2005 Fiscal Year Final Research Report Summary
Analysis of various type thrombosis with decreased ADAMTS13 activity
| Project/Area Number |
15591017
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Hematology
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| Research Institution | Nara Medical University |
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Principal Investigator |
FUJIMURA Yoshihiro Nara Medical University, Faculty of Medicine, Professor, 医学部, 教授 (80118033)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUMOTO Masanori Nara Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (60316081)
ISHIZASHI Hiromichi Nara Medical University, School of Medicine, Assistant Professor, 医学部, 講師 (50260807)
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| Project Period (FY) |
2003 – 2005
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| Keywords | ADAMTS13 / TTP / HUS / UL-VWFM / stellate cell |
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| Research Abstract |
Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are both life-threatening generalized disorders categorized as thrombotic microangiopathy (TMA). TMA is characterized by microangiopathic hemolytic anemia, destructive thrombocytopenia and organ dysfunction caused by microvascular platelet thrombi. Recently, it has been shown that von Willebrand factor (VWF) cleaving-protease, termed ADAMTS13 is a critical marker to differentiate types of TMA.
Thus, in this study we have analyzed ADAMTS13 in patients with TMA, and the results are the followings :
1)The autoantibodies to ADAMTS13 in patients with acquired TTP bind to the cysteine-rich/spacer domains of ADAMTS13 and inhibit its enzymatic activity.
2)Minimal region cleaved by ADAMTS13 consists of 73 amino acid residues from D1596 to R1668 of VWF-A2 domain.
3)We have measured ADAMTS13 activity in a total of 643 patients with TMA, collected across Japan.
4)We have identified the ADAMTS13 gene mutations in 7 Japanese pa
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tients with Upshaw-Schulman syndrome.
5)We have found the mechanism of thrombocytopenia associated with intravascular lymohoma as a deficiency of ADAMTS13 with its inhibitor.
6)The local expression of placental ecto-NTPDase in injured arteries of mice prevented arterial thrombosis.
7)We have reported a patient with HCV-liver cirrhosis having the same type of inhibitor to ADAMTS13 as acquired TTP.
8)We have identified that ADAMTS13 localized exclusively in hepatic stellate cells (Itoh cells).
9)We have reported a case with refractory relapsing TTP successfully treated with rituximab, a chimeric monoclonal antibody against CD20.
10)We have demonstrated that enhanced production of unusually large-VWF multimers (UL-VWF) and decreased ADAMTS13 activity may contribute to the development of multiorgan failure in patients with alcoholic hepatitis.
11)We have found that the recipients of living-donor related liver transplantation have decreased ADAMTS13 activity and presence of UL-VWFM, together with thrombocytopenia, soon after transplantation. This finding provided a novel EBM for blood transfusions in those patients ; contraindication of preventive platelet transfusions and effective supplementation of ADAMTS13 with infusions of fresh frozen plasma. Less
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[Journal Article] Localization of ADAMTS13 to the stellate cells of human liver.2005
Author(s)
Uemura M, Tatsumi K, Matsumoto M, Fujimoto M, Matsuyama T, Ishikawa M, Iwamoto T, Mon T, Wanaka A, Fukui H, Fujimura Y.
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Journal Title
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome.2004
Author(s)
Matsumoto M, Kokame K, Soejima K, Miura M, Hayashi S, Fujii Y, Iwai A, Ito E, Tsuji Y, Takeda-Shitaka M, Iwadate M, Umeyama H, Yagi H, Ishizashi H, Banno F, Nakagaki T, Miyata T, Fujimura Y.
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Journal Title
Blood 103
Pages: 1305-1310
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Identification of novel mutations in ADAMTS13 in an adult patient with congenital thrombotic thrombocytopenic purpura.2004
Author(s)
Uchida T, Wada H, Mizutani M, Iwashita M, Ishihara H, Shibano T, Suzuki M, Matsubara Y, Soejima K, Matsumoto M, Fujimura Y, Ikeda Y, Murata M.
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Journal Title
Blood 104
Pages: 2081-2083
Description
「研究成果報告書概要(欧文)」より
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