Adrian Wiestner, Hearn J. Cho, Adam S.Asch, MaryAnn Michelis, JackA. Zeller, Ellinor I. B. Peerschke,
Babette B. Weksler, and Geraldine P. Schechter
Autoantibodies against factor VIII (FVIII)
are rare but can cause life-threatening
bleeding requiring costly factor replace-
ment and prolonged immunosuppres-
sion. We report 4 consecutively treated
patients whose acquired FVIII inhibitors
responded rapidly to immunosuppres-
sive regimens that included rituximab,
a monoclonal antibody against CD20?
B cells. Three patients had spontane-
ously occurring inhibitors. The fourth, a
patient with mild hemophilia A, devel-
oped both an autoantibody and an alloan-
tibody following recombinant FVIII treat-
ment. Pretreatment FVIII activities ranged
from less than 1% to 4% and inhibitor
titers from 5 to 60 Bethesda units (BU).
One patient with polymyalgia rheumatica
who developed the inhibitor while receiv-
ing prednisone responded to single agent
rituximab. The hemophilia patient had
rapid resolution of the autoantibody,
whereas the alloantibody persisted for
months. Responses continue off treat-
ment from more than 7 to more than 12
months. This report adds to the growing
evidence that rituximab has efficacy in
immune disorders resulting from auto-
antibody formation. (Blood. 2002;100:
© 2002 by TheAmerican Society of Hematology
Autoantibodies against factor VIII (FVIII) develop in less than one
individual per million per year and have a reported mortality
between 6% and 22%.1-3Most cases are idiopathic; up to 50% are
associated with autoimmune diseases, malignancies, drugs, or the
postpartum period.1,4Human or porcine FVIII, prothrombin com-
plex concentrates, or recombinant human FVIIa may be required to
control bleeding.2,5,6To suppress inhibitor formation most patients
receive immunosuppressive drugs,1,3,7such as prednisone,8cyclo-
phosphamide,9-11azathioprine, or cyclosporine.12,13
The anti-CD20 monoclonal antibody rituximab rapidly elimi-
nates most circulating B cells, suggesting that it could be beneficial
in autoantibody-mediated diseases by targeting the autoreactive B
cells.14Early reports of responses in immune thrombocytopenia
(ITP) and autoimmune hemolytic anemia (AIHA) appear to
confirm this notion,14-16prompting consideration of its use for
Four consecutive patients diagnosed with acquired FVIII inhibitors at our
institutions received either 4 (patients 1-3) or 2 (patient 4) weekly infusions
of rituximab, 375 mg/m2. Except for patient 3, each patient received a brief
course of prednisone at 1 mg/kg/d that was rapidly tapered (Figure 1 and 2).
All patients gave informed consent. FVIII inhibitors were titered by the
Bethesda assay.17The STACLOT LA test by Diagnostica Stago (Asnieres-
sur-Seine, France) was used to detect lupus anticoagulants.
Patient 1, a 69-year-old man with chronic renal failure, presented with
melena, bleeding from an arthrocentesis site, hemoglobin of 5.6 g/dL,
partial thromboplastin time (PTT) of 94 sec, FVIII activity (FVIIIc) of 4%,
and inhibitor titer of 5 Bethesda units (BU). He required 7 units of red cells.
Bleeding resolved following treatment with recombinant human FVIII (100
U/kg loading, 10 U/kg/h maintenance), desmopressin acetate (DDAVP),
and conjugated estrogen. Prednisone was started on day 1 and rituximab on
day 3. Pretreatment serum electrophoresis revealed a very small monoclo-
nal immunoglobulin G (IgG) ? paraprotein. Total ?-globulin level was 0.92
g/dL(normal range, 0.6-1.6 g/dL).
Patient 2, a 38-year-old man with ascites and lymphadenopathy of
unknown etiology, PTT of 67 sec, FVIIIc less than 1%, inhibitor titer of 23
BU, and a lupus anticoagulant, developed a large hematoma at a venepunc-
ture site and a 2 g/dL fall in hemoglobin. One week after treatment with
FVIII inhibitor bypassing activity (FEIBA) 50 IU/kg four times a day, 1 g
cyclophosphamide intravenously, and prednisone, FVIIIc was 3%, and
treatment with rituximab was initiated because of lack of clinical improve-
ment. FEIBAwas safely discontinued 1 wk after rituximab was initiated.
Patient 3, a 79-year-old woman on prednisone and azathioprine for
polymyalgia, developed spontaneous giant ecchymoses; the largest was
20 ? 25 cm. Investigations revealed a PTT of 58 sec, FVIIIc of 2%,
inhibitor titer of 8 BU, and a lupus anticoagulant. Azathioprine was
discontinued, prednisone maintained, and weekly rituximab initiated.
Within 1 week, the ecchymoses resolved.
Patient 4, a 39-year-old man with mild hemophiliaAand FVIIIc level of
15% because of an Arg2150His mutation received recombinant human
FVIII perioperatively. Six days after the operation, on a regimen of FEIBA
and DDAVP, an inhibitor of 60 BU was detected, but FVIIIc was unchanged
at 15%. Two weeks later FVIIIc fell to 2% with only a minimal increase
following DDAVPprompting treatment with rituximab and prednisone.
Results and discussion
Our patients who presented with bleeding had rapid clinical
improvement following initiation of immunosuppressive treatment
that included rituximab. This improvement was most striking in
From the Hematology Branch, National Heart, Lung, and Blood Institute,
National Institutes of Health, Bethesda, MD; Weill Medical College, Cornell
University, NewYork, NY; Hackensack University Medical Center, Hackensack,
NJ; and Veterans Affairs Medical Center and George Washington University,
Submitted March 11, 2002; accepted June 17, 2002. Prepublished online as
Blood First Edition Paper, July 12, 2002; DOI 10.1182/blood-2002-03-0765.
