Fibrinogen as predictor of ischemic stro
Journal of Thrombosis and Haemostasis, 1: 2450±2459
LETTERS TO THE EDITORS
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 Haemost 2003; 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 8 per 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 perfusion for surgical procedure with or without new product introduction [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 introduction of B-domain-deleted recombinant factor VIII
(BDDrFVIII).
Three patients (1, 2 and 3; aged 27, 32 and 65 years respectively), 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 hemophiliac >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 hemophilia could be determined in patients 2 and 1, respectively,
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
Received 28 April 2003, accepted 28 May 2003
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 infusions 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 interferon-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 8 months. 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.
# 2003 International Society on Thrombosis and Haemostasis
$&'!
! // )5
5 4
;5 B
;(
D%
?)
?
% % F
?)
. 1988; 71:
344±8.
, B
B 8 4G
60 4/ 4H
4 / '
6
I
/ D ) 0 5 6 I
4
J
%
8
. 1993; 81: 2180±6.
+ 9 G
D J DJ 'B D/ D% 0
&
(
.
1993; 69: 115±8.
. 9 G
D J / J DJ ; B D!"
,3>!"2
$&'7
1
/'!+
">+.
4:
">!"
4:%
(
1
'
0
#+.$%
1
/'!+
LETTERS TO THE EDITORS
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 Haemost 2003; 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 8 per 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 perfusion for surgical procedure with or without new product introduction [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 introduction of B-domain-deleted recombinant factor VIII
(BDDrFVIII).
Three patients (1, 2 and 3; aged 27, 32 and 65 years respectively), 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 hemophiliac >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 hemophilia could be determined in patients 2 and 1, respectively,
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
Received 28 April 2003, accepted 28 May 2003
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 infusions 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 interferon-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 8 months. 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.
# 2003 International Society on Thrombosis and Haemostasis
$&'!
! // )5
5 4
;5 B
;(
D%
?)
?
% % F
?)
. 1988; 71:
344±8.
, B
B 8 4G
60 4/ 4H
4 / '
6
I
/ D ) 0 5 6 I
4
J
%
8
. 1993; 81: 2180±6.
+ 9 G
D J DJ 'B D/ D% 0
&
(
.
1993; 69: 115±8.
. 9 G
D J / J DJ ; B D!"
,3>!"2
$&'7
1
/'!+
">+.
4:
">!"
4:%
(
1
'
0
#+.$%
1
/'!+