Project Summary
The advent of non-factor replacement therapies like the bispecific antibody emicizumab has revolutionized care
for previously untreated patients with hemophilia A as well as those with and without inhibitors (neutralizing anti-
factor VIII (FVIII) antibodies). However, these therapies are only effective as a prophylaxis to prevent bleeding
and do not treat bleeds or provide protection against bleeding during major surgeries, resulting in the continued
need for replacement FVIII therapy. Thus, several critical concerns surrounding the immediate and long-term
management of these patients, and especially those with inhibitors still remain in this new treatment era. It is
recognized that patients can generate different immune responses to FVIII: (1) no antibodies, (2) non-neutralizing
antibodies, (3) transient inhibitors (inhibitors that resolve without the need of therapeutic interventions and
despite continued FVIII treatment), or (4) low or high inhibitor titers that persist or wane to undetectable levels
when FVIII treatment is withdrawn. However, why patients form distinct inhibitor responses remains an enigma.
Our preclinical data suggest that differential inhibitor responses maybe due to the engagement of distinct B cell
pathways of antibody production, with transient or waning inhibitors resulting from the development of an
extrafollicular B cell response to FVIII and persistent inhibitors from a classical germinal center B cell response.
Corroborating this, clinical reports indicate that some patients with hemophilia A fail to generate an anamnestic
response to FVIII and demonstrate a loss of inhibitor titers in the absence of FVIII treatment. As germinal center
B cell responses are responsible for the production of life-long immunity that comes in the form of memory B
cells and long-lived plasma cells, we hypothesize that the B cell response to FVIII in patients with waning
inhibitors occurs through an extrafollicular B cell process, while persistent inhibitors are generated through the
long proposed classical germinal center response. The current proposal is thus focused on gaining a mechanistic
understanding of the extrafollicular B cell response to FVIII in patients with severe hemophilia A, the relationship
between the type of B cell response a patient develops and their inhibitor status, and factors that associate with
the formation of an extrafollicular or germinal B cell response to FVIII by evaluating the immune response to
FVIII in severe hemophilia A patients with a history of inhibitors.