American Journal of Hematology 71:105–108 (2002)

Successful Treatment of Severe Thrombotic

Thrombocytopenic Purpura With the Monoclonal
Antibody Rituximab
Jens Chemnitz,* Andreas Draube, Christof Scheid, Peter Staib, Armin Schulz, Volker Diehl,
and Dietmar Söhngen
Department I of Internal Medicine, University of Cologne, Germany

The only established treatment for patients with thrombotic thrombocytopenic purpura
(TTP) is plasma exchange against fresh frozen plasma. For cases refractory to plasma
exchange, no generally treatment schedule exists. One option is immunosuppressive
therapy with corticosteroids and vincristine. Rituximab is a chimeric monoclonal anti-
body directed against the CD20 antigen, and it has been successfully used in B-cell
malignancies and is being investigated in autoimmune diseases. Its efficacy in TTP has
not yet been determined. We report two female patients with severe TTP refractory to
multiple courses of plasmapheresis, high-dose steroid treatment, and vincristine who
responded after adding rituximab while continuing plasmapheresis. Am. J. Hematol. 71:
105–108, 2002. © 2002 Wiley-Liss, Inc.

Key words: thrombotic-thrombocytopenic-purpura; treatment; plasmapheresis; immuno-

suppressive therapy; rituximab

INTRODUCTION currently being tested for a variety of immunological

Thrombotic thrombocytopenic purpura is a life-
threatening, multisystem disease characterized by throm-
bocytopenia, microangiopathic haemolytic anaemia, neu-
rological changes, progressive renal dysfunction, and
fever. Idiopathic cases occur at a rate of 3.7 per year per
million persons, and the mortality rate for promptly
treated cases ranges from 10% to 20% [1]. After endo-
thelial cell injury, unusually large von Willebrand factors
(vWF) are found in the plasma of patients with TTP. A
specific protease cleaving these large vWF recently has
been isolated in normal human plasma [2,3]. Patients
with the classic form of TTP have less activity of this
protease [4]. There is also evidence of a hereditary TTP
form, also showing less protease concentrations in the
plasma of these patients [5]. For the cases of non-familial
TTP, it could be demonstrated that the lack of the spe-
cific vWF cleaving protease is caused by the presence of
a soluble inhibitor. Recent data suggest that this inhibitor
is an immunoglobulin of the IgG subtype [6]. This could
explain the effect of immunosuppressive therapy in some
cases of TTP [7]. Rituximab is a chimeric antibody di-
rected against the CD20 antigen present on B cells. It has
been successfully used to treat B-cell malignancies and is
© 2002 Wiley-Liss, Inc.
diseases such as rheumatoid arthritis and idiopathic
thrombocytopenic purpura.
CASE REPORT
Patient 1
The 39-year-old female patient was referred to our
department for further differential diagnosis and therapy
of haemolytic anaemia. The medical history revealed no
previous disease or permanent medication. On examina-
tion she was found to be lethargic and showed petechiae
on the lower extremities. Laboratory results showed a
marked anemia (haemoglobin 7.7 g/dL; normal value:
12.0–16.0 g/dL) and thrombocytopenia (9,000/␮L; nor-
*Correspondence to: Jens Chemnitz, M.D., Department I of Internal
Medicine, University of Cologne, Joseph-Stelzmann-Straße 9, 50924
Cologne, Germany. E-mail: jens.chemnitz@uni-koeln.de
Received for publication 15 February 2002; Accepted 15 June 2002
Published online in Wiley InterScience (www.interscience.wiley.
com). DOI: 10.1002/ajh.10204
106 Case Report: Chemnitz et al.
Fig. 1. Clinical course and treatment of patient 1.
mal value: 150,000–400,000/␮L). Lactate dehydroge-
nase (2,260 U/L; normal value: 120–240 U/L) and serum
bilirubin (108 ␮mol/L; normal value: <17 ␮mol/L) were
elevated whereas haptoglobin was not measurable, indi-
cating intravascular haemolysis. Prothrombin time and
partial thromboplastin time were normal, as were serum
urea and creatinine levels. Peripheral blood smears re-
vealed 15% fragmented red cells. On the basis of these
findings the diagnosis of TTP was established. The ac-
tivity of the von Willebrand-cleaving protease was found
to be below 1% before treatment, and an inhibitor against
the protease was also found (1 mL of our patient’s
plasma neutralized the protease activity in 0.8 mL of
normal plasma). Treatment consisted of plasma exchange
against fresh frozen plasma (40–60 mL plasma/kg BW
per day) and high-dose steroids (250 mg of prednisolone
per day). However, neither thrombocytopenia nor hae-
molysis improved, and the clinical course deteriorated
with evidence of cerebral ischemia and myocardial in-
farction. Treatment with plasma exchange and steroids
was continued, and vincristine was added (initially 3 × 2
mg i.v. followed by 1 mg i.v. per week up to a total dose
of 8 mg). After the first two doses of vincristine, LDH
