| 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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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2005: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 2004: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | ADAMTS13 / TTP / HUS / UL-VWFM / stellate cell / 肝墨細胞 / VWF |
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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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