Púrpura trombótica trombocitopénica en pediatría. Reporte de un caso / Thrombotic thrombocytopenic purpura in pediatrics. A case report

La púrpura trombótica trombocitopénica es una entidad poco frecuente en pediatría, pero de alta mortalidad sin tratamiento adecuado y oportuno. Se caracteriza por presentar anemia hemolítica microangiopática asociada a signos y síntomas neurológicos, cardíacos, abdominales y menos frecuentemente renales; puede estar acompañada de fiebre. En niños, el diagnóstico se basa en los hallazgos clínicos y de laboratorio. La actividad de ADAMTS13 <10 % apoya, pero no confirma el diagnóstico y, dada la gravedad de la patología, el resultado no debe retrasar el inicio del tratamiento. Se presenta una paciente de 15 años, previamente sana, con signos neurológicos asociados a anemia hemolítica y trombocitopenia. Durante su internación, se arribó al diagnóstico de púrpura trombótica trombocitopénica adquirida.

Thrombotic thrombocytopenic purpura is a rare disease in pediatrics, but it has a high mortality if not managed in an adequate and timely manner. It is characterized by microangiopathic hemolytic anemia associated with neurological, cardiac, abdominal, and less frequently, renal signs and symptoms; it may be accompanied by fever. In children, diagnosis is based on clinical and laboratory findings. ADAMTS13 activity < 10% supports the diagnosis but does not confirm it and, given its severity, the result should not delay treatment initiation. Here we describe the case of a previously healthy 15-year-old female patient with neurological signs associated with hemolytic anemia and thrombocytopenia. During hospitalization, she was diagnosed with acquired thrombotic thrombocytopenic purpura.

Clinical diagnosis and treatment of hereditary thrombocytopenia and purpura: a report of five cases and literature review / 中华血液学杂志

Objective: To report the clinical manifestations and laboratory features of five patients with congenital thrombotic thrombocytopenic purpura (cTTP) and explore its standardized clinical diagnosis and treatment along with a review of literature. Methods: Clinical data of patients, such as age of onset, disease manifestation, personal history, family history, and misdiagnosed disease, were collected. Treatment outcomes, therapeutic effects of plasma infusion, and organ function evaluation were observed. The relationship among the clinical manifestations, treatment outcomes, and ADAMTS13 gene mutation of patients with cTTP was analyzed. Additionally, detection of ADAMTS13 activity and analysis of ADAMTS13 gene mutation were explored. Results: The age of onset of cTTP was either in childhood or adulthood except in one case, which was at the age of 1. The primary manifestations were obvious thrombocytopenia, anemia, and different degrees of nervous system involvement. Most of the patients were initially suspected of having immune thrombocytopenia. Acute cTTP was induced by pregnancy and infection in two and one case, respectively. ADAMTS13 gene mutation was detected in all cases, and there was an inherent relationship between the mutation site, clinical manifestations, and degree of organ injury. Therapeutic or prophylactic plasma transfusion was effective for treating cTTP. Conclusions: The clinical manifestations of cTTP vary among individuals, resulting in frequent misdiagnosis that delays treatment. ADAMTS13 activity detection in plasma and ADAMTS13 gene mutation analysis are important bases to diagnose cTTP. Prophylactic plasma transfusion is vital to prevent the onset of the disease.

A combined regimen based on bortezomib and glucocorticoids for 6 patients with recurrent/refractory immune thrombotic thrombocytopenic purpura / 中华血液学杂志

