Thrombotic Thrombocytopenic Purpura In Children Research Articles

Congenital thrombotic thrombocytopenic purpura in children

Introduction. Congenital thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening genetic disorder characterized by recurrent episodes of microangiopathic hemolytic anemia, thrombocytopenia, and organ dysfunction due to the defi ciency or dysfunction of the ADAMTS13 enzyme. Despite the availability of clinical and laboratory diagnostic criteria the diagnosis remains challenging due to a wide range of diseases with similar appearance.Aim: to analyze the clinical manifestations and treatment results of identifi ed cases of congenital TTP at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology.Methods. This article reviews 11 clinical cases with congenital TTP genetically confi rmed or with typical clinical and laboratory signs.Results. Clinical and laboratory signs of TTP are highly variable and nonspecifi c, which was observed in the described cohort of patients. One of the trigger factors is often an acute respiratory viral infection, and stabilization of the disease can occur after transfusions of blood components. A delay of diagnosis can often lead not only to a delay of correct therapy, but also to the prescription of wrong therapy. The main diagnosis confi rmatory method was a molecular genetic test, which was carried out in 8 cases. All patients diagnosed with congenital TTP were successfully treated with FFP therapy.Conclusion. Early diagnosis of TTP is diffi cult due to the lack of specifi c clinical manifestations and easily accessible laboratory tests

Expert consensus on diagnosis and treatment of hereditary thrombotic thrombocytopenic purpura in children

儿童遗传性血栓性血小板减少性紫癜（hTTP）是一种少见但严重，甚至可致命的儿童血栓性微血管病，其发病机制为血管性血友病因子裂解酶（ADAMTS13）基因突变所导致的ADAMTS13活性持续严重缺乏。相较于成人，儿童期起病的hTTP更易出现脑或肾远期并发症，对预防性替代治疗的需求更迫切。本共识涵盖hTTP的定义、诊断、鉴别诊断及治疗，旨在为中国儿科医师开展儿童hTTP规范化诊治提供参考。.

Molecular Diagnosis Is Vital to the Accurate Classification and Management of Thrombotic Thrombocytopenic Purpura in Children.

Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially life-threatening hematologic disease, presenting a myriad of diagnostic and management challenges in children. Here, we provide a review of this disorder and discuss 2 exemplary cases of TTP occurring in adolescents, emphasizing the need for consideration of late-onset congenital TTP (cTTP). We demonstrate the importance of early confirmation of ADAMTS13 enzyme deficiency and the presence or absence of ADAMTS13 inhibitor in order to rapidly initiate the appropriate life-saving therapies. Ultimately, molecular testing is paramount to distinguishing between congenital and acquired immune-mediated TTP.

Predictors of In-Hospital Mortality in Thrombotic Thrombocytopenic Purpura in Children in the United States: A Population Analysis.

Despite proven efficacy and increased availability of therapeutic plasma exchange, thrombotic thrombocytopenic purpura (TTP) is associated with significant morbidity and mortality. This study utilized the Kids' Inpatient Database and National Inpatient Sample (2003 to 2016) to study predictors of in-hospital mortality in hospitalized TTP patients. Adjusted odds ratios of death with various putative risk factors were calculated using multiple regression analysis. Among 1568 hospitalizations with TTP as primary admission diagnosis who underwent therapeutic plasma exchange, 69 deaths were identified (all-cause mortality, 0.04%; median time-to-death, 6 wk). Overall, hospitalizations rates were fairly similar across the study period. The overall incidence of TTP related hospitalizations is 1.51 per 100,000 hospitalizations. A total of 69 deaths were reported with an all-cause in-hospital mortality rate of 0.04% (69/1568). The median time-to-death was 6 weeks. The majority of deaths occurred in age 16 to 20 years (58%), females (56.5%), and African American (42.9%) as shown in Table 2. Mean age for nonsurvivors was 14 years and the mean age of 15 years for survivors (P=0.01). Younger age, male sex, African-American ethnicity, malignancy, sepsis, acute kidney injury, platelet transfusion was significantly associated with mortality in patients with TTP. Early and targeted therapy for high risk individuals should be used to guide management of TTP patients for improved survival outcomes.

The Diagnostic Challenge of Acquired Thrombotic Thrombocytopenic Purpura in Children: Case Report and Review of the Literature.

Acquired thrombotic thrombocytopenic purpura (TTP) is a rare disease in children. Despite advances in diagnosis and treatment, acquired TTP remains a challenging disease due to the lack of a simple diagnostic test and the variable response to plasma exchange. Herein, we describe a case of a 5-year-old of black ethnicity boy who presented with a sudden onset of fatigue and body aches. Laboratory investigations revealed a thrombotic microangiopathic manifestation. TTP was diagnosed, and plasma exchange and corticosteroids were initiated, with an excellent response. Subsequently, reduced disintegrin and metalloprotease with thrombospodin-2-like repeats (ADAMTS-13) activity and human immunodeficiency virus (HIV) were confirmed. Antiretroviral treatment was started as long-term management. At last follow-up, he continues in stable remission.

