Table 1 Characterization of thrombotic microangiopathies (TMAs) Diseases TTP HUS Thrombotic thromobocytopenic purpura Hemolytic uremic syndrome (Mosch
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1 Online publication December 10, 2009 総 説 第 48 回 総 会 シンポジウム 7 循 環 領 域 における 血 栓 止 血 学 のトピックス 血 栓 性 血 小 板 減 少 性 紫 斑 病 要 旨 : EBM 2001 von Willebrand VWF ADAMTS13 TTP VWF ADAMTS13 J Jpn Coll Angiol, 2009, 49: Key words: TMA, TTP/HUS, ADAMTS13, UL-VWFM はじめに thrombotic thrombocytopenic pupura, TTP 1924 Moschcowitz Amorosi & Ultmann Moschcowitz Gasser hemolytic uremic syndrome, HUS TTP HUS TTP HUS 1 3 thrombotic microangiopathy, TMA 4 Table 1 TTP HUS TTP ADAMTS13 TTP ADAMTS13 HUS HUS 90 O157:H7 ADAMTS13 TTP UL-VWFMとADAMTS13 von Willebrand VWF VIII VWF 2050 head-to-head tail-to-tail SS multimer, M 5 VWFM Weibel- Palade WPB 6 VWF unusually large VWFM UL-VWFM VWFM THE JOURNAL of JAPANESE COLLEGE of ANGIOLOGY Vol. 49,
2 Table 1 Characterization of thrombotic microangiopathies (TMAs) Diseases TTP HUS Thrombotic thromobocytopenic purpura Hemolytic uremic syndrome (Moschcowitz: 1924) (Gasser et al: 1955) Clinical signs (Classic) Pentad (Amorosi & Ultmann: 1966) Triad Hemolytic anemia (microangiopathic) + + Thrombocytopenia (destructive) + + Renal insufficiency + + Fever + Neurological signs (fluctuated) + Classification (Present) Congenital (gene mutations) ADAMTS13 Complement regulatory factors Acquired Positive antibodies to ADAMTS13 Children infected by E. coli O157: H7 WPB P-selectin P-selectin UL-VWFM UL-VWFM ADAMTS13 Fig. 1 VWF type 3 von Willebrand VWD WPB VWF WPB Sanquin, Jan A. van Mourik ADAMTS13 ADAMTS13 a disintegrin-like and metalloproteinase with thrombospondine type 1 motifs cdna 7 ADAMTS 13 ADAMTS13 ADAMTS13 9q34 29 exon 4281pb Soejima 9 Cys-rich/Spacer (C/Sp) VWF TTP ADAMTS13 IgG C/Sp Fig. 2 ADAMTS13 産 生 細 胞 ADAMTS13 10 Disse Uemura 11 ADAMTS13 ADAMTS13 podocyte ADAMTS13によるUL-VWFMのin vivo 切 断 τ =μ du dr ADAMTS VWF ADAMTS13 substrate, S=UL-VWFM enzyme, E=ADAMTS13E/S 360 脈 管 学 Vol. 49, 2009
3 2 TTP ADAMTS13 活 性 測 定 ADAMTS VWF 2004 Kokame 12 ADAMTS13 VWF VWF-A2 73 VWF73 ADAMTS13 FRETS- VWF73 13 Technoclone GmbH Kato 14 chromogenic ADAMTS13-act-ELISA VWF-A2 ADAMTS13 Tyr1605 N VWFM r=0.85 Kainos Lab Inc Technoclone GmbH ADAMTS13 FRETS-VWF73 SRL < chromogenic ADAMTS13-act-ELISA ADAMTS13 < co.jp/> 鑑 別 診 断 ADAMTS13 TTP ADAMTS13 TTP ADAMTS13 IgG Figure 1 A proposed mechanism of formed platelet thrombi, resulting in thrombocytopenia and organ damages in patients with TTP. Unusually large von Willebrand factor multimers (UL-VWFMs), held together by intersubunit dislufide bonds (SS), are produced in vascular endothelial cells, stored in Weibel-palade bodies (WPB), and then released into circulation constitutively or upon stimulation. P-selectin is also stored in WPB, and released together with UL-VWFMs. UL- VWFMs are linked to vascular endothelial cell surface via P-selectin, and under generation of high shear stress the UL-VWFMs change their molecular conformation to the extended form, to which