Objective: To observe the efficacy and adverse reactions of a combination therapy regimen based on bortezomib and glucocorticoids in recurrent/refractory immune thrombocytopenic purpura (iTTP) . Methods: Six patients with recurrent/refractory TTP were included and treated with a glucocorticoid and two courses of bortezomib-based regimen. The clinical remission status of patients, changes in ADAMTS13 activity/ADAMTS13 inhibitor, and the occurrence of treatment-related adverse reactions were observed. Results: Of the 6 patients, 2 were males and 4 were females, with a median age of 21.5 (18-68) years. Refractory TTP was found in 1 case and recurrent TTP in 5 cases. Glucocorticoids were administered with reference to prednisone at 1 mg·kg(-1)·d(-1), and gradually reduced in dosage after achieving clinical remission. Bortezomib is subcutaneously administered at 1.3 mg/m(2) on days 1, 4, 8, and 11 with a 28-day treatment course consisting of 2 courses. Six patients achieved clinical remission after receiving bortezomib as the main treatment. ADMATS13 activity returned to normal in all patients with TTP after treatment, and the ADAMTS13 inhibitor turned negative. Thrombocytopenia is the most common adverse reaction after treatment, with other adverse reactions, including peripheral neuritis and abdominal pain, but ultimately all patients returned to normal. In a median follow-up of 26 (9-41) months, 5 patients maintained sustained remission, and 1 patient relapsed after 16 months of bortezomib treatment. Conclusion: Combination therapy of bortezomib and glucocorticoids has a satisfactory therapeutic effect and controllable adverse reactions for recurrent/refractory iTTP.

Microangiopatía trombótica como complicación de una pancreatitis aguda / Thrombotic microangiopathy as a complication of acute pancreatitis / Microangiopatia trombótica como complicação da pancreatite aguda

La púrpura trombótica trombocitopénica (PTT) es una microangiopatía trombótica poco frecuente, que se caracteriza por anemia hemolítica y plaquetopenia, con una elevada morbimortalidad. Su forma más frecuente es la PTT inmune, también denominada adquirida, provocada por la deficiencia de la enzima disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) secundaria a la presencia en plasma de autoanticuerpos. Presentamos el caso de un paciente con diagnóstico de pancreatitis aguda (PA) complicada con PTT, asociación de presentación excepcional en la práctica clínica.

Summary: Thrombotic thrombocytopenic purpura is rather an unusual thrombotic microangiopathy characterized by hemolytic anemia and plateletopenia which results in high morbimortality rates. The most frequent form of this disease is immune thrombotic thrombocytopenic purpura, also known as acquired thrombotic thrombocytopenic purpura, which is caused by enzime deficiency disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) that is secondary to antibodies in plasma. The study presents the case of a patient with a diagnosis of acute pancreatitis with a rare complication of thrombotic thrombocytopenic purpura which is exceptional in the clinical practice.

A púrpura trombocitopênica trombótica (PTT) é uma microangiopatia trombótica rara, caracterizada por anemia hemolítica e trombocitopenia, com alta morbimortalidade. Sua forma mais comum é a TTP imune, também conhecida como adquirida, que é causada pela deficiência da enzima ADAMTS13 (em inglês A disintegrin-like and metalloprotease with thrombospondin type 1 motif no. 13) secundária à presença de autoanticorpos no plasma. Apresentamos o caso de um paciente com diagnóstico de pancreatite aguda (PA) complicada por PTT, associação com apresentação excepcional na prática clínica.

Evaluation of Sysmex XN-3000 for Detection of Schistocyte / 中国实验血液学杂志

OBJECTIVE@#Compared with the method of optical microscopy, to evaluate the accuracy of fragmented red cells(FRC) detection by Sysmex XN-3000.@*METHODS@#A total of 111 samples were collected from patients diagnosed as thrombotic thrombocytopenic purpura, autoimmune disease, hematological disease, malignant tumor and health examination in our hospital from June 2019 to February 2021, including 74 cases in the case group and 37 cases in the healthy control group. All samples were detected by optical microscope and Sysmex XN-3000, respectively. ROC was used to evaluate the detection ability of Sysmex XN-3000 for schistocyte. Bland-Altman method was used to evaluate the consistency of the results of the two methods for detection of schistocyte, and Pearson correlation analysis was conducted for the difference of the results.@*RESULTS@#The area under the ROC curve was 0.890(95% CI: 0.828-0.952, P<0.01). Sysmex XN-3000 count did not quantitatively agree with schistocyte counts by microscopy in the case group(mean of difference:-1.53, 95% limits of agreement: -8.78~5.72). There was a weak positive correlation between platelet count and the difference of analyzer and microscopic results (r=0.32,P<0.05).@*CONCLUSION@#Sysmex XN-3000 can be used as a reference for qualitative determination of schistocyte. However, the sensitivity of Sysmex XN-3000 should be improved. It is still necessary to combine with manual microscopy. The quantitative results are not reliable now and cannot be used as a reference for monitoring the results of schistocyte in clinical patients after treatment.

