The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development
| Autor: | Amy D. Shapiro, B. Gangadharan, J. Bowen, Christoph Male, Helmut Schweiger, C. J. Hofbauer, Verena Berg, Elena Santagostino, Michael Recht, Margaret V. Ragni, Janice M. Staber, Deborah L Brown, Jenny Klintman, Shannon L. Meeks, Birgit M. Reipert, Karin Fijnvandraat, Hassan M. Yaish, Jan Blatny, Catherine E. McGuinn, Eric S. Mullins, Vlad C. Radulescu |
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| Přispěvatelé: | Paediatric Haematology, ARD - Amsterdam Reproduction and Development |
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty congenital hereditary and neonatal diseases and abnormalities animal diseases 030204 cardiovascular system & hematology Hemophilia A Immunoglobulin G Hemostatics law.invention Thrombosis and Hemostasis 03 medical and health sciences 0302 clinical medicine Immune system law Internal medicine Fviii inhibitor hemic and lymphatic diseases medicine Humans In patient Prospective Studies Prospective cohort study Hematology Factor VIII biology business.industry 3. Good health 030104 developmental biology Immunology biology.protein Recombinant DNA Antibody business Biomarkers |
| Zdroj: | Blood Adv Blood advances, 4(22), 5785-5796. American Society of Hematology |
| ISSN: | 2473-9529 |
| Popis: | Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products (“true PUPs”) and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development. |
| Databáze: | OpenAIRE |
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