Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks

Autores
Rossetti, Liliana Carmen; Szurkalo, Irupé; Radic, Claudia Pamela; Abelleyro, Miguel Martin; Primiani, Laura; Neme, Daniela; Miguel, Candela; Pérez Bianco, Raúl; De Tezanos Pinto, Miguel; Larripa, Irene Beatriz; de Brasi, Carlos Daniel
Año de publicación
2013
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Inhibitor development against exogenous factor VIII is a severe impairment of replacement therapy affecting 18% of Argentine patients with severe haemophilia A (HA). To study the molecular predisposition for inhibitor development, we genotyped 260 HA patients with and without inhibitors, countrywide. The inhibitor-positive population (19 transients, 15 low responders, LR and 70 high responders, HR) of 104 severe-HA patients showed 59 Inv22 (intron 22 inversions), 18 small ins/del-frameshifts, 12 gross deletions, 12 nonsense, one splicing defect and two missense, p.Arg531Pro and p.Leu575Pro, both LR and thought to impair FVIII A2 domain secondary structure. In addition, a patient with mild HA and HR showed the missense p.Glu1704Lys associated with two neutral intronic substitutions potentially affecting the A3 domain. A case/control study (84/143) permitted estimation of F8 genotype-specific inhibitor risks [OR; prevalence (CI)] in severe-HA patients classifying a high-risk group including multi-exon deletions [3.66; 55% (19-100)], Inv22 [1.8; 24% (19-100)] and nonsense in FVIII-LCh [1.2; 21% (7-59)]; an average risk group including single-exon deletions, indel frameshifts and nonsense-HCh; and a low-risk group represented by missense defects [0.14; 3% (0.6-11)]. Analysis of inhibitor concordance/discordance in related patients indicated additional genetic factors other than F8 genotype for inhibitor formation. No significant inhibitor-predisposing factors related to FVIII product exposure were found in age- and F8 genotype-stratified populations of severe-HA patients. In conclusion, the Argentine HA patient series presents similar global and mutation-specific inhibitor risks than the HA database and other published series. This case-specific information will help in designing fitted therapies and follow-up protocols in Argentina.
Fil: Rossetti, Liliana Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Szurkalo, Irupé. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Radic, Claudia Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Abelleyro, Miguel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Primiani, Laura. Fundación de la Hemofilia Dr. Alfredo Pavlovsky; Argentina
Fil: Neme, Daniela. Fundación de la Hemofilia Dr. Alfredo Pavlovsky; Argentina
Fil: Miguel, Candela. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Pérez Bianco, Raúl. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: De Tezanos Pinto, Miguel. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: de Brasi, Carlos Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Materia
F8
Fviii Inhibitors
Hema
Mutation Characterization
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/82875
Acceder
id CONICETDig_74f2594aa35a0739af62e6324e4ff98b
oai_identifier_str oai:ri.conicet.gov.ar:11336/82875
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risksRossetti, Liliana CarmenSzurkalo, IrupéRadic, Claudia PamelaAbelleyro, Miguel MartinPrimiani, LauraNeme, DanielaMiguel, CandelaPérez Bianco, RaúlDe Tezanos Pinto, MiguelLarripa, Irene Beatrizde Brasi, Carlos DanielF8Fviii InhibitorsHemaMutation Characterizationhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1Inhibitor development against exogenous factor VIII is a severe impairment of replacement therapy affecting 18% of Argentine patients with severe haemophilia A (HA). To study the molecular predisposition for inhibitor development, we genotyped 260 HA patients with and without inhibitors, countrywide. The inhibitor-positive population (19 transients, 15 low responders, LR and 70 high responders, HR) of 104 severe-HA patients showed 59 Inv22 (intron 22 inversions), 18 small ins/del-frameshifts, 12 gross deletions, 12 nonsense, one splicing defect and two missense, p.Arg531Pro and p.Leu575Pro, both LR and thought to impair FVIII A2 domain secondary structure. In addition, a patient with mild HA and HR showed the missense p.Glu1704Lys associated with two neutral intronic substitutions potentially affecting the A3 domain. A case/control study (84/143) permitted estimation of F8 genotype-specific inhibitor risks [OR; prevalence (CI)] in severe-HA patients classifying a high-risk group including multi-exon deletions [3.66; 55% (19-100)], Inv22 [1.8; 24% (19-100)] and nonsense in FVIII-LCh [1.2; 21% (7-59)]; an average risk group including single-exon deletions, indel frameshifts and nonsense-HCh; and a low-risk group represented by missense defects [0.14; 3% (0.6-11)]. Analysis of inhibitor concordance/discordance in related patients indicated additional genetic factors other than F8 genotype for inhibitor formation. No significant inhibitor-predisposing factors related to FVIII product exposure were found in age- and F8 genotype-stratified populations of severe-HA patients. In conclusion, the Argentine HA patient series presents similar global and mutation-specific inhibitor risks than the HA database and other published series. This case-specific information will help in designing fitted therapies and follow-up protocols in Argentina.Fil: Rossetti, Liliana Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Szurkalo, Irupé. