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Blood, 1 May 2003, Vol. 101, No. 9, pp. 3753-3754
CORRESPONDENCE
To the editor:
Acquired high-titer factor VIII inhibitor: fatal bleeding
despite multimodal treatment including rituximab preceded by multiple
plasmaphereses
Acquired factor VIII (FVIII) inhibitors can cause
life-threatening bleeding. Rapid restoration of coagulation is vital.
Therapeutic approaches include factor substitution,1,2
immunosuppression (eg, steroids, cyclophosphamide3), and
plasmapheresis.4 A novel treatment option is rituximab, a
chimeric monoclonal antibody targeting the CD20 antigen and blocking
proliferation of normal B cells.5 Recently, Wiestner et al reported on the reduction of acquired FVIII
inhibitors in 4 patients by an immunosuppressive regimen including
rituximab.6 Patients presented with FVIII activity (FVIIIc) ranging from less than 1% to 4% (normal range,
70%-200%) and inhibitor titers ranging from 5 to 60 Bethesda units
(BU). In 3 patients, FVIIIc normalized after the first of 1 to
4 treatment courses. The inhibitor became undetectable within 3 to 12 weeks. Plasmaphereses were not necessary. Here, we describe the clinical course of a patient suffering from
acquired idiopathic FVIII inhibitors with extraordinarily high titer.
The 71-year-old male was admitted for the development of a large
painful mass in his left gluteal region. He had received an
intramuscular injection for lumbalgia 4 days prior. Patient history included years of chronic obstructive pulmonary
disease but was otherwise unremarkable, particularly for
allergic diathesis. There was no family history of autoimmune diseases,
bleeding disorders, or neoplasias. Clinical examination revealed a
large painful mass in his left gluteal region and diffuse mucosal
bleeding. Respiratory sounds were slightly prolonged; liver and spleen
were not enlarged. Laboratory work-up demonstrated pathologic
coagulation studies with a markedly prolonged activated partial
thromboplastin time (aPTT) of 80 seconds, decreased FVIIIc of less than
1%, and high FVIII inhibitor titers of 633 BU. Extensive laboratory
exams did not reveal further pathologic results. After a 2-week treatment with steroids he was transferred to our unit
with persistent bleeding (day 0, Figure
1).
Here, the patient received one dose of FVIII inhibitor bypassing
activity (FEIBA, Baxter BioScience, Heidelberg, Germany),
followed by recombinant FVIIa (NovoSeven, NovoNordisk, Mainz,
Germany) given for 3 days, which did not improve the clinical course.
In need of rapid intervention, cyclophosphamide and vincristine were
applied twice. At this point, as inhibitor titer had even increased to
19 800 BU, plasmapheresis was started. A dramatic decline in inhibitor
titers was observed immediately thereafter (Figure 1). Nevertheless,
the clinical parameters worsened (hematuria, hematemesis, and multiple
cutaneous suggilations). aPTT remained extensively elevated and FVIIIc
was still below the detection level, when rituximab (375 mg/m2) was added to the treatment regimen on days 22 and 31 after admission. Treatment was well tolerated. At one week
after the first application, B lymphocytes were already reduced to
13/µL (normal range, 74-394/µL). Despite multimodal treatment, the
patient died on day 39 with one of numerous large hematomas occluding
the upper airways. No further pathologic findings were reported in
postmortem examination, particularly no clonal B-cell
disorder.
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| Figure 1.
Multimodal treatment of acquired factor VIII inhibitor.
Time course of activated partial thromboplastin time (aPTT,
 ), factor VIII ( ), and factor VIII inhibitor ( ). A rapid
decline in factor VIII inhibitor is accomplished by
plasmapheresis. FEIBA indicates factor VIII inhibitor
bypassing activity.
