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Fatal thrombosis of antithrombin deficient mice is rescued differently in the heart and liver by intercrossing with low tissue factor mice

Research Project

Project/Area Number 16590933
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionNagoya University

Principal Investigator

MATSUSHITA Tadashi  Nagoya Univ., University Hospital, Assistant Professor, 医学部附属病院, 講師 (30314008)

Co-Investigator(Kenkyū-buntansha) KIYOI Hitoshi  Nagoya University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (90314004)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥1,800,000 (Direct Cost: ¥1,800,000)
KeywordsAntithrombin / Tissue factor / Genetically altered mice / portal vein / coronary artery / transgenic muse / thrombosis / hemostasis / 組織因子 / ノックアウトマウス / アンチトロンビン / 血栓症 / 凝固異常症
Research Abstract

We previously reported that targeted disruption of murine antithrombin (AT) gene resulted in embryonic lethality before 16.5gd because of severe cardiac and hepatic thrombosis. To investigate influences of lowered tissue factor (TF) activity upon hypercoagulation of AT^<-/-> embryos, we crossed AT^<+/-> with low TF (mTF^<-/->hTF^+) mice to yield homozygous AT deficient mice with extremely low TF activity, that is expressed from the inserted human TF mini gene. AT^<-/-> embryos either with 50% TF (AT^<-/->mTF^<+/->hTF^+) or with low (〜1% TF, AT^<-/->mTF^<-/->hTF^+) were not born, although the survival was prolonged until 18.5gd. In both genotypes, histological examination showed disseminated thrombosis in hepatic sinusoidal space or in the portal veins, suggesting that thrombogenesis caused loss of hepatic blood flow. As in original AT^<-/->, AT^<-/->mTF^<+/->hTF^+ showed subcutaneous bleeding and also suffered from myocardial degeneration apparently due to coronary thrombus formation. However, AT^<-/->mTF^<-/->hTF^+ had no skin hemorrhage and the thrombosis and degeneration was completely abolished in the heart. Myocardium of adult low TF mice had exhibited fibrosis secondary to hemorrhage, however, it was significantly decreased in low TF mice with AT^<+/->. Our current model suggest that in the heart, TF plays an important role in the thrombogenesis and it counterbalances AT-dependent anticoagulation. AT may be a potent anticoagulant during mice development and the activation and subsequent regulation of TF-procoagulant activity take place differently between the liver and the heart. These differences appear to point to local regulatory mechanisms in murine hemostasis.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (21 results)

All 2006 2005 2004

All Journal Article (19 results) Book (2 results)

  • [Journal Article] Fatal thrombosis of antithrombin-deficient mice is rescued differently in the heart and liver by intercrossing with low tissue factor mice2006

    • Author(s)
      Hayashi M
    • Journal Title

      Journal of Thrombosis and Haemostasis 4

      Pages: 177-185

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Identification of amino acid residues essential for heparin binding by the A1 domain of human von Willebrand factor2006

    • Author(s)
      Adachi T
    • Journal Title

      Biochem Biophys Res Commun 339

      Pages: 1178-83

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] 急性白血病治療時の出血対策2006

    • Author(s)
      松下 正
    • Journal Title

      最新医学 別冊 36

      Pages: 197-209

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] 貧血・血小板低下・DICとその対策2006

    • Author(s)
      松下 正
    • Journal Title

      癌の臨床 51

      Pages: 1-8

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] 貧血・血小板低下・DICとその対策2006

    • Author(s)
      松下 正
    • Journal Title

      癌と化学療法 33

      Pages: 6-12

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Management of bleeding after chemotherapy of acute leukemia2006

    • Author(s)
      Matsushita T
    • Journal Title

      Saishin Igaku (suppl) 36

      Pages: 197-209

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] General strategy towards anemia, thrombocytopenia, and DIC in cancer patients2006

    • Author(s)
      Matsushita T
    • Journal Title

      Gan No Rinsho 51

      Pages: 1-8

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Approaches to anemia, thrombocytopenia, and DIC in cancer patients2006

    • Author(s)
      Matsushita T
    • Journal Title

      Gan To Kagaku Ryoho 33

      Pages: 6-12

    • NAID

      40015383675

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Tissue factor2006

    • Author(s)
      Matsushita T
    • Journal Title

      Miwa's Hematology 3rd edition (bunkodo)

      Pages: 2140-2140

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] 凝固制御因子ノックアウトマウス2005

    • Author(s)
      松下 正
    • Journal Title

      別冊・医学の歩み 血液疾患state of arts ver.3

      Pages: 338-342

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] Targeting of genes of coagulation regulation factors2005

    • Author(s)
      Matsushita T
    • Journal Title

      Igaku-no-ayumi state-of-arts of hematologic disorders ver.3. Tokyo

      Pages: 338-3442

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Detection of unique neutrophil non-muscle myosin heavy chain-A localization by immunofluorescence analysis in MYH9 disorder presented with macrothrombocytopenia without leukocyte inclusions and deafness2005

    • Author(s)
      Kunishima S
    • Journal Title

      Eur J Haematol 74

      Pages: 1-5

    • Related Report
      2004 Annual Research Report
  • [Journal Article] First description of somatic mosaicism in MYH9 disorders2005

    • Author(s)
      Kunishima S
    • Journal Title

      Br J Haematol in press

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Targeted disruption of mouse ortholog of the human MYH9 responsible for macrothrombocytopenia with different organ involvement : hematological, nephrological, and otological studies of heterozygous KO mice2004

    • Author(s)
      Matushita T
    • Journal Title

      Biochem Biophys Res Commun 325

      Pages: 1163-1171

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Identification of the Amino Acid Residues of the Platelet Glocoprotein Ib(GPIb) Essential for the von Willebrand Factor Binding by Clustered Charged-to-Alanine Scanning Mutagenesis2004

    • Author(s)
      Shimizu A
    • Journal Title

      J Biol Chem 279

      Pages: 16285-94

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Targeted disruption of mouse ortholog of the human MYH9 responsible for macrothrombocytopenia with different organ involvement : hematological, nephrological, and otological studies of heterozygous KO mice2004

    • Author(s)
      Matsushita T
    • Journal Title

      Biochemical and Biophysical Research Communications 325

      Pages: 1163-1171

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Identification of the Amino Acid Residues of the Platelet Glycoprotein Ib (GPIb) Essential for the von Willebrand Factor Binding by Clustered Charged-to-Alanine Scanning Mutagenesis2004

    • Author(s)
      Shimizu A
    • Journal Title

      J Biol Chem 279

      Pages: 16285-16294

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Targeted disruption of mouse ortholog of the human MYH9 responsible for macrothrombocytopenia with different organ involvement : hematological, nephrological, and2004

    • Author(s)
      Matsushita T
    • Journal Title

      Biochemical and Biophysical Research Communications 325

      Pages: 1163-1171

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Identification of protein Salpha gene mutations including four novel mutationsin eight unrelated patients with protein S deficiency2004

    • Author(s)
      Okada H
    • Journal Title

      Br J Haematol 126(2)

      Pages: 219-225

    • Related Report
      2004 Annual Research Report
  • [Book] 組織因子 三輪血液病学2006

    • Author(s)
      松下 正
    • Total Pages
      2140
    • Publisher
      文光堂
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] 三輪 血液病学2006

    • Author(s)
      松下 正
    • Publisher
      組織因子
    • Related Report
      2005 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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