Acquired idiopathic thrombotic thrombocytopenic purpura successfully treated with intravenous immunoglobulin and glucocorticoid
Hiro NakaoAkira IshiguroNahoko IkomaKentaro NishiChemin SuHisaya NakadateM. KubotaMasaki HayakawaMasanori Matsumoto
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Abstract:
Rationale: Plasma exchange is the principal treatment for acquired thrombotic thrombocytopenic purpura (TTP) but is invasive and may have adverse effects. Reports of immunoglobulin therapy for acquired TTP without plasma exchange are rare. Patient concerns: A 14-year-old girl was admitted because of hemolytic anemia and thrombocytopenia. Diagnosis: Acquired TTP was diagnosed based on low ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, 13) activity and a high ADAMTS13 inhibitor level. Interventions & Outcomes: Fresh frozen plasma was initially effective. Prednisolone and immunoglobulin resolved the condition with no adverse effects and rendered plasma exchange unnecessary. Lessons: Compared with biological agents, immunoglobulin is cost-effective, readily available, and has a proven long-term safety record, making it a possible treatment option for acquired thrombotic thrombocytopenic purpura.Keywords:
ADAMTS13
Prednisolone
Fresh frozen plasma
Thrombocytopenic purpura
In this article, I mainly review the molecular targeted therapy for thrombotic thrombocytopenic purpura (TTP). TTP is one of thrombotic microangiopathies (TMA), which demonstrate hemolytic anemia with red blood cell destruction and thrombocytopenia. Another TTP, hemolytic uremic anemia (HUS) reveals bloody stood and acute kidney failure. As it is difficult to correctly diagnose TTP based on clinical symptoms alone, a confirmation of whether ADAMTS13 activity is lower than 10% is required. In the past few years, TTP was designated as an intractable disease by law, and the clinical application of ADAMTS13 test and rituximab became labeled in Japan. Currently, we are expecting that recombinant ADAMTS13 and caplacizumab for immune TTP will be applied.
ADAMTS13
Microangiopathic hemolytic anemia
Schistocyte
Thrombotic microangiopathy
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Thrombotic thrombocytopenic purpura (TTP) is a rare disorder, with an annual incidence of 1–2/1 000 000. If untreated, mortality is 90% but with early plasma exchange (PEX), this can be reduced to 10–20%. The British Committee for Standards in Haematology (BCSH) guidelines recommend PEX within 4–8 h of the diagnosis of TTP being suspected (Amorosi & Ultmann, 1966; Rock et al, 1991; Terrell et al, 2005; Scully et al, 2012). Early treatment of TTP is crucial as around half of all deaths will occur within 24 h of presentation without treatment (Scully et al, 2008). Given that TTP can be difficult to distinguish clinically from other thrombotic microangiopathies (TMA), empirical PEX is mandated where TTP is a possibility in a patient with a TMA. Therefore, several days of PEX can therefore be unnecessarily given to patients who are eventually diagnosed not to have TTP. The laboratory diagnosis of TTP is confirmed by a Disintegrin And Metalloproteinase with a Thrombospondin type 1 motif, member 13 (ADAMTS13) activity level of <5%, but, until recently, this assay has only been available in specialised centres, with slow turnaround times as many centres only perform weekly runs. A rapid ADAMTS13 activity assay would be invaluable for diagnostic and treatment decisions. In 2015, our institution introduced a rapid automated ADAMTS13 activity assay that is available 24 h per day. This study investigated the effect of this rapid ADAMTS13 assay on patient management, outcomes, safety and potential resource savings. A retrospective audit, registered on the hospital quality system, of requests for rapid ADAMTS13 activity assay (turn around 4–6 h) between 1 September 2015 and 20 June 2017, was performed. Patients were identified from the laboratory database of sample requests. Clinical parameters collected included: treatment, platelet count, ADAMTS13 activity, intensive care unit (ICU) admission, final diagnosis and whether the patient was alive. ADAMTS13 activity was assessed by Technozym ADAMTS13 chromogenic enzyme-linked immunosorbent assay (ELISA; Pathway Diagnostics Ltd, Dorking, Surrey, UK) on a Dynex DS2 analyser (Werfen UK, Warrington, Cheshire, UK). The inter- and intra-assay coefficient of variance (CV) was 3·9% (n = 5) and 2·2% (n = 10), respectively. Where ADAMTS13 activity was <5%, the presence of anti-ADAMTS13 IgG was assessed by Technozym ADAMTS13 chromogenic ELISA (Pathway Diagnostics Ltd) on a Dynex DS2 analyser (Werfen UK,) The inter- and intra-assay CVs were 3·1% (n = 4) and 6·0% (n = 10), respectively. Patients with congenital TTP (i.e. with ADAMTS13 activity <5% without detectable inhibitor) underwent confirmatory genetic studies by ADAMTS13 gene sequencing. There were 22 requests for urgent, rapid ADAMTS13 activity results with a turnaround time of 4·5–6·0 h (median 5 h). 