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

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J. Ingerslev
be established more accurately, although the
prevalence appears to be less than 5%.
Recent research has signaled a close relationship
between the nature of the causative mutation
and the risk of inhibitor development in
hemophilia A (J. Oldenburg , data presented in
this issue), since the intron 22 inversion, and
larger deletions, appear to be responsible for the
majority of cases. Other contributing factors are
still less well understood. Certain histocompatibility
locus class II profiles may be associated
with the risk of inhibitors. 2 Most likely, pre-existing
immunologic features may also influence the
risk of inhibitor formation in an individual.
Among pairs of brothers with hemophilia and
inhibitors registered in a Swedish study, only one
of the two brothers was affected by the inhibitor
complication in almost 50% of the pairs. 3 High
responder inhibitors, i.e. more than 5 Bethesda
Units per mL (BU/mL) of plasma at any time,
are the major clinical challenge. Antibody levels
that remain persistently below 5 BU/mL (low
responders), are more easily managed, and
some even disappear on continued treatment
with ordinary doses of substitution concentrate.
A particularly dangerous complication which
can occur in hemophilia B inhibitor patients is
anaphylactic reactions to factor IX replacement.
This frightening complication is most often seen
in patients with complete deletion of the factor
IX gene. 4
Clinical risk problems
Patients with inhibitors are at increased risk of
sudden death from major uncontrolable bleeding
such as cerebral hemorrhage. Furthermore,
“trivial” hemophilic bleeds that may be quite
easily managed in non-inhibitor patients are
often more difficult to manage in the inhibitor
patient, and disabling long-term complications,
such as long-standing hematoma or persistent
hemarthrosis, are common. The alternative
treatment measures available may be less efficient,
and more costly, and monitoring of their
efficacy may not be feasible.
The new case with inhibitors
A new case of inhibitor development may be
detected during patients’ three monthly routine
check-ups, which are nowadays common practice
in many institutions. More often, inhibitors
are found because of increased bleeding or
insufficient control of bleeds using ordinary doses
of concentrate.
Ideally, a strategy aimed at removing or suppressing
the inhibitors should be used.
Plasmapheresis may be helpful in emergencies
as a very short-lasting remedy in patients with relatively
low inhibitor levels. When no acute problem
calls for immediate action, the patient should
be re-tested after 2-4 weeks to see whether there
is a spontaneous change in inhibitor titer. If
inhibitors are of high-responder nature, an
attempt to induce immune tolerance may be indicated,
but the outcome may be influenced by the
actual titer of the inhibitors when this treatment
is commenced.
Immune tolerance induction
The aforementioned highlights that management
of inhibitors in hemophilia A differs in several
ways from that in hemophilia B. While continued
treatment with factor VIII apparently poses
no immediate physical harm to the patient,
there is a highly significant risk of allergic reactions
in patients with hemophilia B inhibitors following
renewed exposure to factor IX.
Since the first report in 1977 of successful suppression
of a high-responder hemophilia A
inhibitor using high doses of factor VIII, 5
immune tolerance programs have been increasingly
adopted in the several countries. Until now,
the tolerizing effect of factor VIII concentrates
using daily doses greater than 100 IU/kg b.w.
has been documented only in single-case or single-case
series reports, whereas controlled clinical
studies are lacking. Numerous treatment
regimens have been published, some using very
high doses of factor VIII according to the socalled
Bonn protocol or modifications of this
regimen, 6-9 others employing considerably lower
doses of factor VIII. 10,11 Three major data collections
have been compiled in the International
Immune Tolerance Registry, 12 the North American
Immune Tolerance Registry (NAITR), 13 and the German
National Immune Tolerance Registry. 14
With fairly small differences, the first two Registries
recorded an overall success-rate close to
70%. The pre-induction inhibitor titer was a significant
predictor of the outcome of the attempt
to make patients tolerant. If high-dose treatment
was instituted more than five years after
first detection of the inhibitors, the treatment
outcome was less successful. The magnitude of
the dose of factor VIII adopted seemed more
important for the outcome in the European registry
than in its North American counterpart.
Based on most recent data, the German registry
patients displayed an overall success-rate of
81%. The three registries consistently observed
that the peak inhibitor titer level predicted the
outcome of immune tolerance treatment. In the
low responder patient group, all three registries
reported an efficacy rate of between 80% and
100%, supporting the early finding by Rizza et al.
that some of these inhibitors disappear with
continued “on demand” treatment. 15
These registries provide us with only few
Haematologica vol. 85(supplement to n. 10):October 2000