Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.
Neutralizing antibodies (inhibitors) toward factor VIII form a severe complication in nonsevere hemophilia A, profoundly aggravating the bleeding pattern. Identification of high-risk patients is hampered by lack of data that take exposure days to therapeutic factor VIII concentrates into account. In the INSIGHT study, we analyzed the association between F8 mutation and inhibitor development in patients with nonsevere hemophilia A (factor VIII 2-40 IU/dL). This analysis included 1112 nonsevere hemophilia A patients from 14 centers in Europe and Australia that had genotyped at least 70% of their patients. Inhibitor risk was calculated as Kaplan-Meier incidence with cumulative number of exposure days as the time variable. During 44 800 exposure days (median, 24 exposure days per patient; interquartile range [IQR], 7-90), 59 of the 1112 patients developed an inhibitor; cumulative incidence of 5.3% (95% confidence interval [CI], 4.0-6.6) after a median of 28 exposure days (IQR, 12-71). The inhibitor risk at 50 exposure days was 6.7% (95% CI, 4.5-8.9) and at 100 exposure days the risk further increased to 13.3% (95% CI, 9.6-17.0). Among a total of 214 different F8 missense mutations 19 were associated with inhibitor development. These results emphasize the importance of F8 genotyping in nonsevere hemophilia A.
Academic Medical Center, Amsterdam, The Netherlands;
Corien L
CL
Eckhardt
Alice S
AS
van Velzen
Marjolein
M
Peters
Jan
J
Astermark
Paul P
PP
Brons
Giancarlo
G
Castaman
Marjon H
MH
Cnossen
Natasja
N
Dors
Carmen
C
Escuriola-Ettingshausen
Karly
K
Hamulyak
Daniel P
DP
Hart
Charles R M
CR
Hay
Saturnino
S
Haya
Waander L
WL
van Heerde
Cedric
C
Hermans
Margareta
M
Holmström
Victor
V
Jimenez-Yuste
Russell D
RD
Keenan
Robert
R
Klamroth
Britta A P
BA
Laros-van Gorkom
Frank W G
FW
Leebeek
Ri
R
Liesner
Anne
A
Mäkipernaa
Christoph
C
Male
Evelien
E
Mauser-Bunschoten
Maria G
MG
Mazzucconi
Simon
S
McRae
Karina
K
Meijer
Michael
M
Mitchell
Massimo
M
Morfini
Marten
M
Nijziel
Johannes
J
Oldenburg
Kathelijne
K
Peerlinck
Pia
P
Petrini
Helena
H
Platokouki
Sylvia E
SE
Reitter-Pfoertner
Elena
E
Santagostino
Piercarla
P
Schinco
Frans J
FJ
Smiers
Berthold
B
Siegmund
Annarita
A
Tagliaferri
Thynn T
TT
Yee
Pieter Willem
PW
Kamphuisen
Johanna G
JG
van der Bom
Karin
K
Fijnvandraat
D000293:Adolescent; D000328:Adult; D057134:Antibodies, Neutralizing / Q000276:immunology*; D005169:Factor VIII / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D005500:Follow-Up Studies; D005838:Genotype; D006467:Hemophilia A / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D020125:Mutation, Missense; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
D057134:Antibodies, Neutralizing; D005169:Factor VIII