1 non-TTP case from another hospital was excluded due to lack of clinical information. Of the 21 cases studied, seven (33%) had TTP, defined as ADAMTS13 activity <5% and were tested for anti-ADAMTS13 IgG (Table 1). The remaining 14 patients had a range of TMAs (Table 2). The median ADAMTS13 activity in the 14 non-TTP patients was 61·5% (range 36–104%; normal range 66–107%); four patients had low level ADAMTS13 activity (10–40%), currently thought to represent increased consumption (Nguyen et al, 2007). Median platelet count in non-TTP patients was 34 × 109/l (range 5–142 × 109/l; normal range 150–400 × 109/l). Seven of the 14 (50%) non-TTP patients were not in the ICU when the sample for ADAMTS13 activity was sent and were not admitted to ICU whilst the result was awaited as, at our institution, all patients with suspected TTP requiring PEX are admitted to ICU. Given that an ICU bed was estimated to cost £1932 per day compared to £413 for a ward bed (NHS Wales, 2013), preventing ICU admissions has potential cost savings, as well as saving on staff time and opportunity costs in preventing elective surgery cancellations where an ICU bed is unnecessarily occupied. In nine of the 14 (65%) non-TTP cases, neither PEX or plasma infusions were initiated as the diagnosis was equivocal and clinicians felt the risks of waiting 4-6 h for the ADAMTS13 results were acceptable. In the other cases (n = 5) a central line was inserted, but PEX was stopped after one exchange in two patients, after two exchanges in one patient, and one patient had an infusion of solvent detergent treated fresh frozen plasma (SD-FFP) prior to the ADAMTS13 result being available. A typical PEX uses 1–1·5 plasma volume exchange. BCSH guidance recommends the use of SD-FFP for PEX (O'Shaughnessy et al, 2004). A unit of Octaplas (Octapharma, Charlotte, NC, USA), the SD-FFP used at our institution costs £65.00, and a 1·5-volume PEX in a 70-kg man would typically use a minimum of 14 units of Octaplas, so a cost saving of at least £910.00 in SD-FFP would be made for every PEX prevented. In this study, an estimated £8190 in SD-FFP was saved by preventing one-off exchanges. Equipment costs (e.g. central line and apharesis equipment) would also be saved. Complications of plasma infusion include transfusion-related acute lung injury, transfusion-associated cardiac overload, pathogen transmission, severe allergic reactions and febrile reactions. Pulmonary complications of plasma infusion were the leading cause of death in the United Kingdom Serious Hazards Of Transfusion for 2010-16, accounting for 53% of deaths related to transfusion (Bolton-Maggs et al, 2017). Other complications of PEX are intravascular fluid shift between compartments, central venous access, citrate toxicity and hypotension. Avoiding such complications in already critically ill patients is highly desirable. Delayed PEX causes preventable deaths in TTP and, in this study, genuine TTP patients with acute disease had PEX started before the ADAMTS13 activity result was known, showing it does not cause treatment delay but allows early diagnostic refinement (Pereira et al, 1995). However, in patients whose eventual diagnosis was not TTP, the rapid ADAMTS13 result prevented inappropriate administration of plasma and unnecessary ICU admission. In conclusion, rapid ADAMTS13 activity assay is useful in excluding TTP in patients with TMA where there is diagnostic uncertainty. This is helpful where clinicians have little clinical exposure to TTP and lack confidence in diagnosis. In patients whose eventual diagnosis was not TTP, the rapid ADAMTS13 result prevented inappropriate administration of plasma and unnecessary ICU admission. It seems a rapid ADAMTS13 assay is a step forward in diagnosis of TTP and has potential cost savings. Drs Thomas, McDonald and Hunt jointly wrote the manuscript and Drs Cutler and Moore set up the assay and agreed the final manuscript.