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Radic, Claudia Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Abelleyro, Miguel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Primiani, Laura. Fundación de la Hemofilia Dr. Alfredo Pavlovsky; ArgentinaFil: Neme, Daniela. Fundación de la Hemofilia Dr. Alfredo Pavlovsky; ArgentinaFil: Miguel, Candela. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Pérez Bianco, Raúl. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: De Tezanos Pinto, Miguel. Academia Nacional de Medicina de Buenos Aires; ArgentinaFil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: de Brasi, Carlos Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaWiley Blackwell Publishing, Inc2013-07info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/82875Rossetti, Liliana Carmen; Szurkalo, Irupé; Radic, Claudia Pamela; Abelleyro, Miguel Martin; Primiani, Laura; et al.; Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks; Wiley Blackwell Publishing, Inc; Haemophilia The Official Journal Of The World Federation Of Hemophilia; 19; 4; 7-2013; 511-5181351-8216CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/full/10.1111/hae.12105info:eu-repo/semantics/altIdentifier/doi/10.1111/hae.12105info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-10T13:02:50Zoai:ri.conicet.gov.ar:11336/82875instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-10 13:02:50.906CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks
title Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks
spellingShingle Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks
Rossetti, Liliana Carmen
F8
Fviii Inhibitors
Hema
Mutation Characterization
title_short Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks
title_full Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks
title_fullStr Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks
title_full_unstemmed Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks
title_sort Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks
dc.creator.none.fl_str_mv Rossetti, Liliana Carmen
Szurkalo, Irupé
Radic, Claudia Pamela
Abelleyro, Miguel Martin
Primiani, Laura
Neme, Daniela
Miguel, Candela
Pérez Bianco, Raúl
De Tezanos Pinto, Miguel
Larripa, Irene Beatriz
de Brasi, Carlos Daniel
author Rossetti, Liliana Carmen
author_facet Rossetti, Liliana Carmen
Szurkalo, Irupé
Radic, Claudia Pamela
Abelleyro, Miguel Martin
Primiani, Laura
Neme, Daniela
Miguel, Candela
Pérez Bianco, Raúl
De Tezanos Pinto, Miguel
Larripa, Irene Beatriz
de Brasi, Carlos Daniel
author_role author
author2 Szurkalo, Irupé
Radic, Claudia Pamela
Abelleyro, Miguel Martin
Primiani, Laura
Neme, Daniela
Miguel, Candela
Pérez Bianco, Raúl
De Tezanos Pinto, Miguel
Larripa, Irene Beatriz
de Brasi, Carlos Daniel
author2_role author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv F8
Fviii Inhibitors
Hema
Mutation Characterization
topic F8
Fviii Inhibitors
Hema
Mutation Characterization
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv Inhibitor development against exogenous factor VIII is a severe impairment of replacement therapy affecting 18% of Argentine patients with severe haemophilia A (HA). To study the molecular predisposition for inhibitor development, we genotyped 260 HA patients with and without inhibitors, countrywide. The inhibitor-positive population (19 transients, 15 low responders, LR and 70 high responders, HR) of 104 severe-HA patients showed 59 Inv22 (intron 22 inversions), 18 small ins/del-frameshifts, 12 gross deletions, 12 nonsense, one splicing defect and two missense, p.Arg531Pro and p.Leu575Pro, both LR and thought to impair FVIII A2 domain secondary structure. In addition, a patient with mild HA and HR showed the missense p.Glu1704Lys associated with two neutral intronic substitutions potentially affecting the A3 domain. A case/control study (84/143) permitted estimation of F8 genotype-specific inhibitor risks [OR; prevalence (CI)] in severe-HA patients classifying a high-risk group including multi-exon deletions [3.66; 55% (19-100)], Inv22 [1.8; 24% (19-100)] and nonsense in FVIII-LCh [1.2; 21% (7-59)]; an average risk group including single-exon deletions, indel frameshifts and nonsense-HCh; and a low-risk group represented by missense defects [0.14; 3% (0.6-11)]. Analysis of inhibitor concordance/discordance in related patients indicated additional genetic factors other than F8 genotype for inhibitor formation. No significant inhibitor-predisposing factors related to FVIII product exposure were found in age- and F8 genotype-stratified populations of severe-HA patients. In conclusion, the Argentine HA patient series presents similar global and mutation-specific inhibitor risks than the HA database and other published series. This case-specific information will help in designing fitted therapies and follow-up protocols in Argentina.