Child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency: a cohort study of the French national registry for thrombotic microangiopathy

Thrombotic thrombocytopenic purpura is a rare thrombotic microangiopathy, related to a severe ADAMTS13 deficiency (a disintegrin and metalloprotease with thromboSpondin type 1 repeats, member 13; activity <10% of normal). Childhood-onset thrombotic thrombocytopenic purpura is very rare and initially often misdiagnosed, especially when ADAMTS13 deficiency is acquired (ie, not linked to inherited mutations of the ADAMTS13 gene). We aimed to investigate initial presentation, management, and outcome of acquired thrombotic thrombocytopenic purpura in children. Between Jan 1, 2000, and Dec 31, 2015, we studied a cohort of patients with child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura included in the French national registry for thrombotic microangiopathies at presentation and during follow up. The inclusion criteria were: first episode before age 18 years; ADAMTS13 activity less than 10% of normal at presentation; positive anti-ADAMTS13 autoantibodies during an episode, or a recovery of ADAMTS13 activity in remission, or both. ADAMTS13 activity and anti-ADAMTS13 autoantibodies were investigated by a central laboratory, and medical records were extensively reviewed to collect clinical and biological features with a standardised form. This study is registered with ClinicalTrials.gov, number NCT00426686. We enrolled 973 patients with childhood-onset thrombotic microangiopathy, of whom 74 had a severe ADAMTS13 deficiency (activity <10%) at presentation. 24 patients had an inherited thrombotic thrombocytopenic purpura also known as Upshaw-Schulman syndrome and five did not have follow-up data available, thus 45 children had acquired thrombotic thrombocytopenic purpura and were included in our database at presentation. 25 (56%) patients had idiopathic disease and 20 (44%) had miscellaneous associated clinical conditions. At diagnosis, median age was 13 years (IQR 7-16, range 4 months-17 years), with a sex ratio of 2·5 girls to 1 boy. Anti-ADAMTS13 autoantibodies were positive in 37 (82%) of 45 patients (24 [96%] of 25 idiopathic cases and 13 [65%] of 20 non-idiopathic cases). 39 (87%) of 45 patients were given plasma therapy and 21 (47%) received additional rituximab. Four (9%) children died after the first thrombotic thrombocytopenic purpura episode. Long-term follow up of the 41 survivors showed that ten (24%) patients relapsed and systemic lupus erythematosus occurred in two (5%) patients. Preemptive rituximab was used in seven (17%) of 41 patients with acquired thrombotic thrombocytopenic purpura. Our study shows that child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura have specific clinical, biological and therapeutic features. Long-term follow-up is crucial to prevent relapses of the disease, to identify the occurrence of autoimmune disorders, and to evaluate consequences on social life. Child-onset and adolescent-onset acquired thrombotic thrombocytopenic purpura is a crucial diagnosis in the field of paediatric haematologic cytopenias because it is a life-threatening disease requiring a specific management. Assistance Publique-Hôpitaux de Paris, France.

Inherited Thrombotic Thrombocytopenic Purpura in Children

Congenital thrombotic thrombocytopenic purpura (TTP) or Upshaw-Schulman syndrome is caused by homozygous or compound heterozygous mutations in the ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) gene. We investigated 30 patients with congenital TTP and analyzed clinical data and underlying ADAMTS-13 mutations. All patients showed virtually no ADAMTS-13 activity in plasma. Individual disease burden ranged from mild courses with rare episodes of mild thrombocytopenia to severe courses with chronic kidney disease and central nervous system (CNS) lesions. Two patients died due to complications of TTP. If initiated in a timely manner, plasma transfusions offer a reliable treatment to prevent organ damage. We identified 30 different causative mutations in the ADAMTS-13 gene. Our data do not support the idea of a tight correlation between ADAMTS-13 genotype and severity of disease. The type and magnitude of exogenous triggers for acute bouts of TTP as well as endogenous individual factors participating in the inflammatory response likely represent the foremost determinants of individual clinical courses. Future developments should aim at improving early diagnosis of TTP. To improve feasibility of prophylaxis and treatment of congenital TTP, recombinant ADAMTS-13 therapeutics are highly anticipated.

