Abstract
Essentials A residual factor VIII synthesis is likely to be protective towards inhibitor (INH) development. Mutation type-inhibitor risk association was explored in 231 patients with severe hemophilia A. A 2-fold increase in INH development for in silico null vs. non-null mutations was found. A 3.5-fold increase in INH risk for antigen negative vs. antigen positive mutations was found. Summary: Background The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow residual synthesis of factor VIII are likely to play a protective role against alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. Objectives To explore the mutation type–inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) randomized trial. Methods The genetic defects in these patients, consisting of inversions of intron 22 (n = 110) and intron 1 (n = 6), large deletions (n = 16), and nonsense (n = 38), frameshift (n = 28), missense (n = 19) and splicing (n = 14) variants, of which 34 have been previously unreported, were reclassified according to two additional criteria: the functional effects of missense and splicing alterations as predicted by multiple in silico analyses, and the levels of FVIII antigen in patient plasma. Results A two-fold increase in inhibitor development for in silico null mutations as compared with in silico non-null mutations (hazard ratio [HR] 2.08, 95% confidence interval [CI] 0.84–5.17) and a 3.5-fold increase in inhibitor development for antigen-negative mutations as compared with antigen-positive mutations (HR 3.61, 95% CI 0.89–14.74] were found. Conclusions Our findings confirm an association between the synthesis of minute amounts of FVIII and inhibitor protection, and underline the importance of investigating the residual FVIII antigen levels associated with causative variants in order to understand their clinical relevance.
| Original language | English |
|---|---|
| Pages (from-to) | 778-790 |
| Number of pages | 13 |
| Journal | Journal of Thrombosis and Haemostasis |
| Volume | 16 |
| Issue number | 4 |
| DOIs | |
| Publication status | Published - 01-04-2018 |
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All Science Journal Classification (ASJC) codes
- Hematology
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Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement. / the SIPPET Study Group.
In: Journal of Thrombosis and Haemostasis, Vol. 16, No. 4, 01.04.2018, p. 778-790.Research output: Contribution to journal › Article
TY - JOUR
T1 - Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement
AU - the SIPPET Study Group
AU - Spena, S.
AU - Garagiola, I.
AU - Cannavò, A.
AU - Mortarino, M.
AU - Mannucci, P. M.
AU - Rosendaal, F. R.
AU - Peyvandi, F.
AU - El-Beshlawy, A.
AU - Elalfy, M.
AU - Ramanan, V.
AU - Eshghi, P.
AU - Hanagavadi, S.
AU - Varadarajan, R.
AU - Karimi, M.
AU - Manglani, M. V.
AU - Ross, C.
AU - Young, G.
AU - Seth, T.
AU - Apte, S.
AU - Nayak, D. M.
AU - Santagostino, E.
AU - Mancuso, M. E.
AU - Sandoval Gonzalez, A. C.
AU - Mahlangu, J. N.
AU - Bonanad Boix, S.
AU - Cerqueira, M.
AU - Ewing, N. P.
AU - Male, C.
AU - Owaidah, T.
AU - Soto Arellano, V.
AU - Kobrinsky, N. L.
AU - Majumdar, S.
AU - Perez Garrido, R.
AU - Sachdeva, A.
AU - Simpson, M.
AU - Thomas, M.
AU - Zanon, E.
AU - Antmen, B.
AU - Kavakli, K.
AU - Manco-Johnson, M. J.
AU - Martinez, M.
AU - Marzouka, E.
AU - Mazzucconi, M. G.
AU - Neme, D.
AU - Palomo Bravo, A.
AU - Paredes Aguilera, R.
AU - Prezotti, A.
AU - Schmitt, K.
AU - Wicklund, B. M.
AU - Zulfikar, B.
PY - 2018/4/1
Y1 - 2018/4/1
N2 - Essentials A residual factor VIII synthesis is likely to be protective towards inhibitor (INH) development. Mutation type-inhibitor risk association was explored in 231 patients with severe hemophilia A. A 2-fold increase in INH development for in silico null vs. non-null mutations was found. A 3.5-fold increase in INH risk for antigen negative vs. antigen positive mutations was found. Summary: Background The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow residual synthesis of factor VIII are likely to play a protective role against alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. Objectives To explore the mutation type–inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) randomized trial. Methods The genetic defects in these patients, consisting of inversions of intron 22 (n = 110) and intron 1 (n = 6), large deletions (n = 16), and nonsense (n = 38), frameshift (n = 28), missense (n = 19) and splicing (n = 14) variants, of which 34 have been previously unreported, were reclassified according to two additional criteria: the functional effects of missense and splicing alterations as predicted by multiple in silico analyses, and the levels of FVIII antigen in patient plasma. Results A two-fold increase in inhibitor development for in silico null mutations as compared with in silico non-null mutations (hazard ratio [HR] 2.08, 95% confidence interval [CI] 0.84–5.17) and a 3.5-fold increase in inhibitor development for antigen-negative mutations as compared with antigen-positive mutations (HR 3.61, 95% CI 0.89–14.74] were found. Conclusions Our findings confirm an association between the synthesis of minute amounts of FVIII and inhibitor protection, and underline the importance of investigating the residual FVIII antigen levels associated with causative variants in order to understand their clinical relevance.
AB - Essentials A residual factor VIII synthesis is likely to be protective towards inhibitor (INH) development. Mutation type-inhibitor risk association was explored in 231 patients with severe hemophilia A. A 2-fold increase in INH development for in silico null vs. non-null mutations was found. A 3.5-fold increase in INH risk for antigen negative vs. antigen positive mutations was found. Summary: Background The type of F8 mutation is the main predictor of inhibitor development in patients with severe hemophilia A. Mutations expected to allow residual synthesis of factor VIII are likely to play a protective role against alloantibody development by inducing immune tolerance. According to the expected full or partial impairment of FVIII synthesis, F8 variants are commonly classified as null and non-null. Objectives To explore the mutation type–inhibitor risk association in a cohort of 231 patients with severe hemophilia A enrolled in the Survey of Inhibitors in Plasma-Product Exposed Toddlers (SIPPET) randomized trial. Methods The genetic defects in these patients, consisting of inversions of intron 22 (n = 110) and intron 1 (n = 6), large deletions (n = 16), and nonsense (n = 38), frameshift (n = 28), missense (n = 19) and splicing (n = 14) variants, of which 34 have been previously unreported, were reclassified according to two additional criteria: the functional effects of missense and splicing alterations as predicted by multiple in silico analyses, and the levels of FVIII antigen in patient plasma. Results A two-fold increase in inhibitor development for in silico null mutations as compared with in silico non-null mutations (hazard ratio [HR] 2.08, 95% confidence interval [CI] 0.84–5.17) and a 3.5-fold increase in inhibitor development for antigen-negative mutations as compared with antigen-positive mutations (HR 3.61, 95% CI 0.89–14.74] were found. Conclusions Our findings confirm an association between the synthesis of minute amounts of FVIII and inhibitor protection, and underline the importance of investigating the residual FVIII antigen levels associated with causative variants in order to understand their clinical relevance.
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U2 - 10.1111/jth.13961
DO - 10.1111/jth.13961
M3 - Article
AN - SCOPUS:85044325184
VL - 16
SP - 778
EP - 790
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
SN - 1538-7933
IS - 4
ER -