Elucidation of the pathogenesis of thrombosis caused by abnormal prothrombin with thrombomodulin resistance

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K22869
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Kanazawa University
• Principal Investigator: NAGAYA Satomi 金沢大学, 保健学系, 助教 (00882309)
• Project Period (FY): 2020-09-11 – 2022-03-31
• Keywords: 異常プロトロンビン / 血栓傾向 / アンチトロンビン抵抗性 / トロンボモジュリン抵抗性

Outline of Final Research Achievements

Recombinant prothrombin with asymptomatic or thrombophilic mutations among congenital prothrombin abnormalities was produced and evaluated for coagulation activity (clotting time method and chromogenic method) and antithrombin resistance (ATR), an indicator of thrombophilia. ATR was detected in R596L and E509A, which have already been reported to show ATR, and the assay system was confirmed. In the asymptomatic abnormal prothrombin identified by the applicants, R431H had a mild ATR and M380T showed little ATR. We will continue to evaluate ATR using Biacore, detect thrombomodulin resistance (TMR), and elucidate the mechanism by which compound heterozygotes of M380T and R431H become asymptomatic.

Free Research Field

病態検査学

Academic Significance and Societal Importance of the Research Achievements

本研究では、異常プロトロンビンのアンチトロンビン抵抗性 (ATR) に加え、トロンボモジュリン抵抗性 (TMR)による血栓傾向に着目した。申請者らが同定した複合ヘテロ接合体症例は出血も血栓も呈さない無症候性であり、そのメカニズムの解明を試みた。M380TおよびR431Hは凝固活性の低下 (出血傾向)、アンチトロンビン抵抗性 (ATR) は軽度~なし (血栓傾向軽度) と発端者は出血症状を呈しうる結果であり、TMRまたはプロテインCとの結合障害など、ATR以外の血栓傾向を有している可能性が示唆された。これらを解明することで新たな血栓性素因の発見や新規治療薬の開発につながる可能性がある。