Chronic Relapsing Thrombotic Thrombocytopenic Purpura Research Articles

Rituximab in Relapsing acquired Thrombotic Thrombocytopenic Purpura: Experience and Evidence

Thrombotic Thrombocytopenic Purpura (TTP), first described in the early twentieth century, was fatal in the majority of cases until the advent of plasma therapy. Mortality has declined dramatically since the 1980s, and in the 1990s the pathophysiology was elucidated through the discovery and understanding of the central role of a deficiency of the metalloprotease ADAMTS13. The vast majority of cases occur due to an autoimmune process, with a minority of cases due to an underlying mutation. Since the turn of this century, Rituximab, a monoclonal antibody targeting CD20 expressed on B-lymphocytes, has become widely used to treat patients with a wide spectrum of autoimmune diseases, including TTP. However, Rituximab remains “off-label” in the setting of TTP. We recently encountered a patient with chronic relapsing TTP, whose clinical relapses have responded to Rituximab-based therapy without need to resort to plasmapheresis. The clinical course of this patient is described, and the literature focusing on the use of Rituximab in prophylaxis to prevent recurrent TTP is reviewed.

Bortezomib for chronic relapsing thrombotic thrombocytopenic purpura: a case report

Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder characterized by a severe deficiency of ADAMTS13 activity. Although therapeutic plasma exchange (PLEX) is the standard of care, 30% to 50% patients develop exacerbation or relapse, requiring immunomodulatory agents. Of these agents, glucocorticoids, rituximab, and cyclosporine A are the most frequently used. We report a case of chronic relapsing TTP in a patient who had eight relapses over a 14-year period. After her seventh relapse, the patient demonstrated only partial response to glucocorticoids, two courses of rituximab, and cyclophosphamide. The eighth relapse occurred 58 days after her last PLEX and subsequent to this she received a course of bortezomib (Velcade, Millennium Pharmaceuticals, Inc.). After treatment with bortezomib the patient demonstrated a complete response with a progressive increase in ADAMTS13 activity from less than 5% to 22% accompanied by undetectable inhibitor, and she has remained PLEX free for more than 169 days. Bortezomib may serve as an adjunct treatment in patients with acquired TTP who exhibit an incomplete response or are refractory to conventional management.

Rituximab as prophylaxis in chronic relapsing thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder that most often arises from inhibition of the enzyme ADAMTS13 by autoantibodies. This provides the rationale for the use of rituximab, an anti-CD20 monoclonal antibody, as an effective treatment. Multiple reports have indicated success employing it in patients with TTP, but only a few have reported its use during remission as a prophylaxis to prevent a relapse. Herein, we report the case of a patient with chronic relapsing TTP who was successfully treated with prophylactic rituximab. We also provide a review of the literature on this topic.

Efficacy and safety of rituximab in adult patients with idiopathic relapsing or refractory thrombotic thrombocytopenic purpura: Results of a Spanish multicenter study

BackgroundBetween 30% and 60% of patients with thrombotic thrombocytopenic purpura (TTP) relapse and mortality remains at 15–20%. Limited clinical data suggest that the administration of anti-CD20 antibody (rituximab) may be useful in preventing acute refractory and chronic relapsing TTP. Design and methodsWe studied the clinical response to rituximab in 24 adult patients (median age 42years, range 24–72years) from 15 Spanish centers with an acute refractory (14 patients) or acute relapsing (10 patients) episode of idiopathic TTP. On admission, every patient received daily plasma exchange (PE). Rituximab was administered at a dose of 375mg/m2 weekly for a median of 13days (range 0–57days) after starting PE for a median of 4 doses (range 1–8 doses). ResultsNo severe acute or delayed toxicity was observed in the patients treated with rituximab. Three (12.5%) patients died because of TTP-related causes. The remaining 21 (87.5%) patients achieved complete remission in a median of 21days (range 2–35days) after initiating rituximab. After a median follow-up of 30months (range 7.5–74months), 18 patients are in remission and 3 patients have relapsed at 7, 29, and 29months. ConclusionsRituximab appears to be a safe, effective therapy and has a high response rate for the treatment of acute refractory or relapsing idiopathic TTP in adult patients.