Reprints: Geraldine P. Schechter, Hematology Section, Room 4D113,
Veterans Affairs Medical Center, 50 Irving St NW, Washington, DC 20422;
The publication costs of this article were defrayed in part by page charge
payment. Therefore, and solely to indicate this fact, this article is hereby
marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
© 2002 by TheAmerican Society of Hematology
3426BLOOD, 1 NOVEMBER 2002?VOLUME 100, NUMBER 9
patient 3 whose giant ecchymoses resolved rapidly following the
first dose of rituximab, her sole treatment. In patients 1 to 3, FVIIIc
normalized, and the inhibitor became undetectable between 3 and
12 weeks from the start of rituximab (Figure 1). Patient 1 had a
normal FVIIIc within 2 weeks and resolution of the inhibitor at 3
weeks. The antigenic stimulation by the FVIII infusions patient 1
received may have had a role in his rapid response.10In patient 4
(Figure 2), endogenous FVIIIc returned to baseline within 1 week,
indicating resolution of the autoantibody, whereas antibody di-
rected against wild-type FVIII persisted for more than 2 months.
All patients remain in remission from more than 7 to more than 12
months off treatment.
Spontaneous resolution of FVIII inhibitors occurs in up to 30%
of patients, most frequently when the inhibitors develop in the
postpartum period.18Because the median time to spontaneous
resolution is 21 months, most patients are treated with immunosup-
pressive drugs to induce more rapid resolution.1,3,7Single-agent
prednisone has a reported response rate of 30%8,9and could have
accounted for the responses seen in 3 of our patients. However,
patients who respond to prednisone frequently require long-term
maintenance therapy to prevent relapse.8In contrast, we were able
to taper prednisone rapidly without relapse in our patients.
The combination of prednisone with cyclophosphamide is
effective in 70% to 100% of patients, and inhibitors resolve within
3 to 37 weeks.10,11The time to response in our patients treated with
rituximab appears shorter, and potential complications associated
with combination prednisone and cyclophosphamide therapy such
as neutropenic fever, herpes zoster, myelodysplasia, and cata-
Inhibitor titers in our patients were of intermediate strength and
comparable to those reported in many studies.3,10Although patients
with low-level inhibitors respond more easily to immunosuppres-
sive treatment, inhibitor titer is not directly related to bleeding
complications, and even patients with low titer inhibitors can have
The addition of short courses of prednisone to rituximab may have
enhanced the response in our patients.Apreliminary report found only
partial remissions in 3 patients with FVIII inhibitors treated with
that single-agent rituximab can suffice. Two of our patients (patients 1
and 2) may have had an underlying lymphoproliferative disorder,
Rituximab was well tolerated in our study. ?-Globulin levels
decreased by 16% at 3 months in patient 1 and returned to pretreatment
levels by 7 months. In the context of recent reports on viral infections
FVIII inhibitors have been reported in several kindreds with
mild hemophilia because of missense mutations, usually arising
after factor replacement and causing a bleeding pattern similar
to acquired hemophilia.23Patient 4’s course was similar to these
previously reported experiences (Figure 2). Consistent with an
alloresponse, the high titer inhibitor initially spares the endoge-
nous FVIII, but a subsequent drop in the FVIII level indicates
the formation of autoantibodies. In our patient, prednisone and
rituximab led to a rise in FVIIIc back to his baseline level within
a week. However, measurable antibody against wild-type FVIII
Figure 1. Response to treatment in 3 patients with acquired FVIII inhibitors.
Upper half of the figure shows percentages of FVIII activity (FVIIIc). Lower half shows
inhibitor titer in Bethesda units. Rituximab 375 mg/m2(open arrows) was started at
week 0 and repeated weekly for 4 doses. Prednisone at 1 mg/kg/d is indicated by a
mide 1 g intravenously. In patient 3, azathioprine (A) was stopped, and prednisone
30 mg every day was continued unchanged as indicated by the broken line.
Figure 2. Response to treatment in a patient with mild hemophilia A and an
acquired FVIII inhibitor. Upper half of the figure shows percentage of FVIII activity
(FVIIIc). Lower half shows inhibitor titer in Bethesda units. Rituximab 375 mg/m2
(open arrows) was given at week 0 and week 1. Prednisone at 1 mg/kg/d is indicated
by a solid line; broken line indicates prednisone taper.
RITUXIMAB FORACQUIRED FACTOR VIII INHIBITORS3427BLOOD, 1 NOVEMBER 2002?VOLUME 100, NUMBER 9
persisted for more than 2 months, suggesting that rituximab eliminated Download full-text
Rituximab has been used with varying success in other autoanti-
body-mediated disorders. Reported response rates range from 30%
in ITP15to 100% in childhood AIHA.16Different response rates
may be due to differences in pathogenesis or expression levels of
CD20 on the antibody-producing B-cell population.14During
maturation of B cells to plasma cells, CD20 expression is
down-regulated. Therefore, timing may be critical for response
because rituximab may not be effective if a CD20?plasma cell
population has become established. The patients with ITP received
rituximab a median of 15 months from diagnosis,15whereas patients in
our study were treated within weeks of diagnosis. Early reports also
suggest that rituximab may have efficacy in rheumatoid arthritis24and
not improve following treatment with rituximab. However, the lupus
anticoagulants in patients 2 and 3 and the monoclonal gammopathy in
We conclude that rituximab appears to be an effective and safe
treatment for patients with FVIII inhibitors and merits further
study. Early treatment and combination with prednisone may be
required for maximal benefit.
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3428WIESTNER et alBLOOD, 1 NOVEMBER 2002?VOLUME 100, NUMBER 9