TY - JOUR
T1 - Influence of factor 5 rs6025 and factor 2 rs1799963 mutation on inhibitor development in patients with hemophilia A - An Israeli-German multicenter database study
AU - Kenet, Gili
AU - Bidlingmaier, Christoph
AU - Bogdanova, Nadja
AU - Ettingshausen, Carmen Escuriola
AU - Goldenberg, Neil
AU - Gutsche, Sven
AU - Halimeh, Susan
AU - Holzhauer, Susanne
AU - Kurnik, Karin
AU - Limperger, Verena
AU - Junker, Ralf
AU - Nowak-Göttl, Ulrike
N1 - Funding Information:
The study was sponsored by unrestricted grants of Bayer Vital GmbH [Germany] , Intersero [Germany] , CSL Behring [Germany] , Octapharma GmbH [Germany] , and the Clinical Research Award CRA01/09 [IZKF: Univ. of Münster, Germany] .
PY - 2014/4
Y1 - 2014/4
N2 - Objective The present cohort study was performed to investigate the impact of the factor 5 rs6025 [F5] and the factor 2 rs1799963 [F2] mutations on high-titer inhibitor development [HRI] in patients with severe/moderate-severe hemophilia A [HA]. Patients and Methods 216 patients with F8 < 2% born between 1980 and 2011 were followed after initial HA diagnosis over the first 200 exposure days. The first HA patient per family who presented for diagnosis was included in the present study. Results 32 of 216 children [14.8%] tested for F5/F2 carried either the F5 or the F2 variant. HRI occurred in 14 out of 32 F5/F2-carriers compared with 40 of 184 without F5/F2. Multivariate analysis adjusted for F8 genotype, treatment intensity, first-line use of plasma derived FVIII versus recombinant FVIII concentrates revealed that the presence of F5/F2 independently increases the risk of HRI development to odds [OR] of 3.4. Large deletions in the F8 gene [OR: 5.10], patients from Israel [OR: 4.0], the increase of FVIII per one IU/kgbw [OR: 1.05] and birth year [OR: 1.12] were significantly associated with the risk to develop HRI. Conclusion Data presented here suggest that HRI development is of multifactorial origin and that F5 and F2 mutations may contribute to this risk.
AB - Objective The present cohort study was performed to investigate the impact of the factor 5 rs6025 [F5] and the factor 2 rs1799963 [F2] mutations on high-titer inhibitor development [HRI] in patients with severe/moderate-severe hemophilia A [HA]. Patients and Methods 216 patients with F8 < 2% born between 1980 and 2011 were followed after initial HA diagnosis over the first 200 exposure days. The first HA patient per family who presented for diagnosis was included in the present study. Results 32 of 216 children [14.8%] tested for F5/F2 carried either the F5 or the F2 variant. HRI occurred in 14 out of 32 F5/F2-carriers compared with 40 of 184 without F5/F2. Multivariate analysis adjusted for F8 genotype, treatment intensity, first-line use of plasma derived FVIII versus recombinant FVIII concentrates revealed that the presence of F5/F2 independently increases the risk of HRI development to odds [OR] of 3.4. Large deletions in the F8 gene [OR: 5.10], patients from Israel [OR: 4.0], the increase of FVIII per one IU/kgbw [OR: 1.05] and birth year [OR: 1.12] were significantly associated with the risk to develop HRI. Conclusion Data presented here suggest that HRI development is of multifactorial origin and that F5 and F2 mutations may contribute to this risk.
KW - F2 rs1799963 mutation
KW - F5 rs6025
KW - Hemophilia A
KW - High-titer inhibitor development
UR - https://www.scopus.com/pages/publications/84896112380
U2 - 10.1016/j.thromres.2014.01.005
DO - 10.1016/j.thromres.2014.01.005
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C2 - 24485400
AN - SCOPUS:84896112380
SN - 0049-3848
VL - 133
SP - 544
EP - 549
JO - Thrombosis Research
JF - Thrombosis Research
IS - 4
ER -