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.

Recomendaciones para el abordaje clínico de pacientes con púrpura trombocitopénica trombótica / Recommendations for the diagnosis and treatment of patients with thrombotic thrombocytopenic purpura

La púrpura trombocitopénica trombótica (PTT) es una microangiopatía trombótica (MAT) caracterizada por el desarrollo de anemia hemolítica microangiopática, trombocitopenia y disfunción orgánica isquémica asociada a niveles de ADAMTS13 inferiores al 10% en la mayoría de los casos.Recientemente se han producido numerosos avances en el campo de la PTT. Se han desarrollado nuevas técnicas rápidas y accesibles capaces de cuantificar los niveles de ADAMTS13 y los posibles inhibidores. Los sistemas de secuenciación masiva del gen ADAMTS13 facilitan la identificación de polimorfismos en este gen. Además, han aparecido nuevos fármacos como caplacizumab y se plantean estrategias de prevención de recaídas con el uso de rituximab.Los registros de pacientes con PTT permiten ahondar en el conocimiento de esta enfermedad, pero la gran variabilidad en el diagnóstico y tratamiento hace necesaria la elaboración de un documento que homogenice la terminología y la práctica clínica.Las recomendaciones recogidas en el presente documento se han elaborado siguiendo la metodología AGREE. Las preguntas de investigación se formularon de acuerdo con el formato PICO. Se realizó una búsqueda bibliográfica de la literatura publicada durante los últimos 10 años. Las recomendaciones se establecieron por consenso entre todo el grupo puntualizando las fortalezas y limitaciones existentes de acuerdo al nivel de evidencia obtenido.En conclusión, en el presente documento se recogen recomendaciones sobre el tratamiento, diagnóstico y tratamiento de la PTT con el objetivo final de elaborar pautas basadas en la evidencia publicada hasta la fecha que permitan a los profesionales sanitarios optimizar el tratamiento de la PTT. (AU)

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) characterized by the development of microangiopathic haemolytic anaemia, thrombocytopenia, and ischaemic organ dysfunction associated with ADAMTS13 levels lower than 10% in most cases.Recently there have been numerous advances in the field of PTT, new, rapid and accessible techniques capable of quantifying ADAMTS13 activity and inhibitors. The massive sequencing systems facilitate the identification of polymorphisms in the ADAMTS13 gene. In addition, new drugs such as caplacizumab have appeared and relapse prevention strategies are being proposed with the use of rituximab.The existence of TTP patient registries allow a deeper understanding of this disease but the great variability in the diagnosis and treatment makes it necessary to elaborate guidelines that homogenize terminology and clinical practice.The recommendations set out in this document were prepared following the AGREE methodology. The research questions were formulated according to the PICO format. A search of the literature published during the last 10 years was carried out. The recommendations were established by consensus among the entire group, specifying the existing strengths and limitations according to the level of evidence obtained.In conclusion, this document contains recommendations on the management, diagnosis, and treatment of TTP with the ultimate objective of developing guidelines based on the evidence published to date that allow healthcare professionals to optimize TTP treatment. (AU)

Diagnostic-therapeutic algorithm for thrombotic microangiopathy. A report of two cases.

Thrombotic microangiopathies (TMA) are a group of clinical syndromes associated with haemolytic anaemia, thrombocytopenia and organ dysfunction, mainly renal or neurological. They are associated with significant morbidity and mortality, so early diagnosis and treatment are essential. In this article we report two cases of TMA; a patient with thrombotic thrombocytopenic purpura (TTP) and a patient with atypical haemolytic uraemic syndrome (aHUS).

