Inhibitory antibodies to factor VIII develop in approximately 30% of patients with severe and moderately severe hemophilia A in response to infusions of factor VIII. Inhibitor development is associated with a lower quality of life and an increased economic burden. Consequently, inhibitor development currently is considered the most significant complication of the management of in hemophilia A. Additionally, factor VIII inhibitors can occur in nonhemophiliacs, producing an autoimmune condition called acquired hemophilia A. Recent developments have made it possible to ask increasingly focused questions regarding the pathogenesis of factor VIII inhibitor development and to test novel diagnostic and therapeutic approaches to the problem. There are two Specific Aims in this project.
In Aim 1, novel immunodominant epitopes recognized by anti-factor VIII antibodies produced in a murine hemophilia A immunogenicity model will be identified and characterized. This will be accomplished using several methods, including domain-specific antibody mapping, homolog and site-directed mutagenesis of factor VIII, and functional analysis of anti-factor VIII antibodies. Additionally, the pathogenicity of anti-factor VIII antibodies will be evaluated in hemophilia A mice.
In Aim 2, murine antibodies of defined specificity produced in Aim 1 will be used to identify novel factor VIII antibody epitopes recognized by human hemophilia A patients.

Public Health Relevance

Patients with hemophilia A have a deficiency in the blood coagulation protein factor VIII. Some patients with hemophilia A develop antibodies to factor VIII that worsens their bleeding problems and makes therapy difficult and expensive. In this project, we will develop a better understanding of how the antibodies form, which may lead to better treatment alternatives.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hemostasis and Thrombosis Study Section (HT)
Program Officer
Link, Rebecca P
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Emory University
Schools of Medicine
United States
Zip Code
Lollar, Pete; Winzor, Donald J (2014) Reconciliation of classical and reacted-site probability approaches to allowance for ligand multivalence in binding studies. J Mol Recognit 27:73-81
Grushin, K; Miller, J; Dalm, D et al. (2014) Lack of recombinant factor VIII B-domain induces phospholipid vesicle aggregation: implications for the immunogenicity of factor VIII. Haemophilia 20:723-31
Nguyen, Phuong-Cac T; Lewis, Kenneth B; Ettinger, Ruth A et al. (2014) High-resolution mapping of epitopes on the C2 domain of factor VIII by analysis of point mutants using surface plasmon resonance. Blood 123:2732-9
Markovitz, Rebecca C; Healey, John F; Parker, Ernest T et al. (2013) The diversity of the immune response to the A2 domain of human factor VIII. Blood 121:2785-95
Walter, Justin D; Werther, Rachel A; Brison, Caileen M et al. (2013) Structure of the factor VIII C2 domain in a ternary complex with 2 inhibitor antibodies reveals classical and nonclassical epitopes. Blood 122:4270-8
Walter, Justin D; Werther, Rachel A; Polozova, Maria S et al. (2013) Characterization and solution structure of the factor VIII C2 domain in a ternary complex with classical and non-classical inhibitor antibodies. J Biol Chem 288:9905-14
Meeks, Shannon L; Cox, Courtney L; Healey, John F et al. (2012) A major determinant of the immunogenicity of factor VIII in a murine model is independent of its procoagulant function. Blood 120:2512-20
Summers, Ryan J; Meeks, Shannon L; Healey, John F et al. (2011) Factor VIII A3 domain substitution N1922S results in hemophilia A due to domain-specific misfolding and hyposecretion of functional protein. Blood 117:3190-8
Meeks, S L; Healey, J F; Parker, E T et al. (2009) Non-classical anti-factor VIII C2 domain antibodies are pathogenic in a murine in vivo bleeding model. J Thromb Haemost 7:658-64
Healey, John F; Parker, Ernest T; Barrow, Rachel T et al. (2009) The comparative immunogenicity of human and porcine factor VIII in haemophilia A mice. Thromb Haemost 102:35-41

Showing the most recent 10 out of 14 publications