ADAMTS13
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ADAMTS13(a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13),又稱溫韋伯氏因子裂解酶(von Willebrand factor-cleaving protease,VWFCP)是一種含锌的金屬蛋白酶。ADAMTS13可以裂解一種稱為溫韋伯氏因子(vWf)的大型凝血因子。為一種主要由肝臟星狀細胞(stellate cell)製造的蛋白酶,少量由血管內皮細胞、血小板、腎臟足細胞及腎小管上皮細胞分泌[6],在人體與動物實驗中皆發現受試者接受部分肝切除手術後,ADAMTS13的活性會下降至正常值的30~40%,可見肝臟對ADAMTS13的製造具有重要的貢獻。本酵素存在於血液之中,降解vWf多聚體,以降低它們的活性[7]。
遺傳學
ADAMTS13基因存在於第九對染色体(9q34)上[7]。
發現
自1982年時,人們就知道遺傳性血栓性血小板減少性紫癜(TTP,一種微血管病性溶血性貧血)患者的血漿中,存在異常巨大的溫韋伯氏因子多聚體(ULVWF)[7]。
1994年,發現在高剪力下時,有一種血漿金屬酶會從vWF第1605位的酪氨酸及1606位的甲硫氨酸間切割。1996年,兩個獨立研究團隊分別發現該酵素。自接下來的兩年,同樣的兩個團隊證明了vWF裂解酶與小血管的血小板血栓生成相關。此外他們還報導了在大部分非遺傳性TTP患者身上,能發現對抗ADAMTS13的IgG抗体[7]。
蛋白質組學
ADAMTS家族目前共已知有19種蛋白質,ADAMTS13屬於其中一員,與其他金屬蛋白酶族同樣有一個14個相異的結構域組成的結構,包括金屬蛋白酶(metalloprotease)、解整合素(disintegrin)、TSP1(first thrombospondin type 1 repeat)和間隔域(spacer domain) ,但ADAMTS13並不具備穿膜蛋白結構 ,因此其不存在細胞膜上,而是隨著血液循環在大小血管內作用。該家族的蛋白質擁有蛋白酶結構域,可以水解蛋白質,鄰近則有解聚素結構域,且含有多個血小板反應蛋白結構域。ADAMTS13含有8個血小板反應蛋白結構域,且無輸水穿膜段,所以該蛋白並非膜蛋白[7]。
臨床角色
ADAMTS13缺乏症最早發現於Upshaw Schulman Syndrome,為一種復發性遺傳性血栓性血小板減少性紫癜。當時學界認為該病屬於一種自體免疫疾病,因為該疾病使用血漿置換及IgG抑制劑。在ADAMTS13發現後,研究人員發現這些自體抗體會對抗該蛋白上的抗原表位[7][8][9]。ADAMTS13具有裂解溫韋伯氏因子多聚體(UL-VWFM)並降低溫韋伯氏因子活性的功能 ,能抑止血小板堆積於微血管形成血栓。[10]由血管內皮細胞分泌的ADAMTS13,可能負責大部分新生溫韋伯氏因子多聚體的裂解,以達到即刻性抑止血栓形成的作用。當ADAMTS13受到自身抗體的攻擊而導致活性下降(小於正常活性10%),即可能造成呈現巨分子狀態的溫韋伯氏因子(也就是溫韋伯氏因子多聚體)沉積後黏附於血管內皮細胞表層,促使微小血管中血小板凝集,使血液中游離的血小板數量不足,同時血管中的纖維蛋白增加亦破壞紅血球結構,形成不正常型態的血球 (例如:裂細胞Schistocyte)與發生溶血現象,導致產生獲得性血栓性血小板減少性紫斑症的臨床症狀。
研究中發現ADAMTS13低下除了與獲得性血栓性血小板減少性紫斑症的形成密切相關外,在其他栓塞性微血管病變(thrombotic microangiopathy,TMA)中ADAMTS13有不同程度的下降[11] ,在敗血症、惡性高血壓病患及自體免疫患者中也有發生相似的變化[12][13] ,因此合理的推論ADAMTS13活性下降雖然不一定成為直接造成上述疾病的成因,但極有可能在這些病症中擔任促成因子的角色。
參見
參考文獻
- ^ 與ADAMTS13相關的疾病;在維基數據上查看/編輯參考.
- ^ 2.0 2.1 2.2 GRCh38: Ensembl release 89: ENSG00000160323、ENSG00000281244 - Ensembl, May 2017
- ^ 3.0 3.1 3.2 GRCm38: Ensembl release 89: ENSMUSG00000014852 - Ensembl, May 2017
- ^ Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ [Turner N, Nolasco L, Tao Z, et al. Human endothelial cells synthesize and release ADAMTS-13. J Thromb Haemost. 2006;4:1396–1404.]
- ^ 7.0 7.1 7.2 7.3 7.4 7.5 Levy GG, Motto DG, Ginsburg D. ADAMTS13 turns 3. Blood. 2005, 106 (1): 11–7 [2016-12-20]. PMID 15774620. doi:10.1182/blood-2004-10-4097. (原始内容存档于2010-08-24).
- ^ Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J. Am. Soc. Nephrol. 2003, 14 (4): 1072–81 [2016-12-20]. PMID 12660343. doi:10.1097/01.ASN.0000060805.04118.4C. (原始内容存档于2007-10-20).
- ^ Furlan M, Lämmle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol. 2001, 14 (2): 437–54. PMID 11686108. doi:10.1053/beha.2001.0142.
- ^ [Levy GG, Motto DG, Ginsburg D. ADAMTS13 turns 3. Blood. 2005, 106 (1): 11–7]
- ^ [Martin K, Borgel D, Lerolle N, et al. Decreased ADAMTS-13 (A disintegrin-like and metalloprotease with thrombospondin type 1 repeats) is associated with a poor prognosis in sepsis-induced organ failure. Crit Care Med. 2007;35(10):2375-2382.]