Algoritmo diagnóstico-terapéutico de las microangiopatías trombóticas. A propósito de 2 casos / Diagnostic-therapeutic algorithm for thrombotic microangiopathy. A report of two cases

Las microangiopatías trombóticas (MAT) son un conjunto de síndromes clínicos que asocian anemia hemolítica, trombocitopenia y disfunción orgánica, principalmente renal o neurológica. Están asociados a una morbimortalidad significativa, por lo que su diagnóstico y tratamiento precoz son esenciales. En este artículo detallamos 2 casos de MAT; una paciente con una púrpura trombocitopénica trombótica (PTT) y otra paciente con un síndrome hemolítico urémico atípico (SHUa).(AU)

Thrombotic microangiopathies (TMA) are a group of clinical syndromes associated with haemolytic anaemia, thrombocytopenia and organ dysfunction, mainly renal or neurological. They are associated with significant morbidity and mortality, so early diagnosis and treatment are essential. In this article we report two cases of TMA; a patient with thrombotic thrombocytopenic purpura (TTP) and a patient with atypical haemolytic uraemic syndrome (aHUS).(AU)

Recommendations for the diagnosis and treatment of patients with thrombotic thrombocytopenic purpura. / Recomendaciones para el abordaje clínico de pacientes con púrpura trombocitopénica trombótica.

Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) characterized by the development of microangiopathic haemolytic anaemia, thrombocytopenia, and ischaemic organ dysfunction associated with ADAMTS13 levels lower than 10% in most cases. Recently there have been numerous advances in the field of PTT, new, rapid and accessible techniques capable of quantifying ADAMTS13 activity and inhibitors. The massive sequencing systems facilitate the identification of polymorphisms in the ADAMTS13 gene. In addition, new drugs such as caplacizumab have appeared and relapse prevention strategies are being proposed with the use of rituximab. The existence of TTP patient registries allow a deeper understanding of this disease but the great variability in the diagnosis and treatment makes it necessary to elaborate guidelines that homogenize terminology and clinical practice. The recommendations set out in this document were prepared following the AGREE methodology. The research questions were formulated according to the PICO format. A search of the literature published during the last 10 years was carried out. The recommendations were established by consensus among the entire group, specifying the existing strengths and limitations according to the level of evidence obtained. In conclusion, this document contains recommendations on the management, diagnosis, and treatment of TTP with the ultimate objective of developing guidelines based on the evidence published to date that allow healthcare professionals to optimize TTP treatment.

Diagnostic-therapeutic algorithm for thrombotic microangiopathy. A report of two cases. / Algoritmo diagnóstico-terapéutico de las microangiopatías trombóticas. A propósito de 2 casos.

Thrombotic microangiopathies (TMA) are a group of clinical syndromes associated with haemolytic anaemia, thrombocytopenia and organ dysfunction, mainly renal or neurological. They are associated with significant morbidity and mortality, so early diagnosis and treatment are essential. In this article we report two cases of TMA; a patient with thrombotic thrombocytopenic purpura (TTP) and a patient with atypical haemolytic uraemic syndrome (aHUS).

Manejo oportuno de púrpura trombocitopénica trombótica en paciente con lupus eritematoso sistémico: reporte de caso / Timely management of thrombotic thrombocytopenic purpura in a patient with systemic lupus erythematosus: case report

Introducción: La púrpura trombocitopénica trombótica puede presentarse en menos del 2 por ciento de los pacientes con lupus eritematoso sistémico. Esta asociación implica un aumento de la mortalidad y un periodo de remisión más prolongado. Objetivo: Se presenta el caso de paciente peruana que desarrolló esta asociación y presentó complicaciones relacionadas con shock séptico. Caso clínico: Paciente femenina, con antecedente de púrpura trombocitopénica inmunológica y lupus eritematoso sistémico, acudió a emergencia por presentar palidez cutánea generalizada, petequias en miembros inferiores y hematuria. Posteriormente, su estado de salud se complicó con un shock séptico y deterioro del nivel de conciencia. Por todo esto, es referida a un hospital de mayor complejidad y hace su ingreso a la unidad de cuidados intensivos. La clínica y los exámenes de laboratorio revelaron hallazgos compatibles con púrpura trombocitopénica trombótica (anemia grave, plaquetopenia, esquistositosis) y lupus eritematoso sistémico activo grave. Antes de ser referida, recibió pulsos de metilprednisona y prednisona. Ya en unidad de cuidados intensivos, se cambió a soporte ventilatorio y tratamiento antibiótico. Con el diagnóstico presuntivo de púrpura trombocitopénica trombótica, asociada a lupus eritematoso sistémico activo grave, se inició tratamiento oportuno con plasmaféresis, corticoterapia y ciclofosfamida. La paciente recuperó los niveles plaquetarios y el nivel óptimo de conciencia. Actualmente acude a controles. Conclusiones: La púrpura trombocitopénica trombótica es una emergencia hematológica con alta mortalidad en ausencia de tratamiento. Su reconocimiento oportuno, sin dosificación de la proteína ADAMTS13, en esta asociación poco frecuente con lupus eritematoso sistémico es importante en el buen pronóstico del paciente(AU)

