Factor VIII gene (F8) mutation and risk of inhibitor development in nonsevere hemophilia A.

Fecha de publicación: 12/09/2013

Autores de IIS La Fe

Saturnino Haya Guaita

Autor

Participantes ajenos a IIS La Fe

Eckhardt CL
van Velzen AS
Peters M
Astermark J
Brons PP
Castaman G
Cnossen MH
Dors N
Escuriola-Ettingshausen C
Hamulyak K
Hart DP
Hay CR
van Heerde WL
Hermans C
Holmström M
Jimenez-Yuste V
Keenan RD
Klamroth R
Laros-van Gorkom BA
Leebeek FW
Liesner R
Mäkipernaa A
Male C
Mauser-Bunschoten E
Mazzucconi MG
McRae S
Meijer K
Mitchell M
Morfini M
Nijziel M
Oldenburg J
Peerlinck K
Petrini P
Platokouki H
Reitter-Pfoertner SE
Santagostino E
Schinco P
Smiers FJ
Siegmund B
Tagliaferri A
Yee TT
Kamphuisen PW
van der Bom JG
Fijnvandraat K
INSIGHT Study Group

Grupos

Hemostasia, Trombosis, Arteriosclerosis y Biología vascular

Investigador Principal

Pilar Medina Badenes

Abstract

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.