Baylor University Medical Center Proceedings July 2017 - 344

autoantibodies acting against the factor VIII molecule and
interfering with the coagulant activity of factor VIII (4). Factor VIII inhibitors interfere with factor VIII binding to factor
IXa and disrupt the binding of factor VIII to von Willebrand
factor and phospholipids (3). Given the rarity of the disease,
no case-controlled studies have been performed to discern
appropriate treatment of AHA (5). Initial management of
AHA focuses on achieving control of bleeding episodes and
inhibitor suppression (6). Long-term inhibitor suppression
or eradication often requires immunosuppressive therapy.
Achieving complete remission (CR) (undetectable inhibitor
level) is crucial because patients who do not achieve CR have
worsened survival (7). The combination of prednisone and
cyclophosphamide is the current mainstay of treatment and
leads to remission in 66.7% of patients (3). Rituximab is often
considered a second-line treatment, but some believe it should
Figure 2. A bone marrow biopsy showing markedly increased cellularity, estibe used ﬁrst line with prednisone and cyclophosphamide if
mated at approximately 70%, with evidence of trilineage maturation with ample
the inhibitor titer is >5 (4).
megakaryocytes, erythroid precursors, and maturing granulocytes. Multiple lymThe European Acquired Haemophilia Registry is the largest
phocytic aggregates are identified.
dataset analyzing immunosuppressive treatment in AHA (7).
Based on results from the registry, steroids combined with cythe inhibitor titer returned to 0, and the spleen was no longer
clophosphamide achieved the best remission rates, showing CR
palpable. Prednisone was tapered and cyclophosphamide was
in 70% of patients (7). The registry also showed increased rates
continued, resulting in durable remission over 3 years to date.
of relapse with the use of steroids with cyclophosphamide when
compared with rituximab-based regimens. Rituximab-based
regimens had a CR of 59% and a 3% relapse rate (compared
DISCUSSION
with a relapse rate of 12% with steroids and cyclophosphamide)
An acquired factor VIII deﬁciency is a rare bleeding disor(7). Rituximab alone was least likely to achieve a stable CR and
der usually presenting with purpura and/or soft tissue bleedrequired a longer time to achieve negligible inhibitor levels and
ing. Factor VIII inhibitors mostly consist of IgG1 and IgG4
normal factor VIII levels in the
registry (6).
a
b
The diagnosis of WAHA is
confirmed when other forms
of anemia have been excluded
and there are laboratory signs
of hemolysis. Hemolysis in CLL
develops secondary to IgG antibodies produced by nonmalignant B-cell clones directed
against red blood cell antigens,
leading to clearance by the spleen
and extravascular hemolysis (8).
d
c
The ﬁrst-line treatment is steroids, 1 mg/kg/day, but this results in long-term remission in
<15% to 20% of patients (9).
Second-line treatments include
azathioprine at 3 to 4 mg/kg/
day, cyclophosphamide (low
or high dose), or rituximab at
375 mg/m2. Rituximab results in
response rates of 60% to 70%,
but only 20% of patients achieve
Figure 3. Immunohistochemical stains showing strong positivity for (a) PAX-5, (b) CD20, (c) CD5, and (d) kappa 5 years of remission (9).
Treatment of WAHA and
(magnification 400×). Strong positivity was also shown for Zap-70, and lambda showed nonspecific staining. This was
CLL has been found to be
interpreted as consistent with CLL with about a 40% involvement of the marrow.
344

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