Hemophilia A treatments may shape children’s immune responses

In a small study, children with hemophilia A had distinct changes in certain immune cells and inflammatory signaling molecules compared with healthy children, and the type of preventive treatment they receive may shape those immune responses in different ways, according to the researchers.

In lab experiments, macrophages — immune cells that help coordinate inflammatory responses and fight infections — generated from blood samples of children receiving replacement therapy that provides the missing clotting factor VIII (FVIII) showed a stronger proinflammatory response than those from children treated with Hemlibra (emicizumab).

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Treatments may shape immune responses

The findings suggest that preventive therapies may do more than control bleeding. By shaping the immune environment in different ways, they could influence how the body responds to FVIII over time, potentially affecting the development of inhibitors — antibodies that mistake infused FVIII for something foreign and block its activity, making treatment less effective.

“Ultimately, this study contributes valuable insights to paediatric [haemophilia A] patients, expanding the understanding necessary to optimize therapeutic strategies while minimizing or preventing adverse effects,” the researchers wrote.

The study, “Myeloid Cell Function and Cytokine Profiles in Paediatric Haemophilia A: Insights From FVIII and Emicizumab Prophylaxis,” was published in the Journal of Cellular and Molecular Medicine.

Hemophilia A is an inherited bleeding disorder caused by a lack of FVIII, a protein needed for normal blood clotting. As a result, people with the condition experience abnormally prolonged or spontaneous bleeding. Standard treatment to prevent bleeds involves regular infusions with FVIII replacement therapy. However, about 30% of children with severe hemophilia A develop inhibitors.

Hemlibra is a bispecific antibody that works by mimicking the function of FVIII rather than replacing it. Initially approved in the U.S. in 2017 for routine preventive treatment in children and adults with hemophilia A who have FVIII inhibitors, the approval was later extended to include patients with hemophilia A without FVIII inhibitors.

Researchers looked at immune effects

Despite these advances, researchers still know relatively little about how FVIII replacement therapy and Hemlibra affect the immune system, particularly in children. Earlier studies suggest that the innate immune system — the body’s first line of defense against infections and other threats — may play a key role in the development or persistence of inhibitors.

“Thus, a better understanding of how these therapies may affect immune cell profiles in children could inform both treatment decisions and broader questions related to immune development in the context of [hemophilia A] management,” the researchers wrote.

To address this gap, researchers in Italy analyzed blood samples from 24 children with hemophilia A receiving preventive treatment, including 16 treated with Hemlibra and eight receiving FVIII replacement therapy. They also included seven children with hemophilia B receiving factor IX replacement therapy as a comparison group, along with healthy children. Some laboratory analyses included different numbers of comparator samples, depending on sample availability and experimental suitability. The hemophilia B group helped distinguish immune changes related to FVIII treatment from those associated with hemophilia itself.

Overall, routine blood counts and most immune cell populations were similar across the study groups, with many of the observed differences likely reflecting age rather than disease or treatment. However, a closer look at myeloid cells — innate immune cells that include monocytes and macrophages — revealed differences between the groups.

Children with hemophilia A showed greater activation of circulating monocytes, which are immune cells that can develop into macrophages, than healthy children. Blood levels of several inflammatory signaling proteins, called cytokines, that are linked to monocyte and macrophage activity were also higher in children with hemophilia A than in healthy children, pointing to a more inflammatory immune environment.

Macrophages showed treatment-linked differences

Because these findings suggested that macrophages could be involved in these immune changes, the researchers generated macrophages from the children’s blood monocytes and studied their responses to FVIII in the lab.

While macrophages from children with hemophilia A and healthy children behaved similarly overall, differences emerged when the researchers compared preventive treatments. Macrophages from children receiving FVIII replacement therapy produced higher levels of inflammatory cytokines than those from children treated with Hemlibra, whether or not they were exposed to FVIII in the lab.

Further analyses suggested that FVIII stimulation shifted macrophages from children with hemophilia A toward a more proinflammatory, or M1-like, state. This proinflammatory profile was most evident in macrophages from children receiving FVIII replacement therapy, which the researchers suggested may reflect repeated exposure to FVIII.

By contrast, macrophages from children treated with Hemlibra showed features of a more immune-regulating profile, possibly because the therapy works without directly exposing the immune system to FVIII.

“Our findings suggest that the type of prophylactic treatment may not only control bleeding but also shape the immune landscape in a way that could impact long-term immunogenicity to FVIII and inhibitor development,” the researchers wrote. They added that a better understanding of these immune changes could help optimize treatment strategies while minimizing unwanted immune responses.