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

33
until recently and lack of any defined standard
method for ITI.
The success rate with ITI is poor in hemophilia
B with inhibitors and occurrence of nephrotic
syndrome during ITI in patients with concurrent
allergy has further reduced the success with
ITI. Nine cases of nephrotic syndrome have been
reported so far (Table 2). All were receiving large
doses of high purity factor IX products for ITI
when they developed nephrotic syndrome. The
median duration of ITI prior to the occurrence
of nephrotic syndrome is 9 months (ranged 6-15
months).
Renal biopsy results available in one patient
showed membranous glomerulonephritis with
no histochemical evidence of deposits containing
FIX. The response to immunosuppressive
treatment was poor in these patients. However,
most of the patients responded to either reduction
or discontinuation of FIX infusions. This
clinical observation clearly suggests a direct
causal relationship between nephrotic syndrome
and ITI.
Conclusions and Recommendations
In view of the life-threatening nature of anaphylaxis,
the following suggestions may be considered
when treating children with severe hemophilia
B:
1. identify the children at risk by obtaining
molecular diagnosis (gene defect) of severe
hemophilia B at the time of initial presentation.
Those with large deletions or frameshift mutations
can then be monitored closely during the
early period of treatment at a medical facility
equipped to handle life-threatening emergencies;
2. at the time of initial discussion with the
family, mention these complications of treatment
and counsel the family accordingly;
3. based on the case reports of nephrotic syndrome
during ITI in patients with concurrent
allergy, ITI should be considered only for those
patients without allergy to FIX.
Further studies are required to determine the
characteristics of FIX inhibitors especially in
respect to anaphylaxis. An international registry
to collect data regarding FIX antibodies, occurrence
of anaphylaxis, ITI and complications will
help us further our knowledge with regards to
prevention of treatment-related complications
in hemophilia.
REFERENCES
1. Katz J. Prevalence of FIX inhibitors among patients
with hemophilia B: results of a large scale North American
survey. Haemophilia 1996; 2:28-31.
2. Brettler DB. Inhibitors in congenital hemophilia. Clin
Haematol 1996; 9:319.
3. High KA. Factor IX: molecular structure epitopes and
mutations associated with inhibitor formation. In:
Aledort LM, Hoyer LW, Lusher JM, Reisner HM, White
GC. II eds., Inhibitors to coagulation factors, New
York: Plenum Press, 1995:79-86.
4. Green PM, Montandon AJ, Bentley DR, Giannelli F.
Genetics and molecular biology of haemophilia A & B.
Blood Coagul Fibrin 1991; 2:539.
5. Warrier I, Ewenstein B, Koerper M, et al. FIX inhibitors
and anaphylaxis in hemophilia B. J Pediatr Hematol
Oncol 1997; 19:23-7.
6. Warrier I, Lusher JM. Development of anaphylactic
shock in haemophilia B patients with inhibitors. Blood
Coagul Fibrin 1989; 9(Suppl. 1):S125-8.
7. Mariani G, Ghirardini A, Bellocco R. Immune tolerance
in hemophilia - principal results from the International
Registry - report of the Factor VIII and IX Subcomittee.
Thromb Haemost 1994; 72:155-8.
DISCUSSION 15 Antibodies to FIX
Warrier I (Detroit, USA)
DI MICHELE: The issue of product on which
this problem develops is an important one to
clarify because I know that Dr. Katzs’ survey did
not mention this but on the other hand we’ve
had a much more heightened awareness which
might be a secondary effect in terms of the
results you have got in your study. There is a
patient in Chicago who developed this problem
twenty years ago on PCCs and also in the registry
there is a patient who developed this problem of
an allergic reaction with an inhibitor developing
in the pre-ultrapure product era and I would like
to know if, in your registry, you know how many
and exactly when these inhibitors were detected
vis à vis the products in use at that time
WARRIER: Most of the young children on that
study are on purer products. There are a few older
children and the median age was up to twelve
with inhibitor development as early as six
months. So, we do see a large variation and
those twelve year olds are the ones who were
treated prior to the development of newer products
or ultrapure products. Nevertheless the ITI
information is rather new and I don’t think very
many people put them on ITI because we
haven’t had a safe product to start them on ITI.
I don’t think PCC was considered as a choice
because of the thrombogenicity and in addition
I don’t believe that there were many people on
ITI.
DI MICHELE: I was referring to your statement
Haematologica vol. 85(supplement to n. 10):October 2000