Children and adults with thrombotic thrombocytopenic purpura associated with severe, acquired Adamts13 deficiency: Comparison of incidence, demographic and clinical features

Thrombotic thrombocytopenic purpura (TTP) associated with severe, acquired ADAMTS13 deficiency is uncommonly reported in children. The incidence, demographic, and clinical features of these children, compared to adults, have not been described. This study focused on children (<18 years old) and adults with TTP associated with severe, acquired ADAMTS13 deficiency, defined as activity <10%. The incidence rates for TTP in children and adults were calculated from patients enrolled in the Oklahoma TTP-HUS (Hemolytic-Uremic syndrome) Registry, 1996-2012. To describe demographic and clinical features, children with TTP were also identified from a systematic review of published reports and from samples sent to a reference laboratory for analysis of ADAMTS13. The standardized annual incidence rate of TTP in children was 0.09 × 10(6) children per year, 3% of the incidence rate among adults (2.88 × 10(6) adults per year). Among the 79 children who were identified (one from the Oklahoma Registry, 55 from published reports, 23 from the reference laboratory), TTP appeared to be more common among females, similar to the relative increased frequency of women among adults with TTP, and more common in older children. Clinical data were available on 52 children; the frequency of severe renal failure, relapse, treatment with rituximab, and systemic lupus erythematosus in these children was similar to adults with TTP. TTP associated with severe, acquired ADAMTS13 deficiency is uncommon in children. The demographic and clinical features of these children are similar to the features of adults with TTP.

Thrombotic thrombocytopenic purpura in children

Thrombotic thrombocytopenic purpura (TTP) is a rare life-threatening disease in children, due to a severe deficiency of ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeats, member 13), inherited in congenital TTP or secondary to anti-ADAMTS13 antibodies in acquired TTP. Rapid techniques for ADAMTS 13 assays, long-term follow-up of patients, phenotype-genotype analysis, improved therapeutic schedules, and new therapies have emerged. Rapid techniques for ADAMTS13 assays now permit rapid confirmation of diagnosis. In congenital TTP, mutations affecting the N-terminal domains of ADAMTS13 are associated with lower residual ADAMTS13 activity and more severe phenotype. Early initiation of plasma infusion treatment and lifelong prophylactic plasma infusion have decreased mortality and sequels and prevent relapses. In acquired TTP, a disease of adolescents but also of children less than 2, adding rituximab to plasma exchange is beneficial. Recombinant ADAMTS13 ought to be soon available for congenital TTP, while acquired TTP children might benefit from its administration, alone or in association with rituximab, to avoid or limit plasma exchange duration. Progress in the understanding of TTP has boosted physicians' awareness that diagnosis and treatment are medical emergencies. New therapies hopefully will decrease treatment burden and improve prognosis.

Acquired Thrombotic Thrombocytopenic Purpura in Children: A Single Institution Experience

To describe the clinical features, treatment and prognosis of acquired thrombotic thrombocytopenic purpura (TTP) in children based on a single institution experience. This study is a retrospective review of all 12 children with TTP seen at New York Medical College- Westchester Medical Center during a period of 15 y from 1993 to 2008. There were 7 females and 5 males with acquired TTP, with a median age of 13 (range, 6-17); and no cases of congenital TTP. The classic pentad of TTP (microangiopathic hemolytic anemia, thrombocytopenia, neurologic symptoms, renal dysfunction and fever) was seen in only three patients. Nine had renal involvement; eight had neurologic symptoms; and four had fever. All 12 patients had thrombocytopenia, anemia, and elevated LDH. Nine had idiopathic TTP. Three patients had one of the following underlying disorders: systemic lupus erythematosus, mixed connective tissue disorder, and aplastic anemia (post-bone marrow transplant on cyclosporine). ADAMTS13 level was decreased in 7 of 8 patients studied. Eight of 10 patients achieved remission with plasmapheresis alone. Two needed additional treatment before achieving remission. Two had one or more relapses, requiring immunosupressive treatment with vincrisine, prednisone, or rituximab. The patient with aplastic anemia died of pulmonary hypertension 5 y after bone marrow transplantation. All other 11 patients are alive and free of TTP for a median follow-up of 12 mo (range, 3-72 mo). Acquired pediatric TTP responds well to plasmapheresis. However, many patients do require additional treatment because of refractoriness to plasmapheresis or relapse. The clinical features, response to treatment, and relapse rate of pediatric TTP appear similar to those of adult TTP.

