Abstract Number: PB0209
Meeting: ISTH 2020 Congress
Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors
Background: The Hemophilia Inhibitor PUPs study (HIPS) is a prospective longitudinal study of previously untreated patients with severe Hemophilia A during their first 50 exposure days (EDs) to a single source of recombinant FVIII, Advate. Among the 23 HIPS subjects who completed 50 EDs, 4 distinct antibody signatures were identified: Subgroup 1 (7) had no FVIII inhibitors or FVIII-specific antibodies, Subgroup 2 (7) had no inhibitors but had FVIII-Specific IgG1, Subgroup 3 (2) had low titer or transient FVIII inhibitors with FVIII specific IgG1 but without IgG3 or IgG4, and Subgroup 4 (7) had high titer inhibitors with high-affinity IgG1 and class-switched antibodies (IgG3, IgG4; rarely IgG2).
Aims: To compare T-cell subpopulations using highly sensitive epigenetic markers among the 4 subgroups at baseline and throughout the 1st 50 EDs.
Methods: HIPS subjects had blood samples drawn at baseline and after ED1, ED5, ED10, ED20, ED30, ED40, and ED50. Epigenetic studies using DNA markers which are unique and highly specific for CD3+ T cells, FOXP3+ Tregs, IL-17A+ Th17 cells, follicular helper T cells (Tfh) were used to quantify each cell type (Precision for Medicine; Berlin, GE).
Results: 1. There was a significant difference in baseline % Tfh between subgroups 1, 2 and 4 (Figure 1).
2. There were no differences in baseline % of for total FOXP3+ Tregs, IL-17A+ Th17 cells.
3. There was a significant difference in the rate of increase of % TH17/CD3 cells during 50 EDs between subgroups 1, 2, and 3 and subgroup 4 (Figure 2).
Conclusions: Proportion of Tfh cells is significantly higher at baseline in patients who develop high titer, high-affinity IgG class-switched antibodies. Proportion of Th17 cells increases at a higher rate than FOXP3+ Tregs in patients who develop high titer, high affinity antibodies which likely reflects activation of adaptive immunity predisposing to inhibitor formation.
To cite this abstract in AMA style:
Brown D, Berg V, Blatny J, Fijnvandraat K, Klintman J, Male C, McGuinn C, Meeks S, Mullins E, Radelescu V, Ragni M, Recht M, Santagostino E, Shapiro A, Staber J, Yaish H, LeBeau P, Bowen J, Gangadharan B, Reipert B. Circulating T Helper 17 Cells (Th17) Increase at a Higher Rate than Tregs in Previously Untreated Patients with Severe Hemophilia A Who Develop Inhibitors During the First 50 Exposure Days to rFVIII [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/circulating-t-helper-17-cells-th17-increase-at-a-higher-rate-than-tregs-in-previously-untreated-patients-with-severe-hemophilia-a-who-develop-inhibitors-during-the-first-50-exposure-days-to-rfviii/. Accessed September 29, 2023.« Back to ISTH 2020 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/circulating-t-helper-17-cells-th17-increase-at-a-higher-rate-than-tregs-in-previously-untreated-patients-with-severe-hemophilia-a-who-develop-inhibitors-during-the-first-50-exposure-days-to-rfviii/