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Molecular pathology of novel two variants of antithrombin III

Research Project

Project/Area Number 04671529
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Hematology
Research InstitutionKumamoto University

Principal Investigator

OKAJIMA Kenji  Kumamoto Univ.Med.Sch., Lecturer, 医学部, 講師 (60152295)

Co-Investigator(Kenkyū-buntansha) SAKATA Kenmei  Kumamoto Univ.Hospital, Assistant professor, 医学部・附属病院, 助手 (60225795)
Project Period (FY) 1992 – 1993
Project Status Completed (Fiscal Year 1993)
Budget Amount *help
¥2,100,000 (Direct Cost: ¥2,100,000)
Fiscal Year 1993: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1992: ¥1,400,000 (Direct Cost: ¥1,400,000)
KeywordsAntithrombin III / Congenital prethrombotic state / Thrombosis / Heparin / Gene analysis
Research Abstract

To know the molecular mechanism by which antitrhombin III (AT III) regulates the coagulation cascade, we analyzed the fnction and structure of two novel variant antithrombin III molecules found in patients with thrombosis. A variant AT III found in the first case bound heaprin normally, but it did not inhibit thrombin as the normal AT III.Analysis of the whole base sequence of the propositus' AT III gene revealed a Arg393-His conversion and that the propsitus was a heterozygote for the abnormality. Purified abnormal AT III did not inhibit thrombin and the affinity for heparin was increased, suggesting that Arg393-His conversion might affect the affnity for heparin. A variant AT III found in the second case did not bind heaprin, but it inhibited thrombin normally. Whole base sequence analysis of the AT III gene disclosed a Ser116-Pro conversion. Alle-specific oligonucleotide hybridization demonstrated that the propositus was a heterozygote and the same mutation was found in his father's AT III gene. Such a substitution was first demonstrated among variants AT III so far reported. Although thrombosis was not associated with a heterozygous state for heparin binding defect in most cases, the propositus suffered from recurrent arterial thrombosis probably due to his heavy smoking habit. Thus, a heterozygous state for heparin binding defect would lead to a predisposition to thrombosis when associated with risk factors for thrombosis.

Report

(2 results)
  • 1993 Annual Research Report   Final Research Report Summary
  • Research Products

    (20 results)

All Other

All Publications (20 results)

  • [Publications] Yoshimura,T.: "Recurrent thromboembolism in a patient with antithrombin III deficiency despite prophyractic Administration of ATIII during labor" Int.J.Feto-Maternal Med.4. 241-244 (1991)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Arima,T.: "Cerebral infarction in a heterozygote with variant antithrombin III" Stroke. 23. 1822-1825 (1992)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Okajima,K.: "Antithrombin III“Nagasaki"(Ser116-Pro):a heterozygous variant with defective heparin binding associated with thrombosis." Blood. 81. 1300-1305 (1993)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Okajima,K.: "Direct evidence for systemic fibrinogenolysis in patients with acguired α_2-plasmin inhibitor deficiency" American Journal of Hematology. 45. 16-24 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Abe,H.: "Granulocyte proteases and hydrogen peroxide synergistically inactivate thrombomodulin of endothelial cells in vitro" Journal of Laboratory and Clinical Medicine. (発表予定). (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Uchiba,M.: "Effect of Nafamostat Mosilate on the activity of extrinsic pathway of coagulation" Thrombosis Research. (発表予定). (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] 阿部弘樹: "検査血液学-血液疾患の遺伝子検査:血液凝固" 臨床病理刊行会(発表予定), (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Yoshimura, T.et al.: "Recurrent thromboembolism in a petient with antithrombin III deficiency despite prophyractic antithrombin III administration during labor and early puerperium." Int.J.Feto-Maternal Med.4. 241-244 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Arima, T.et al.: "Cerebral infarction in a heterozygote with variant antithrombin III" Stroke. 23. 1822-1825 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Okajima, K.et al.: "Antithrombin III "Nagasaki" (Ser116-Pro) : a heterozygote variant with defective heparin binding associated with thrombosis" Blood. 81. 1300-1305 (1993)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Okajima, K.et al.: "Direct evidence for systemic fibrino-genolysis in patients with acquired alpha-2-plasmin inhibitor deficiency." Am.J.Hematol. 45. 16-24 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Abe, H.et al.: "Granulocyte proteases and hydrogen peroxide synergistically inactivate thrombomodulin of endothelial cells in vitro." J.Lab.Clin.Med.in press. (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Uchiba, M.et al.: "Effect of Nafamostat Mesilate on the activity of extrinsic pathway of coagulation" Thromb.Res.in press. (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1993 Final Research Report Summary
  • [Publications] Arima,T.: "Cerebrad infarction in a heterozygote with variant AT III" Stroke. 23. 1822-1825 (1992)

    • Related Report
      1993 Annual Research Report
  • [Publications] Okajima,K.: "Antithrombin III Nagasaki (Ser116-Pro):A heterozygous variant with defective heparin binding" Blood. 81. 1300-1305 (1993)

    • Related Report
      1993 Annual Research Report
  • [Publications] Okajima,K.: "Direct evidence for systemic fibrinogenolysis in a patient with motastatic prostatic cancer" Thromb.Res.66. 717-727 (1992)

    • Related Report
      1993 Annual Research Report
  • [Publications] Okajima,K.: "Direct evidence for systemic fibrinogenolysis in patients with acquired alpha-2-antiplasmin deficiency." Am.J.Hematol.45. 16-24 (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Abe,H.: "Granulocyte proteases and hydrogen peroxide synergistically inactivate thrombomodulin" J.Lab.Clin.Med.(in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] Uchiba,M.: "Effect of nafamostat mesilate,a synthetic protease inhibitor,on tissue factor-VIIa complex activity" Thromb.Res.(in press). (1994)

    • Related Report
      1993 Annual Research Report
  • [Publications] 阿部弘樹: "検査血液学-血液疾患の遺伝子検査:血液凝固" 臨床病理刊行会、(印刷中), (1994)

    • Related Report
      1993 Annual Research Report

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Published: 1992-04-01   Modified: 2016-04-21  

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