Treatment of Thrombotic Thrombocytopenic Purpura Using Solvent Detergent Treated Plasma.

Abstract Background: Patients with Thrombotic Thrombocytopenic Purpura require immediate therapy with large volumes of plasma. They have been reported to respond well to plasma exchange (PE) with FFP (78%)1 and CSP (95%)2. We initiated a randomized prospective trial with CSP and solvent detergent treated plasma (SDP) intended to show non inferiority. Methods: Patients were randomized to receive either of the exchange fluids at 1.5 PV x 3 days then 1 PV x 4–6 days. Laboratory values were followed with ADAMTS-13 levels measured according to Furlan3. The primary end point was survival at 6 months. Results: A total of 62 of the required 280 patients entered the study then the supply of SDP was discontinued. 3/35 patients receiving CSP and 1/27 on SDP died before 1 month. These values are not significant but the study is underpowered so statistical analysis is not possible. FVIII and vWF levels were elevated in all patients at entry. 34/50 patients tested also had antibodies to CD36. 9 patients had no ADAMTS-3 at entry, 19 had between 5–50%, 9 patients had 50–100% and 15/62 patients tested had normal levels. Inhibitors were present at between 5–50% levels in 22/50 patients tested whereas 9 patients had complete inhibition of ADAMTS-13 and 18 had normal enzyme activity. Conclusions: Patients with TTP appear to respond well to SDP thereby offering a relatively safer therapeutic option for PE. An insufficient number of patients were entered to achieve statistical significance. Both the ADAMTS-13 and the inhibitor levels show great variation and are not prognostic.

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Rituximab as pre-emptive treatment in patients with thrombotic thrombocytopenic purpura and evidence of anti-ADAMTS13 autoantibodies

Thrombosis and Haemostasis ◽

10.1160/th07-12-0753 ◽

2009 ◽

Vol 101 (02) ◽

pp. 233-238 ◽

Cited By ~ 62

Author(s):

Sara Gastoldi ◽

Erica Daina ◽

Daniela Belotti ◽

Enrico Pogliani ◽

Paolo Perseghin ◽

...

Keyword(s):

Thrombotic Thrombocytopenic Purpura ◽

Therapeutic Option ◽

Severe Disease ◽

Renal Involvement ◽

First Episode ◽

High Morbidity ◽

Sustained Remission ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura ◽

Haemolytic Anemia

SummaryThrombotic thrombocytopenic purpura (TTP) is a rare and severe disease characterized by thrombocytopenia, microangiopathic haemolytic anemia, neurological and renal involvement associated with deficiency of the von Willebrand factor-cleaving protease, ADAMTS13. Persistence of high titers of anti-ADAMTS13 autoantibodies predisposes to relapsing TTP. Since relapses are associated with high morbidity and mortality rates, the optimal therapeutic option should be a pre-emptive treatment able to deplete anti-ADAMTS13 autoantibodies and avoid relapses. Five patients who presented with persistence of undetectable ADAMTS13 activity and high titers of autoantibodies, were treated with rituximab as pre-emptive therapy during remission. Four of them were affected by relapsing TTP and one was treated after the first episode. ADAMTS13 activity ranging from 15% to 75% with disappearance of inhibitors was achieved after three months in all patients, and persisted >20% without inhibitors at six months. In three patients disease-free status is still ongoing after 29, 24 and six months, respectively. Relapses were documented in two patients during follow-up: in one patient remission lasted 51 months; while in the other patient relapse occurred after 13 months. Results demonstrated that rituximab used as pre-emptive treatment may be effective in maintaining a sustained remission in patients with anti-ADAMTS13 antibodies in whom other treatments failed to limit the production of inhibitors, and suggests that re-treatment with rituximab should be considered when ADAMTS13 activity decreases and inhibitors reappear into the circulation, to avoid a new relapse.

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Low doses v conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial in 160 children, 223 adults

Blood ◽

10.1182/blood.v71.4.1165.1165 ◽

1988 ◽

Vol 71 (4) ◽

pp. 1165-1169 ◽

Cited By ~ 58

Author(s):

S Bellucci ◽

Y Charpak ◽

C Chastang ◽

G Tobelem

Keyword(s):

Clinical Trial ◽

Randomized Clinical Trial ◽

Immune Thrombocytopenic Purpura ◽

Prospective Trial ◽

Low Doses ◽

Thrombocytopenic Purpura ◽

Significant Difference ◽

Adults And Children ◽

Randomized Prospective Trial ◽

Acute Itp

Abstract A randomized clinical trial was performed in 160 children and 223 adults with acute immune thrombocytopenic purpura (ITP). The role of corticoids at this phase of the disease is still controversial. Therefore, patients were randomized to receive either conventional doses (1 mg/kg/day) of corticotherapy or low doses (0.25 mg/kg/day) for 3 weeks. The remission, defined by platelet count superior to 100,000/microliter was studied for adults and children after 6 months and 12 months, respectively. The statistical analysis showed no significant difference between the two corticotherapy regimens neither in children nor in adults. Overall, 74% of children and 41% of adults were in remission. For the first time in acute ITP, a randomized prospective trial showed that both in children and adults low dose corticotherapy (0.25 mg/kg/day) proves to have the same efficacy as conventional doses (1 mg/kg/day).

