臨床検査64巻12号

2020年12月発行

今月の特集1 血栓止血学のトピックス—求められる検査の原点と進化

血友病の抗体医薬療法とそのモニタリング

著者： 野上恵嗣¹

所属機関： ¹奈良県立医科大学小児科

ページ範囲：P.1387 - P.1393

Point

●エミシズマブ（ヘムライブラ^®．以下，本剤）は一方の抗原結合部位に活性型第Ⅸ因子，もう一方に第Ⅹ因子を認識するヒト型bispecific抗体であり，活性型第Ⅷ因子機能を代替する製剤である．

●本剤を定期的に皮下投与することによって，インヒビターの有無に関係なく血友病A患者において著明な出血予防効果を示す．

●本剤は通常の活性化部分トロンボプラスチン時間（aPTT）では正確に止血能を評価することはできない．

●本剤の止血モニタリングには種々の包括的凝固機能検査が臨床応用されてきている．

参考文献

1）Manco-Johnson MJ, Abshire TC, Shapiro AD, et al：Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med　357：535-544，2007

2）Kitazawa T, Igawa T, Sampei Z, et al：A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model. Nat Med　18：1570-1574，2012

3）Shima M, Hanabusa H, Taki M, et al：Factor VIII-Mimetic Function of Humanized Bispecific Antibody in Hemophilia A. N Engl J Med　374：2044-2053，2016

4）Shima M, Hanabusa H, Taki M, et al：Long-term safety and efficacy of emicizumab in a phase 1/2 study in patients with hemophilia A with or without inhibitors. Blood Adv　1：1891-1899，2017

5）Minami H, Nogami K, Soeda T, et al：The factor VIII heavy chain improves emicizumab-tenase assembly to enhance the factor VIII-mimicking cofactor activity. Thromb Res　166：77-79，2018

6）Shimonishi N, Nogami K, Ogiwara K, et al：Emicizumab improves the stability and structure of fibrin clot derived from factor VIII-deficient plasma, similar to the addition of factor VIII. Haemophilia　26：e97-e105，2020

7）Yada K, Nogami K, Shinozawa K, et al：Emicizumab-mediated haemostatic function in patients with haemophilia A is down-regulated by activated protein C through inactivation of activated factor V. Br J Haematol　183：257-266，2018

8）Noguchi-Sasaki M, Soeda T, Ueyama A, et al：Emicizumab, A Bispecific Antibody to Factors IX/IXa and X/Xa, Does Not Interfere with Antithrombin or TFPI Activity In Vitro. TH Open　2：e96-e103，2018

9）Nakajima Y, Nogami K, Yada K, et al：Emicizumab Improves Ex Vivo Clotting Function in Patients with Mild/Moderate Hemophilia A. Thromb Haemost　120：968-976，2020

10）Takeyama M, Nogami K, Matsumoto T, et al：An anti-factor IXa/factor X bispecific antibody, emicizumab, improves ex vivo coagulant potentials in plasma from patients with acquired hemophilia A. J Thromb Haemost　18：825-833，2020

11）Minami H, Nogami K, Yada K, et al：Emicizumab, the bispecific antibody to factors IX/IXa and X/Xa, potentiates coagulation function in factor XI-deficient plasma in vitro. J Thromb Haemost　17：126-137，2019

12）Oldenburg J, Mahlangu JN, Kim B, et al：Emicizumab Prophylaxis in Hemophilia A with Inhibitors. N Engl J Med　377：809-818，2017

13）Mahlangu J, Oldenburg J, Paz-Priel I, et al：Emicizumab Prophylaxis in Patients Who Have Hemophilia A without Inhibitors. N Engl J Med　379：811-822，2018

14）Pipe SW, Shima M, Lehle M, et al：Efficacy, safety, and pharmacokinetics of emicizumab prophylaxis given every 4 weeks in people with haemophilia A (HAVEN 4): a multicentre, open-label, non-randomised phase 3 study. Lancet Haematol　6：e295-e305，2019

15）Young G, Liesner R, Chang T, et al：A multicenter, open-label phase 3 study of emicizumab prophylaxis in children with hemophilia A with inhibitors. Blood　134：2127-2138，2019

16）Shima M, Nogami K, Nagami S, et al：A multicentre, open-label study of emicizumab given every 2 or 4 weeks in children with severe haemophilia A without inhibitors. Haemophilia　25：979-987，2019

17）Nogami K, Soeda T, Matsumoto T, et al：Routine measurements of factor VIII activity and inhibitor titer in the presence of emicizumab utilizing anti-idiotype monoclonal antibodies. J Thromb Haemost　16：1383-1390，2018

18）Muto A, Yoshihashi K, Takeda M, et al：Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A. Blood　124：3165-3171，2014

19）Nogami K, Matsumoto T, Tabuchi Y, et al：Modified clot waveform analysis to measure plasma coagulation potential in the presence of the anti-factor IXa/factor X bispecific antibody emicizumab. J Thromb Haemost　16：1078-1088，2018

20）Furukawa S, Nogami K, Shimonishi N, et al：Prediction of the haemostatic effects of bypassing therapy using comprehensive coagulation assays in emicizumab prophylaxis-treated haemophilia A patients with inhibitors. Br J Haemato, 2020, in press

21）Yada K, Nogami K, Ogiwara K, et al：Global coagulation function assessed by rotational thromboelastometry predicts coagulation-steady state in individual hemophilia A patients receiving emicizumab prophylaxis. Int J Hematol　110：419-430，2019