Introduction: Thrombotic thrombocytopenic purpura may occur in less than 2 percent of patients with systemic lupus erythematosus. This association implies an increase in mortality and a longer remission period. Objective: We present the case of a Peruvian woman who developed this association, and complicating herself with septic shock. Clinical case: A female patient, with a history of immunological thrombocytopenic purpura and systemic lupus erythematosus, comes to the emergency room due to generalized skin pallor, lower limb petechiae and hematuria. Subsequently, her state of health gets complicated with a septic shock and deterioration of the level of consciousness. For all of this, she was referred to a hospital of greater complexity and makes admission to an intensive care unit. Clinical and laboratory tests revealed findings compatible with thrombotic thrombocytopenic purpura (severe anemia, platelet disease, schistositosis) and severe active systemic lupus erythematosus. Before being referred, she received pulses of methylprednisone and prednisone. When already in the intensive care unit, it was changed to ventilatory support andantibiotic treatment. With the presumptive diagnosis of thrombotic thrombocytopenic purpura, associated with severe active systemic lupus erythematosus, a timely treatment was initiated with plasmapheresis, corticosteroids and cyclophosphamide. The patient recovered platelet levels and optimal level of consciousness. She is currently going to controls. Conclusions: Thrombotic thrombocytopenic purpura is a hematological emergency with high mortality in the absence of treatment. Its timely recognition, without dosing of ADAMTS13 protein, in this rare association with systemic lupus erythematosus is important in the good prognosis of the patient(AU)

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

Relapse of congenital thrombotic thrombocytopenic purpura, after spontaneous remission, in a second-trimester primigravida: case report and review of the literature / Recidiva, após remissão espontânea, de púrpura trombocitopênica trombótica congênita em primigesta no segundo trimestre de gestação: relato de caso e revisão da literatura

ABSTRACT CONTEXT: Thrombotic microangiopathy syndrome or thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) describes distinct diseases sharing common pathological features: microangiopathic hemolytic anemia and thrombocytopenia, without any other apparent cause. CASE REPORT: An 18-year-old second-trimester primigravida presented with a history of fifteen days of intense weakness, followed by diarrhea over the past six days. She reported having had low platelets since childhood, but said that she had never had bleeding or menstrual abnormalities. Laboratory investigation showed anemia with schistocytes, thrombocytopenia and hypohaptoglobulinemia. Red blood cell concentrate and platelet transfusions were performed. The hypothesis of TTP or HUS was put forward and ADAMTS13 enzyme activity was investigated. The patient evolved with increasing platelet counts, even without specific treatment, and she was discharged. One month afterwards, she returned presenting weakness and swollen face and legs, which had developed one day earlier. The ADAMTS13 activity was less than 5%, without presence of autoantibodies. Regarding the two previous admissions (at 9 and 16 years of age), with similar clinical features, there was spontaneous remission on the first occasion and, on the second, the diagnosis of TTP was suspected and plasmapheresis was performed, but ADAMTS13 activity was not investigated. CONCLUSION: To date, this is the only report of congenital TTP with two spontaneous remissions in the literature This report reveals the importance of suspicion of this condition in the presence of microangiopathic hemolytic anemia and thrombocytopenia without any other apparent cause.