Research Advance in Treatment of Thrombotic Thrombocytopenic Purpura --Review / 中国实验血液学杂志

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy, in which a severe deficiency of von Willebrand factor lyase results in thrombocytopenic clots that block blood vessels and eventually lead to terminal organ failure. Therapeutic plasma exchange is the cornerstone of TTP treatment which can greatly improves the survival rate of the patients. With the further exploration to the pathophysiological mechanism of TTP, other alternative therapies, new immunosuppressive agents, targeted antagonists, gene therapy and other emerging means gradually emerge, which are expected to further reduce the mortality and recurrence rate of the patients. In this review, the new developments in TTP treatment were summarized briefly.

Advance in the diagnosis and treatment of hereditary thrombotic thrombocytopenic purpura / 中华医学遗传学杂志

Congenital thrombotic thrombocytopenic purpura, also known as Upshaw-Schulman syndrome, is a rare autosomal recessive genetic disorder. The main pathogenesis is homozygous or compound heterozygous variants of von Willebrand factor lyase (ADAMTS13) gene mapped to chromosome 9q34, which may result in severe lack of ADAMTS13 which cleaves von Willebrand factor (vWF) multimers in the plasma and increase the risk of microvascular thrombosis, leading to various complications. The advance of research on the pathogenesis of cTTP, recombinant human ADAMTS13 and gene therapy have made breakthroughs which may lead to cure of cTTP. This article has provided a review for the latest progress made in the diagnosis and treatment of cTTP.

Reference range for ADAMTS13 antigen, activity and anti-ADAMTS13 antibody in the healthy adult Singapore population

INTRODUCTION@#ADAMTS13 (a disintegrin-like and metalloproteinase with a thrombospondin Type 1 motif, member 13) plays a fundamental role in the regulation of haemostasis and thrombosis. Its deficiency leads to an accumulation of ultra-large von Willebrand multimers, inducing spontaneous platelet aggregation, thrombosis in the microvasculature, and thrombotic thrombocytopenic purpura (TTP), a condition with 90% mortality when left untreated. Prompt quantification of ADAMTS13 antigen, activity and autoantibody plays a crucial role in the diagnosis and management of TTP and can help differentiate it from other thrombotic microangiopathies (TMAs). Reference ranges for ADAMTS13 are generally derived from Caucasian patients. Given that polymorphism in the ADAMTS13 gene can be associated with variable ADAMTS13 levels, we aimed to establish the first reference range in Singapore and provide a crucial laboratory test for institutions here and elsewhere.@*METHODS@#150 healthy voluntary donors (75 men, 75 women) aged 21-60 years, with an ethnic mix mirroring Singapore's population profile, were recruited. ADAMTS13 antigen, activity and autoantibody levels were measured using the fluorescence resonance energy transfer-vWF73 and enzyme-linked immunosorbent assay methodologies.@*RESULTS@#Levels (activity 0.65-1.79 IU/mL, antigen 0.36-1.17 IU/mL, autoantibody 1.4-12.5 U/mL) were not statistically different between the genders and various age groups.@*CONCLUSION@#TTP and TMAs are encountered in a wide range of specialties. The availability of new assays in Singapore will aid clinicians in the timely management of these conditions. Standardising reference ranges established for Singapore against World Health Organization standards allows harmonisation of measurements between laboratories and for future research collaborations.