and serum bilirubin began to decrease but the platelet
count showed no significant response. After 12 days of
treatment, the decision was made to use rituximab on a
compassionate-use basis with a dose of 375 mg/m2 re-
peated every week. After 4 courses of rituximab, the
condition improved gradually and laboratory values
completely normalized. Concomitantly the neurological
situation improved. After 44 days the patient was dis-
charged. No further therapy was required, even after ta-
pering off prednisolone. The protease activity after treat-
ment was found to be 100%, a soluble inhibitor was no
longer detectable. The clinical course and treatment are
shown in Figure 1. The patient remained in complete
remission for at least 2 months; after that time she was
unfortunately lost to follow up.
Patient 2
The clinical course of the second patient was nearly
identical to the first patient described above. A 37-year-
old female patient was referred to our department for
thrombocytopenia. The prior medical history was un-
eventful, and she had no permanent medication. The
clinical examination was inconspicuous and showed no
evidence of neurological symptoms. Laboratory results
indicated haemolytic anaemia with decreased hemoglo-
bin (10.1 g/dL), elevated LDH (722 U/L), and bilirubin
(74 ␮mol/L). Haptoglobin was not measurable, and
thrombocytes were reduced to 10,000/␮L. Serum urea
and creatinine levels were normal. In the peripheral
blood smear 10% fragmented red cells were detected. On
the basis of these findings the diagnosis of thrombotic
thrombocytopenic purpura was established. Treatment
with plasma exchange against fresh frozen plasma (40–
60 mL/kg BW) and steroids (250 mg prednisolone/day)
was initiated but without clinical benefit; instead, the
patient deteriorated, showing signs of cerebral and car-
diac involvement. Additional therapy consisted of che-
motherapy with vincristine (initial 1.5 mg i.v., followed
by 1 mg up to a total dose of 4.5 mg). After 11 days we
decided to treat with the monoclonal antibody rituximab
(375 mg/m2; repeated every week). The patient was
treated with 2 cycles of rituximab, after which a response
could be noted. After 45 days she could be discharged
 Case Report: Treatment of Severe TTP With Rituximab
Fig. 2. Clinical course and treatment of patient 2.
from our department. The laboratory values completely
normalized after 77 days. The clinical course and treat-
ment is illustrated in Figure 2. The patient remains in
complete remission, now for almost one year after treat-
ment. No severe rituximab-related side effects were ob-
served in these two patients.
DISCUSSION
Recent work focusing on the pathophysiology of TTP
showed a decrease in von Willebrand factor-cleaving
protease activity that was innate in hereditary TTP and
related to the presence of inhibitory IgG antibodies in the
classic form of the disease [7]. Most patients with the
classic form of TTP achieve complete remission with
plasma exchanges against fresh frozen plasma, though
sometimes several weeks of treatment are required. How-
ever, up to 14% do not respond to therapy. In case of
stem cell transplantation-associated TTP the clinical
course is much more serious and the mortality rates are
significantly higher, possibly due to a different patho-
physiology [8]. In the plasma of TTP patients after stem
cell transplantation, no unusually large von Willebrand
factors could be found and the activity of the specific
protease seems to be normal [9].
In case of classic TTP the treatment of patients refrac-
tory to plasma exchange is difficult and no standardized
therapeutic concepts exist. As plasma exchange is the
only treatment modality with proven efficacy for these
patients, all other modalities are secondary, adjunctive
treatments. Some authors recommend a treatment with
vincristine after 3 days of ineffective plasma exchange.
107
Splenectomy could be a therapeutic modality in some
cases, but the surgical procedure carries a high risk be-
cause of the thrombocytopenia in the acute phase of the
disease [10]. The use of platelet inhibitors such as ace-
tylsalicylic acid or dipyridamole is highly controversial,
especially as antiplatelet agents as ticlopidine or clopi-
dogrel have been found to induce TTP in some patients
[1]. The role of treatment with high-dose immunoglob-
ulin, immunosuppressive agents as cyclosporin A, or
chemotherapy with cyclophosphamide in refractory TTP
is not defined.
On the basis of the new findings concerning the patho-
physiology of the disease, we decided to treat two pa-
tients refractory to daily plasmapheresis, steroids, and
vincristine with the monoclonal anti-CD20 antibody rit-
uximab. Rituximab is a chimeric monoclonal antibody
directed against the CD20 antigen, expressed on the sur-
face of most B lymphocytes. The antibody activates cell-
