The effects of changing patterns of factor VIII exposure in the current era of hemophilia treatment Restricted; Files Only
Schwartz, Anna (Spring 2026)
Abstract
Congenital hemophilia A (HA) is a genetically inherited bleeding disorder caused by
pathogenic variants in the F8 gene, resulting in reduced or absent coagulation factor VIII (FVIII).
Deficiency of FVIII results in both trauma-induced and spontaneous bleeding. Treatment
typically involves exogenous FVIII infusions; however, some patients develop neutralizing anti-
FVIII IgG antibodies (“inhibitors”) that render FVIII treatment ineffective. Emicizumab, a
bispecific antibody that mimics the FVIII activity, has emerged as an alternative prophylactic
therapy that substantially reduces bleeding and FVIII infusion rates. While immune tolerance
induction (ITI) is commonly used to eradicate inhibitors, its role in patients receiving
emicizumab remains unclear. This thesis studies inhibitor development and persistence over
time through two retrospective studies: a chart review of severe HA patients at Children’s
Healthcare of Atlanta (CHOA) and a cohort analysis of the CDC Community Counts Dataset. In
the CHOA cohort, inhibitor rates were similar between participants born before and after
emicizumab (p=0.263). However, inhibitor rates were lower in patients whose intended initial
prophylaxis regimen was emicizumab compared to FVIII (p=0.032). Patients in the emicizumab
group generally had fewer than five FVIII exposure days (EDs), and ITI utilization was
significantly lower among patients born after emicizumab licensure (p < 0.0001, p=0.026,
respectively). The CDC study examined longitudinal changes in anti-FVIII IgG1 (non-neutralizing)
and IgG4 (neutralizing) antibody titers in severe HA patients who had or had not achieved
immune tolerance prior to starting emicizumab. IgG1 and IgG4 titers decreased in non-tolerized
participants from baseline to end of study (p=0.002, p<0.001, respectively). However, a greater
proportion of non-tolerized patients experienced increases in IgG levels following FVIII
exposure (IgG1 10%, IgG4 5%) compared to those without FVIII exposure (IgG1 5%, IgG4 0%),
suggesting a risk of anamnestic immune response. Although inhibitor rates were lower among
patients with intended initial emicizumab prophylaxis, these patients received fewer FVIII EDs,
making the long-term risk of inhibitor development uncertain. Despite reduced ITI utilization,
increases in IgG titers following FVIII exposure in non-tolerized patients indicate a continued
risk of anamnestic responses. These data underscore the importance of ongoing inhibitor
surveillance in patients receiving emicizumab therapy.
Table of Contents
Introduction ................................................................................................................. 1
Physiology of Hemostasis ...................................................................................................... 1
Hemophilia A ....................................................................................................................... 2
Inhibitors in hemophilia A .................................................................................................................... 3
Emicizumab: a new era in treatment of hemophilia A ............................................................................. 8
Questions in the current treatment era ................................................................................. 10
Rates of inhibitor development and immune tolerance in children with severe hemophilia A in
the era of emicizumab ................................................................................................. 12
Rationale and Aims............................................................................................................. 12
Methods ........................................................................................................................... 12
Study Design and Participants ............................................................................................................. 12
Definitions .......................................................................................................................................... 13
Data Abstraction ................................................................................................................................. 14
Statistical Analysis .............................................................................................................................. 14
Results .............................................................................................................................. 15
Demographic Characteristics................................................................................................................ 15
Primary Objectives .............................................................................................................................. 15
Secondary Objectives ........................................................................................................................... 17
Discussion ......................................................................................................................... 17
Natural history of anti-FVIII IgG and inhibitor titers among persons with hemophilia
on emicizumab therapy ................................................................................................ 20
Background ....................................................................................................................... 20
Rationale/Aims .................................................................................................................. 21
Methods ........................................................................................................................... 22
Study Design........................................................................................................................................ 22
Participant Groups and Definitions ....................................................................................................... 22
Statistical Analysis .............................................................................................................................. 23
Results .............................................................................................................................. 23
Demographic Characteristics............................................................................................................... 23
Baseline IgG and Bethesda Titers by Group ............................................................................................ 24
Longitudinal IgG Titers by Group .......................................................................................................... 24
Discussion ......................................................................................................................... 25
Conclusion .................................................................................................................. 28
Tables ........................................................................................................................ 29
Figures ....................................................................................................................... 32
Supplemental Figures .................................................................................................. 36
References.................................................................................................................. 37
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File download under embargo until 28 May 2028 | 2026-04-01 18:33:30 -0400 | File download under embargo until 28 May 2028 |
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