RESUMO CONTEXTO: A síndrome de microangiopatia trombótica, ou púrpura trombocitopênica trombótica-síndrome hemolítico urêmica (PTT-SHU), descreve doenças diversas com clínica e achados patológicos comuns: anemia hemolítica microangiopática e trombocitopenia, na ausência de outra causa aparente. RELATO DO CASO: Primigesta de 18 anos no segundo trimestre apresenta-se com quadro de 15 dias de fraqueza intensa seguida por diarreia há seis dias. Relata ter plaquetas baixas desde a infância e nega sangramentos e anormalidades menstruais. Investigação laboratorial identificou anemia com esquizócitos, plaquetopenia e hipo-haptoglobulinemia. Foi realizada transfusão de plaquetas e concentrado de hemácias. A hipótese de PTT ou SHU foi aventada e realizou-se pesquisa da atividade da enzima ADAMTS13. A paciente evoluiu com elevação das plaquetas, mesmo sem tratamento específico, tendo alta. Retornou após um mês da alta com queixa de fraqueza há um dia e inchaço de face e pernas. A atividade da ADAMTS13 foi menor que 5%, sem autoanticorpos. Nas duas internações anteriores (aos 9 e 16 anos), com quadros similares, houve remissão espontânea na primeira internação e, na segunda, o diagnóstico de PTT foi suspeitado e foi realizada plasmaférese, porém sem a pesquisa da atividade da ADAMTS13. CONCLUSÃO: Até esta data, este é único relato de TTP congênita com duas remissões espontâneas na literatura. Este relato revela a importância da suspeição desta patologia na presença de anemia hemolítica microangiopática e trombocitopenia sem outra causa aparente.

Púrpura trombocitopénica en mujer adulta

Se presenta el caso de una mujer adulta mayor, previamente sana, que ingresa con antecedente de cuadro confusional, debilidad generalizada, cambio de coloración de piel y mucosas, síntomas gastrointestinales y fiebre. En estudios de imagen no se evidencian lesiones encefálicas. Ante cuadro clínico y hallazgos laboratoriales se realiza frotis de sangre periférica, confirmándose diagnóstico de púrpura trombocitopénica trombótica. Se indica plasmaféresis, sin embargo, la paciente no responde a la terapia y fallece.

This is the case of old adult woman, previously healthy, admitted with history of confusion symptoms, general weakness, change of skin and mucous color, gastrointestinal symptoms and fever. Medical imaging studies do not show evidences of encephalic lesions. Considering the clinical symptoms and laboratory findings, a smear of peripheral blood is made confirming a diagnosis of thrombotic thrombocytopenic purpura. Although plasmapheresis is indicated, the patient does not respond to the therapy and die.

Púrpura trombocitopénica trombótica secundaria a lupus eritematoso sistémico / Thrombotic thrombocytopenic purpura secondary to systemic lupus erythematosus

La púrpura trombocitopénica trombótica asociada a lupus eritematoso sistémico es muy poco frecuente. Se presentó una paciente con síndrome febril prolongado, poliartralgias, cefalea, papiledema bilateral y cambios conductuales. Se describen la evolución clínica, los estudios imagenológicos, de laboratorio e inmunológicos que permitieron hacer el diagnóstico de púrpura trombocitopénica trombótica secundaria a lupus eritematoso sistémico. Se consideró importante presentar este caso por la poca frecuencia con que se diagnostica la asociación de ambas entidades, además, porque el diagnóstico constituyó un reto para especialistas y residentes de medicina interna(AU)

Thrombotic thrombocytopenic purpura associated with systemic lupus erythematosus is very rare. One patient with prolonged febrile syndrome, polyarthralgia, headache, bilateral papilledema and behavioral changes is presented here. The clinical course, the imaging, laboratory and immunological studies that allowed the diagnosis of thrombotic thrombocytopenic purpura secondary to systemic lupus erythematosus are described. It was considered important to present this case by the infrequency with which the association of both entities also diagnosed because the diagnosis was a challenge for specialists and internal medicine residents(AU)

[Diagnostic and therapeutic guidelines of thrombotic microangiopathies of the Spanish Apheresis Group]. / Guía diagnóstica y terapéutica de las microangiopatías trombóticas del Grupo Español de Aféresis.