Rituximab therapy in two children with autoimmune thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare disease among pediatric patients, in whom it may be mistaken for hemolytic uremic syndrome (HUS) and idiopathic thrombocytopenic purpura (ITP). Familial forms are caused by mutations in the ADAMTS13 gene, whereas acquired forms may result from an inhibitory antibody directed against ADAMTS13, a metalloprotease that cleaves very large multimers of Von Willebrand factor (VWF), thereby preventing platelet aggregation in blood vessels. We report two cases of TTP. The first was a 15-year-old girl with her first episode of TTP that failed to respond after 10 days of plasmapheresis and was treated with rituximab; she has remained in remission at 12 months of follow-up. The second was a 6-year-old boy with acquired relapsing TTP previously managed with plasmapheresis and prednisolone, who presented with a third relapse that was treated with plasmapheresis and rituximab; he remains in remission 17 months after treatment. Rituximab has been used by pediatricians for treating B cell malignancy, autoimmune diseases and antibody-mediated diseases, such as the Factor VIII inhibitors in hemophilia A, and may also have a promising role in children with acute refractory or chronic relapsing TTP.

Efficacy and Safety of Rituximab in Adult Patients with Idiopathic Relapsed or Refractory Thrombotic Thrombocytopenic Purpura (TTP). Results of a Spanish Multicenter Study.

Background: Therapeutic plasma exchange (PE) is the mainstay of treatment of thrombotic thrombocytopenic purpura (TTP). In many patients, prolonged PE is required to achieve remission and between 30% and 60% of patients relapse after a variable period of months to years, with a further episode of TTP or a chronic picture of recurrent relapses. Various immunosuppressive agents have been used in acute refractory and chronic relapsing cases. Despite advances in treatment, mortality remains at 15–20%. Limited clinical data from small groups of patients suggest that the administration of anti-CD20 antibody (Rituximab) may also be useful in acute refractory and chronic relapsing TTP. However, whether rituximab could be and effective strategy for adults with relapsed or refractory TTP remains unresolved.Patients and Methods: We have studied the clinical response to rituximab in 22 adult patients (16 F/6 M; median age, 43 years, range 24–72) from 11 Spanish centers who presented with acute refractory (13 cases) or an acute relapse (9 cases) episode of idiopathic TTP. Second-line therapies previously administered included vincristine (11 cases) and splenectomy (2 cases). At the time of the study, five (28%) patients presented neurological symptoms, three (17%) renal failure, and two (17%) fever. On admission, every patient received daily PE and corticosteroids during the acute episode.Results: Rituximab was administered a median of 16 days (range, 7–53) after starting PE. It was administered immediately after PE at a dose of 375 mg/m2 each week for a median (range) of 4 (1–8) doses. No severe acute or delayed toxicity associated with rituximab was observed. Two (9%) patients died due to TTP-related causes 24 and 48 hours after relapse and were not evaluable for response. The remaining 20 (91%) patients achieved complete remission in a median of 21 days after initiating rituximab (range, 2–35). After a median follow-up of 13 months (range, 1.5–33), 17 patients are in remission and 3 patients have relapsed at 7, 29, and 29 months after rituximab administration.Conclusion: Based on these results, rituximab appears a safe, effective, targeted therapy associated with a high response rate in adult patients with acute refractory/relapsing idiopathic TTP.

P057 Chronic relapsing thrombotic thrombocytopenic purpura in a 32 years old diabetic male with ADAMTS 13 protease deficiency treated succesfully with plasma infusions and steroids

P057 Chronic relapsing thrombotic thrombocytopenic purpura in a 32 years old diabetic male with ADAMTS 13 protease deficiency treated succesfully with plasma infusions and steroids

Successful repeat therapy with rituximab for relapsed thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening disease that is treated successfully with therapeutic plasma exchange (TPE) and often with corticosteroids; however, almost one third of TTP patients have treatment failures that require either long-term TPEs or other adjunct therapies. Recent insights into the autoimmune-pathophysiology of this disease provide the rationale for immune-based therapies. Cumulative evidence suggests that rituximab, an anti-CD20 antibody that depletes B-cells temporarily, is an effective therapy in patients with refractory or relapsing TTP. We report here two patients with chronic relapsing TTP who were treated successfully with rituximab. However, both experienced TTP relapse following sustained and prolonged remissions for 21 and 37 months, respectively. They responded favorably with repeat therapy with rituximab. The benefits of rituximab treatment for refractory or relapsing TTP as well as in the prevention of recurrences are discussed.