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Thrombotic microangiopathies (TMAs) include several diseases, most prominently thrombotic thrombocy- topenic purpura (TTP) and hemolytic uremic syndrome (HUS) characterized by profound thrombocytopenia and microangiopathic hemolytic anemia. Usually congenital TTP is due to mutations in the gene ADAMTS13 or idiopathic when autoantibodies against ADAMTS13 are defined. The differential diagnosis of TTP from other TMAs can be sometimes challenging even with the discovery of ADAMTS13 for more than a decade. The presence of ADAMTS13 activity does not rule out TTP and ultra-large von Willebrand factor (ULVWF) multimers not always present in plasma of patients with TTP. Pathogenesis of TTP is related to massive intravascular aggregation of platelets as a result of lack of degradation of ULVWF multimers because of a lack of ADAMTS13 or secretion of excessive ultra-large multimers by endothelial cells. Diagnostic criteria of TTP are based on clinical features of neurological and renal disfunction along with hemolytic anemia, severe thrombocytopenia, low ADAMTS13 activity, and mutation in ADAMTS13 gene when congenital TTP is suspected. The standard treatment of TTP includes plasma exchange or plasma infusion. Splenectomy, protein A immunoadsorbtion, immunosuppressive drugs, and CD20 antibodies against B cells like rituximab are also used. Recombinant ADAMTS13 in congenital TTP is still to be used only in clinical trials. In HUS plasmapheresis is not efficient. Treatment of other TMA diseases is based on their underlying conditions.
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The identification, characterization, and clinical observation of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin-1-like domains) have provided important insights into the pathogenesis of thrombotic thrombocytopenic purpura (TTP). ADAMTS13 is a plasma enzyme essential for postsecretion proteolytic processing of von Willebrand factor (VWF). Absence of ADAMTS13 is associated with the occurrence of abnormally large multimers of VWF and is also associated with the occurrence of TTP. Initial assumptions that absent ADAMTS13 was itself the etiology of TTP have been tempered by subsequent observations that ADAMTS13 activity can be severely deficient without clinical abnormalities and that patients can have characteristic clinical features of TTP without severe ADAMTS13 deficiency. A current interpretation of these observations is that ADAMTS13 deficiency is a major risk factor for the development of TTP, but it is neither always necessary nor sufficient to cause TTP. This interpretation is consistent with other vascular and thrombotic disorders in which multiple risk factors and associated conditions contribute to the etiology of acute events.
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During the last three decades knowledge regarding the pathophysiology of thrombotic thrombocytopenic purpura (TTP) has dramatically increased. The discovery of ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13) deficiency in a subset of patients with TTP has been an important milestone. Apart from this, the use of therapeutic plasma exchange has reduced mortality rates in TTP from 80–90% to 10–20%. Nevertheless, TTP remains a possibly lethal disorder, in which early recognition of symptoms remains extremely important. In the last few years some interesting new insights into TTP have arisen. Firstly, promising reports on rituximab in the treatment of refractory and relapsing cases of TTP have been published. Secondly, risk stratification by means of ADAMTS13 deficiency and ADAMTS13 antibodies might lead to a more tailored approach in treating TTP patients.
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ADAMTS13 is a plasma metalloprotease with the primary function of cleaving VWF to maintain hemostasis. Circulating ADAMTS13 is in the closed conformation until blood vessel injury triggers a VWF-dependant activation to the open active form of the protein. ADAMTS13 is a multi-domain protein with the domains broadly functioning to interact and cleave VWF or maintain global latency of ADAMTS13. Thrombotic Thrombocytopenic Purpura is a disease characterized by excessive thrombi formation in the microvasculature, diagnosis is made when ADAMTS13 activity is <10%. In the hereditary form, a variety of mutations are found throughout all domains of ADAMTS13, examples are given alongside details of each domain in this article. ADAMTS13 mutations can inhibit the binding and cleavage of VWF directly or indirectly through reduced secretion, leading to increased size of VWF multimers and platelet recruitment. Molecular characterization of ADAMTS13 may provide insight into the mechanisms of TTP to aid in both scientific and clinical research.
