Ciclosporin and plasma exchange in thrombotic thrombocytopenic purpura: long-term follow-up with serial analysis of ADAMTS13 activity

Recently, we showed that during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP), ADAMTS13 circulates in an open conformation. Although the cause of this conformational change in acute iTTP remains elusive, ADAMTS13 is mainly closed in iTTP patients (i) in remission with an ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, and (ii) after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, IgGs from 18 acute iTTP patients were purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14/18 (78%) samples, proving that indeed anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n=197) that also included plasma samples of iTTP patients in remission where ADAMTS13 activity was <50%. The open ADAMTS13 conformation was not only found during acute iTTP but also in patients in remission with an ADAMTS13 activity <50% and in half of the patients with an ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus open ADAMTS13 is not only a hallmark of acute iTTP, but also a novel biomarker to detect subclinical iTTP in patients in remission. Finally, a long term follow-up study in one iTTP patient showed that the open conformation precedes a severe drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.

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Long-term Efficacy of Rituximab Treatment in Thrombotic Thrombocytopenic Purpura

European Oncology & Haematology ◽

10.17925/eoh.2011.07.02.143 ◽

2011 ◽

Vol 07 (02) ◽

pp. 143

Author(s):

Jens M Chemnitz ◽

Michael Hallek ◽

Christof Scheid ◽

◽

...

Keyword(s):

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

Case Reports ◽

Therapeutic Option ◽

Case Series ◽

Current Data ◽

Thrombocytopenic Purpura ◽

Long Term Follow Up

The use of therapeutic plasma exchange has reduced mortality rates in thrombotic thrombocytopenic purpura (TTP) from 90 to 1020%. 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.

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How I treat patients with thrombotic thrombocytopenic purpura–hemolytic uremic syndrome

Blood ◽

10.1182/blood.v96.4.1223 ◽

2000 ◽

Vol 96 (4) ◽

pp. 1223-1229 ◽

Cited By ~ 237

Author(s):

James N. George

Keyword(s):

Renal Failure ◽

Hemolytic Uremic Syndrome ◽

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

Survival Rates ◽

Thrombocytopenic Purpura ◽

Long Term Follow Up ◽

Uremic Syndrome

Abstract Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are, in adults, clinically and pathologically indistinguishable except for the severity of renal failure. They are best described as a single disorder, TTP-HUS, because the diagnostic evaluation and initial management are the same. Treatment with plasma exchange, available for more than 20 years, has dramatically altered the course of disease in adults with TTP-HUS. Plasma exchange has improved survival rates from 10% to between 75% and 92%, creating urgency for the initiation of treatment. This has resulted in decreased stringency of diagnostic criteria, which in turn has resulted in a broader spectrum of disorders for which the diagnosis of TTP-HUS is considered. Long-term follow-up has revealed increasing frequencies of relapse and of chronic renal failure. Although the increased survival rate is dramatic and recent advances in understanding the pathogenesis of these syndromes are remarkable, clinical decisions remain empirical. Therefore, the management decisions for patients with suspected TTP-HUS rely on individual experience and opinion, resulting in many different practice patterns. Multipractice clinical trials are required to define optimal management.

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How I treat patients with thrombotic thrombocytopenic purpura–hemolytic uremic syndrome

Blood ◽

10.1182/blood.v96.4.1223.h8001223_1223_1229 ◽

2000 ◽

Vol 96 (4) ◽

pp. 1223-1229 ◽

Cited By ~ 2

Author(s):

James N. George

Keyword(s):

Renal Failure ◽

Hemolytic Uremic Syndrome ◽

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

Survival Rates ◽

Thrombocytopenic Purpura ◽

Long Term Follow Up ◽

Uremic Syndrome

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are, in adults, clinically and pathologically indistinguishable except for the severity of renal failure. They are best described as a single disorder, TTP-HUS, because the diagnostic evaluation and initial management are the same. Treatment with plasma exchange, available for more than 20 years, has dramatically altered the course of disease in adults with TTP-HUS. Plasma exchange has improved survival rates from 10% to between 75% and 92%, creating urgency for the initiation of treatment. This has resulted in decreased stringency of diagnostic criteria, which in turn has resulted in a broader spectrum of disorders for which the diagnosis of TTP-HUS is considered. Long-term follow-up has revealed increasing frequencies of relapse and of chronic renal failure. Although the increased survival rate is dramatic and recent advances in understanding the pathogenesis of these syndromes are remarkable, clinical decisions remain empirical. Therefore, the management decisions for patients with suspected TTP-HUS rely on individual experience and opinion, resulting in many different practice patterns. Multipractice clinical trials are required to define optimal management.

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Preemptive rituximab prevents long-term relapses in immune-mediated thrombotic thrombocytopenic purpura

Blood ◽

10.1182/blood-2018-04-840090 ◽

2018 ◽

Vol 132 (20) ◽

pp. 2143-2153 ◽

Cited By ~ 36

Author(s):

Matthieu Jestin ◽

Ygal Benhamou ◽

An-Sofie Schelpe ◽

Elien Roose ◽

François Provôt ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Relapse Rate ◽

Thrombocytopenic Purpura ◽

Immune Mediated ◽

Key Points ◽

Long Term Follow Up ◽

Adamts13 Deficiency ◽

Risk Balance

Key Points TTP patients who display persistent and severe ADAMTS13 deficiency after remission have a relapse rate of 74% during long-term follow-up. Preemptive rituximab can decrease TTP relapses in 85% of patients with a favorable benefit-risk balance.