ADAMTS13 is easily accessible. However, in the absence of ADAMTS13 activity, the uncleaved UL-VWFMs induce platelet aggregation/thrombi, resulting in thrombocytopenia and organ damages in the patients Figure 2 Structure of ADAMTS13, and its nomenclature originated from the myth of Adam and Eve. Lower panel indicates the binding site of autoantibodies (IgG inhibitors) present in patient plasmas with acquired TTP. HUS ADAMTS13 15 ADAMTS13 TTP ADAMTS Bethesda U/mL TTP 脈 管 学 Vol. 49,
4 Upshaw-Schulman USS TTP Bethesda U/mL ADAMTS13 ADAMTS13 TTP HUS 16 ADAMTS13 disseminated intravascular coagulation, DIC heparin-induced thrombocytopenia, HIT DIC ADAMTS13 UL- VWFM TTP 17 TMAの 分 類 1998 Furlan 15 VWF 2005 Kato 14 chromogenic-act-elisa ADAMTS ADAMTS13 TMA 919 Table 2 18 TMA DIC <12g/ dl < /L 3 TMA TTP-HUS TTP-HUS ADAMTS13 TTP USS Factor H Factor I CD46 TMA HIV 19 ADAMTS13 IgG TTP TMA 1/3 TTPの 治 療 TTP USS USS idiopathic thrombocytopenic purpura, ITP Evans TTP TTP ITP Evans HELLP USS TTP 2 nd -3 rd trimester VWF USS TTP fresh frozen plasma, FFP ADAMTS13 16 TTP ADAMTS13 TTP plasma exchange, PE TMA PE evidence-based medicine EBM ADAMTS13 ADAMTS13 UL-VWFM VWF TTP 20 CD20 B IgG ADAMTS13 PE TTP TTP PE 362 脈 管 学 Vol. 49, 2009
5 2 Table 2 Plasma levels of ADAMTS13:AC and ADAMTS13:INH in 919 patients with thrombotic microangiopathies (TMAs) registered at Nara Medical University during July 1998-December 2008 (Internal Medicine 2009) Congenital TMAs Acquired TMAs Total Idiopathic Secondary (n=919) Others (Liver cirrhosis, etc) (n=46) E. coli O157: H7 infection (n=32) Drug-induced Conective tissue diseases Pregnancy (n=15) Hematopoietic stem cell transplantation (HSCT) (n=54) Malignancies (n=61) and Autoimmune diseases (CTDs/ADs) (n=221) Pegylatedinterferon (n=1)/ Sildenafil (n=1) Hemolyticuremic syndroime (HUS) (n=106) Thrombotic thrombocytopenic purpura (TTP) (n=284) Unknown etiology (n=24) Mitomycin C (n=10) Ticlopidine (n=22)/ Clopidogrel (n=1) Upshaw- Schulman syndrome (USS) (n=41) (n=41) (n=24) (n=284) (n=106) (n=22/n=1) (n=10) (n=1/n=1) (n=221) (n=61) (n=54) (n=15) (n=32) (n=46) (n=919) ADAMTS13: AC (%) < < < (n=41) (n=23) (n=282) (n=43) (n=22/n=1) (n=7) (n=1/n=1) (n=187) (n=26) (n=15) (n=8) (n=17) (n=23) (n=697) ADAMTS13: INH (U/ml) < < ( ) Sample number determined ADAMTS13 TTP PE TTP TTP TTP TTP 21 PE おわりに ADAMTS13 10 TTP PE FFP EBM TTP ITP TTP ADAMTS13 文 献 1 Moschcowitz E: Hyaline thrombosis of the terminal arterioles and capillaries: a hitherto undescribed disease. Proc N Y Patholl Soc, 1924, 24: Amorosi EL, Ultmann JE: Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature. Medicine, 1966, 45: Gasser C, Gautier E, Steck A et al: Hämolytisch-urämische Syndrome: bilaterale Nierenrindennekrosen bei akuten erworbenen hämolytischen Anämien. Schweiz Med Wochenschr, 1955, 85: Fujimura Y, Matsumoto M: Registry of 919 脈 管 学 Vol. 49,