Fil: Rossetti, Liliana Carmen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Szurkalo, Irupé. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Radic, Claudia Pamela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Abelleyro, Miguel Martin. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: Primiani, Laura. Fundación de la Hemofilia Dr. Alfredo Pavlovsky; Argentina
Fil: Neme, Daniela. Fundación de la Hemofilia Dr. Alfredo Pavlovsky; Argentina
Fil: Miguel, Candela. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Pérez Bianco, Raúl. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: De Tezanos Pinto, Miguel. Academia Nacional de Medicina de Buenos Aires; Argentina
Fil: Larripa, Irene Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
Fil: de Brasi, Carlos Daniel. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina
description Inhibitor development against exogenous factor VIII is a severe impairment of replacement therapy affecting 18% of Argentine patients with severe haemophilia A (HA). To study the molecular predisposition for inhibitor development, we genotyped 260 HA patients with and without inhibitors, countrywide. The inhibitor-positive population (19 transients, 15 low responders, LR and 70 high responders, HR) of 104 severe-HA patients showed 59 Inv22 (intron 22 inversions), 18 small ins/del-frameshifts, 12 gross deletions, 12 nonsense, one splicing defect and two missense, p.Arg531Pro and p.Leu575Pro, both LR and thought to impair FVIII A2 domain secondary structure. In addition, a patient with mild HA and HR showed the missense p.Glu1704Lys associated with two neutral intronic substitutions potentially affecting the A3 domain. A case/control study (84/143) permitted estimation of F8 genotype-specific inhibitor risks [OR; prevalence (CI)] in severe-HA patients classifying a high-risk group including multi-exon deletions [3.66; 55% (19-100)], Inv22 [1.8; 24% (19-100)] and nonsense in FVIII-LCh [1.2; 21% (7-59)]; an average risk group including single-exon deletions, indel frameshifts and nonsense-HCh; and a low-risk group represented by missense defects [0.14; 3% (0.6-11)]. Analysis of inhibitor concordance/discordance in related patients indicated additional genetic factors other than F8 genotype for inhibitor formation. No significant inhibitor-predisposing factors related to FVIII product exposure were found in age- and F8 genotype-stratified populations of severe-HA patients. In conclusion, the Argentine HA patient series presents similar global and mutation-specific inhibitor risks than the HA database and other published series. This case-specific information will help in designing fitted therapies and follow-up protocols in Argentina.
publishDate 2013
dc.date.none.fl_str_mv 2013-07
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/82875
Rossetti, Liliana Carmen; Szurkalo, Irupé; Radic, Claudia Pamela; Abelleyro, Miguel Martin; Primiani, Laura; et al.; Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks; Wiley Blackwell Publishing, Inc; Haemophilia The Official Journal Of The World Federation Of Hemophilia; 19; 4; 7-2013; 511-518
1351-8216
CONICET Digital
CONICET
url http://hdl.handle.net/11336/82875
identifier_str_mv Rossetti, Liliana Carmen; Szurkalo, Irupé; Radic, Claudia Pamela; Abelleyro, Miguel Martin; Primiani, Laura; et al.; Factor VIII genotype characterization of haemophilia A affected patients with transient and permanent inhibitors: A comprehensive Argentine study of inhibitor risks; Wiley Blackwell Publishing, Inc; Haemophilia The Official Journal Of The World Federation Of Hemophilia; 19; 4; 7-2013; 511-518
1351-8216
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://onlinelibrary.wiley.com/doi/full/10.1111/hae.12105
info:eu-repo/semantics/altIdentifier/doi/10.1111/hae.12105
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
publisher.none.fl_str_mv Wiley Blackwell Publishing, Inc
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
_version_ 1842980043838455808
score 12.993085

Publicaciones similares