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Recombinant porcine factor VIII corrects thrombin generation in vitro in plasma from patients with congenital hemophilia A and inhibitors

BACKGROUND: Neutralizing factor VIII (FVIII) antibodies are a major complication in hemophilia A. Antihemophilic factor VIII (recombinant), porcine sequence (rpFVIII; susoctocog alfa; Baxalta US Inc., a Takeda company) has low cross‐reactivity to anti‐human FVIII antibodies and can provide functiona...

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Detalles Bibliográficos
Autores principales: Négrier, Claude, Oldenburg, Johannes, Kenet, Gili, Meeks, Shannon L., Bordet, Jean‐Claude, Müller, Jens, Le Quellec, Sandra, Turecek, Peter L., Tripkovic, Nikola, Dargaud, Yesim
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9207117/
https://www.ncbi.nlm.nih.gov/pubmed/35765670
http://dx.doi.org/10.1002/rth2.12731
Descripción
Sumario:BACKGROUND: Neutralizing factor VIII (FVIII) antibodies are a major complication in hemophilia A. Antihemophilic factor VIII (recombinant), porcine sequence (rpFVIII; susoctocog alfa; Baxalta US Inc., a Takeda company) has low cross‐reactivity to anti‐human FVIII antibodies and can provide functional FVIII activity in the presence of FVIII inhibitors. OBJECTIVES: Evaluate in vitro thrombin generation and clot formation responses to rpFVIII in blood from patients with congenital hemophilia A. METHODS: In this multicenter study, blood was obtained for in vitro analyses that included human and porcine FVIII inhibitors, low <5 Bethesda units (BU)/ml or high ≥5 BU/ml titer (Nijmegen‐modified Bethesda assay); thrombin generation assay (TGA), clot viscoelasticity (thromboelastography), fibrin clot structure analysis (scanning electron microscopy), and epitope mapping. RESULTS: Blood samples were from 20 patients with congenital hemophilia A (FVIII activity <1%, mean [range] inhibitor titers: anti‐human FVIII, 14 [1–427] BU/ml [n = 13 high, n = 6 low, n = 1 data unavailable]); anti‐porcine FVIII, 12 (0–886) BU/ml (n = 11 high, n = 8 low, n = 1 data unavailable). Porcine inhibitor titer and TGA response measured by endogenous thrombin potential showed an inverse correlation (2.7–10.8 U/ml rpFVIII Spearman correlation coefficient: −0.594 to −0.773; p < 0.01). Clot structures in low anti‐porcine inhibitor titer plasmas were similar to those in noninhibitor plasma. CONCLUSIONS: Recombinant porcine factor VIII demonstrated a dose‐dependent correction of thrombin generation and clot formation in vitro, dependent on the anti‐porcine FVIII inhibitor titer. Procoagulant responses to rpFVIII occurred in plasma containing FVIII inhibitors.