OC 47.2 - Prevalence and characteristics of non-neutralizing FVIII-specific antibodies in persons with hemophilia A – preliminary results

Monday, July 11, 2022

3:00 PM – 3:15 PM

Location: ExCel Center, ICC Capital Suite Room 2-4

Presentation Format: In-Person

Presenting Author(s)

Ilja Oomen, MD

PhD student, MD
Amsterdam UMC location University of Amsterdam, Department of Pediatric Hematology, Meibergdreef 9, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands

Co-Author(s)

Mariarosaria Miranda, MA

PhD student
Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
PA

Peter Allacher

Head of Operations
Institute Krems Bioanalytics, IMC University of Applied Sciences Krems, Krems, Austria
Krems, Oberosterreich, Austria
EB

Erik A.M. Beckers

Head of Haematology
Department of Hematology, Maastricht University Medical Center + and Maastricht University, Maastricht, The Netherlands
Maastricht, Limburg, Netherlands
Michiel Coppens, MD, PhD

Medical Specialist
Department of Vascular Medicine, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
MD

Mariëtte Driessens

Dutch Association of Hemophilia Patients
Dutch Association of Hemophilia Patients
Leiden, Zuid-Holland, Netherlands
JE

Jeroen C.J. Eikenboom

Professor, Internist, Head of Div. T&H
Department of Internal Medicine, Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
KF

Karin Fijnvandraat

Professor of Pediatric Hematology
Department of Pediatric Hematology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
Amsterdam, Noord-Holland, Netherlands
SH

Shermarke Hassan

Post-doc
Centre for Tropical Medicine and Global Health
Oxfort, England, United Kingdom
LH

Louise Hooijmeijer

Hematologist
Division of Hematology/Oncology, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
Groningen, Groningen, Netherlands
PK

Paul Kaijen

Analyst
Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
Frank W.G. Leebeek, MD, PhD

Professor and Head of Department of Hematology
Erasmus MC, University Medical Center Rotterdam, The Netherlands
Rotterdam, Zuid-Holland, Netherlands
FR

Frits R. R. Rosendaal

Professor
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
Leiden, Zuid-Holland, Netherlands
SS

Saskia E.M. Schols

Internist-hematologist
Department of Hematology, Radboud university medical center, Nijmegen, The Netherlands. Hemophilia Treatment Center Nijmegen – Eindhoven – Maastricht, The Netherlands
Nijmegen, Gelderland, Netherlands
HS

Helmut Schweiger

Group Lead
Institute Krems Bioanalytics, IMC University of Applied Sciences Krems, Krems, Austria
Krems, Oberosterreich, Austria
CS

Cees Smit

Patient advocate
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands
Leiden, Zuid-Holland, Netherlands
Lv

Lize F.D. van Vulpen

Internist Hematologist
Center for Benign Haematology, Thrombosis and Haemostasis, Van Creveldkliniek, University Medical Center Utrecht, Utrecht University, The Netherlands
Utrecht, Utrecht, Netherlands
Jv

Johanna van der Bom

Professor of Epidemiology
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden University, Leiden, the Netherlands
Leiden, Zuid-Holland, Netherlands
JV

Jan Voorberg

Professor, Principal investigator
Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory
Amsterdam, Noord-Holland, Netherlands
SG

Samantha C. Gouw, MD, PhD

Pediatric Hematologist
Amsterdam UMC, University of Amsterdam, Emma Children’s Hospital, Pediatric Hematology, Meibergdreef 9, Amsterdam, Netherlands; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
Amsterdam, Noord-Holland, Netherlands

Background: Development of neutralizing antibodies (inhibitors) is a major complication of hemophilia A treatment, which renders replacement therapy ineffective and increases susceptibility to major bleeding. Non-neutralizing FVIII-specific antibodies (NNA) that appear to increase clearance of exogenous clotting factors and limit its hemostatic efficacy have been identified recently. We hypothesize that FVIII-binding antibodies form a spectrum from low titer, low affinity NNA and high affinity antibodies with or without neutralizing potential, to inhibitors detectable with the widely used Bethesda assay, depicted in Figure 1. We further hypothesize that a subset of NNA are in fact low-titer inhibitors with titers below the lowest detection limit of the Bethesda assay.

Aims: To assess the prevalence and characteristics of NNA among persons with hemophilia A (PwHA), and to investigate whether these NNA have neutralizing potential.

Methods: PwHA with an available plasma sample were included from the cross-sectional unselected nationwide ‘Hemophilia in the Netherlands’ (HIN) cohort. The NNA prevalence and isotype characteristics (IgA, IgM and IgG subclasses) are assessed in the overall population using a highly sensitive and fully validated ELISA. Samples with confirmed specificity for FVIII will be assessed for apparent affinity with a competition-based ELISA approach. The presence of inhibitors will be assessed using the Nijmegen Bethesda assay and the novel Nijmegen low-titer inhibitor assay.

Results: In total, 801 PwHA were included. 71 patients (8.9%) had a positive Nijmegen low-titer inhibitor assay, of whom 15 (21.1%) had also a positive Nijmegen Bethesda Assay (Figure 2). Results of NNA prevalence and characteristics will be available at the time of the ISTH 2022.

Conclusion(s): This study is the first to describe the full spectrum of anti-FVIII antibodies in an unselected population of PwHA. Improved knowledge of the prevalence and characteristics of NNA will eventually contribute to understanding of differences in pharmacokinetics and potentially identify patients at risk for inhibitor development.