Thirty percent of patients with severe hemophilia treated with factor fVIII (fVlll) develop anti-fVIII antibodies (inhibitors). This is the most significant complication in the management of patients with hemophilia A leading to significant increases In morbidity as well as cost of treatment. Antibodies to fVIII can also develop in patients with previously normal coagulation leading to acquired hemophilia. These antibodies that develop can inhibit the biological activity of fVIII and necessitate the use of bypassing agents for the treatment of bleeding episodes. However, for unknown reasons, some patients display poor hemostatic response to bypass therapy. Thus, improved treatment options are needed, especially for severe or life-threatening bleeding events. Some biological determinants have been identified that increase the risk of inhibitor development. However, little is known about how hemophilia genotype relates to the ultimate epitope spectrum of the B-cell response or how the epitope spectrum affects the response to treatment and immune tolerance. We have recently shown that epitope specificity and inhibitor kinetics within the C2 domain are more important than inhibitor titer in response to fVlll in acquired hemophilia plasma and a murine monoclonal antibody (MAb) system. The central hypothesis of this project is that the inhibitor epitope spectrum of an individual patient can be used to predict the response to infusions of fVIII with or without bypassing agents. We propose to define further the epitopes on fVIII using a large panel of non-overlapping antl-fVIII MAbs in multiple in vitro assays (Aim 1). Given known discrepancies between the different in vitro assays and bleeding phenotype we will study the importance of different epitopes on murine in vivo bleeding phenotypes and fibrin clot structure (Aim 2).
In Aim 3, we will adapt our novel ELISA-based epitope mapping protocol to a more robust microsphere-based assay and investigate in a cross-sectional study how polyclonal patient plasma epitope maps correlate with the response to fVIII and bypassing agents in vitro. Ultimately these results could provide a simple clinical test that may predict response to fVIII and bypassing agents in high titer acquired and congenital hemophilia patients.

Public Health Relevance

Inhibitor development is the most significant complication in the management of pafients with hemophilia A. These inhibitors block the biological activity of N and necessitate the use of bypassing agents for the treatment of bleeding episodes. This goal of this project is to increase our knowledge of different types inhibitors and to provide an assay that better predicts an individual patient's response to treatment

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54HL112309-03
Application #
8656796
Study Section
Special Emphasis Panel (ZHL1)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Type
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Batsuli, Glaivy; Deng, Wei; Healey, John F et al. (2016) High-affinity, non-inhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors. Blood :
Zakas, Philip M; Brown, Harrison C; Knight, Kristopher et al. (2016) Enhancing the pharmaceutical properties of protein drugs by ancestral sequence reconstruction. Nat Biotechnol :
Myers, David R; Qiu, Yongzhi; Fay, Meredith E et al. (2016) Single-platelet nanomechanics measured by high-throughput cytometry. Nat Mater :
Eubanks, Joshua; Baldwin, W Hunter; Markovitz, Rebecca et al. (2016) A subset of high-titer anti-factor VIII A2 domain antibodies is responsive to treatment with factor VIII. Blood 127:2028-34
Chao, B N; Baldwin, W H; Healey, J F et al. (2016) Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene. J Thromb Haemost 14:346-55
Ciciliano, Jordan C; Sakurai, Yumiko; Myers, David R et al. (2015) Resolving the multifaceted mechanisms of the ferric chloride thrombosis model using an interdisciplinary microfluidic approach. Blood 126:817-24
Qiu, Yongzhi; Ciciliano, Jordan; Myers, David R et al. (2015) Platelets and physics: How platelets ""feel"" and respond to their mechanical microenvironment. Blood Rev 29:377-86
Kahle, Joerg; Orlowski, Aleksander; Stichel, Diana et al. (2015) Epitope mapping via selection of anti-FVIII antibody-specific phage-presented peptide ligands that mimic the antibody binding sites. Thromb Haemost 113:396-405
Mannino, Robert G; Myers, David R; Ahn, Byungwook et al. (2015) ""Do-it-yourself in vitro vasculature that recapitulates in vivo geometries for investigating endothelial-blood cell interactions"". Sci Rep 5:12401
Zakas, P M; Vanijcharoenkarn, K; Markovitz, R C et al. (2015) Expanding the ortholog approach for hemophilia treatment complicated by factor VIII inhibitors. J Thromb Haemost 13:72-81

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