Influence of factor 5 rs6025 and factor 2 rs1799963 mutation on inhibitor development in patients with hemophilia A--an Israeli-German multicenter database study.
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].


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 32F5/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.


CONCLUSIONS
Data presented here suggest that HRI development is of multifactorial origin and that F5 and F2 mutations may contribute to this risk.
Thrombosis Unit, National Hemophilia Center, Tel Hashomer and the Sackler Medical School, Tel Aviv University, Israel.
Gili
G
Kenet
Dr. von Haunersches Kinderspital [Univ. Children Hospital], Munich, Germany.
Christoph
C
Bidlingmaier
Institut für Humangenetik, Univ. Hospital Münster, Germany.
Nadja
N
Bogdanova
Pediatric Hematology/Oncology, Univ. Hospital Frankfurt, Frankfurt, Germany.
Carmen Escuriola
CE
Ettingshausen
All Children's Hospital, Divisions of Hematology, Departments of Pediatrics and Medicine, Johns Hopkins University School of Medicine, and All Children's Research Institute, St. Petersburg, FL, USA.
Neil
N
Goldenberg
Pediatric Outpatient Clinics, Lubbock, Germany.
Sven
S
Gutsche
Thrombosis and Hemophilia Treatment Center, Coagulation Center Rhine-Ruhr, Duisburg, Germany.
Susan
S
Halimeh
Department of Pediatric Hematology/Oncology, Charite, Berlin, Germany.
Susanne
S
Holzhauer
Dr. von Haunersches Kinderspital [Univ. Children Hospital], Munich, Germany.
Karin
K
Kurnik
Institute of Clinical Chemistry, Univ. Hospital Schleswig-Holstein, Kiel, Germany.
Verena
V
Limperger
Institute of Clinical Chemistry, Univ. Hospital Schleswig-Holstein, Kiel, Germany.
Ralf
R
Junker
Thrombosis & Hemophilia Treatment Center, Institute of Clinical Chemistry, Univ. Hospital Schleswig-Holstein, Kiel, Germany. Electronic address: leagottl@uksh.de.
Ulrike
U
Nowak-Göttl
D000293:Adolescent; D000328:Adult; D001323:Autoantibodies / Q000096:biosynthesis / Q000276:immunology; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005165:Factor V / Q000235:genetics*; D005169:Factor VIII / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism / Q000627:therapeutic use; D005260:Female; D005838:Genotype; D005858:Germany; D006467:Hemophilia A / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007557:Israel; D008297:Male; D009154:Mutation; D012307:Risk Factors; D055815:Young Adult
D001323:Autoantibodies; D005165:Factor V; D005169:Factor VIII
F2 rs1799963 mutation; F5 rs6025; Hemophilia A; High-titer inhibitor development