- ^ [Farkas P, Csuka D, Mikes B, et al. Complement activation, inflammation and relative ADAMTS13 deficiency in secondary thrombotic microangiopathies. Immunobiology. 2017;222(2):119-127.]
- ^ [Khanal N, Dahal S, Upadhyay S, Bhatt VR, Bierman PJ. Differentiating malignant hypertension-induced thrombotic microangiopathy from thrombotic thrombocytopenic purpura. Ther Adv Hematol. 2015;6(3):97-102..]
延伸閱讀
- Furlan M, Lammle B. Aetiology and pathogenesis of thrombotic thrombocytopenic purpura and haemolytic uraemic syndrome: the role of von Willebrand factor-cleaving protease. Best Pract Res Clin Haematol 2001;14:437-54. PMID 11686108.
- Tsai HM. Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 2003;14:1072-81. PMID 12660343.
- Tang BL. ADAMTS: a novel family of extracellular matrix proteases.. Int. J. Biochem. Cell Biol. 2001, 33 (1): 33–44. PMID 11167130. doi:10.1016/S1357-2725(00)00061-3.
- Fujimura Y, Matsumoto M, Yagi H, et al. Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome.. Int. J. Hematol. 2002, 75 (1): 25–34. PMID 11843286. doi:10.1007/BF02981975.
- Zheng X, Majerus EM, Sadler JE. ADAMTS13 and TTP.. Curr. Opin. Hematol. 2003, 9 (5): 389–94. PMID 12172456. doi:10.1097/00062752-200209000-00001.
- Tsai HM. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura.. J. Mol. Med. 2003, 80 (10): 639–47. PMID 12395148. doi:10.1007/s00109-002-0369-8.
- Tsai HM. Platelet activation and the formation of the platelet plug: deficiency of ADAMTS13 causes thrombotic thrombocytopenic purpura.. Arterioscler. Thromb. Vasc. Biol. 2003, 23 (3): 388–96. PMID 12615692. doi:10.1161/01.ATV.0000058401.34021.D4.
- Tsai HM. Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes.. J. Thromb. Haemost. 2003, 1 (4): 625–31. PMID 12871390. doi:10.1046/j.1538-7836.2003.00169.x.
- Remuzzi G. Is ADAMTS-13 deficiency specific for thrombotic thrombocytopenic purpura? No.. J. Thromb. Haemost. 2003, 1 (4): 632–4. PMID 12871391. doi:10.1046/j.1538-7836.2003.00170.x.
- Moake JL. von Willebrand factor, ADAMTS-13, and thrombotic thrombocytopenic purpura.. Semin. Hematol. 2004, 41 (1): 4–14. PMID 14727254. doi:10.1053/j.seminhematol.2003.10.003.
- López JA, Dong JF. Cleavage of von Willebrand factor by ADAMTS-13 on endothelial cells.. Semin. Hematol. 2004, 41 (1): 15–23. PMID 14727255. doi:10.1053/j.seminhematol.2003.10.004.
- Plaimauer B, Scheiflinger F. Expression and characterization of recombinant human ADAMTS-13.. Semin. Hematol. 2004, 41 (1): 24–33. PMID 14727256. doi:10.1053/j.seminhematol.2003.10.006.
- Kokame K, Miyata T. Genetic defects leading to hereditary thrombotic thrombocytopenic purpura.. Semin. Hematol. 2004, 41 (1): 34–40. PMID 14727257. doi:10.1053/j.seminhematol.2003.10.002.
- Schneppenheim R, Budde U, Hassenpflug W, Obser T. Severe ADAMTS-13 deficiency in childhood.. Semin. Hematol. 2004, 41 (1): 83–9. PMID 14727263. doi:10.1053/j.seminhematol.2003.10.007.
- Kremer Hovinga JA, Studt JD, Lämmle B. The von Willebrand factor-cleaving protease (ADAMTS-13) and the diagnosis of thrombotic thrombocytopenic purpura (TTP).. Pathophysiol. Haemost. Thromb. 2005, 33 (5-6): 417–21. PMID 15692254. doi:10.1159/000083839.
- Levy GG, Motto DG, Ginsburg D. ADAMTS13 turns 3.. Blood. 2005, 106 (1): 11–7. PMID 15774620. doi:10.1182/blood-2004-10-4097.
- George JN. ADAMTS13, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome.. Curr. Hematol. Rep. 2005, 4 (3): 167–9. PMID 15865866.
- Dong JF. Cleavage of ultra-large von Willebrand factor by ADAMTS-13 under flow conditions.. J. Thromb. Haemost. 2005, 3 (8): 1710–6. PMID 16102037. doi:10.1111/j.1538-7836.2005.01360.x.
- Matsukawa, M.; Kaikita, K.; Soejima, K.; Fuchigami, S.; Nakamura, Y.; Honda, T.; Tsujita, K.; Nagayoshi, Y.; Kojima, S.; Shimomura, H.; Sugiyama, S.; Fujimoto, K.; Yoshimura, M.; Nakagaki, T.; Ogawa, H. Serial Changes in von Willebrand Factor-Cleaving Protease (ADAMTS13) and Prognosis After Acute Myocardial Infarction. The American Journal of Cardiology. 2007, 100 (5): 758–763. PMID 17719316. doi:10.1016/j.amjcard.2007.03.095.
外部連結
- The MEROPS online database for peptidases and their inhibitors: M12.241[失效連結]
- OMIM 274150
- Secreted protein database entry
- Human ADAMTS13 genome location and ADAMTS13 gene details page in the UCSC Genome Browser.
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