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In 30% of patients, spontaneous resolution of acquired FVIII
inhibitors has been described after an average of 21 months.7 However, in the case of bleeding and high
antibody titers, rapid restoration of coagulation is required. This
often is not achieved by current immunosuppressive regimen. With regard
to novel treatment options, the successful application of
2-chloro-deoxyadenosine has recently been reported.8 Here,
the median time to reach nadir inhibitor titers was 137 days; the
median time for a 50% increase in FVIIIc was 117 days. Concerning
efficacy of rituximab, data of Wiestner and colleagues suggest a faster
FVIII recovery (3-12 weeks). Despite the promising treatment results
with rituximab in several immunoglobulin-mediated
disorders,9 it remains a concern whether the nadir of
FVIII inhibitors can be achieved fast enough in high-risk cases. To maximize treatment efficacy in our critically ill patient, we
combined standard immunosuppressive therapy with plasmapheresis and
rituximab. Plasmapheresis was intended to rapidly reduce autoantibody levels and allow for infusion of large amounts of plasma with procoagulant activities. Indeed, we experienced a decline in inhibitor titers after initiation of plasmapheresis. Within 25 days, a 200-fold reduction of inhibitors was achieved. Yet, it is of note that the
remaining FVIII inhibitor titer of 94 BU still was high enough to cause
fatal bleeding. As the number of B cells at that time had already been markedly
reduced, half-life of autoantibodies should be
investigated.10 Whereas the combination of rituximab and
plasmapheresis was effective in significantly reducing FVIII inhibitor
titer, the autoimmune process with its enormous initial inhibitor
burden was not overcome. Given the efficacy of combining rituximab with
plasmapheresis, however, we strongly suggest its implementation in the
very early clinical course in patients with extremely high antibody
titers, when rapid elimination of antibodies is required to prevent
fatal bleeding. This combined approach may be one way to solve the
clinical problem of life-threatening bleeding upon FVIII inhibitors in the future.
Karl-Georg Fischer, Barbara Deschler, and Michael Lübbert
Correspondence: Karl-Georg Fischer, University Hospital
Freiburg, Department of Medicine, Division of Nephrology and General
Medicine, Hugstetter Str 55, D-79106 Freiburg, Germany;
e-mail: fischer{at}med1.ukl.uni-freiburg.de
References
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Use of recombinant activated factor VII for treatment of a retropharyngeal hemorrhage in a hemophilic patient with a high titer inhibitor.
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Recombinant factor VIII for the treatment of previously untreated patients with hemophilia A safety, efficacy, and development of inhibitors: Kogenate Previously Untreated Patient Study Group.
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1993;328:453-459[Abstract/Free Full Text].
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Green D, Rademaker AW, Briet E.
A prospective, randomized trial of prednisone and cyclophosphamide in the treatment of patients with factor VIII autoantibodies.
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Bona RD, Pasquale DN, Kalish RI, Witter BA.
Porcine factor VIII and plasmapheresis in the management of hemophiliac patients with inhibitors.
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Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis.
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Wiestner A, Cho HJ, Asch AS, et al.
Rituximab in the treatment of acquired factor VIII inhibitors.
Blood.
2002;100:3426-3428[Abstract/Free Full Text].
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Lottenberg R, Kentro TB, Kitchens CS.
Acquired hemophilia: a natural history study of 16 patients with factor VIII inhibitors receiving little or no therapy.
Arch Intern Med.
1987;147:1077-1081[Abstract].
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Sallah S, Wan JY.
Efficacy of 2-chlorodeoxyadenosine in refractory factor VIII inhibitors in persons without hemophilia.
Blood.
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Engelhardt M, Jakob A, Rüter B, Trepel M, Hirsch F, Lübbert M.
Severe cold hemagglutinin disease (CHD) successfully treated with rituximab.
Blood.
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Looney RJ.
Treating autoimmune disease by depleting B cells.
Ann Rheum Dis.
2002;61:863-866[Free Full Text].
