Mechanisms of fibrin polymerization based on analysis for dysfunctional fibrinogen variants

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09009
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Shinshu University
• Principal Investigator: Okumura Nobuo 信州大学, 学術研究院保健学系, 教授 (60252110)
• Co-Investigator(Kenkyū-buntansha): 平 千明 信州大学, 学術研究院保健学系, 助教 (40779310)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: フィブリノゲン / フィブリン重合反応 / aホール / Ca結合部位 / D:D結合能部位 / A:a結合 / B:b結合 / トロンビン

Outline of Final Research Achievements

We analyzed the IgA-λ type M-protein influenced fibrin polymerization. Some of patient's fibrinogen bound to M-protein causes the alteration of fibrin clot formation. We identified the thrombogenic homozygous dysfibrinogememia (BβA68T) and analyzed the fibrin polymerization. The variant's polymerization was improved at the conditions closed to in vivo. Therefore this patient needs to prevent thrombosis but not bleeding complications.Recombinant γΔN319D320 and γD318Y fibrinogen were found to be completely no polymerization by thrombin. The reason was suggested that marked changes in the tertiary structure of the γ-module of variants influenced the the location and/or orientation of the adjacent β-module, which led to impaired “B-b” interactions.

Free Research Field

臨床検査学

Academic Significance and Societal Importance of the Research Achievements

フィブリノゲン(Fbg)機能異常症の原因は先天性と後天性に大別される．M蛋白の存在は後天性異常の原因として高頻度である．今回の研究ではその詳細機序を明らかにした．
先天性異常では、血栓症例と出血症例に大別される．血栓形成性BβAla68ThrホモFbgのFbn転換は生理的条件下では正常に近く出血の危険性は低いと推測した．一方，Fbn転換が欠如し出血の危険があるγΔN319D320の機能解析の結果，残念ながら製剤輸注以外適切な治療薬がないことが明らかになった。
以上，Fbgの機能異常症の原因と症状は患者ごとに違いが大きく，今後も丁寧な診断と詳細な解析が患者QOL改善に役立つと考える．