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Inhibition of von Willebrand factor by ARC1779 in patients with acute thrombotic thrombocytopenic purpura

Thrombosis and Haemostasis ◽

10.1160/th10-08-0520 ◽

2011 ◽

Vol 105 (03) ◽

pp. 545-552 ◽

Cited By ~ 64

Author(s):

Bernd Jilma ◽

Jolanta Siller-Matula ◽

James Gilbert ◽

Paul Knöbl ◽

Petra Jilma-Stohlawetz ◽

...

Keyword(s):

Steady State ◽

Thrombotic Thrombocytopenic Purpura ◽

Plasma Concentrations ◽

Prospective Trial ◽

Organ Damage ◽

Pharmacokinetics And Pharmacodynamics ◽

Thrombocytopenic Purpura ◽

Platelet Counts ◽

Baseline Activity ◽

Von Willebrand

SummaryThrombotic thrombocytopenic purpura (TTP) can cause severe organ damage due to enhanced platelet aggregation by ultra-large von Wille-brand factor (VWF) multimers. Thus inhibition of VWF by the anti-VWF ARC1779 might potentially be beneficial for TTP patients. This prospective trial tested the safety, pharmacokinetics and pharmacodynamics of the anti-VWF aptamer ARC1779 added to plasma exchange therapy (PEX) in patients with acute TTP. Seven patients received bolus primed continuous i.v. infusions of ARC1779 (1–2 μg/kg/min) in addition to PEX until remission of TTP was induced or for 14 days. Mean steady state ARC1779 plasma concentrations of 9.9 μg/ml reduced VWF activity to 5% (mean baseline activity was 125% in TTP patients compared to a reference plasma). PEX reduced ARC1779 levels by 50%, but steady state concentrations were restored rapidly with a mini-bolus. After discontinuation of PEX, ARC1779 alone further increased platelet counts in one patient. Stopping ARC1779 was associated with an immediate drop of platelet counts in this patient. This suggests that ARC1779 can block the progression of TTP in patients with severe ADAMTS13 is deficiency. ARC1779 was generally well tolerated without any signs of bleeding. Pharmacokinetics and pharmacodynamics of ARC1779 were well predictable and in agreement with those observed in a previous trial with healthy volunteers. Based on its mechanism of action and the observed effect on platelet counts, ARC1779 used as an adjunctive to PEX may help accelerate recovery from organ dysfunction.

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Osteosarcoma: A Randomized, Prospective Trial of the Addition of Ifosfamide and/or Muramyl Tripeptide to Cisplatin, Doxorubicin, and High-Dose Methotrexate

Journal of Clinical Oncology ◽

10.1200/jco.2005.06.031 ◽

2005 ◽

Vol 23 (9) ◽

pp. 2004-2011 ◽

Cited By ~ 450

Author(s):

Paul A. Meyers ◽

Cindy L. Schwartz ◽

Mark Krailo ◽

Eugenie S. Kleinerman ◽

Donna Betcher ◽

...

Keyword(s):

Factorial Design ◽

Prospective Trial ◽

Dose Schedule ◽

High Dose ◽

High Dose Methotrexate ◽

Standard Chemotherapy ◽

Free Survival ◽

Dose Methotrexate ◽

Randomized Prospective Trial ◽

To Receive

Purpose To determine whether the addition of ifosfamide and/or muramyl tripeptide (MTP) encapsulated in liposomes to cisplatin, doxorubicin, and high-dose methotrexate (HDMTX) could improve the probability for event-free survival (EFS) in newly diagnosed patients with osteosarcoma (OS). Patients and Methods Six hundred seventy-seven patients with OS without clinically detectable metastatic disease were treated with one of four prospectively randomized treatments. All patients received identical cumulative doses of cisplatin, doxorubicin, and HDMTX and underwent definitive surgical resection of the primary tumor. Patients were randomly assigned to receive or not to receive ifosfamide and/or MTP in a 2 × 2 factorial design. The primary end point for analysis was EFS. Results Patients treated with the standard arm of therapy had a 3-year EFS of 71%. We could not analyze the results by factorial design because we observed an interaction between the addition of ifosfamide and the addition of MTP. The addition of MTP to standard chemotherapy achieved a 3-year EFS rate of 68%. The addition of ifosfamide to standard chemotherapy achieved a 3-year EFS rate of 61%. The addition of both ifosfamide and MTP resulted in a 3-year EFS rate of 78%. Conclusion The addition of ifosfamide in this dose schedule to standard chemotherapy did not enhance EFS. The addition of MTP to chemotherapy might improve EFS, but additional clinical and laboratory investigation will be necessary to explain the interaction between ifosfamide and MTP.

