Additional Information About Hemophilia and Inhibitors

Hemophilia A is a rare X-linked disorder affecting 1:5000 males worldwide. Hemophilia A patients with severe disease have undetectable plasma levels of clotting FVIII. As a result, they are at high risk for hemorrhaging into their muscles, joints, and organ systems and have the potential for significant morbidity and disability. Fortunately, with the widespread use of prophylactic clotting factor replacement therapies, the majority of affected children can now expect to live active lives with few bleeding episodes and a normal life expectancy. However, FVIII replacement therapy is highly immunogenic in 25-30% of the most severely affected patients. Antibodies to FVIII develop at a median age of 15 months, typically following a median of 14 exposures to FVIII. Although inherited and treatment-related risk factors have been identified, models based on these risk factors cannot accurately predict anti-FVIII antibody development in newly diagnosed patients.  

Inhibitor development diminishes or abrogates the effectiveness of therapeutically administered FVIII, and consequently represents the single-most significant obstacle to an excellent quality of life for persons with hemophilia A by substantially increasing their risk of hemorrhage-related morbidity and mortality. Furthermore, current tolerance strategies are only employed once the antibodies have developed, are difficult and costly to administer, are not based in a thorough knowledge of the immunology of FVIII antibody development, and therefore, have unpredictable outcomes. Consequently, the overall cost of care associated with this complication can exceed $700,000 yearly.

Despite significant investigator-initiated NHLBI-funded advances in FVIII biochemistry and characterization of the immune response to this immunogen, gaps in the fundamental knowledge of FVIII biology and triggers of inhibitor development remain. Novel cross-disciplinary collaborations, as well as the application of cutting edge technologies to the mechanistic study of FVIII immunogenicity are therefore critically needed. The intent of this program is the establishment of FVIII Centers that facilitate interactions within and among teams of researchers from diverse scientific fields will catalyze the breakthrough research that will allow physicians to accurately predict risk for neutralizing antibody development among newly diagnosed children with severe hemophilia A; inform approaches to the design and/or delivery of less immunogenic therapeutics with the goal of inhibitor prevention in all affected individuals with hemophilia A; and guide the future safe, rapid, and targeted induction of long-term tolerance in those patients with existing inhibitors.  

The scientific goal of this program is to generate actionable knowledge about the fundamental mechanisms of FVIII inhibitor formation that will rapidly translate into successful strategies for the prevention or elimination of FVIII neutralizing antibodies in patients with hemophilia A. Therefore, scientific programs are to be bold, innovative, and multi-disciplinary, and utilize novel science and cutting edge technologies to advance our scientific knowledge of FVIII immunogenicity. The utilization of new or cutting-edge technologies such as single cell analysis, exosome analysis, genomics, transcriptomics, proteomics, metabolomics, cryo-electron microscopy, in silico modeling, and others was encouraged.