L E T T E R S T O T H E E D I T O R S
Factor VIII inhibitors development following introduction
of B-domain-deleted recombinant factor VIII in four
hemophilia A previously treated patients
V . R O U S S E L - R O B E R T , M . F . T O R C H E T ,
F . L E G R A N D ,
C . R O T H S C H I L D
and N . S T I E L T J E S
Haemophilia Center, Cochin Hospital and
Haemophilia Center, Necker Hospital, Paris, France
To cite this article:Roussel-Robert V, Torchet MF, Legrand F, Rothschild C, Stieltjes N. Factor VIII inhibitors development following introduction of B-domain deleted recombinant factor VIII in four hemophilia A previously treated patients.J Thromb Haemost2003;1: 2450±1.
Dear Sir,
The development of factor (F)VIII inhibitors in hemophilia A previously treated patients (PTPs) is a rare event, with a described incidence of 8per 1000 patient years [1]. An increased incidence of inhibitors in PTPs after exposure to an intermediate-purity pasteurized concentrate (FVIII CPS-P) in 1993 [2,3] and to a double virus-inactivated plasma derived FVIII concentrate (FVIII-SDP) in 1997 has been reported [4]. Moreover, some case reports show that emergence of inhibitors is favored by speci®c circumstances, such as continuous perfu-sion for surgical procedure with or without new product intro-duction [5,6], immune restoration by ef®cient antiretroviral therapy in human immunode®ciency virus (HIV) patients [7], and hepatitis C (HCV) interferon-alfa therapy [8].
We report the observation of four hemophilia A patients, previously treated by plasma and full-length recombinant FVIII concentrates, who developed FVIII inhibitors following intro-duction of B-domain-deleted recombinant factor VIII (BDDrFVIII).
Three patients (1, 2 and 3; aged 27, 32 and 65 years respec-tively), had severe hemophilia A, and one patient (no. 4), aged 46 years, had mild hemophilia A. The two younger patients were HIV-infected, with more than 300 CD4 cells per microlitre, and were on antiretroviral therapy without recent modi®cation. All had chronic hepatitis C. The three severe hemophiliacs had>120
exposure days to other FVIII concentrates and the mild hemo-philiac>20 exposure days. None had personal or family histories
of inhibitors. No inhibitors were detectable at the time of BDDrFVIII introduction. The mutation responsible for hemo-philia could be determined in patients 2 and 1, respectively,
consisting of a stop codon due to, respectively, a small deletion in exon 14 and a point mutation in exon 16.
Inhibitors were identi®ed after, respectively, 28, 19, 63 and 14 exposure days to BDDrFVIII. In patients 1 and 2, inhibitors were suspected because of inef®cacy of repeated FVIII infu-sions for hemarthrosis. In patient 3, inhibitors were diagnosed at the time of a hematuria 6 weeks after a prostatic adenoma surgical resection. This patient had been treated with interfer-on-alfa for 2 months for HCV infection. In the mild hemophiliac (patient 4), inhibitors were detected because of reduction of FVIII levels during continuous infusion for cholecystectomy and liver biopsy without hemorrhagic complication.
Maximum titres were, respectively, 1.3, 5.5, 8.9 and 0.9 Bethesda units (BU) per mL. In patient 1, further treatment for bleeding episodes required higher doses of BDDrFVIII. Inhibitors disappeared after 3 months and recovery normalized after 8months. Patient 2 was given secondary treatment with recombinant FVIIa (rFVIIa), and inhibitors were still detectable 13 months later at 0.6 BU. Patient 3 was also treated with rFVIIa, and inhibitors decreased to 0.9 BU 4 months later. In this patient, an anamnestic response was observed on two occasions, after exposure to plasma-derived FVIII for a femur neck fracture (40 BU) and for a bowel hematoma (300 BU). Inhibitors disappeared 4 months after FVIII withdrawal in patient 4.
In our two centers, 49 severe hemophiliac PTPs and 21 moderate or mild hemophiliacs are treated with BDDrFVIII. The prevalence of inhibitors is 6.1% in severe PTPs, which is more than the 0.9% [1/113] recorded in the PTPs study [9].There are no data for mild hemophilia. In two of the patients discussed here, speci®c circumstances were present at the time of inhibitors detection: continuous infusion of high doses of FVIII for patient 4, surgery and interferon therapy for patient 3. However, no predisposing circumstances were noticed in the other two patients. The four patients were treated with different batches of BDDrFVIII.
A close prospective follow-up of all patients treated with BDDrFVIII is necessary to assess the immunogenicity of this concentrate thoroughly.
Journal of Thrombosis and Haemostasis,1: 2450±2459
Correspondence: ValeÂrie Roussel-Robert, Center de Traitement et d'accueil des HeÂmophiles, CHU Cochin, 27 Rue de Faubourg Saint-Jacques 75679 Paris cedex 14, France.
Tel.:33 1 5841 2013; fax:33 1 5841 2010; e-mail: valerie.roussel-robert@ cch.ap-hop-paris.fr
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