Response:
Rituximab in the treatment of acquired factor VIII inhibitors
The letter by Fischer et al highlights the clinical
challenge presented by patients with acquired factor VIII (FVIII)
inhibitors. Fatal bleeding remains a dreaded complication despite the
availability of several hemostatic agents and a choice of
immunosuppressive drugs. Their patient had an extremely high FVIII
inhibitor titer and was treated initially with prednisone alone for 2 weeks, followed by combination chemotherapy, plasmapheresis, and 2 doses of rituximab. While there was a significant decline in inhibitor
titer, the patient succumbed to bleeding complications 4 weeks after
the start of polychemotherapy and 2 weeks after the initiation of rituximab. The 4 patients with autoimmune hemophilia that we reported had lower inhibitor titers (5 to 60 Bethesda units [BU]) at
presentation. Following treatment with rituximab and prednisone, plus
cyclophosphamide in the patient with the highest titer, all had rapid
clinical improvement and complete resolution within 3 to 12 weeks.1 The responses have been durable, lasting to date
+ 17 to + 22 months without any maintenance treatment. A
comparable experience has been reported by Kain et al2 in
a patient who had autoimmune hemophilia for 10 years who was refractory
to standard immunosuppressive drugs. Their patient's high titer
inhibitor (268 BU) resolved over a 4-month period following 4 weekly
doses of rituximab (375 mg/m2) alone and remained less
than 1 BU for + 7 months. What should the role of rituximab be in the treatment of patients with
FVIII inhibitors? Unfortunately it is unlikely that controlled studies
will be possible in this rare disease. Perhaps experiences with this
agent in the more common autoimmune disorders, for example immune
thrombocytopenic purpura (ITP)3 and rheumatoid arthritis (RA),4 may serve to guide treatment decisions in patients with acquired FVIII inhibitors. Similar to the responses in
our FVIII inhibitor patients, clinical improvement appears often
surprisingly rapid in these autoimmune diseases and does not fully
correlate with the resolution of antibody titers. While there are
numerous reports that rituximab alone may suffice, it appears, at least
for patients with RA, that combination therapy with cyclophosphamide
may be superior.4 Rituximab is not effective in all RA
patients and relapse is frequent, occurring typically following B-cell
recovery 6 to 9 months from the start of therapy. Patients who relapse
after an initial response may respond to second courses of rituximab.
The question of maintenance therapy has hardly been addressed. At this time we would certainly agree with Fischer et al that rituximab
should be considered early in the management of patients with active
bleeding and/or high titer FVIII inhibitors. In patients with very high
antibody burden, it seems appropriate to use combination chemotherapy
including prednisone, cyclophosphamide, and rituximab at the time of
diagnosis. It is well known that FVIII inhibitors can resolve
spontaneously in up to 30% of patients,5 and prednisone alone or in combination with cyclophosphamide will effect remissions in
a substantial proportion of patients.6 However time to
resolution of the antibody with these agents is usually slow, taking
months, and prolonged treatment with prednisone and cyclophosphamide
may be associated with significant side effects. If the response rate to rituxmab continues to be confirmed, it is likely to be shown cost-effective in those patients who require factor replacement. A full
course of 4 weekly doses of rituximab is less expensive than one day of
replacement therapy with recombinant FVIII and a fraction of the cost
of FVIIa (NovoSeven). In patients with low-titer inhibitors it may not
even be necessary to give a full course of 4 doses of rituximab once a
clear improvement has been detected.
Adrian Wiestner, Babette B. Weksler, and Geraldine P. Schechter
Correspondence: Geraldine P. Schechter, VA Medical Center,
50 Irving St, NW, Washington, DC 20422-0001; e-mail:
g.p.schechter{at}med.va.gov
References
1.
Wiestner A, Cho HJ, Asch AS, et al.
Rituximab in the treatment of acquired factor VIII inhibitors.
Blood.
2002;100:3426-3428[Abstract/Free Full Text].
2.
Kain S, Copeland T-S, Leahy MF.
Treatment of refractory autoimmune (acquired) haemophilia with anti-CD20 (rituximab) (letter).
Brit J Haem.
2002;119:578[CrossRef][Medline]
[Order article via Infotrieve].
3.
Stasi R, Pagano A, Stipa E, Amadori S.
Rituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura.
Blood.
2001;98:952-957[Abstract/Free Full Text].
4.
Leandro MJ, Edwards JC, Cambridge G.
Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion.
Ann Rheum Dis.
2002;61:883-888[Abstract/Free Full Text].
5.
Lottenberg R, Kentro TB, Kitchens CS.
Acquired hemophilia: a natural history study of 16 patients with factor VIII inhibitors receiving little or no therapy.
Arch Intern Med.
1987;147:1077-1081[Abstract].
6.
Green D, Rademaker AW, Briet E.
A prospective randomized trial of prednisone and cyclophosphamide in the treatment of patients with factor VIII autoantibodies.
Thromb Haemost.
1993;70:753-757[Medline]
[Order article via Infotrieve].
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