Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement

the SIPPET Study Group

Research output: Contribution to journalArticle

3 Citations (Scopus)

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 languageEnglish
Pages (from-to)778-790
Number of pages13
JournalJournal of Thrombosis and Haemostasis
Volume16
Issue number4
DOIs
Publication statusPublished - 01-04-2018

Fingerprint

Factor VIII
Cohort Studies
Antigens
Mutation
Computer Simulation
Hemophilia A
Introns
Surveys and Questionnaires
Confidence Intervals
Isoantibodies
Immune Tolerance
varespladib methyl

All Science Journal Classification (ASJC) codes

  • Hematology

Cite this

@article{b4abb5a6fa2f48859356bba83683d5cf,
title = "Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement",
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.",
author = "{the SIPPET Study Group} and S. Spena and I. Garagiola and A. Cannav{\`o} and M. Mortarino and Mannucci, {P. M.} and Rosendaal, {F. R.} and F. Peyvandi and A. El-Beshlawy and M. Elalfy and V. Ramanan and P. Eshghi and S. Hanagavadi and R. Varadarajan and M. Karimi and Manglani, {M. V.} and C. Ross and G. Young and T. Seth and S. Apte and Nayak, {D. M.} and E. Santagostino and Mancuso, {M. E.} and {Sandoval Gonzalez}, {A. C.} and Mahlangu, {J. N.} and {Bonanad Boix}, S. and M. Cerqueira and Ewing, {N. P.} and C. Male and T. Owaidah and {Soto Arellano}, V. and Kobrinsky, {N. L.} and S. Majumdar and {Perez Garrido}, R. and A. Sachdeva and M. Simpson and M. Thomas and E. Zanon and B. Antmen and K. Kavakli and Manco-Johnson, {M. J.} and M. Martinez and E. Marzouka and Mazzucconi, {M. G.} and D. Neme and {Palomo Bravo}, A. and {Paredes Aguilera}, R. and A. Prezotti and K. Schmitt and Wicklund, {B. M.} and B. Zulfikar",
year = "2018",
month = "4",
day = "1",
doi = "10.1111/jth.13961",
language = "English",
volume = "16",
pages = "778--790",
journal = "Journal of Thrombosis and Haemostasis",
issn = "1538-7933",
publisher = "Wiley-Blackwell",
number = "4",

}

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 journalArticle

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.

UR - http://www.scopus.com/inward/record.url?scp=85044325184&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85044325184&partnerID=8YFLogxK

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 -