PB0152 - The spectrum of FVIII-specific antibodies in persons with hemophilia A: a cross-sectional nationwide population study

Sunday, June 25, 2023

18:30 – 19:30 ET

Room: Exhibition

Presenting Author(s)

Ilja Oomen, MD (she/her/hers)

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

Co-Author(s)

Marieke Verhagen, MD

PhD student, MD
Department of Hematology, Radboud University Medical Center, Nijmegen, the Netherlands. Hemophilia Treatment Center Nijmegen-Eindhoven-Maastricht, Nijmegen, the Netherlands. Laboratory of hematology, Radboud university medical center, Nijmegen, the Netherlands
Nijmegen, Gelderland, Netherlands
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
PK

Paul Kaijen

Analyst
Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory, Amsterdam, The Netherlands
Amsterdam, Noord-Holland, Netherlands
SH

Shermarke Hassan

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

Daniëlle Meijer

Clinical chemist
Department of Laboratory Medicine, Laboratory of Hematology, Radboud university medical center, Nijmegen, the Netherlands
Nijmegen, Gelderland, Netherlands
Sanna R. Rijpma, PhD

Clinical chemist
Department of Laboratory Medicine, Laboratory of Hematology, Radboud university medical center, Nijmegen, the Netherlands
Radboud, Gelderland, Netherlands
HS

Helmut Schweiger

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

Karin Fijnvandraat

Professor
Amsterdam UMC, University of Amsterdam, Emma Children’s Hospital, Pediatric Hematology Amsterdam, Netherlands
Amsterdam, Noord-Holland, Netherlands
JV

Jan Voorberg

Professor, Principal investigator
Department of Molecular Hematology, Sanquin Research and Landsteiner Laboratory
Amsterdam, Noord-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
Samantha Gouw, MD, PhD (she/her/hers)

Pediatric Hematologist
The University of Amsterdam
Amsterdam, Noord-Holland, Netherlands

Background: It is known that anti-factor VIII (FVIII) antibodies may have neutralizing as well as non-neutralizing characteristics. We hypothesize that FVIII-binding antibodies form a spectrum consisting of non-neutralizing antibodies (NNA), low-titer neutralizing antibodies below the detection limit of the widely used Nijmegen Bethesda assay (NBA), and low and high responding inhibitors detectable with the NBA (figure 1).

Aims: We aim to assess the prevalence and characteristics of FVIII-specific antibodies in an unselected cross-sectional cohort of persons with hemophilia A.

Methods: All persons with hemophilia A (mild/moderate/severe) who participated in the nationwide multicenter Hemophilia in the Netherlands-6 study with an available plasma sample were included. Presence of FVIII-binding antibodies of immunoglobulin (Ig) A, M, and G isotypes and IgG subclasses, and titers were assessed using direct-binding ELISAs. FVIII-specificity was assessed using a competition-based ELISA approach. Presence of low-titer neutralizing antibodies below the detection limit of the NBA was assessed using the novel Nijmegen ultra-sensitive Bethesda assay (NusBA), with detection limit of ≥0.1 Nijmegen ultra-sensitive Bethesda units (NusBU/mL). The NBA was used as described earlier.

Results: In total, 788 persons with congenital hemophilia A were included (336 (42.6%) mild, 123 (15.6%) moderate, 329 (41.8%) severe). FVIII-specific antibodies were detected in 158 (20.1%) persons. IgG1 was the most abundant antibody, present in 95 (12.1%) individuals. Highest titer levels were found for IgG1 and IgG4. As hypothesized a spectrum of FVIII-specific antibodies was present in our population: 621 (78.8%) persons with no detectable FVIII-specific antibodies, 137 (17.4%) with FVIII-specific NNA, 4 (0.5%) with low-titer neutralizing antibodies measured by NusBA, 3 (0.4%) with low-titer inhibitors or inhibitors (NBA data pending), and 5 (0.6%) with Nijmegen Bethesda positive inhibitors (figure 2).

Conclusion(s): This cross-sectional nationwide cohort study reveals the full spectrum of FVIII-specific NNA, low-titer inhibitory antibodies and inhibitors, in a cohort of 788 persons with hemophilia of all severities.