Unraveling the immunologic response in thrombotic thrombocytopenic purpura.

Unraveling the immunologic response in thrombotic thrombocytopenic purpura.

Two generations with familial thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura (TTP) is a rare multi-system disease characterised by the pentad of microangiopathic haemolytic anaemia, thrombocytopenia, renal dysfunction, fever and neurologic changes. A hereditary form of recurrent familial TTP has been described, which usually presents in adolescence or early adulthood and can lead to recurrent or chronic relapsing TTP. Genetic analyses of patients with familial TTP have linked the disease to chromosome 9q34, and an increased incidence is seen in people with HLA-B40 group antigens. We describe here an 11-year-old Egyptian girl with no significant past medical history who presented with new onset of bruising, petechial rash, fatigue and fevers and was diagnosed with familial TTP. Further testing revealed that both the patient and her father had the HLA-B40 group antigen and also had ADAMTS-13 von Willebrand factor-cleaving protease deficiency as well as factor-H deficiency.

Chronic Relapsing Thrombotic Thrombocytopenic Purpura Successfully Treated with Rituximab: Case Report

Plasma therapy is a cornerstone in the treatment of idiopathic Thrombotic Thrombocytopenic Purpura (TTP); however about one-third of patients relapse. In this subset of patients different immunosuppressive approaches have been reported with variable efficacy. We describe the case of an 11-year-long chronic relapsing TTP, requiring frequent plasma exchange procedures and treated unsuccessfully with several immunosuppressive agents. On the occasion of a further relapse, the patient was treated with rituximab, and achieved normalization of hematological values and clinical status for about one year. Upon further relapse, rituximab therapy was started again successfully. A monthly administration was performed with the aim of maintaining the clinical and hematological response stable. In conclusion, rituximab is a safe and effective alternative to other immunosuppressive therapies for chronic relapsing TTP patients.

An In-Frame Deletion of Six Amino Acids and a Point Mutation in the Disintegrin Domain of ADAMTS-13 Associates with a Case of Congenital Thrombotic Thromocytopenic Purpura.

Thrombotic thrombocytopenic purpura (TTP) is characterized by severe thrombocytopenia, hemolytic anemia, and diffuse and non-focal neurological findings. Microthrombi found in these patients are predominantly composed of platelets and von Willebrand factor (VWF). Recent studies suggest that the systemic thrombosis in TTP is mostly due to the congenital or acquired deficiency of the VWF-cleaving metalloprotease ADAMTS-13, which cleaves the ultra-large and hyperreactive VWF to smaller and less active form found in plasma. Most congenital cases of TTP have so far been identified in children. Here, we report a 60-year-old Caucasian man with a history of chronic relapsing TTP over thirty years, requiring plasma transfusion every 24 days in recent years. Repeat assays showed no ADAMTS13 activity in patient's plasma under both static and flow conditions without inhibitors being detected. We therefore examined the possible genetic defects in the ADAMTS-13 gene of this patient. Genomic DNA was extracted from patient's white blood cells and exons of ADAMTS-13 gene were amplified by polymerase chain reaction. The amplified DNA fragments were then screened for mutations by direct DNA sequencing. We identified a deletion of 18 base pairs from G1095 to G1112 (GTGCTCCAAGGGTCGCTG) in the exon10 of ADAMTS-13 gene, resulting in a deletion of six amino acids (C366 to C371) in the disintegrin domain of the metalloprotease. A point mutation (W365C) occurred immediately before the deletion due to a nucleotide realignment. The patient is heterozygote for the deletion. This is the first report of a deletion mutant (without frame shift and truncations) in the disintegrin region that has previously been demonstrated as critical for the ADAMTS-13 function by in vitro mutagenesis, epitope mapping of autoantibody to the metalloprotease in patients with adult acquired TTP, and identification of natural occurring mutations in patients with congenital TTP. Our ongoing studies are to determine the impact of these two mutations on the synthesis, release, and cleavage of ADAMTS-13.

Defective processing of unusually large von Willebrand factor multimers and thrombotic thrombocytopenic purpura

Defective processing of unusually large von Willebrand factor multimers and thrombotic thrombocytopenic purpura

Proteolytic cleavage of von Willebrand factor by ADAMTS‐13 prevents uninvited clumping of blood platelets

Proteolytic cleavage of von Willebrand factor by ADAMTS‐13 prevents uninvited clumping of blood platelets

Consistency of ADAMTS-13 activity assays: a moderately optimistic view

Consistency of ADAMTS-13 activity assays: a moderately optimistic view

Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome.

