Thrombotic Thrombocytopenic Purpura in a ChildWithSystemic Lupus Erythematosus
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We report a child with thrombotic thrombocytopenic purpura (TTP) secondary to systemic lupus erythematosus. The diagnosis was confirmed by low ADAMTS13 activity (<5%) along with the presence of a low titer inhibitor. Her clinical course was complicated by systemic lupus erythematosus, immunosuppressant therapy, and septic shock. She responded to plasma exchange and ADAMTS13 activity levels recovered. This case illustrates the heterogeneity of TTP and the difficulty of making a diagnosis of TTP. ADAMTS13 activity assay can be useful in the differential diagnosis of diseases with clinical features of thrombotic microangiopathy in pediatric patients. However, treatment needs to be decided carefully case-by-case.Keywords:
Thrombotic microangiopathy
ADAMTS13
Microangiopathy
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.
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Microangiopathic hemolytic anemia
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Thrombotic microangiopathy
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Background. Thrombotic microangiopathy (TMA) is a well-known complication after renal allograft transplantation. In most cases, calcineurin inhibitor is believed to play a role in the development of this disorder. Recent studies have shown that a deficiency in the activity of the von Willebrand factor–cleaving metalloprotease ADAMTS13 causes thrombotic thrombocytopenic purpura. A similar mechanism occurring in patients who develop TMA after renal transplantation has not been described. Methods. Analysis of plasma samples from a patient who developed TMA after receiving a cadaveric renal allograft revealed undetectable ADAMTS13 activity and the presence of its inhibitors. Results. Discontinuation of cyclosporine and daily plasma exchange increased the ADAMTS13 activity, which was followed by resolution of the microangiopathic hemolysis and improvement of the graft function. At 3-month follow-up, the ADAMTS13 activity remained in the normal range and no inhibitors were detected. Conclusions. This is the first case to demonstrate a correlation between the presence of ADAMTS13 inhibitors and transplant-associated TMA. Autoimmune inhibitors of ADAMTS13 should be considered in patients with transplant-associated thrombotic microangiopathy. The role of calcineurin inhibitor in the formation of autoantibodies to ADAMTS13 remains to be explored.
Thrombotic microangiopathy
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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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Abstract We present a unique case of a 68‐year‐old male who was diagnosed with COVID‐19. His hospital course was complicated by widespread thrombosis, renal failure, and thrombocytopenia. Thrombotic thrombocytopenic purpura was initially suspected, yet plasma exchange and steroids did not improve his disease. Ultimately, he was diagnosed with COVID‐19‐induced thrombotic microangiopathy.
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症例は20歳の男性. 生来健康であったが, 頭痛と全身倦怠感を主訴に近医を受診し, 腎機能障害, 貧血, 血小板減少, 著明な高血圧のため入院となった. 血小板減少と破砕赤血球を伴う溶血性貧血から血栓性微小血管障害症 (thrombotic microangiopathy ; TMA) を呈していたため血漿交換, ステロイド薬の投与, カルシウム拮抗薬による降圧療法を開始したが, 血漿中のvon Willebrand因子特異的切断酵素 (von Willebrand factor cleaving protease ; vWF-CP)/ADAMTS13活性が正常であったことより悪性高血圧に合併したTMAと診断した. 血小板減少と溶血性貧血は治療後速やかに改善したが, 腎不全は改善せずうっ血性心不全も呈した. 持続的血液濾過透析 (continuous hemodiafiltration ; CHDF) を行い, アンジオテンシン変換酵素阻害薬とアンジオテンシン受容体拮抗薬を併用したところ, 全身状態や腎機能障害の改善がみられた. 以後CHDFなどの血液浄化療法は不要となり外来通院となった. 回復期に施行した腎生検では細動脈内膜の浮腫性肥厚を認め, 悪性腎硬化症に合致する所見を得た. TMAの原疾患は多岐にわたり, 臨床症状だけでは鑑別がしばしば困難であるが, 本症例ではADAMTS13活性の測定が有用であったので, 若干の文献的考察を加え報告する.
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ADAMTS13
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Thrombotic microangiopathy
ADAMTS13
Plasmapheresis
Microangiopathic hemolytic anemia
Etiology
Microangiopathy
Schistocyte
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ADAMTS13
Thrombotic microangiopathy
Schistocyte
Purpura (gastropod)
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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
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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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