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Thrombotic Thrombocytopenic Purpura

Long-term Efficacy of Rituximab Treatment in Thrombotic Thrombocytopenic Purpura

Jens M Chemnitz,1 Michael Hallek2 and Christof Scheid1 1. Specialist; 2. Professor of Medicine, Director and Chair, Department of Internal Medicine I, University of Cologne


The use of therapeutic plasma exchange has reduced mortality rates in thrombotic thrombocytopenic purpura (TTP) from 90 to 10–20%. However, TTP is a potentially lethal disorder, and management of patients with TTP refractory to plasma exchange or frequently recurrent disease is difficult. In those cases, rituximab might be a therapeutic option, although current data are based primarily on case reports and smaller case series. While initial response rates to rituximab are reported to be high, long-term follow-up data of patients treated with rituximab are rare; however, it is important to estimate the safety and benefit of this treatment. In this article we focus on current experience with rituximab in the treatment of TTP, including recent results with long-term follow-up.


Thrombotic microangiopathy, thrombotic thrombocytopenic purpura, treatment, therapeutic plasma exchange, rituximab, follow-up, ADAMTS13, CD20

Disclosure: The authors have no conflicts of interest to declare. Received: 22 October 2010 Accepted: 7 March 2011 Citation: European Oncology & Haematology, 2011;7(2):143–6 Correspondence: Jens M Chemnitz, Department of Internal Medicine I, University Hospital of Cologne, Kerpener Strasse 62; 50924 Cologne, Germany. E:

Thrombotic thrombocytopenic pupura (TTP) is a life-threatening disease characterised by microangiopathic haemolytic anaemia, consumptive thrombocytopenia and various organ dysfunctions, such as neurological symptoms, renal damage and fever.1

In order to ensure

best treatment responses, early diagnosis and appropriate intervention are crucial. Therefore, it was proposed to reduce the diagnostic criteria to three conditions: thrombocytopenia and microangiopathic haemolytic anaemia in the absence of an alternative explanation for thrombocytopenia and microangiopathic hemolytic anaemia, thereby abandoning the previous pentad of symptoms.2

The decreased

diagnostic threshold has resulted in a sevenfold increase of TTP incidence.3

The classification of TTP according to Sadler4 distinguishes

idiopathic (primary) TTP from secondary TTP following predisposing conditions such as cancer, eclampsia, drug toxicity or haematopoietic stem cell transplantation. The acquired form of idiopathic TTP is further distinguished from hereditary disease (Upshaw–Schulman syndrome).

Rationale for Rituximab Therapy in Thrombotic Thrombocytopenic Pupura Much progress has been made in recent years in understanding the pathophysiology of TTP. Moake et al. described unusually large von Willebrand factor (vWF) multimers in the plasma of patients with relapsing, acquired or congenital TTP causing intravascular platelet aggregation and occlusion of the microvasculature.5

vWF is a

glycoprotein produced within the vascular endothelial cells and the megakaryocytes. In its multimer form, vWF has maximal capacity to aggregate and bind blood platelets. Under normal conditions, increased platelet aggregation is prevented by cleavage of the vWF multimers. Tsai et al.6

and Furlan et al.7 independently identified a vWF-cleaving protease © TOUCH BRIEFINGS 2011

(ADAMTS13) missing from the plasma of patients with congenital TTP8


and severely deficient in patients with acquired idiopathic TTP.

Mutations in the ADAMTS13 gene were shown to cause congenital TTP,9

so far more than 90 mutations of the ADAMTS13 gene have been

Much more common than hereditary TTP is the idiopathic form of TTP caused by auto-antibodies. These inhibitory antibodies – mostly immunoglobulin G (IgG) antibodies – bind to the cystine-rich domain of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) and lead to a decreased function of the enzyme.10,11

The major role of B cells in the production of inflammatory cytokines and auto-antibodies, as well as the ability to act as antigen-presenting cells, is the basis for B-cell-depleting therapies in immune-mediated disorders. Due to the autoimmune nature of acquired idiopathic TTP, rituximab has been used as a second-line immunosuppressive intervention in TTP cases refractory to plasma exchange as well as in frequently relapsing patients.12–21

Rituximab, a chimeric monoclonal

antibody directed against the CD20 antigen present on B lymphocytes, is used in lymphoma therapy as well as in autoimmune diseases such as rheumatoid arthritis and immune thrombocytopenia. Its effect relies on clearance of B lymphocytes by complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity or directly by inducing apoptosis. However, several lines of evidence indicate that the T-cell compartment may also be modulated by these interventions.22,23

Standard Treatment

The standard treatment of acquired idiopathic TTP consists of plasma exchange with fresh frozen plasma,24,25

143 thereby removing large vWF

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