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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
medicine
Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement
Journal of Thrombosis and Haemostasis, Volume 16, No. 4, Year 2018
Notification
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Description
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. © 2018 International Society on Thrombosis and Haemostasis
Authors & Co-Authors
Garagiola, Isabella
Italy, Milan
Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
Mannucci, Piermannuccio Mannuccio M.
Italy, Milan
Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
Rosendaal, Frits Richard
Netherlands, Leiden
Leids Universitair Medisch Centrum
Peyvandi, Flora A.
Italy, Milan
Università Degli Studi Di Milano
Italy, Milan
Fondazione Irccs Ca' Granda Ospedale Maggiore Policlinico
El-Beshlawy, Amal M.
Unknown Affiliation
ElAlfy, Mohsen Saleh
Unknown Affiliation
Ramanan, Vijay
Unknown Affiliation
Eshghi, Peyman
Unknown Affiliation
Hanagavadi, Suresha
Unknown Affiliation
Varadarajan, R.
Unknown Affiliation
Karimi, Mehran A.
Unknown Affiliation
Manglani, Mamta V.
Unknown Affiliation
Ross, Cecil Reuben
Unknown Affiliation
Young, Guy Aaron
Unknown Affiliation
Seth, Tulika
Unknown Affiliation
Apte, Shashikant Janardan
Unknown Affiliation
Nayak, Dinesh M.
Unknown Affiliation
Santagostino, Elena M.
Unknown Affiliation
Mancuso, Maria Elisa
Unknown Affiliation
Sandoval-González, Adriana Carolina
Unknown Affiliation
Mahlangu, Johnny Ndoni
Unknown Affiliation
Bonanad, Santiago
Unknown Affiliation
Cerqueira, Mônica Hermida
Unknown Affiliation
Ewing, Nadia P.
Unknown Affiliation
Male, Christoph
Unknown Affiliation
Owaidah, Tarek Mustafa A.
Unknown Affiliation
Kobrinsky, Nathan L.
Unknown Affiliation
Majumdar, Suvankar
Unknown Affiliation
Pérez-Garrido, Rosario
Unknown Affiliation
Sachdeva, Anupam K.
Unknown Affiliation
Simpson, Mindy L.
Unknown Affiliation
Thomas, Matthew P.
Unknown Affiliation
Zanon, Ezio
Unknown Affiliation
Antmen, Bul̈ent Ali
Unknown Affiliation
Kavaklı, Kaan R.
Unknown Affiliation
Manco-Johnson, Marilyn Jean
Unknown Affiliation
Martínez, Mónica
Unknown Affiliation
Marzouka, E.
Unknown Affiliation
Mazzucconi, Maria Gabriella
Unknown Affiliation
Neme, Daniela
Unknown Affiliation
Palomo Bravo, Ángeles
Unknown Affiliation
Paredes-Aguilera, Rogelio Alejandro
Unknown Affiliation
Prezotti, Alessandra Nunes Loureiro
Unknown Affiliation
Schmitt, Klaus
Unknown Affiliation
Wicklund, Brian M.
Unknown Affiliation
Zul̈fikar, Bul̈ent
Unknown Affiliation
Statistics
Citations: 20
Authors: 46
Affiliations: 3
Identifiers
Doi:
10.1111/jth.13961
ISSN:
15387933
Research Areas
Cancer
Environmental
Genetics And Genomics
Health System And Policy
Study Design
Cross Sectional Study
Cohort Study
Study Approach
Quantitative