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Rituximab prevents recurrence of thrombotic thrombocytopenic purpura: a case report

Blood ◽

10.1182/blood-2004-12-4885 ◽

2005 ◽

Vol 106 (3) ◽

pp. 925-928 ◽

Cited By ~ 38

Author(s):

Miriam Galbusera ◽

Elena Bresin ◽

Marina Noris ◽

Sara Gastoldi ◽

Daniela Belotti ◽

...

Keyword(s):

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

Therapeutic Option ◽

Close Monitoring ◽

Thrombocytopenic Purpura ◽

Small Vessels ◽

Von Willebrand ◽

Willebrand Factor ◽

Substantial Morbidity

AbstractThrombotic thrombocytopenic purpura (TTP) is a rare disorder of small vessels that is associated with deficiency of the von Willebrand factor–cleaving protease, ADAMTS13. The presence of anti-ADAMTS13 autoantibodies is considered a factor predisposing to relapses. Despite close monitoring and intensive plasma treatment, in these patients acute episodes are still associated with substantial morbidity and mortality rates, and the optimal therapeutic option should be prevention of relapses. This study was conducted in a patient with recurrent TTP due to high titers of ADAMTS13 inhibitors, who used to have 2 relapses of TTP a year. The study compared the standard treatment plasma exchange with rituximab. Results documented that plasma exchange had only a small transient effect on ADAMTS13 activity and inhibitors; on the contrary, prophylaxis with rituximab was associated with disappearance of anti-ADAMTS13 antibodies, a progressive recovery of protease activity, and it allowed the patient to maintain a disease-free state during a more than 2-year follow-up.

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How I treat refractory thrombotic thrombocytopenic purpura

Blood ◽

10.1182/blood-2014-11-551580 ◽

2015 ◽

Vol 125 (25) ◽

pp. 3860-3867 ◽

Cited By ~ 76

Author(s):

Farzana A. Sayani ◽

Charles S. Abrams

Keyword(s):

Plasma Exchange ◽

Thrombotic Thrombocytopenic Purpura ◽

Clinical Symptoms ◽

Thrombocytopenic Purpura ◽

New Therapeutic Approaches ◽

Number Of Patients ◽

A Disintegrin And Metalloproteinase ◽

Von Willebrand ◽

Willebrand Factor

Abstract Acquired thrombotic thrombocytopenic purpura (TTP) is characterized by thrombocytopenia and microangiopathic hemolytic anemia (MAHA) without an obvious cause, and may include fever, mild renal failure, and neurologic deficits. It is characterized by a deficiency of the von Willebrand factor (VWF) cleaving enzyme, ADAMTS13 (a disintegrin and metalloproteinase, with a thrombospondin type 1 motif, member 13), resulting in formation of microthrombi in the high sheer environment of the microvasculature. This causes microvascular occlusion, MAHA, and organ ischemia. Diagnosis is based on the presence of clinical symptoms, laboratory aberrations consistent with MAHA, decreased ADAMTS13 activity, and possibly presence of anti-ADAMTS13 autoantibodies. Upfront treatment of acute TTP includes plasma exchange and corticosteroids. A significant number of patients are refractory to this treatment and will require further interventions. There are limited data and consensus on the management of the refractory TTP patient. Management involves simultaneously ruling out other causes of thrombocytopenia and MAHA, while also considering other treatments. In this article, we describe our management of the patient with refractory TTP, and discuss use of rituximab, increased plasma exchange, splenectomy, and immunosuppressive options, including cyclophosphamide, vincristine, and cyclosporine. We also review recent evidence for the potential roles of bortezomib and N-acetylcysteine, and explore new therapeutic approaches, including recombinant ADAMTS13 and anti-VWF therapy.

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Low doses v conventional doses of corticoids in immune thrombocytopenic purpura (ITP): results of a randomized clinical trial in 160 children, 223 adults

Blood ◽

10.1182/blood.v71.4.1165.bloodjournal7141165 ◽

1988 ◽

Vol 71 (4) ◽

pp. 1165-1169 ◽

Cited By ~ 1

Author(s):

S Bellucci ◽

Y Charpak ◽

C Chastang ◽

G Tobelem

Keyword(s):

