Congenital thrombotic thrombocytopenic purpura (cTTP) with two novel mutations

Congenital thrombotic thrombocytopenic purpura (cTTP) is a rare disorder of childhood that has clinical and laboratory similarities to other, more common conditions. Prompt recognition is required as delays in therapy are associated with significant morbidity and failure to treat may lead to death. While the principles of treatment have not changed, enormous progress in the genetic and molecular understanding has taken place. Emerging treatment options may offer some hope of improved quality of life in future. We describe a Chinese patient with cTTP which resulted from two previously undescribed mutations in the ADAMTS13 gene. Pediatr Blood Cancer 2012; 59: 1296–1298. © 2012 Wiley Periodicals, Inc.     

Severe vitamin B-12 deficiency in a child mimicking thrombotic thrombocytopenic purpura

We report a case of severe vitamin B-12 deficiency in a child who had a clinical presentation of hemolysis and thrombocytopenia that suggested the diagnosis of thrombotic thrombocytopenic purpura (TTP) and was associated with decreased ADAMTS13 activity. In this report, we review vitamin B-12 deficiency in children, the relationship between ADAMTS13 activity and TTP and discuss other conditions associated with decreased ADAMTS13 activity.     

系统性红斑狼疮合并血栓性血小板减少性紫癜1 例分析

目的探讨系统性红斑狼疮(SLE)合并血栓性血小板减少性紫癜(TTP)的临床特点、诊断和治疗。方法回顾分析1例重症SLE合并TTP患儿的临床资料,并复习相关文献。结果患儿,女,13岁,以肾病综合征起病,诊断重症SLE、狼疮性肾炎。初治好转后再现头痛、血小板减少、贫血、急性肾损伤及发热。血涂片破碎红细胞2%,诊断合并TTP。经激素冲击、血浆置换、免疫抑制剂等综合性治疗后病情缓解。结论 SLE合并TTP较为少见,病死率高,早期识别、合理治疗可改善预后。     

儿童继发性血栓性血小板减少性紫癜1例并文献复习

目的 提高对儿童不典型继发性血栓性PLT减少性紫癜（TTP）的认识。 方法 总结1例无神经系统受累的继发性TTP患儿的临床资料、实验室检查结果、ADAMTS13酶活性和Anti-ADAMTS13抗体检测结果,行系统文献检索并文献复习。 结果 男性患儿,12岁,急性起病,病初有发热,双下肢可见瘀点,PLT及Hb进行下降,血涂片可见破碎RBC,高胆红素血症,LDH明显升高,镜下血尿,肾功能正常,补体正常,考虑血栓性微血管病(TTP或非典型溶血尿毒综合征)。为进一步明确诊断, 行ADAMTS13酶活性检测2.3%（正常值40％~130%）,ADAMTS13抗体检测90 U·mL-1（正常值＜12 U·mL-1）,确诊继发性TTP,予血浆置换和激素治疗。4个月后患儿停用所有药物,目前停药6月无复发。系统检索中国知网、万方和PubMed数据库,共有14篇英文文献中40例继发性TTP进入本文分析,发病年龄（10.2±5.2）岁,男19例,女21例,发热36例（90%）,神经系统受累28例（70%）,肾脏受累18例（45%）,均有贫血和PLT降低。3例死亡,37例血浆置换+激素治疗,31例（83.8%）对血浆置换治疗即时反应好,1例因血浆过敏和1例血浆置换导管相关感染改为激素+利妥昔单抗治疗反应好,1例难治性继发性TTP加长春新碱（利妥昔单抗上市前）随访时复发,2例发生血浆置换依赖,加环孢素后治疗反应好,1例治疗反应不好,加长春新碱后治疗反应好,,4例失访（10.8%）,平均随访时间29月（3~72个月）,13例（39.4%）出现复发,9/13例加利妥昔单抗中仍有2例复发。 结论 贫血和PLT降低应怀疑TTP,需行ADAMTS13酶活性及其抗体的检测,有助于区别遗传性和获得性TTP;血浆置换+激素,或+利妥昔单抗是TTP的治疗组合选项。     

Successful treatment of recurrent thrombotic thrombocytopenic purpura with plasmapheresis and vincristine

An adolescent girl with severe thrombotic thrombocytopenic purpura (TTP) remained in a critical condition after 3, weeks of combined treatment with antiplatelet drugs, plasma infusions and plasma exchange. The introduction of vincristine resulted in gradual improvement and eventual complete remission which lasted for 2 years. When she relapsed, immediate improvement was observed with the combined treatment of plasmapheresis and vincristine. She has now been in complete remission again for 10 months. It is suggested that plasmapheresis plus vincristine should be used as the initial treatment for children with TTP.     

