Key discovery could prevent treatment failure in people with severe hemophilia A

Recently, a team of researchers achieved a crucial discovery that could mitigate and eliminate immune responses causing treatment failure in almost one-third of people with acute hemophilia A.

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Hemophilia is the most prevalent acute congenital bleeding disorder found in men. The disease impacts 1 in 10,000 males across the world and is caused by the deficiency of blood clotting factor VIII or FVIII. The treatment for both adults and children suffering from hemophilia A (80% of all hemophilia) is the infusion of FVIII protein into the bloodstream.

But nearly 30% of the patients tend to develop an immune response in the form of antibodies to FVIII, or inhibitors. This makes the treatment ineffective and increases the risk of mortality.

Options for immune tolerance induction (ITI) in inhibitor-positive patients are invasive, inadequate, and expensive. As part of an NIH-funded U54 initiative, scientists from Indiana University School of Medicine, Children’s Hospital of Philadelphia, and the University of Pennsylvania collaborated to examine immune responses to FVIII.

Headed by Moanaro Biswas, Ph.D., from IU School of Medicine and Valder R. Arruda, MD, Ph.D., from Children’s Hospital of Philadelphia and the University of Pennsylvania, the study is titled “B cell-activating factor modulates the factor VIII immune response in hemophilia.” It was recently published in the Journal of Clinical Investigation. The first author of the study is Bhavya Doshi, MD, from Children’s Hospital of Philadelphia.

As part of the study, the researchers used plasma samples from adult and pediatric hemophilia A patients as well as animal models to find whether BAFF plays a role in the creation and maintenance of FVIII inhibitors.

The team also attempted to combine the antibody to BAFF with a CD20 antibody (rituximab) as part of an ITI approach. In earlier studies on hemophilia A, only rituximab has exhibited combined results in eliminating inhibitors when used alone.

Given below are the key findings of the study:

• The levels of BAFF in plasma are elevated in both adult and pediatric hemophilia A patients presenting persistent FVIII inhibitors. These levels also correlate with FVIII antibody titers, which indicates that BAFF could be a promising precursor to an ongoing humoral immune response to FVIII.
• An elevation in the levels of BAFF following rituximab-based therapy precludes tolerance to FVIII.
• Inhibition of BAFF proves effective in preventing FVIII inhibitors in an animal model of hemophilia A.
• Combination CD20/BAFF monoclonal antibody therapy stimulates tolerance in a hemophilia A animal model with standard FVIII inhibitors. This is because of a collective impact of the combination therapy on plasma cells and memory B cells.

In the future, the team will conduct detailed mechanistic investigations to find more BAFF modifiers, which might offer further insights into the pathways that cause BAFF elevation and inhibitor formation.

This information also has a significant translational capability for inhibitors in hemophilia A. This is because there is an FDA-approved anti-BAFF antibody that is being used now as part of immunosuppressive regimens for autoimmune diseases.