CHOP-led research study identifies key target in treatment-resistant hemophilia A


Hemophilia A is the most common inherited bleeding disease, affecting 1 in 10,000 men worldwide. The disease is the result of a missing clotting factor known as factor VIII (FVIII), which leads to uncontrolled bleeding episodes, joint disease and an increased risk of death. To control the disease, patients are given infusions of the FVIII protein to replace the missing clotting factor, but for reasons that scientists have not fully understood, about 30% of patients with severe hemophilia A develop antibodies. neutralizers called FVIII inhibitors that prevent treatment from working, which negatively affects disease management.

Some patients resistant to FVIII protein replacement therapy receive immune tolerance induction (ITI), in which high doses of FVIII are given over a period of one to two years to enhance tolerance. However, ITI is demanding on patients and families, and the treatment – both expensive and invasive – is not always effective.

To both uncover the mechanism behind the anti-FVIII immune response and expose a potential target, the researchers explored the possible role of BAFF in the regulation of FVIII inhibitors. Previous studies have shown that high plasma levels of BAFF are implicated in certain autoimmune diseases, as well as in antibody-induced transplant rejection. Using samples from adult and pediatric hemophilia A patients and mouse models with hemophilia A, the researchers explored their hypothesis that BAFF may play a role in the generation and maintenance of anti -FVIII.

The research team, led by CHOP and Indiana University School of Medicine, found that BAFF levels were elevated in pediatric and adult patients resistant to FVIII replacement therapy; after a successful ITI, these BAFF levels decreased to levels similar to those of non-inhibitory patients. In patients for whom ITI failed, BAFF levels remained elevated. Working in mouse models, the researchers found that administering anti-BAFF prophylactic therapy to mice before treatment with FVIII prevented inhibitors. In mice with established inhibitors, researchers found that treating mice with both anti-BAFF and rituximab, a chimeric antibody that depletes mature B cells, significantly reduced titers of FVIII inhibitors. by reducing, at least in part, the FVIII-specific plasma cells.

“Our data suggest that BAFF may regulate the generation and maintenance of FVIII inhibitors, as well as anti-FVIII B cells,” said the co-lead author Valder R. Arruda, MD, PhD, Researcher in the Division of Hematology, CHOP and Director of the NIH-funded Factor VIII Immunogenicity Investigation Center of CHOP. “Since an FDA-approved anti-BAFF antibody is currently used to suppress the immune response in autoimmune diseases, future research should explore the use of this treatment in combination with rituximab for better results. in patients with hemophilia A resistant to FVIII protein replacement therapy. . “

In addition to Bhavya Doshi, MD of the Hematology Division of CHOP and collaborators from Indiana University School of Medicine, the research included contributions from researchers from University of Pennsylvania Perelman School of Medicine, the Center for Bleeding Disorders and Coagulation at Careggi University Hospital, the Aflac Cancer Center and the Blood Disorders Center at Children’s Healthcare in Atlanta, Emory School of medicine, and Tulane University Medicine School.

Doshi BS et al. “The B cell activating factor modulates the factor VIII immune response in hemophilia A,” Clinical investigation journal, April 15, 2021, DOI: 10.1172 / JCI142906

About the Children’s Hospital of Philadelphia cream: Children’s hospital Philadelphia cream was founded in 1855 as the country’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric health professionals, and initiating major research initiatives, the Children’s Hospital has fostered many discoveries that have benefited children around the world. whole. Its pediatric research program is one of the largest in the country. In addition, its unique family-centered care and public service programs have made the 595-bed hospital recognized as a leading advocate for children and adolescents. For more information, visit

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