Acquired, noncongenital thrombotic thrombocytopenic purpura in children and adolescents: clinical management and the use of ADAMTS 13 assays

Thrombotic thrombocytopenic purpura (TTP) in children is rare and is often thought to be due to congenital ADAMTS13 deficiency. We report seven new cases of noncongenital TTP in children and adolescents and perform a review of the literature where ADAMTS13 assays have been performed in paediatric acquired TTP. All new cases were female and the median age was 13 years. Presenting clinical features included bruising/petechiae or bleeding, fever, neurological, and renal impairment. Median Hb and platelet counts on admission were 66 g/l and 10 x 10(9)/l respectively. Two cases had raised Troponin T levels and one had an abnormal ECG. All cases had ADAMTS13 activity less than 5% and an inhibitor to ADAMTS13. The median number of plasma exchange to remission was 22.5. Six cases received rituximab. Three achieved normal ADAMTS13 activity and remain in remission. Two had persistently low ADAMTS13 activity with high anti-ADAMTS13 IgG levels and one of these relapsed. One had moderately reduced levels of ADAMTS13 in remission with no inhibitor, however, a fall in ADAMTS13 activity and increase in anti-ADAMTS13 IgG heralded clinical relapse. The literature review identified 12 acquired cases showing low ADAMTS13 activity and inhibition of ADAMTS13 (in 95%). In children and adolescents TTP may be due to acquired deficiency of ADAMTS13, associated with an inhibitor/Anti-ADAMTS13 IgG antibodies. Treatment of acquired disease requires PEX and usually immunosuppressive treatment. Rituximab appears to be an effective adjunctive treatment modality.

Thrombotic Thrombocytopenic Purpura Associated with von Willebrand Factor-Cleaving Protease (ADAMTS13) Deficiency in Children

The physiopathology of thrombotic thrombocytopenic purpura (TTP) has been clarified since 1998, when it was shown that TTP in adults was most often associated with an acquired deficiency of von Willebrand factor-cleaving protease (ADAMTS13) due to autoantibodies, whereas TTP in children was most often associated with a hereditary autosomal recessive severe deficiency of ADAMTS13. The hereditary form of TPP (Upshaw-Schulman syndrome) is a very rare but life-threatening disease if adequate treatment (plasma therapy) is not administered. First manifestations occur before age 10 in two thirds of cases and as soon as birth in most cases. The subsequent course is characterized by recurrent hemolytic and thrombocytopenic crises, with intervals between relapses from every 3 to 4 weeks in two thirds of cases to several months or years in one third of cases. TTP crises are associated with cerebral vascular accidents in at least 30% of patients, with a risk of neurologic sequelae in approximately 20% of patients. Renal involvement includes frequent acute renal failure due to hemoglobinuria and/or thrombotic microangiopathy during hemolytic crisis and progressive renal deterioration in approximately 50% of cases, leading to chronic or end-stage renal failure in approximately 20% of patients. The clinical phenotype may vary from the typical congenital recurrent TTP. Some mild forms are limited to a fluctuating thrombocytopenia and may be misdiagnosed as idiopathic thrombocytopenic purpura. Phenotypic variability may be observed within a single family, which suggests a role of modifier genes. Fresh frozen plasma (FFP) replaces active ADAMTS13. Ten milliliters per kilogram FFP every 2 to 4 weeks suffices to maintain remission. FFP infusions are best used preventively, given that rescue infusions may not prevent central nervous system and renal involvement. It is hoped that plasmatic or recombinant purified ADAMTS13 will be available in the years to come.

Case series of thrombotic thrombocytopenic purpura in children and adolescents.

Thrombotic thrombocytopenic purpura (TTP) is a well-described entity in adults but is rarely observed in children. The authors describe a series of seven children with suspected acquired TTP. Clinical findings included petechiae, purpura, or jaundice ( 6), central nervous system events ( 5), fever ( 3), diarrhea ( 3), renal insufficiency ( 2), and hematuria ( 2). Significant central nervous system events included cerebral vascular accidents ( 2), altered mental status ( 2), seizures ( 1), and hemiparesis ( 1). Patients were treated with daily plasma infusions (1/7) or plasma exchange (5/7). Response was prompt, although relapses were frequent. Decreased vWF-protease activity was found in four of five cases and vWF-protease inhibitors were found in three of five cases. Although rare, TTP is a life-threatening illness that does occur in children and should be considered in the differential diagnosis of thrombocytopenia with hemolytic anemia.

Thrombotic Thrombocytopenic Purpura in Childhood

Abstract (1) Two cases of thrombotic thrombocytopenic purpura (TTP) occurring in childhood are described. Case 1 is unique in that the patient survived for 12 years. (2) The clinical features of 19 reported cases of TTP in children are reviewed. (3) The presence of morphologic abnormalities of red blood cells and the regular occurrence of kidney involvement in this disorder is emphasized. In one patient (Case 2), histologic changes of the disease were limited to the kidney. (4) Certain hematologic and histologic features shared by TTP and eclampsia are described. (5) Unusual histologic lesions of renal vessels are described.