@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",
note = "Funding Information: The authors thank M. Biganzoli and M. Boscolo (Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione IRCCS Ca{\textquoteright} Granda Ospedale Maggiore Poli-clinico, Milan, Italy) for detection of genetic variants and biochemical analyses. This work was supported by the non-profit Angelo Bianchi Bonomi Foundation (Milan, Italy) and the Italian Ministry of Health (Progetti Finaliz-zati and Agenzia Italiana del Farmaco); Grifols, Kedrion and LFB provided unrestricted grants to Angelo Bianchi Bonomi Foundation. The funders had no role in study design, protocol preparation, patient recruitment, data collection, handling, analysis and interpretation, or writing of this report. Funding Information: Nordisk, and Sobi. She is member of the following advisory boards: Ablynx and F. Hoffmann-La Roche. P. Esh-ghi reports receiving personal fees from Aryogen, Baxter, CSL, and Novo Nordisk; and grants from Aryogen and Novo Nordisk. G. Young reports receiving personal fees from Baxalta, Biogen, Bayer, Grifols, Kedrion, and Novo Nordisk. E. Santagostino reports receiving personal fees from Baxalta, Baxter, Bayer, Biogen, CSL Behring, Gri-fols, Kedrion, Novo Nordisk, Octapharma, Pfizer, Roche, and Sobi; and grants from Pfizer. M. E. Mancuso reports receiving personal fees from Baxter, Bayer, CSL Behring, Novo Nordisk, Pfizer, and Sobi/Biogen. J. N. Mahlangu reports receiving personal fees from Amgen, Biogen, Biot-est, Novo Nordisk, Pfeizer, and Roche; and grants from Bayer, Biogen, CSL Behring, and Novo Nordisk. M. Cer-queira reports receiving personal fees from Baxter and Novo Nordisk. N. P. Ewing reports receiving personal fees from Alpha Therapeutic, Baxter, Bayer, Biogen Idec, and Novo Nordisk. C. Male reports receiving personal fees and non-financial support from Baxter, Bayer, Biot-est, CSL Behring, Novo Nordisk, and Pfizer; and grants from CSL Behring. T. Owaidah reports receiving honoraria for participating as speaker at satellite symposia and educational meetings organized by Alexion, Bayer, CSL Behring, Novo Nordisk, Octapharma, and Sobi; and he has received research grant funding from Novo Nordisk and consulting fees for serving on scientific advisory boards from Alexion and Novo Nordisk. M. Simpson reports receiving personal fees from Baxter, Biogen Idec, CSL Behring, and Octapharma. E. Zanon reports receiving personal fees from Baxalta, Bayer, CSL Behring, Gri-fols, Novo Nordisk, and Pfizer; and grants from Bayer. K. Kavakli reports receiving personal fees from Biotest; personal fees and non-financial support from Baxalta, Bayer, and Pfizer; and non-financial support from Octa-pharma and LFB. M. J. Manco-Johnson reports receiving personal fees from Baxter, Bayer, Biogen Idec, CSL Behring, and Novo Nordisk; and grants from Bayer. M. G. Mazzucconi reports receiving personal fees from Bayer, Baxter, Kedrion, Novo Nordisk, and Pfizer. D. Neme reports receiving personal fees from Novo Nordisk and Pfizer. B. M. Wicklund reports receiving personal fees from Baxalta, Bayer, Biogen, CSL Behring, and Novo Nordsisk, and other support from the American Thrombosis and Hemostasis Network and the National Hemophilia Foundation. B. Zulfikar reports receiving grants and personal fees from Bayer, Eczacibasi Baxter, Erkim LFB, Novo Nordisk, and Pfizer. The other authors state that they have no conflict of interest. Publisher Copyright: {\textcopyright} 2018 International Society on Thrombosis and Haemostasis",
year = "2018",
month = apr,
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",
}