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Emicizumab-mediated haemostatic function in patients with haemophilia A is down-regulated by activated protein C through inactivation of activated factor V.
Yada, Koji; Nogami, Keiji; Shinozawa, Keiko; Kitazawa, Takehisa; Hattori, Kunihiro; Amano, Kagehiro; Fukutake, Katsuyuki; Shima, Midori.
Afiliação
  • Yada K; Department of Paediatrics, Nara Medical University, Kashihara, Japan.
  • Nogami K; Department of Paediatrics, Nara Medical University, Kashihara, Japan.
  • Shinozawa K; Department of Molecular Genetics of Coagulation Disorders, Tokyo Medical University, Tokyo, Japan.
  • Kitazawa T; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
  • Hattori K; Research Division, Chugai Pharmaceutical Co., Ltd., Kamakura, Japan.
  • Amano K; Department of Molecular Genetics of Coagulation Disorders, Tokyo Medical University, Tokyo, Japan.
  • Fukutake K; Laboratory Medicine, Tokyo Medical University, Tokyo, Japan.
  • Shima M; Department of Molecular Genetics of Coagulation Disorders, Tokyo Medical University, Tokyo, Japan.
Br J Haematol ; 183(2): 257-266, 2018 10.
Article em En | MEDLINE | ID: mdl-30125997
Activated protein C (APC) inactivates activated factor V (FVa) and moderates FVIIIa by restricting FV cofactor function. Emicizumab is a humanized anti-FIXa/FX bispecific monoclonal antibody that mimicks FVIIIa cofactor function. In recent clinical trials in haemophilia A patients, once-weekly subcutaneous administration of emicizumab was remarkably effective in preventing bleeding events, but the mechanisms controlling the regulation of emicizumab-mediated haemostasis remain to be explored. We investigated the role of APC-mediated reactions in these circumstances. APC dose-dependently depressed thrombin generation (TG) initiated by emicizumab in FVIII-deficient plasmas, and in normal plasmas preincubated with an anti-FVIII antibody (FVIII-depleted). FVIIIa-independent FXa generation with emicizumab was not affected by the presence of APC, protein S and FV. The results suggested that APC-induced down-regulation of emicizumab-dependent TG was accomplished by direct inactivation of FVa. The addition of APC to emicizumab mixed with FVIII-depleted FV-deficient plasma in the presence of various concentrations of exogenous FV demonstrated similar attenuation of TG, irrespective of specific FV concentrations. Emicizumab-related TG in FVIII-depleted FVLeiden plasma was decreased by APC more than that observed with native FVLeiden plasma. The findings indicated that emicizumab-driven haemostasis was down regulated by APC-mediated FVa inactivation in plasma from haemophilia A patients without or with FV defects.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína C / Hemostáticos / Anticorpos Biespecíficos / Anticorpos Monoclonais Humanizados / Hemofilia A / Hemostasia Limite: Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteína C / Hemostáticos / Anticorpos Biespecíficos / Anticorpos Monoclonais Humanizados / Hemofilia A / Hemostasia Limite: Humans Idioma: En Ano de publicação: 2018 Tipo de documento: Article