Thrombotic microangiopathies (TMA) are disorders defined by the presence of a microangiopathic hemolytic anemia (with the characteristic hallmark of schistocytes in the peripheral blood smear), thrombocytopenia and organ malfunction of variable intensity. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are the most important forms of TMA and, without the adequate treatment, they are associated with high morbimortality. In recent years, significant advances in the knowledge of the pathophysiology of TMA have occurred. Those advances have allowed us to move from a syndromic diagnosis with a similar treatment to all entities to the search of etiologic diagnosis which would lead to a specific treatment, finally leading to a better outcome of the patient. This document pretends to summarize the current status of knowledge of the pathophysiology of TMA and the therapeutic options available, and to offer a diagnostic and therapeutic practical tool to the professionals caring for the patients.

Aspergilosis traqueobronquial invasiva en un paciente con púrpura trombocitopénica trombótica tratada con Anti-CD20 / Invasive tracheobronchial aspergillosis in a patient with thrombotic thrombocytopenic purpura (TTP) and immunosuppressed due to the use of steroids and anti-CD20

La aspergilosis invasiva es una complicación que se presenta con mayor frecuencia en pacientes con inmunosupresión. La aspergilosis traqueobronquial es una complicación muy rara con mínimas manifestaciones clínicas. Se informa de una paciente de 53 años con diagnóstico de púrpura trombocitopénica trombótica (PTT) con inmunosupresión por el uso de esteroides y anti CD-20, que presentó hemoptisis en 2 ocasiones; la segunda fue masiva y ocasionó la muerte. Previo al segundo evento de la hemoptisis se logró realizar broncoscopía, que mostró pseudomembranas y ulceración del epitelio bronquial. En el postmortem se logró documentar la presencia de Aspergillus tanto en la biopsia como en el cultivo. Es de gran importancia la sospecha y un reconocimiento temprano de esta patología en pacientes con inmunosupresión por su alta mortalidad.

Invasive aspergillosis is a complication most commonly developed in immunosuppressed patients. Tracheobronquial aspergillosis is an extremely rare complication with minimal clinical expression. We present the case of a 53-year-old female patient diagnosed with thrombotic thrombocytopenic purpura (TTP) and immunosuppressed due to the use of steroids and anti-CD20, who presented hemoptisis twice; being the second one massive leading to death. Before the second event of hemoptisis, bronchoscopy was performed, which showed pseudomembranes and ulceration of the bronchial epithelium. In the post-mortem examination, the presence of Aspergillus was evidenced by both biopsy and culture. The presumption and early diagnosis of this condition are paramount for immunosuppressed patients due to its high mortality.

Púrpura trombocitopénica trombótica: Informe de un caso y revisión de la fisiopatología / Thrombotic thrombocytopenic purpura: A case and review of its physiopathology

Se informa un caso compatible con púrpura trombocitopénica trombótica así como los hallazgos de autopsia con una breve revisión de la literatura. Paciente de 19 años de edad con antecedente de HELLP en su primer embarazo, que cursó con alteraciones neurológicas, trombocitopenia y anemia hemolítica. Falleció a 15 días después de su hospitalización. El estudio posmortem reveló numerosos trombos en los vasos de pequeño calibre de diversos órganos. La púrpura trombocitopénica trombótica es un padecimiento raro cuya expresión morfológica es la formación de microtrombos que obliteran el lecho capilar de diversas estructuras vitales. Moschcowitz fue el primero en informar el hallazgo de múltiples trombos hialinos en los vasos de pequeño calibre en una autopsia parcial. Se consideró la posible existencia de "un veneno con capacidad trombótica y aglutinante", que más tarde se identificó como polímeros ultralargos del factor de Von Willebrand cuya persistencia se debe a la carencia de la metaloproteinasa ADAMTS13.

We report a case compatible with thrombotic thrombocytopenic purpura, autopsy findings and make a brief review of the literature. 19 year old woman with HELLP syndrome in her previous pregnancy who presented with neurological signs, thrombocytopenia and microangiopathic haemolytic anemia until her pass away fifteen days after being admitted to the hospital. Autopsy findings showed multiple thrombi in small sized vessels of several organs. Thrombotic thrombocitopenic purpura is a rare disease with a morphological expression featured of many microthrombi in the terminal arterioles of several vital structures. Moschcowitz was the first to inform multiple hyaline thrombi as the primordial finding of a partial autopsy case. He proposed that "a powerful poison with both agglutinative and hemolytic properties" was the causative agent but it was identified years later as unusually large fragments of Von Willebrand factor caused by a deficiency of ADAMTS13, a newly discovered metalloproteinase.