To evaluate the usefulness and feasibility of measuring plasma von Willebrand factor (vWF)-cleaving metalloprotease activity (ADAMTS 13) in the differential diagnosis of thrombotic thrombocytopenic purpura (TTP), the hemolytic uremic syndrome, and other thrombotic microangiopathies. Articles published in the medical literature. In TTP, a multimeric form of vWF that is larger than that ordinarily found in the plasma may cause systemic platelet aggregation under the high-shear conditions of the microcirculation. ADAMTS 13 is a divalent cation-activated, vWF-cleaving metalloprotease that converts unusually large vWF multimers derived from endothelial cells into smaller vWF forms in normal plasma. ADAMTS 13 is severely reduced or absent in most patients with TTP. The vWF-cleaving metalloprotease is present in fresh-frozen plasma, cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The enzyme is defective in children with chronic relapsing TTP. Infusion of any of the plasma products that contain the vWF-cleaving metalloprotease stops or prevents (for about 3 weeks) TTP episodes in these patients. An immunoglobulin (Ig) G autoantibody to the vWF-cleaving metalloprotease is found transiently in many adult patients with acquired acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. Patients with acquired TTP require plasma exchange, that is, both infusion of a plasma product containing vWF-cleaving metalloprotease and removal of autoantibody and/or unusually large vWF multimers by plasmapheresis. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy-associated thrombotic microangiopathy, as well as in hemolytic uremic syndrome, is not established. In neither condition is there a severe decrease in plasma vWF-cleaving metalloprotease activity, as there is in TTP. The presently available lengthy and complicated procedure for estimation of plasma vWF-cleaving metalloprotease activity is not yet practical for rapid diagnostic use. This test has supplanted the equally lengthy and difficult, less specific analysis of plasma vWF multimeric pattern. If the clinical distinction between TTP and hemolytic uremic syndrome is uncertain, it is appropriate to acquire (before therapy) a citrate-plasma sample for the ultimate determination of vWF-cleaving metalloprotease activity.

Thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome.

○ Objective.-To evaluate the usefulness and feasibility of measuring plasma von Willebrand factor (vWF)-cleaving metalloprotease activity (ADAMTS 13) in the differential diagnosis of thrombotic thrombocytopenic purpura (TTP), the hemolytic uremic syndrome, and other thrombotic microangiopathies. Data Sources.-Articles published in the medical literature. Data Extraction and Synthesis.-In TTP, a multimeric form of vWF that is larger than that ordinarily found in the plasma may cause systemic platelet aggregation under the high-shear conditions of the microcirculation. ADAMTS 13 is a divalent cation-activated, vWF-cleaving metalloprotease that converts unusually large vWF multimers derived from endothelial cells into smaller vWF forms in normal plasma. ADAMTS 13 is severely reduced or absent in most patients with TTP. The vWF-cleaving metalloprotease is present in fresh-frozen plasma, cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The enzyme is defective in children with chronic relapsing TTP. Infusion of any of the plasma products that contain the vWF-cleaving metalloprotease stops or prevents (for about 3 weeks) TTP episodes in these patients. An immunoglobulin (Ig) G autoantibody to the vWF-cleaving metalloprotease is found transiently in many adult patients with acquired acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. Patients with acquired TTP require plasma exchange, that is, both infusion of a plasma product containing vWF-cleaving metalloprotease and removal of autoantibody and/or unusually large vWF multimers by plasmapheresis. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy-associated thrombotic microangiopathy, as well as in hemolytic uremic syndrome, is not established. In neither condition is there a severe decrease in plasma vWF-cleaving metalloprotease activity, as there is in TTP. Conclusions.-The presently available lengthy and complicated procedure for estimation of plasma vWF-cleaving metalloprotease activity is not yet practical for rapid diagnostic use. This test has supplanted the equally lengthy and difficult, less specific analysis of plasma vWF multimeric pattern. If the clinical distinction between TTP and hemolytic uremic syndrome is uncertain, it is appropriate to acquire (before therapy) a citrate-plasma sample for the ultimate determination of vWF-cleaving metalloprotease activity.