Hemolytic uremic syndrome caused by Shiga toxin-producing Escherichia coli in a renal transplant recipient case report / Síndrome hemolítico-urêmica causada por Escherichia coli produtora de toxina Shiga em um relato de caso de receptor de transplante renal

Abstract Thrombotic microangiopathies are disorders characterized by nonimmune microangiopathic hemolytic anemia, thrombocytopenia, and multi-systemic failure. They are classified as thrombotic thrombocytopenic purpura, atypical hemolytic-uremic syndrome, and typical hemolytic uremic syndrome. The latter is associated with intestinal infections by Shiga toxin-producing bacteria. Typical hemolytic uremic syndrome in adults is an extremely rare condition, characterized by high morbidity and mortality. It has been seldom described in solid organ transplant recipients. Here is presented the case of a kidney transplant recipient who had typical hemolytic uremic syndrome with multisystem commitment, refractory to management and with a fatal outcome.

Resumo Microangiopatias trombóticas são distúrbios caracterizados por anemia hemolítica microangiopática não imune, trombocitopenia e insuficiência multissistêmica. Elas são classificadas como púrpura trombocitopênica trombótica, síndrome hemolítico-urêmica atípica e síndrome urêmica hemolítica típica. Essa última está associada a infecções intestinais por bactérias produtoras da toxina Shiga. A síndrome hemolítica urêmica típica em adultos é uma condição extremamente rara, caracterizada por alta morbimortalidade. Esta é raramente descrita em receptores de transplantes de órgãos sólidos. Apresentamos aqui o caso de um receptor de transplante renal que apresentava síndrome hemolítico-urêmica típica com comprometimento multissistêmico, refratário ao tratamento, e com desfecho fatal.

Nephrotic syndrome associated with primary atypical hemolytic uremic syndrome / Síndrome nefrótica associada à síndrome hemolítico-urêmica atípica primária

Abstract Primary atypical hemolytic-uremic syndrome is a rare disease characterized by non-immune microangiopathic hemolytic anemia, thrombocytopenia, and renal dysfunction; it is related to alterations in the regulation of the alternative pathway of complement due to genetic mutations. The association with nephrotic syndrome is unusual. We present here a pediatric patient diagnosed with primary atypical hemolytic-uremic syndrome associated with nephrotic syndrome who responded to eculizumab treatment.

Resumo A síndrome hemolítico-urêmica atípica primária é uma doença rara, caracterizada por anemia hemolítica microangiopática não-imune, trombocitopenia e disfunção renal; está relacionado a alterações na regulação da via alternativa do complemento devido a mutações genéticas. A associação com a síndrome nefrótica é incomum. Apresentamos aqui um paciente pediátrico com diagnóstico de síndrome hemolítico-urêmica atípica primária associada à síndrome nefrótica que respondeu ao tratamento com eculizumab.

Púrpura trombocitopénica trombótica en un paciente con infección por VIH / Thrombotic thrombocytopenic purpura, in a HIV-infected patient: case report

Resumen Las manifestaciones hematológicas de la infección por el VIH son frecuentes y variadas debido a su capacidad de afectar prácticamente todas las líneas celulares. Dentro de éstas, la púrpura trombocitopénica trombótica (PTT) es una de las entidades que constituyen las microangiopatías trombóticas. Se caracteriza por la presencia de trombocitopenia y anemia hemolítica microangiopática con alteración de la función renal. Actualmente, la co-existencia de estas dos entidades es poco frecuente debido a la terapia anti-retroviral de alta efectividad (TARV) Presentamos el caso de un paciente de 28 años, quien consultó por fiebre asociada a episodios de gingivorragia, palidez mucocutánea generalizada y debilidad progresiva. Los estudios evidenciaron una anemia y trombocitopenia grave. Se encontraron esquistocitos y microesferocitos en el frotis de sangre periférica con actividad de la enzima ADAMTS 13 disminuida (6,8%). Se confirmó el diagnóstico de una PTT como manifestación inicial de una infección por VIH. Se indicó manejo con plasmaféresis e inicio de TARV con buena respuesta.

