Haematologica 2000;85:supplement to no. 10 - Supplements ...

Haematologica 2000; 85(suppl. to n.10)
p. 64-68
Acquired Factor VIII
Inhibitors
New protocol for immune tolerance induction in acquired
hemophilia
LASZLO NEMES,* ERVIN PITLIK°
*Hemophilia Center, National Institute of Hematology and Immunology; °Department of Internal Medicine,
Semmelweis University Medical School; Budapest, Hungary
Abstract
Background and objectives. Immune tolerance
induction (ITI) regimens with human factor VIII concentrates
are rarely if ever implemented in adult
patients with auto-inhibitors, in contrast to alloantibody
suppression, which is used primarily in
young children with congenital hemophilia. On the
basis of some earlier experience with synchronization
of plasma exchange therapy of various autoimmune
disorders we have developed a new aggressive
protocol for the treatment of patients with
acquired factor VIII (FVIII) antibody. We have evaluated
the outcome of 14 consecutive nonhemophilic
FVIII inhibitor patients treated in a single center
with our ITI protocol between 1992 and 1999,
comparing them to 6 historical control patients,
treated with traditional immunosuppression therapy
(steroid ± cyclophosphamide) between 1988 and
1992.
Design and Methods. Our ITI protocol consists of
three weeks of treatment with 1) human FVIII concentrates
(30 U/kg/day for the 1st week, 20
U/kg/day for the 2nd, and 15 U/kg/day for the 3rd
week), plus 2) iv. cyclophosphamide (200mg/day to
a total dose of 2-3 grams), plus 3) methylprednisolone
(100 mg/day iv. for one week and than
tapering down the dose gradually over the next two
weeks). The treatment of acute bleeding episodes
in the two groups was not different. High purity and
ultra-high purity factor VIII concentrates were used
for the ITI. We performed aPTT and mixing tests
before and after two hours of incubation, Bethesda
inhibitor assay, porcine FVIII cross-reactivity,
FVIII:C before and after FVIII administration (recovery),
three times a week. The sex ratio and mean
age (64 years for the ITI group versus 57 years for
the controls), the initial and peak inhibitor titers,
and residual FVIII: C values at the diagnosis were
similar in the two groups.
Results. Eradication of the inhibitor occurred in
13/14 patients in the ITI vs. 4/6 patients in the control
group. The main difference between the two
groups was in the time needed for the complete
disappearance of the inhibitor (4.6 weeks for ITI vs.
Correspondence: Dr. Laszlo Nemes , National Institute of Hematology
and Immunology, Hemophilia Center, Budapest, Daroczi u. 24,
H-1113 Hungary; Phone: international 36-1-3852457 – Fax: international
36-1-2092311 E-mail address: peer@bel2.sote.hu
28.3 weeks for controls). In the ITI group we have
observed only two relapses during the relatively
long follow-up period (26 months), and in both cases
the same re-induction protocol was successful
again. No bleeding-related mortality occurred in
this group in contrast to that of 33 % in the controls.
Apart from the well-known adverse effects of
glucocorticoid therapy, we have observed only one
patient with transient cytopenia. We have not seen
any adverse event which could be attributed to the
use of FVIII concentrates.
Interpretation and Conclusions. We conclude that
the ITI protocol described here is highly effective
for the treatment of acquired hemophilia, induces
quick therapeutic responses and favorably influences
the underlying autoimmune disorder. We
suggest that our ITI protocol is suitable for the
eradication of idiopathic and autoimmune-associated
FVIII autoantibodies in patients presenting
with severe bleeding.
©2000, Ferrata Storti Foundation
Key words: acquired hemophilia, FVIII autoantibodies,
immunosuppression therapy, immune tolerance induction
Acquired hemophilia is caused by IgG1-
IgG4 anti-factor VIII autoantibodies
emerging either spontaneously (idiopathic
inhibitor in the elderly) or in connection with
pregnancy, various autoimmune and malignant
diseases and drug therapy. The reported incidence
of this rare condition is 0.2-1.0/10 6 population/year.
1 The bleeding manifestations are
often dramatic with 80-90% major hemorrhage
and 10-22% mortality rates directly or indirectly
attributable to the inhibitor. 2
The long-term management of acquired
hemophilia is still controversial. It is possible
that different treatments should be used for different
subgroups of patients (a conservative
approach for children, peripartum and druginduced
cases in whom spontaneous remission
can be reasonably expected, and combined
immunomodulatory therapy for idiopathic and
autoimmune-associated cases). 3 However, indi-
Haematologica vol. 85(supplement to n. 10):October 2000