Journal of thrombosis and haemostasis : JTH · 2024
Concizumab improves clot formation in hemophilia A under flow.
СтатьяПоддержка NIH: внешняя программаНазвание и аннотация: Перевод пока не подготовлен
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Jewell Megan P, Ashour Zaina, Baird Christine H, Manco Johnson Marilyn, Warren Beth Boulden, Wufsus Adam R, Pallini Chiara, Dockal Michael, Kjalke Marianne, Neeves Keith B
Аннотация
BACKGROUND: Inhibition of tissue factor pathway inhibitor (TFPI) is an emerging therapeutic strategy for treatment of hemophilia. Concizumab is a monoclonal antibody that binds TFPI and blocks its inhibition of factor (F)Xa thereby extending the initiation of coagulation and compensating for lack of FVIII or FIX.
OBJECTIVES: The objective of this in vitro study was to evaluate how concizumab affects clot formation in hemophilia A under flow.
METHODS: Blood was collected from normal controls or people with hemophilia A. An anti-FVIII antibody was added to normal controls to simulate hemophilia A with inhibitory antibodies to FVIII. Whole blood and recombinant activated FVII (rFVIIa, 25 nM) or concizumab (200, 1000, and 4000 ng/mL) were perfused at 100 s-1 over a surface micropatterned with tissue factor (TF) and collagen-related peptide. Platelet and fibrin(ogen) accumulation were measured by confocal microscopy. Static thrombin generation in plasma was measured in response to rFVIIa and concizumab.
RESULTS: Concizumab (1000 and 4000 ng/mL) and rFVIIa both rescued (93%-101%) total platelet accumulation, but only partially rescued (53%-63%) fibrin(ogen) incorporation to normal control levels in simulated hemophilia A. Results using congenital hemophilia A blood confirmed effects of rFVIIa and concizumab. While these 2 agents had similar effect on clot formation under flow, concizumab enhanced thrombin generation in plasma under static conditions to a greater extent than rFVIIa.
CONCLUSION: TFPI inhibition by concizumab enhanced activation and aggregation of platelets and fibrin clot formation in hemophilia A to levels comparable with that of rFVIIa.
OBJECTIVES: The objective of this in vitro study was to evaluate how concizumab affects clot formation in hemophilia A under flow.
METHODS: Blood was collected from normal controls or people with hemophilia A. An anti-FVIII antibody was added to normal controls to simulate hemophilia A with inhibitory antibodies to FVIII. Whole blood and recombinant activated FVII (rFVIIa, 25 nM) or concizumab (200, 1000, and 4000 ng/mL) were perfused at 100 s-1 over a surface micropatterned with tissue factor (TF) and collagen-related peptide. Platelet and fibrin(ogen) accumulation were measured by confocal microscopy. Static thrombin generation in plasma was measured in response to rFVIIa and concizumab.
RESULTS: Concizumab (1000 and 4000 ng/mL) and rFVIIa both rescued (93%-101%) total platelet accumulation, but only partially rescued (53%-63%) fibrin(ogen) incorporation to normal control levels in simulated hemophilia A. Results using congenital hemophilia A blood confirmed effects of rFVIIa and concizumab. While these 2 agents had similar effect on clot formation under flow, concizumab enhanced thrombin generation in plasma under static conditions to a greater extent than rFVIIa.
CONCLUSION: TFPI inhibition by concizumab enhanced activation and aggregation of platelets and fibrin clot formation in hemophilia A to levels comparable with that of rFVIIa.