Abstract Hematological manifestations for human immunodeficiency virus (HIV) infection are frequent and diverse due to its ability to affect almost all cell lines. Among these, thrombotic thrombocytopenic purpura (TTP) is one of the thrombotic microangiopathies syndromes, characterized by the presence of thrombocytopenia and microangiopathic hemolytic anemia with impaired renal function. Nowadays, the relationship between these two entities is rare given the current highly active antiretroviral therapy (HAART). We report the case of a 28-year-old patient, who presented with fever associated with gingival bleeding, generalized mucocutaneous pallor and progressive weakness. Routine investigations showed anemia and severe thrombocytopenia, schistocytes and micro spherocytes in peripheral blood smear. Required blood transfusion, with decreased ADAMTS 13 enzyme activity (6.8%). With these findings,TTP was diagnosed as the initial manifestation of the HIV infection. The patient received management with five sessions of plasmapheresis and HAART with subsequent improvement.

Microangiopatías trombóticas primarias: una revisión narrativa / Primary thrombotic microangiopathies: a narrative review

La microangiopatía trombótica (MAT) es un síndrome donde hay formación de microtrombos en la circulación que llevan a anemia hemolítica microangiopática (AHMA) y trombocitopenia con falla multiorgánica, debido a la isquemia de los tejidos. Las MAT pueden ser primarias sin causa subyacente asociada, como la púrpura trombocitopénica trombótica debida a deficiencia de la enzima ADAMTS13, el síndrome hemolítico urémico debido a la toxina Shiga de Escherichia coli enterohemorrágica, y la MAT producida por alteraciones en la regulación del complemento. Adicionalmente, pueden ser secundarias a enfermedades malignas, infecciosas, metabólicas, autoinmunes o inducidas por el embarazo. Estas patologías requieren diagnóstico y tratamiento oportunos debido a que tienen alta morbimortalidad y se asocian a complicaciones que incluyen enfermedad renal, alteraciones neurológicas como convulsiones, accidente cerebrovascular, coma y muerte. El tratamiento es multidisciplinario y se enfoca en el soporte hemodinámico, transfusional y en el manejo de la etiología cuando esta es identificada. La siguiente revisión pretende explicar de forma clara y precisa los aspectos generales de las MAT primarias

Thrombotic microangiopathy (TMA) is a syndrome characterized by the formation of microthrombi in the circulation leading to microangiopathic hemolytic anemia (MAHA) and thrombocytopenia, with multiorgan failure due to tissue ischemia. TMA can be primary with no associated underlying cause, such as thrombotic thrombocytopenic purpura due to ADAMTS13 deficiency, hemolytic uremic syndrome due to the Shiga toxin from enterohemorrhagic Escherichia coli, or due to complement dysregulation. Furthermore, TMA can be secondary to malignant, infectious, metabolic or autoimmune diseases, or induced by pregnancy. These conditions require a timely diagnosis and treatment due to their associated high morbidity and mortality, and complications like renal disease, neurological disorders such as seizures, stroke, coma and death. Treatment is multidisciplinary and focuses on hemodynamic and transfusion support, and on the management of the etiology when it is identified (daily plasma exchange, eculizumab or management of underlying disease). This review aims to discuss the general aspects of primary thrombotic microangiopathies

Biological Function of CysR Domain of ADAMTS13 / 中国实验血液学杂志

OBJECTIVE@#To investigate the biological function of Cysteine rich (CysR) domain of a disintegrin and metalloprotease with thrombospondin type 1 repeats-13 (ADAMTS13) on cleavage of von Willebrand factor (vWF) and provide experimental evidence for exploring the pathogenesis of thrombotic thrombocytopenic purpura (TTP).@*METHODS@#The six amino acids (EDGTLS) in ADAMTS13 CysR domain were point mutated one by one, and the mutant ADAMTS13 proteins were expressed and purified. The cleavage products of vWF polymer by wild-type or mutant ADAMTS13 under denaturing condition or shear stress were separated by 1% SeaKem HGT agarose gel and detected by Western blot.@*RESULTS@#The mutant ADAMTS13 plasmids (M1: Glu515Ala; M2: Asp516Ala; M3: Gly517Ala; M4: Thr518Ala; M5: Leu519Ala; M6: Ser520Ala) were successfully constructed and the proteins of wild-type and mutant ADAMTS13 were purified. Wild-type ADAMTS13 almost completely cleaved the vWF polymer under denaturing condition, while the cleavage activity of M1 mutant was significantly reduced in the same condition (P<0.01). The cleavage activity of M1 mutant of ADAMTS13 was also significantly reduced compared with that of the wild-type under shear stress (P<0.01). The activity of M1 mutant to cleave the FRETS-vWF73 was dramatically reduced compared with that of wild-type ADAMTS13. However, the binding ability of M1 mutant to vWF was similar with that of wild-type ADAMTS13.@*CONCLUSION@#The CysR domain of ADAMTS13 plays an important role in the digestion of vWF under denaturing condition and shear stress. The Glu515 amino acid residue might be an important site for substrate recognition.

