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

Research and practice in thrombosis and haemostasis

Authors: Claude Négrier, Johannes Oldenburg, Gili Kenet, Shannon L Meeks, Jean-Claude Bordet, Jens Müller, Sandra Le Quellec, Peter L Turecek, Nikola Tripkovic, Yesim Dargaud

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 [ = 13 high,  = 6 low,  = 1 data unavailable]); anti-porcine FVIII, 12 (0-886) BU/ml ( = 11 high,  = 8 low,  = 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; < 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.

© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).

PMID: 35765670

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