Remission of thrombotic thrombocytopenic purpura in a patient with compound heterozygous deficiency of von Willebrand factor-cleaving protease by infusion of solvent/detergent plasma

Plasma exchange or plasma infusion is considered to be the therapy of choice in patients with thrombotic thrombocytopenic purpura (TTP) who are deficient in von Willebrand factor-cleaving protease (VWF-CP). Recently, mutations in the ADAMTS 13 gene were identified as being responsible for VWF-CP deficiency in patients with familial TTP (VWF-CP deficiency in the absence of an inhibitor). Here we report on a girl who presented with recurrent thrombocytopenia and anaemia since birth, developing the full pentad of characteristic TTP at the age of 16 y. Congenital TTP was confirmed on the basis of severe VWF-CP deficiency in the absence of an acquired inhibitor. The patient was found to be compound heterozygous for two hitherto undescribed mutations in the ADAMTS 13 gene: a truncating frame shift mutation, 4143insA in exon 29, and the nonsense mutation 3100A >T in exon 24 (R1034X). After infusion of solvent/detergent plasma, the patient went into remission and remained asymptomatic under regular plasma therapy at 2-wk intervals for over two years. Conclusion: TTP in childhood may be mild and oligosymptomatic. Determination of VWF-CP activity is helpful in the differential diagnosis of thrombocytopenia.     

Thrombotic thrombocytopenic purpura in childhood

Thrombotic thrombocytopenic purpura (TTP) is a rare disease, especially in childhood, and has a high mortality rate in the absence of appropriate treatment. It is characterised by microangiopathic haemolytic anaemia and consumptive thrombocytopenia. TTP may be difficult to distinguish from haemolytic uraemic syndrome (HUS) because of similar clinical manifestations and laboratory findings. In the past, TTP and HUS have often been considered to represent variable expressions of a single entity. Our increased understanding of the pathogenesis of TTP has in turn resulted in significant improvements in its treatment and outcomes. Several immunomodulating agents are currently being used with variable outcomes. Pediatr Blood Cancer 2009;53:537–542. © 2009 Wiley‐Liss, Inc.     

儿童血栓性血小板减少性紫癜

血栓性血小板减少性紫癜（TTP）在儿童病例中甚为少见,但如未能及时诊断及施予治疗,其后果则极为严重。其最常见之5种病症为：血小板减少、微血管溶血性贫血、急性肾衰竭、发热及中枢神经系统症状。但临床病例中,并不一定会同时出现上述5种症状。故此医疗人员对此病必须有极高之警觉性。TTP之病理特征包括：外周血涂片可见裂体细胞,Coombs 试验阴性,血清乳酸脱氢酶增高及中度或重度血小板减少。TTP发病机理主因缺乏ADAMTS13,从而引发微血管溶血性贫血及血小板减少。TTP可概括分为家族性TTP（Upshaw Schulman 综合征）和继发性TTP。家族性TTP是由于先天性ADAMTS13缺乏所致,其急性治疗法为血浆置换,当病情稳定后,可输注新鲜冰冻血浆以防止病情复发。继发性TTP是指患者因体内产生抗体而导致ADAMTS13功能减退,主要治疗方法亦为血浆置换,最新之临床文献显示rituxiamb对此症亦颇有治疗价值。     

Neglect‐induced pseudo‐thrombotic thrombocytopenic purpura due to vitamin B12 deficiency

Although thrombotic thrombocytopenic purpura (TTP) is rare, early diagnosis and treatment are important for decreasing the mortality rate. Acquired vitamin B12 deficiency is frequently overlooked because of its rarity in developed countries, particularly in children and adolescents. The hematological changes in vitamin B12 deficiency present as megaloblastic anemia, increased lactate dehydrogenase, vasoconstriction, increased platelet aggregation, and abnormal activation of the coagulation followed by microangiopathy as well as neutropenia and thrombocytopenia. We report herein the case of a 15‐year‐old girl who had been neglected, which might have caused pseudo‐TTP through malnutrition, particularly vitamin B12 deficiency. When we encounter cases of TTP in children, clinicians must be aware of the possibility of malnutrition, particularly with vitamin B12 deficiency, even in developed countries, and investigate the cause of malnutrition including neglect.     

Treatment of an infant with severe acute refractory immune thrombocytopenic purpura using combination therapy including rituximab

Some infants with acute immune thrombocytopenic purpura (ITP) do not respond to first‐line therapy, and currently there is no consensus on therapy for these refractory cases. We describe a 12‐week‐old infant with acute ITP who was unresponsive to intravenous immunoglobulin and corticosteroid, and developed gastrointestinal bleeding. Several combination therapies were unsuccessful. After four doses of rituximab followed by intravenous immunoglobulin and corticosteroid, his platelet counts gradually increased. Combined therapy which includes rituximab may be a promising treatment for severe acute refractory ITP. Pediatr Blood Cancer 2009;53:203–205. © 2009 Wiley‐Liss, Inc.     