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The Oklahoma thrombotic thrombocytopenic purpura-haemolytic uraemic syndrome Registry

Hämostaseologie ◽

10.5482/hamo-12-10-0016 ◽

2013 ◽

Vol 33 (02) ◽

pp. 105-112 ◽

Cited By ~ 10

Author(s):

S. K. Vesely ◽

D. R. Terrell ◽

C. C. Deford ◽

J. A. Reese ◽

Z. L. Al-Nouri ◽

...

Keyword(s):

Patient Care ◽

Thrombotic Thrombocytopenic Purpura ◽

Haemolytic Uraemic Syndrome ◽

Registry Data ◽

Thrombocytopenic Purpura ◽

Research Education ◽

Long Term Follow Up ◽

And Function

SummaryThe Oklahoma Thrombotic Thrombocytopenic Purpura-Haemolytic Uraemic Syndrome (TTPHUS) Registry has a 24 year record of success for collaborative clinical research, education, and patient care. This article tells the story of how the Registry began and it describes the Registry’s structure and function. The Registry provides a model for using a cohort of consecutive patients to investigate a rare disorder. Collaboration between Oklahoma, United States and Bern, Switzerland has been the basis for successful interpretation of Registry data.Registry data have provided new insights into the evaluation and management of TTP. Because recovery from acute episodes of TTP has been assumed to be complete, the increased prevalence of hypertension, diabetes, depression, and death documented by long-term follow-up was unexpected. Registry data have provided opportunities for projects for students and trainees, education of physicians and nurses, and also for patients themselves. During our follow-up, patients have also educated Registry investigators about problems that persist after recovery from an acute episode of TTP. Most important, Registry data have resulted in important improvements for patient care.

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Increased morbidity during long-term follow-up of survivors of thrombotic thrombocytopenic purpura

American Journal of Hematology ◽

10.1002/ajh.24138 ◽

2015 ◽

Vol 90 (10) ◽

pp. E208-E208 ◽

Cited By ~ 5

Author(s):

Shruti Chaturvedi ◽

Hashim Abbas ◽

Keith R. McCrae

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Thrombocytopenic Purpura ◽

Long Term Follow Up

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Long-Term Follow-up of Rituximab Treatment of Non-Familial Idiopathic Thrombotic Thrombocytopenic Purpura (TTP).

Blood ◽

10.1182/blood.v114.22.3513.3513 ◽

2009 ◽

Vol 114 (22) ◽

pp. 3513-3513

Author(s):

Jens Chemnitz ◽

Jens Uener ◽

Michael Hallek ◽

Christof Scheid

Keyword(s):

Side Effects ◽

Maintenance Therapy ◽

Plasma Exchange ◽

Standard Therapy ◽

Recurrent Disease ◽

Adamts13 Activity ◽

Long Term Follow Up ◽

Disease Free

Abstract Abstract 3513 Poster Board III-450 Introduction Rituximab is an accepted treatment modality for patients with TTP refractory to plasma exchange or recurrent disease. While initial treatment response rates are at a high level, long-term follow-up of patients treated with Rituximab is not accessible to date. However this data implies important information, since overall and progression free survival, side effects and a possible need for a maintenance therapy must be taken in consideration. Methods 12 patients with TTP refractory to plasma exchange or with recurrent disease treated with Rituximab at the haematology department of the University of Cologne between 2000 and 2008 were re-examined. All patients suffered from non-familial idiopathic TTP, cases with secondary TTP following stem cell transplantation or underlying diseases such as cancer or rheumatologic disorders were excluded. Additional to physical examination, ADAMTS13 activity and the presence of an ADAMTS13 inhibitor were analyzed. Results The median age of the patients was 43.2 years and 75% of the patients were female. The majority of patients received Rituximab either because of refractory disease or severe allergic reactions during standard therapy with plasma exchange. 4 patients suffered from relapsing disease after standard therapy with plasma exchange during the first episode. Dose schedule of Rituximab treatment consisted of 4 times 375 mg/m2 per week in parallel to continuing plasma exchange when possible. No acute severe side effects were seen after application of Rituximab. The median follow-up was 48.8 months, ranging from 10 to 98 months. All patients had an initial complete response after Rituximab treatment. At the time of re-examination, all 12 patients presented in good clinical condition, thus overall survival accounted 100%. 10 patients remained long-term disease free after initial therapy with Rituximab, two patients had recurrent disease but responded to subsequent Rituximab treatment. One patient is treated with ongoing maintenance therapy with Rituximab consisting of 375 mg/m2 every 4 weeks and remains disease free under these conditions. In our patient cohort, no long-term side effects of Rituximab treatment were noted. ADAMTS13 enzyme activity at time of re-evaluation was impaired in 50% of the patients, however no patient had an enzyme activity of less then 5%. Inhibitors against ADAMTS13 at time of re-evaluation were detected in three patients. Conclusions Rituximab is a safe and effective treatment for patients with non-familial idiopathic TTP after failure of standard therapy with plasma exchange. More than 80% of patients remain disease free during long-term follow-up, and relapses can be treated with subsequent Rituximab. Maintenance therapy is an option for frequent relapsing patients. ADAMTS13 activity might be reasonable to analyze on a regular basis to identify patients who benefit from pre-emptive Rituximab treatment. Disclosures: No relevant conflicts of interest to declare.

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