Abstract Number: OC 55.3
Meeting: ISTH 2021 Congress
Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Clinical
Background: The SIPPET Study found that null mutations increased factor FVIII (FVIII) inhibitor risk 2-fold and FVIII antigen (Ag) < 1% increased risk 3.5-fold (JTH 2018;16:778-90).
Aims: To investigate mutations and FVIII:Ag in hemophilia A (HemA) inhibitors.
Methods: This study retrospectively analyzed an approved consented cohort study. Clinical data included hemophilia severity, inhibitor history, and mutation analysis. High risk mutations included all null plus the Arg593Cys mutation highly associated with inhibitors. FVIII:activity (FVIII:Act) was determined using clotting assays. FVIII:Ag was assayed using ELISA. Thrombin generation was measured using the calibrated automated thrombogram (CAT). Data analysis utilized ROC-curve sensitivity and specificity analysis, paired comparisons, Phi Coefficient and Point Biserial Correlations.
Results: 272 participants with HemA were included. Among all severities there was a weak positive relationship between FVIII:Ag <1% and inhibitor formation (p = 0.07) and no relationship within severe HemA (p=0.84). ROC curve showed an optimal dysfunctional protein (FVIII:Ag/Act) cut-off ratio of >1 best discriminated inhibitor formation. Inhibitor prevalence is shown on Table 1. There was no relationship between dysproteinemia and inhibitors overall or in mild or moderate HemA, but increased risk in severe (p=0.02), where high-risk mutations predominated. High risk mutations were associated with inhibitors overall (p=0.001) and in mild HemA (p<0.001), driven by the Arg593Cys mutation. Table 2 shows thrombin generation relative to dysproteinemia. There was no hemostatic effect of dysfunctional protein except for decreased CAT ETP (p=0.003) and max thrombin peak (p=0.01) in mild HemA with dysproteinemia.
Demographics: | N | FVIII Ag/Act ≥ 1 | High-Risk Mutation |
Overall | 272 | 47% | 43% |
Mild | 87 | 55% | 14% |
Moderate | 48 | 66% | 6% |
Severe | 137 | 34% | 75% |
Inhibitor Rate: | All pts | FVIII Ag/Act ≥ 1 | High-Risk Mutation |
Overall | 15% | 18% | 24% |
Mild | 7% | 7% | 33% |
Moderate | 8% | 10% | 0% |
Severe | 23% | 36% | 23% |
Hemophilia Severity | FVIII Ag/Act < 1 CAT (% normal) |
FVIII Ag/Act ≥ 1 CAT (% normal) |
||
ETP* | Max Peak+ | ETP | Max Peak | |
Mild | 61 | 75 | 46 | 48 |
Moderate | 39 | 43 | 33 | 31 |
Severe | 19 | 16 | 19 | 17 |
*ETP = endogenous thrombin potential +Max Peak = maximum peak thrombin |
Conclusions: High-risk mutations contributed the greatest effect on inhibitor formation; FVIII Ag < 1 did not increase risk. Dysproteinemia was common in all severities but increased inhibitor risk only in severe HemA. Thrombin generation was inhibited by dysproteinemia in mild HemA. Future work to understand mutation types and dysfunctional FVIII in promotion of inhibitors, inhibition of thrombin generation and impact on HemA outcomes is needed.
To cite this abstract in AMA style:
Kuldanek S, Thornhill D, Tran A, Briones N, Baird C, Jacobson L, Warren B, Manco-Johnson M. Factor VIII Inhibitors: Effects of Mutation and FVIII Antigen Revisited [abstract]. Res Pract Thromb Haemost. 2021; 5 (Suppl 2). https://abstracts.isth.org/abstract/factor-viii-inhibitors-effects-of-mutation-and-fviii-antigen-revisited/. Accessed March 22, 2024.« Back to ISTH 2021 Congress
ISTH Congress Abstracts - https://abstracts.isth.org/abstract/factor-viii-inhibitors-effects-of-mutation-and-fviii-antigen-revisited/