6 patients with thrombotic microangiopathies across Japan: Database of Nara Medical University during Internal Medicine, 2009 (in press). 5 Fujimura Y, Titani K: Structure and function of von Willebrand factor. In: Haemostasis and Thrombosis. Bloom AL, Forbes CD, Thomas DP et al eds. Edinburgh, London, Madrid, Melbourne, New York, Tokyo, Churchill Livingstone, 1994, Metcalf DJ, Nightingale TD, Zenner HL et al: Formation and function of Weibel-Palade bodies. J Cell Sci, 2008, 121 (Pt 1): Soejima K, Mimura N, Hirashima M et al: A novel human metalloprotease synthesized in the liver and secreted into the blood: possibly, the von Willebrand factor-cleaving protease? J Biochem, 2001, 130: ADAMTS13 TMA Soejima K, Matsumoto M, Kokame K et al: ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage. Blood, 2003, 102: Uemura M, Tatsumi K, Matsumoto M et al: Localization of ADAMTS13 to the stellate cells of human liver. Blood, 2005, 106: Uemura M, Fujimura Y, Matsumoto M et al: Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis. Thromb Haemost, 2008, 99: Kokame K, Matsumoto M, Fujimura Y et al: VWF73, a region from D1596 to R1668 of von Willebrand factor, provides a minimal substrate for ADAMTS-13. Blood, 2004, 103: Kokame K, Nobe Y, Kokubo Y et al: FRETS-VWF73, a first fluologenic substrate for ADAMTS13 assay. Br J Haematol, 2005, 129: Kato S, Matsumoto M, Matsuyama T et al: Novel monoclonal antibody-based enzyme immunoassay for determining plasma levels of ADAMTS13 activity. Transfusion, 2006, 46: Furlan M, Robles R, Galbusera M et al: von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N Engl J Med, 1998, 339: Upshaw-Schulman Ono T, Mimuro J, Madoiwa S et al: Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation: its correlation with development of renal failure. Blood, 2006, 107: Matsumoto M, Yagi H, Ishizashi H et al: The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Semin Hematol, 2004, 41: Rituximab Vincristine Bennett CL, Kim B, Zakarija A et al: Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RADAR Project. J Am Coll Cardiol, 2007, 50: Thrombotic Thrombocytopenic Purpura Ayami Isonishi, Masanori Matsumoto, and Yoshihiro Fujimura Department of Blood Transfusion Medicine, Nara Medical University, Nara, Japan Key words: TMA, TTP/HUS, ADAMTS13, UL-VWFM Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder, characterized by the pentad (Amorosi and Ultmann, 1966). Since the early 1990 s, plasma exchange (PE) became the first line of treatment for TTP, but the mechanism by which PE is effective in this clinical situation has not been well understood. After the discovery of ADAMTS13 in 2001, however, its specific role to cleave unusually large von Willebrand factor multimers (UL-VWFMS), which are biologically the most active forms of VWF, has documented that acquired TTP showing a severely decreased ADAMTS13 activity is caused by developing its autoantibodies. Further, convenient and rapid assays for determining ADAMTS13 activity have been established by Japanese researchers, and are now widely used in the world. (J Jpn Coll Angiol, 2009, 49: ) Online publication December 10, 脈 管 学 Vol. 49, 2009
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