ADAMTS13 and TTP

Thrombotic thrombocytopenic purpura (TTP) has been a mysterious and deadly disease that often could be treated effectively by plasma exchange, but without real understanding of the underlying pathophysiology. Recent advances now suggest that deficiency of a specific von Willebrand factor (VWF) cleaving protease promotes tissue injury in TTP. VWF multimers participate in the formation of platelet thrombi. Proteolytic cleavage of VWF multimers normally limits platelet thrombus growth, and failure to cleave VWF appears to encourage microvascular thrombosis. The VWF cleaving protease proves to be a new member of the ADAMTS family of metalloproteases, designated ADAMTS13. Autoantibodies that inhibit ADAMTS13 cause sporadic TTP, and mutations in the ADAMTS13 gene cause an autosomal recessive form of chronic relapsing TTP. Further studies of ADAMTS13 seem likely to change our approach to the diagnosis and treatment of TTP and other thrombotic microangiopathies.

Prophylactic treatment with fresh‐frozen plasma in chronic thrombotic thrombocytopenic purpura

We read with interest the article of Barbot et al (2001), which described a patient with chronic relapsing thrombotic thrombocytopenic purpura (TTP) associated with congenital deficiency of von Willebrand factor-cleaving protease who has been treated with regular prophylactic administration of fresh-frozen plasma (FFP) for the last 10 years. This patient has so far received 160 units of FFP and remains free from demonstrable transfusion-associated viral infections. This report suggests that long-term prophylactic therapy with FFP is not only an effective treatment for this condition but also safe. This conclusion is supported by our experience with a patient with TTP who has been treated with fortnightly FFP infusions for 23 years! Our patient, a 46-year-old Caucasian woman, was diagnosed with thrombotic thrombocytopenic purpura in 1978 when she presented with convulsions during pregnancy. However, she has had a history of recurrent anaemia and thrombocytopenia from the age of 18 months. She was commenced on prophylactic therapy with freshfrozen plasma (FFP), initially one unit weekly and subsequently every fortnight. Attempts to tail off the treatment resulted in recrudescence of symptoms. She has therefore been maintained on a fortnightly infusion of FFP ever since. She has had no untoward reactions to the treatment and clinically she remains well. Her haematological parameters including haemoglobin level and platelet count are normal. A virology screen for hepatitis A, B and C was negative. Her base-line (pre-FFP infusion) von Willebrand factor metalloproteinase activity carried out in May 2000 was < 2%, supporting a diagnosis of TTP associated with unusually large von Willebrand factor multimers due to impaired degradation to smaller molecular forms, similar to the case reported by Barbot et al (2001). Our patient has so far received over 650 units of FFP. The clinical history of this patient thus supports the assertion of Barbot et al (2001) that long-term prophylactic treatment with FFP is a feasible, effective and relatively safe option for patients with a chronic relapsing form of TTP.

Thrombotic thrombocytopenic purpura: the systemic clumping "plague".

In thrombotic thrombocytopenic purpura (TTP), a multimeric form of von Willebrand factor (vWf) that is larger than ordinarily found in the plasma causes systemic platelet aggregation under the high-shear conditions of the microcirculation. A divalent cation-activated, vWf-cleaving metalloprotease that metabolizes large vWf multimers to smaller forms in normal plasma is severely reduced or absent in most patients with TTP. The vWf-cleaving metalloprotease either is not produced or is defective in children with chronic relapsing TTP. When the enzyme is provided by the infusion of normal plasma, these patients remain free of TTP symptoms for about three weeks. An IgG autoantibody to the vWf-cleaving metalloprotease is found transiently in many adult patients with acute idiopathic, recurrent, and ticlopidine/clopidogrel-associated TTP. These patients require plasma exchange, i.e., concurrent replacement of the inhibited vWf-cleaving metalloprotease by plasma infusion and plasmapheresis. The vWf-cleaving metalloprotease is present in fresh-frozen plasma, in cryoprecipitate-depleted plasma (cryosupernatant), and in plasma that has been treated with solvent and detergent. The pathophysiology of platelet aggregation in bone marrow transplantation/chemotherapy-associated thrombotic microangiopathy, and in the hemolytic-uremic syndrome, is not established. In neither condition is there a severe decrease in plasma vWf-cleaving metalloprotease activity.