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

• Type of Material: Article
• Authors: Claude Négrier, Hopital Louis Pradel, Universite Lyon1; Johannes Oldenburg, University Clinic Bonn; Gili Kenet, Tel Aviv University; Shannon Meeks, Emory University; Jean-Claude Bordet, Hopital Louis Pradel, Universite Lyon1; Jens Müller, University Clinic Bonn; Sandra Le Quellec, Hopital Louis Pradel, Universite Lyon1; Peter L Turecek, Baxalta Innovations GmbH; Nikola Tripkovic, Takeda Pharmaceuticals International AG; Yesim Dargaud, Hopital Louis Pradel, Universite Lyon1
• Language: English
• Date: 2022-05-01
• Publisher: WILEY
• Publication Version: Final Published Version
• Copyright Statement: © 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).
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1002/rth2.12731
• Title of Journal or Parent Work: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
• Volume: 6
• Issue: 4
• Start Page: e12731
• End Page: e12731
• Keywords: porcine factor VIII; factor VIII inhibitor; SAFETY; OBI-1; SEQUENCE FACTOR-VIII; MANAGEMENT; thrombin; Peripheral Vascular Disease; recombinant; THERAPY; Hematology; Cardiovascular System & Cardiology; Science & Technology; STABILITY; hemophilia A; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

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.