ADAMTS13 phenotype in plasma from normal individuals and patients with thrombotic thrombocytopenic purpura

The activity of ADAMTS13, the von Willebrand factor cleaving protease, is deficient in patients with thrombotic thrombocytopenic purpura (TTP). In the present study, the phenotype of ADAMTS13 in TTP and in normal plasma was demonstrated by immunoblotting. Normal plasma (n = 20) revealed a single band at 190 kD under reducing conditions using a polyclonal antibody, and a single band at 150 kD under non-reducing conditions using a monoclonal antibody. ADAMTS13 was not detected in the plasma from patients with congenital TTP (n = 5) by either antibody, whereas patients with acquired TTP (n = 2) presented the normal phenotype. Following immunoadsorption of immunoglobulins, the ADAMTS13 band was removed from the plasma of the patients with acquired TTP, but not from that of normal individuals. This indicates that ADAMTS13 is complexed with immunoglobulin in these patients. The lack of ADAMTS13 expression in the plasma from patients with hereditary TTP may indicate defective synthesis, impaired cellular secretion, or enhanced degradation in the circulation. This study differentiated between normal and TTP plasma, as well as between congenital and acquired TTP. This method may, therefore, be used as a complement in the diagnosis of TTP.     

Directions for research in autoimmune thrombocytopenic purpura (ITP)

All attendees participated in a round-table discussion regarding directions for research in autoimmune thrombocytopenic purpura (ITP). Suggested areas for study were grouped into five main areas: (i) improved classification of ITP identifying subsets of patients with differing clinical syndromes and response to treatment, and those more likely to have serious bleeding manifestations; identification of patients with reduced thrombopoiesis was emphasized; (ii) studies aimed at elucidating the aetiology and pathophysiology of ITP, with emphasis on distinctions between acute and chronic ITP and between patients responsive or refractory to therapy; these studies focused on measures of humoral and cellular immune dysregulation; (iii) studies of platelet function in ITP, with the intent of defining these abnormalities and correlating them with the clinical manifestations of the disease; (iv) new approaches to treatment, particularly of refractory patients; and (v) a miscellaneous group, which included development of an ITP registry, evaluation of the "burden" of disease, investigation of mood changes in ITP, etc. The discussion was not intended to be all-inclusive, but focused on the content of other talks in this symposium. It is hoped that some of thesesuggestions will be further developed for investigation in multicentre co-operative studies to improve the diagnosis, understanding and treatment of ITP.     

儿童获得性血栓性血小板减少性紫癜五例分析

目的:探讨儿童获得性血栓性血小板减少性紫癜(aTTP)的临床特点、治疗情况以及预后。方法:回顾性病例总结,以2016年1月至2019年7月于首都医科大学附属北京儿童医院住院治疗的5例aTTP患儿为研究对象,分析患儿临床表现、实验室检查、治疗及预后情况。结果:纳入5例aTTP患儿,占同期血栓性血小板减少性紫癜患儿的5/11,其中男2例、女3例,发病年龄8.9(0.8~14.5)岁。5例患儿均存在血小板减少和微血管病性溶血性贫血,仅1例存在经典五联征,3例患儿伴神经系统症状,3例有发热,而肾功能损伤相对少见(1例)。5例患儿均存在重度血小板减低[7(4~14)×10⁹/L]及血红蛋白下降[70(58~100)g/L];血生化检查示3例总胆红素水平升高,均以间接胆红素升高为主,5例乳酸脱氢酶水平均升高,1例尿素氮升高。骨髓穿刺提示巨核细胞数目不低。ADAMTS13活性检查均为0,4例ADAMTS13抑制物阳性,1例为阴性。5例患儿均接受糖皮质激素治疗,并且在疾病早期应用利妥昔单抗治疗,3例患儿接受血浆置换。5例患儿血小板恢复正常的时间为开始治疗后的19(9~29)d。1例患儿在治疗9个月后出现复发,再次予糖皮质激素及利妥昔单抗治疗后病情稳定,随访3年以上确诊为系统性红斑狼疮。截至2020年12月1日,随访24(16~57)个月,5例患儿临床症状消失,未次随访血小板计数为159(125~269)×10⁹/L。结论:儿童aTTP患者较为少见,各年龄段均有发病,临床表现以血小板减少及微血管病性溶血为主,血浆ADAMTS13活性及抑制物检测有助于aTTP的诊断。血浆置换及利妥昔单抗治疗有效,该病需长期随诊监测。