Antithrombin resistance: a new mechanism of inherited thrombophilia

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  • KOJIMA Tetsuhito
    Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine
  • TAKAGI Akira
    Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine
  • MURATA Moe
    Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine
  • TAKAGI Yuki
    Department of Pathophysiological Laboratory Sciences, Nagoya University Graduate School of Medicine

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Other Title
  • アンチトロンビンレジスタンス
  • アンチトロンビンレジスタンス : 新しい遺伝性血栓性素因
  • アンチトロンビンレジスタンス : アタラシイ イデンセイ ケッセンセイ ソイン
  • ―新しい遺伝性血栓性素因―

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Description

Venous thromboembolism is a multifactorial disease resulting from complex interactions among genetic and environmental factors. To date, numerous genetic defects have been found in families with hereditary thrombophilia, but there may still be many undiscovered causative gene mutations. We investigated a possible causative gene defect in a large Japanese family with inherited thrombophilia, and found a novel missense mutation in the prothrombin gene (p.Arg596Leu) resulting in a variant prothrombin (prothrombin Yukuhashi). The mutant prothrombin had moderately lower activity than wild type prothrombin in clotting assays, but formation of the thrombin-antithrombin (TAT) complex was substantially impaired resulting in prolonged thrombin activity. A thrombin generation assay revealed that the peak activity of the mutant prothrombin was fairly low, but its inactivation was extremely slow in reconstituted plasma. The Leu596 substitution caused a gain-of-function mutation in the prothrombin gene, resulting in resistance to antithrombin and susceptibility to thrombosis. We also showed the effects of the prothrombin Yukuhashi mutation on the thrombomodulin-protein C anticoagulation system, recent development of a laboratory test detecting antithrombin resistance in plasma, and another antithrombin resistant mutation found in other thrombophilia families.

Journal

  • Rinsho Ketsueki

    Rinsho Ketsueki 56 (6), 632-638, 2015

    The Japanese Society of Hematology

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