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Thrombotic microangiopathies (TMAs) include several diseases, most prominently thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) characterized by profound thrombocytopenia and microangiopathic hemolytic anemia. Usually congenital TTP is due to mutations in the gene ADAMTS13 or idiopathic when autoantibodies against ADAMTS13 are defined. The differential diagnosis of TTP from other TMAs can be sometimes challenging even with the discovery of ADAMTS13 for more than a decade. The presence of ADAMTS13 activity does not rule out TTP and ultra-large von Willebrand factor (ULVWF) multimers not always present in plasma of patients with TTP. Pathogenesis of TTP is related to massive intravascular aggregation of platelets as a result of lack of degradation of ULVWF multimers because of a lack of ADAMTS13 or secretion of excessive ultra-large multimers by endothelial cells. Diagnostic criteria of TTP are based on clinical features of neurological and renal disfunction along with hemolytic anemia, severe thrombocytopenia, low ADAMTS13 activity, and mutation in ADAMTS13 gene when congenital TTP is suspected. The standard treatment of TTP includes plasma exchange or plasma infusion. Splenectomy, protein A immunoadsorbtion, immunosuppressive drugs, and CD20 antibodies against B cells like rituximab are also used. Recombinant ADAMTS13 in congenital TTP is still to be used only in clinical trials. In HUS plasmapheresis is not efficient. Treatment of other TMA diseases is based on their underlying conditions.
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Microangiopathic hemolytic anemia
Plasmapheresis
Schistocyte
Thrombotic microangiopathy
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Abstract ADAMTS13 (a disintegrin and metalloprotease with a thrombospondin type-1 motif, member 13) and von Willebrand factor (VWF) can be considered as scale weights which control platelet adhesion during primary haemostasis. In a very uncommon condition designated thrombotic thrombocytopenic purpura (TTP), functional absence of ADAMTS13 tips the balance toward VWF-mediated platelet adhesion in the microcirculation. TTP is associated with a high mortality and arises from either a congenital or acquired autoimmune deficiency of the plasma enzyme ADAMTS13. In case of acquired ADAMTS13 deficiency, autoantibodies bind to and inhibit the function of ADAMTS13. Currently available treatments of TTP aim to supply ADAMTS13 through plasma exchange or are aimed at B-cell depletion with rituximab. None of the available therapeutics, however, aims at protection of ADAMTS13 from circulating autoantibodies. In this review, our aim is to describe the structure–function relationship of ADAMTS13 employing homology models and previously published crystal structures. Structural bioinformatics investigation of ADAMTS13 reveals many insights and explains how mutations and autoantibodies may lead to the pathophysiology of TTP. The results of these studies provide a roadmap for the further development of rationally designed therapeutics for the treatment of patients with acquired TTP. In addition, we share our opinion on the state of the art of the open–closed conformations of ADAMTS13 which regulate the activity of this highly specific VWF cleaving protease.
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The clinical presentation of thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies (TMAs) can often be similar. The role of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in diagnosing TTP is accepted by most researchers but continues to be debated in a few studies. We report the experience of our single-centre academic institution, where ADAMTS13 is used to diagnose TTP and guide plasma exchange (PLEX). Patients presenting to our institution with thrombotic microangiopathy (60 patients) between January 2006 and December 2012 were divided into two groups based on ADAMTS13 activity and clinical history. Patients with ADAMTS13 activity <10% were included in the TTP (n = 30) cohort while patients with activity >11% were classified as 'other microangiopathies' (TMA, n = 30). PLEX was only initiated in patients with a high likelihood of TTP and discontinued when the baseline ADAMTS13 activity was >11%. Patients with severe ADAMTS13 deficiency (TTP group) showed significant presenting differences: lower platelet counts, less renal dysfunction, higher presence of neurological abnormalities, and greater haemolysis markers as compared to non-deficient patients (TMA group). Most importantly, patients without severe ADAMTS13 deficiency were safely managed without increased mortality despite receiving no PLEX or discontinuing PLEX after a short course (upon availability of ADAMTS13 results). In conclusion, ADAMTS13 can be used to diagnose TTP and guide appropriate PLEX therapy.
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Thrombotic microangiopathy
ADAMTS
Microangiopathic hemolytic anemia
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