mediated and complement-mediated cytotoxic mecha-
nisms, resulting in cell death [11]. The antibody was first
successfully used to treat non-Hodgkin lymphomas of
B-cell origin, but there is evidence for its efficacy in
other haematological or autoimmune diseases like auto-
immune haemolytic anaemia [12] or chronic idiopathic
thrombocytopenia (ITP). In case of chronic idiopathic
thrombocytopenic purpura the effectiveness and side ef-
fects of this therapeutic modality were recently investi-
gated in a cohort of 25 individuals. All patients had ITP
that had been resistant to 2–5 different therapeutic re-
gimes, including 8 patients who had already failed to
respond to splenectomy. The overall response rate was
52% with rituximab [13]. The possible reason for the
108 Case Report: Chemnitz et al.
clinical benefit is that the antibody-producing clone is
reduced by the anti-CD20 antibody. The role of ritux-
imab in the treatment of TTP resistant to plasma ex-
change is not defined but has gained interest such as in
the recent workshop “von Willebrand factor and throm-
botic thrombocytopenic purpura” from October 2001
[14].
We report the first two cases of severe TTP success-
fully treated with this monoclonal antibody. Because
plasma exchange is the only treatment with proven effi-
cacy for patients with TTP, rituximab could have been
only adjunctive treatment. The role of rituximab used in
conjunction with continued plasma exchange plus vin-
cristine cannot be defined with certainty. Although it is
impossible to prove the exact role of rituximab for the
successful outcome in the reported cases, the change of
clinical and laboratory parameters after initiating the an-
tibody treatment was impressive. Thus, in view of its low
toxicity the use of rituximab in refractory TTP patients
with the classic form of the disease seems to be a thera-
peutic option for selected patients and should be inves-
tigated in prospective clinical trials.
ACKNOWLEDGMENT
We are indebted to Prof. Furlan, University of Bern,
for providing the measurements of the von Willebrand-
cleaving protease.
REFERENCES
1. Bennet CL, Connors JM, Carwile JM, Moake JL, Bell WR, Tarantolo
SR, McCarthy LJ, Sarode R, Hatfield AJ, Feldman MD, Davidson CJ,
Tsai HM. Thrombotic thrombocytopenic purpura associated with clo-
pidogrel. N Engl J Med 2000;342:1773–1777.
2. Furlan M, Robles R, Galbusera M, Remuzzi G, Kyrle PA, Brenner B,
Krause M, Scharrer I, Aumann V, Mittler U, Solenthaler M, Lämmle
B. Von Willebrand factor cleaving protease in thrombotic thrombocy-
topenic purpura and the hemolytic uremic syndrome. N Engl J Med
1998;339:1578–1584.
3. Tsai HM. Physiologic cleavage of von Willebrand factor by a protease
is dependent on its confirmation and requires calcium ion. Blood 1996;
87:4235–4244.
4. Furlan M, Robles R, Solenthaler M, Wassmer M, Sandoz P, Lämmle
B. Deficient activity of von Willebrand factor cleaving protease in
chronic relapsing thrombotic thrombocytopenic purpura. Blood 1997;
89:3097–3103.
5. Furlan M, Lämmle B. Von Willebrand factor in thrombotic thrombo-
cytopenic purpura. Thrombosis Haemost 1999;82:592–600.
6. Tsai HM, Lian EC. Antibodies to von Willebrand cleaving protease in
acute thrombotic thrombocytopenic purpura. N Engl J Med 1998;339:
1585–1594.
7. Moake JL, Rudy CK, Troll JH, Schäfer AI, Weinstein MJ, Colannino
NM, Hong SL. Therapy of chronic relapsing thrombotic thrombocy-
topenic purpura with prednisone and azathioprine. Am J Hematol
185;20:73–79.
8. Chemnitz J, Fuchs M, Hartmann P, Wickenhauser C, Scheid C, Schulz
A, Diehl V, Söhngen D. Fatal thrombotic thrombocytopenic purpura as
a rare complication after allogeneic stem cell transplantation. Ann
Hematol 2000;79:527–529.
9. Van der Plas RM, Schiphorst ME, Huizinga EG, Hene RJ, Verdonck
LF, Sixma JJ, Fijnheer R. Von Willebrand factor proteolysis is differ-
ent in classic, but not in bone marrow transplant associated thrombotic
thrombocytopenic purpura. Blood 1999;93:3798–3802.
10. Coppo P, Lassoued K, Mariette X, Gossot D, Oksenhendler E, Adrie
C, Azoulay E, Schlemmer B, Clauvel JP, Bussel A. Effectiveness of
platelet transfusions after plasma exchange in adult thrombotic throm-
bocytopenic purpura: a report of two cases. Am J Hematol 2001;68:
198–201.
11. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Raab R,
Newman RA, Hanna N, Anderson DR. Depletion of B cells in vivo by
a chimeric mouse human monoclonal antibody to CD20. Blood 1994;
83:435–445.
12. Zecca M, De Stephano P, Nobili B, Locatelli F. Anti-CD20 monoclo-
nal antibody for the treatment of severe, immune-mediated, pure red
cell aplasia and haemolytic anaemia. Blood 2001;97:3995–3997.
13. 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.
14. Moake JL, Sadler JE, Manucci P, Ganguly P. Report on the workshop:
von Willebrand factor and thrombotic thrombocytopenic purpura. Am
J Hematol 2001;68:122–126.