Clinical Trial ◽

Randomized Clinical Trial ◽

Immune Thrombocytopenic Purpura ◽

Prospective Trial ◽

Low Doses ◽

Thrombocytopenic Purpura ◽

Significant Difference ◽

Adults And Children ◽

Randomized Prospective Trial ◽

Acute Itp

A randomized clinical trial was performed in 160 children and 223 adults with acute immune thrombocytopenic purpura (ITP). The role of corticoids at this phase of the disease is still controversial. Therefore, patients were randomized to receive either conventional doses (1 mg/kg/day) of corticotherapy or low doses (0.25 mg/kg/day) for 3 weeks. The remission, defined by platelet count superior to 100,000/microliter was studied for adults and children after 6 months and 12 months, respectively. The statistical analysis showed no significant difference between the two corticotherapy regimens neither in children nor in adults. Overall, 74% of children and 41% of adults were in remission. For the first time in acute ITP, a randomized prospective trial showed that both in children and adults low dose corticotherapy (0.25 mg/kg/day) proves to have the same efficacy as conventional doses (1 mg/kg/day).

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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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Antibody Against Macrophage Receptor with Collagenous Structure (Anti-MARCO IgG) in Thrombotic Thrombocytopenic Purpura Patients.

Blood ◽

10.1182/blood.v120.21.2201.2201 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2201-2201

Author(s):

Phandee Watanaboonyongcharoen ◽

Jessica L. Allen ◽

Yuri D. Fedoriw ◽

Herbert C. Whinna ◽

Rommel P. Lu ◽

...

Keyword(s):

Western Blot ◽

B Cell ◽

Thrombotic Thrombocytopenic Purpura ◽

Area Under The Curve ◽

Healthy Controls ◽

Adamts13 Activity ◽

Thrombocytopenic Purpura ◽

High Background ◽

Number Of Patients ◽

Collagenous Structure

Abstract Abstract 2201 Idiopathic thrombotic thrombocytopenic purpura (TTP) is typically associated with severe ADAMTS13 deficiency due to the production of autoantibodies against ADAMTS13. Recent studies have demonstrated that B cell activating factor (BAFF), a TNF family member known to promote activation and survival of autoreactive B cells, is increased in TTP patients (Thomas et al. 2011 155:620 Br J Haematol; Watanaboonyongcharoen et al. 2011, AABB Abstract # 1118421). We hypothesized that high BAFF levels in TTP results in loss of B cell tolerance and the production of autoantibodies. Since defective clearance of apoptotic cells by macrophages has been found in autoimmune diseases, antibodies against MARCO (Macrophage Receptor with Collagenous structure) represented good candidate for study as a potentially pathophysiologically relevant autoantibody. Such anti-MARCO antibodies may lead to defective apoptotic cell clearance and the development of TTP. We measured anti-MARCO antibodies by ELISA and Western blot in 34 idiopathic TTP patients between 1999 and 2012: 25 female and 9 male with a median age of 40 years (range 25–72). All patients were diagnosed on the clinical basis of microangiopathic hemolytic anemia and thrombocytopenia without any other cause. ADAMTS13 activity and the presence of anti-ADAMTS13 inhibitor tests were performed in all patients. Fifty percent of patients had ADAMTS13 activity less than 10%, while 56% had ADAMTS13 inhibitor. All 34 patients underwent therapeutic plasma exchange (TPE) daily until the platelet count was at least 150 × 109/l for two consecutive days. High dose steroids were initiated immediately after first TPE. While direct binding ELISA did not yield specific results due to high background, specific MARCO bands were detected by Western blotting of recombinant MARCO protein with patient plasma IgG. Ninety-seven percent of patients with TTP (33/34) were positive for anti-MARCO IgG antibody compared to forty percent (10/25) of healthy controls, p < 0.001 (Table 1). As a surrogate for antibody titer, intensity of each Western blot band was quantified by densitometry using NIH ImageJ software. Patients with TTP had significantly increased anti-MARCO IgG as defined by the densitometric area under the curve (1.3 × 103; range 0–8.2 × 103) compared to healthy controls (0, range 0–4.5 × 103), p < 0.001. A cut-off point for high titer anti-MARCO IgG was calculated by using mean + 2SD of the area under the curve (AUC) of anti-MARCO IgG Western blot band density measured in healthy controls. Patients with an increased amount of anti-MARCO IgG (AUC > 2.9× 103) tended to have a higher relapse rate compared to those with normal anti-MARCO IgG (4 of 6 patients [67%] vs. 10 of 28 patients [36%], respectively, p = 0.20), although statistical significance was not reached due to the limited number of patients. Thus, for the first time, we identify anti-MARCO IgG in idiopathic TTP, suggesting a role for macrophage inhibition in the pathophysiology of TTP. Studies of anti-MARCO antibodies in larger numbers of patients may lead to development of a novel prognostic marker for TTP patients. Table 1. Presence of anti-MARCO IgG on Western blot Anti-MARCO IgG Population group TTP n (%) Healthy n (%) Yes, (n = 43) 33 (97) 10 (40) No, (n = 16) 1 (3) 15 (60) p < 0.001. Disclosures: No relevant conflicts of interest to declare.

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