Vol 41 # 3 September 2009 - Kma.org.kw

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Acquired Hemophilia in a Child: Response to Rituximab
September 2009
He received intravenous immunoglobulin (IVIG)
at a dose of 1 g/kg for two days to which he showed
no response. Another course of IVIG was given two
weeks later without any significant change. His FVIII
inhibitor level increased to 258 BU/ml and he was
started on oral prednisolone 1 mg/kg in addition to
further courses of IVIG. He responded with a decline
in inhibitor level to 50-60 BU/ml. Unfortunately, in
February 1996, while still on prednisolone, he had
a rebound in his inhibitor level to 400 BU/ml and
he was started on azathioprine 3 mg/kg per day,
in addition to prednisolone. He responded well
and was maintained on this regimen till inhibitors
were no longer detected by June 1997. Prednisolone
was tapered over six months and azathioprine was
continued for about ten months (until April 1998).
He was in full remission till November 2000,
when his factor VIII level dropped to 9%. He was
asymptomatic; there was no history of preceding
infection, vaccination or drug ingestion. His physical
examination was normal. Repeat CBC, serum
immunoglobulins, ESR, ANA, anti dsDNA were
negative. So he was given IVIG and restarted on
oral prednisolone and azathioprine. Factor VIII level
normalized after two months. He was tapered off his
medication slowly over a one year period and he was
in remission for a year until November 2002 when
he had another relapse and since then he could not
be weaned off prednisolone. He continued to have
ecchymoses and had bleeding into the right thigh
muscles on two occasions with no sequelae and no
life-threatening bleeding. In 2004 he was given a twomonth
trial of mycophenolate, to which he did not
respond. In June 2005 he was evaluated in St. Louis,
MO, USA and given a six-week course of rituximab
375 mg/m 2 /dose, to which he responded promptly.
He did not develop any adverse side effects. When he
was last evaluated in June 2007, he remains well and
currently his factor VIII level is about 150% and his
inhibitor level is undetectable.
DISCUSSION
Acquired hemophilia is uncommon and most of
the published data is on adults. To the best of our
knowledge there are only twenty reported cases
in children, the youngest being a three year old
boy [2] . Our patient was only two years old at initial
presentation, and he had one of the highest reported
levels of inhibitors. He had bronchial asthma during
early childhood, which is one of the conditions that
have been associated with acquired inhibitors [2,3] .
However, we could not establish a causal relationship
and the bronchial asthma could have been simply
coincidental.
Our patient presented with spontaneous soft
tissue bleeding (subcutaneous and intramuscular),
which is the usual mode of presentation in acquired
hemophilia, though serious bleeding episodes have
been reported in some patients [1-3] . The treatment
options are directed at controlling the bleeding as a
first and urgent step and eliminating the inhibitors [3] .
For controlling bleeding, human factor VIII
concentrate in high doses or desmopressin acetate is
effective in patients with low titers of inhibitors and
measurable factor VIII levels [4] . Porcine factor VIII is
another effective alternative [2,3,5] , but the development
of heteroantibodies to porcine factor VIII has been
reported. Therefore, it is recommended to check for
porcine factor VIII inhibitor titers prior to porcine
factor VIII administration. In patients presenting with
severe bleeding or very low FVIII level and very high
inhibitor titers, other alternatives should be used [6] .
Activated prothrombin complex concentrate, with
factor VIII inhibitor-bypassing activity, has proved
to be effective in controlling episodes of bleeding [7] .
Recombinant activated factor VII is effective and it
is not associated with the development of antibodies
but it is expensive and has a short plasma half life
requiring frequent or continuous infusions [8] .
Plasmapharesis or immunoadsorption can rapidly
reduce inhibitor levels but the effect is transient [9,10] .
IVIG at a dose of 1 g/kg/day for two consecutive
days or 400 mg/kg for five consecutive days, has been
used with varying results [11,12] . Immunosuppressive
therapy with corticosteroids and cytotoxic drugs
alone or in combination, is regarded as the mainstay
of treatment [13] . In most of the published data
prednisolone at a dose of 1 mg/kg per day was used
initially and cyclophosphamide, at a dose of 2 mg/
kg/day, was added later, or treatment was initiated
with both drugs at the same time [14] . Several other
immunosuppressive agents, including azathioprine,
mycophenolate, cyclosporine, tacrolimus and
sirolimus have been used with varying success rates [3] .
Our patient responded to prednisolone initially but
relapsed seven months later leading to the addition of
azathioprine. Remission was subsequently achieved,
but his course was variable with relapses. He did not
respond to mycophenolate. We were wary of using
cyclophosphamide because of his age and also since
he never had life-threatening bleeding.
Rituximab, a chimeric anti CD 20 monoclonal
antibody, depletes B-cells and has shown dramatic
success in the treatment of lymphoma. It has been
tried in the treatment of several diseases with an
autoimmune basis both in adults and in children
with very encouraging results [15] . Recent studies have
proved its efficacy in adults with acquired hemophilia
either as a monotherapy or combined with an
immunosuppressive agent in patients with partial
response or high antibody titers [16-18] . To the best of our
knowledge, rituximab had not been tried for acquired