Recurrent thrombocytopenia with hemolytic anemia in a boy aged 3 years / 中国当代儿科杂志

A boy, aged 3 years and 8 months, had recurrent thrombocytopenia with hemolytic anemia for more than 3 years. The physical examination showed no enlargement of the liver, spleen, and lymph nodes or finger deformities. Laboratory results showed a negative result of the direct antiglobulin test, normal coagulation function, and increases in bilirubin, lactate dehydrogenase and reticulocytes. The results of von Willebrand factor-cleaving protease ADAMTS13 activity assay showed extreme deficiency, and antibody assay showed negative ADAMTS13 inhibitory autoantibodies. Next-generation sequence showed compound heterozygous mutation in the

Clinical analysis of 61 patients with thrombotic thrombocytopenic purpura / 北京大学学报(医学版)

OBJECTIVE@#To analyze and summarize the clinical features, diagnosis, treatment and prognosis of 61 patients with thrombotic thrombocytopenic purpura (TTP), so as to improve the ability of diagnosis and treatment.@*METHODS@#The clinical data of 61 TTP patients admitted to Peking University People's Hospital from January 2004 to March 2019 were retrospectively analyzed, and the clinical manifestations, blood routine, hemolysis indicators, and von Willebrand factor lyase (von Willebrand factor-cleaving protease, vWF-CP, also known as ADAMTS13) of these patients were observed. According to the outcome at the time of discharge, they were divided into survival group and death group, and the differences in clinical characteristics, neutrophil to lymphocyte ratio (NLR) and plasma exchange between the two groups were compared. The PLASMIC scores were calculated and compared with ADAMTS13 to determine the accuracy of the PLASMIC score in predicting ADAMTS13.@*RESULTS@#Among the 61 TTP patients, 22 were males and 39 were females, with an average age of (48±17) years. In the study, 48 cases had pentalogy, only 9 had triad, and the remaining 4 had no neuropsychiatric symptoms. Twenty-seven cases (44.3%) died and 34 cases (55.7%) survived. Among the 61 TTP patients, the platelet count was (12.9±9.5)×109/L, the hemoglobin (66.5±20.7) g/L, the percentage of erythrocyte fragments 3% (2%, 7%), and the plasma free hemoglobin increased to 360 (200, 457) mg /L, and the lactate dehydrogenase 1 508 (811, 2 133.8) U/L. The blood clotting was basically normal. The ADAMTS13 value of 30 patients was 49.0 (40.8, 61.3) μg/L, the ADAMTS activity of 10 patients was < 5%, and the remaining 21 patients were not checked. The PLASMIC score was 6-7 in 58 cases, 5 in 2 cases, and 4 in 1 case. The PLASMIC score predicted the decreased activity or the reduction of ADAMTS with a sensitivity as high as 97.5%. The NLR in the death group was higher than that in the survival group, but the difference was not statistically significant (P>0.05). The total amount and frequency of plasma exchange (PEX) in the death group were significantly less than those in the survival group, and the difference was statistically significant (P < 0.05). There was no significant difference in the treatment of glucocorticoids and human immunoglobulin between the two groups (P>0.05).@*CONCLUSION@#PEX can significantly improve the survival rate of TTP patients. PLASMIC score can easily and quickly predict the possibility of ADAMTS13 activity reduction, which is beneficial to the early diagnosis of TTP and PEX treatment. NLR can reflect the systemic inflammatory process, but its significance in TTP needs further study.