and more C4d deposits than those in non-cTTP cases, suggesting that C4d immunostaining provides evidence for complement-mediated glomerular damage in cTTP patients . Our long-term follow-up study investigated 55 cTTP patients also indicated that 41 patients with prophylactic FFP were considered to have a more severe form of the disease, lower platelet counts, and higher serum creatinine levels than 14 patients receiving on-demand FFP and developed more organ damage, including renal impairment, cerebral infarction, and myocardial infarction during follow-up periods. Two deceased cases were in the prophylactic FFP group. Intriguingly, no patient in the on-demand FFP group showed organ damage during the follow-up period. The FFP-dependent group received 13.2 mL/kg of FFP infusion per month (median), lower than the ISTH guideline (20.0–30.0 mL/kg per month). In addition, a very recent interview study of 26 patients in the United States revealed that all patients, except one infant, suffered from more than two neuropsychiatric symptoms, namely, headaches, poor concentration, and depression. Other symptoms included headaches with aura (presumed migraine), vision changes, forgetfulness, fatigue, neuropathy, dysarthria, loss of vision, seizures, transient weakness, falls, and dysphagia. This study also found that 17 (63%) patients suffered from strokes as they aged. Eleven of the 17 patients had stroke-related disabilities. The high incidence of stroke among cTTP patients is similar to that in our previous study. Notably, the reduction of ADAMTS13 activity in patients with iTTP during the remission phase led to an increased risk of stroke |