Autoantibodies against factor VIII are rare but may cause life-threatening
bleeding. Up to 30% of inhibitors may resolve spontaneously, but
immunosuppressive drugs with possible serious adverse effects and costly factor
replacement are usually required. Rituximab (Rituxan), a humanized monoclonal
antibody against CD20-positive B cells, has been reported to be beneficial in
certain antibody-mediated autoimmune diseases. We describe here four
consecutively treated patients whose acquired factor VIII inhibitors responded
rapidly to immunosuppressive regimens that included rituximab administered at
375 mg/m² weekly for 2 to 4 weeks.
Patient 1, a 69-year-old man, presented with melena, bleeding from an
arthrocentesis site, hemoglobin of 5.6 g/dL, partial thromboplastin time (PTT)
of 94 seconds, factor VIII activity of 4%, and an inhibitor titer of 5 Bethesda
units. Bleeding resolved following treatment with recombinant factor VIII,
desmopressin acetate (DDAVP, Stimate), and prednisone. Weekly rituximab (four
doses) was started on day 3. At 4 weeks, factor VIII activity was 186% and
inhibitor titer 0 Bethesda units.
Patient 2, a 38-year-old man with ascites of unknown etiology, PTT of 67
seconds, and factor VIII activity of less than 1% (inhibitor titer, 23 Bethesda
units) developed a large hematoma at a venipuncture site associated with a fall
in hemoglobin of 2 g/dL. One week after treatment with anti-inhibitor coagulant
complex (Feiba VH Immuno), 1 gram of cyclophosphamide × 1, and prednisone,
factor VIII activity was 3%, and treatment with weekly rituximab (four doses)
was initiated. The inhibitor titer fell to 1.1 Bethesda units at 3 weeks and to
0 Bethesda units with factor VIII activity of 72% at 6 weeks.
Patient 3, a 39-year-old man with congenital mild hemophilia A (baseline
factor VIII activity of 15% due to an Arg2150His mutation) developed a high
inhibitor titer of 60 Bethesda units, with a fall in factor VIII level to 2% 6
days postoperatively following prophylactic treatment with recombinant factor
VIII during a laminectomy. After treatment with prednisone and weekly rituximab
(two doses), factor VIII activity was 12% (inhibitor titer of 28 Bethesda units)
at 1 week and 17% (15 Bethesda units) at 2 months, indicating resolution of the
autoantibody but persistence of the alloantibody.
Patient 4, a 79-year-old woman on every-other-day prednisone and azathioprine
for polymyalgia rheumatica developed spontaneous giant ecchymoses with a PTT of
58 seconds and factor VIII activity of 2% (inhibitor titer of 8 Bethesda units).
Weekly rituximab (four doses) was started, azathioprine was discontinued, and
prednisone continued unchanged. All bruising resolved within 1 week; factor VIII
increased to 78% and inhibitor titer fell to 0 Bethesda units by 3 months.
CONCLUSION: Our experience with rituximab is noteworthy in several respects:
(1) All four patients had complete resolution of the inhibitor; (2) the
inhibitor resolved within 3 weeks in two patients, which compares favorably with
reported experience; (3) one patient developed the inhibitor while on
immunosuppression with prednisone and azathioprine but responded to the addition
of rituximab; and (4) no adverse reactions occurred and prednisone could be
tapered rapidly. We conclude that rituximab merits further evaluation in the
treatment of acquired factor VIII inhibitors.