Púrpura trombocitopênica trombótica na apresentação de pacientes com lúpus eritematoso sistêmico juvenil / Thrombotic thrombocytopenic purpura at presentation of juvenile systemic lupus erythematosus patients

Púrpura trombocitopênica trombótica (PTT) é uma alteração hematológica rara e com risco de morte, caracterizada por trombocitopenia, anemia hemolítica microangiopática e alterações neurológicas e/ou renais. A PTT foi descrita em raros pacientes com lúpus eritematoso sistêmico juvenil (LESJ) e, até onde se sabe, a prevalência dessa manifestação em uma população de lúpus pediátrico ainda não foi estudada. Assim, entre janeiro de 1983 e dezembro de 2010, revisamos os prontuários de 5.508 pacientes acompanhados na Unidade de Reumatologia Pediátrica do nosso hospital universitário. Foram identificados 279 (5,1%) casos de LESJ que preencheram os critérios de classificação do American College of Rheumatology. Dois destes (0,7%) apresentavam PTT, ambos no início do LESJ, e foram aqui descritos. Os dois pacientes tinham febre, anemia hemolítica microangiopática (com esquizócitos no sangue periférico) e trombocitopenia. O paciente do gênero masculino apresentava hemiparesia e proteinúria, e a paciente do gênero feminino tinha cefaleia persistente e hematúria. Ambos foram tratados com metilprednisolona endovenosa e plasmaferese quando do diagnóstico de PPT. Após tratamento, não houve recidiva da PTT, e hematócritos, contagens de plaquetas e níveis de desidrogenase lática permaneceram normais. Em conclusão, a PTT é uma rara e grave manifestação no início do LESJ. Os casos relatados reforçam a importância de um diagnóstico precoce e de uma terapia agressiva em pacientes com PTT, devido à sua alta morbidade.

Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening hematological abnormality characterized by thrombocytopenia and microangiopathic hemolytic anemia, with neurological abnormalities and/or renal disease. TTP has been rarely reported in juvenile systemic lupus erythematosus (JSLE) patients and, to our knowledge, its prevalence in a paediatric lupus population has not been studied. Therefore, from January 1983 to December 2010, we reviewed the charts of 5,508 patients followed-up at the Paediatric Rheumatology Unit of our university hospital. We identified 279 (5.1%) JSLE cases that met the American College of Rheumatology classification criteria. Two (0.7%) of them had TTP, both at JSLE onset, and were described herein. Both patients had fever, microangiopathic hemolytic anemia (with schistocytes in blood smears), and thrombocytopenia. The male patient had hemiparesis and proteinuria and the female patient had persistent headache and hematuria. Both were treated with intravenous methylprednisolone and courses of plasma exchange therapy at TTP diagnosis. After treatment, TTP did not recur and their hematocrit, platelet count, and lactic dehydrogenase remained normal. In conclusion, TTP is a rare and severe manifestation at JSLE onset. The case reports reinforce the importance of early diagnosis and early aggressive treatment for patients with TTP, due to its high morbidity.

Púrpura trombocitopénica trombótica Descripción del diagnóstico y manejo de una entidad poco frecuente y de alta mortalidad / Thrombotic thrombocytopenic purpura Description of diagnosis and management of a rare entity with a high mortality

Presentamos dos casos con diagnóstico de púrpura trombocitopénica trombótica idiopática refractarios al tratamiento con recambio plasmático y en los cuales fue necesario emplear un tratamiento adicional. En uno de los casos hubo una adecuada respuesta con rituximab. También analizamos el papel de los niveles de ADAMTS 13 para el manejo y diagnóstico de esta enfermedad. (Acta Med Colomb 2012; 37: 201-206).

We report two patients diagnosed as having idiopathic thrombocytopenic purpura refractory to plasma exchange in which the use of additional treatment was necessary. In one case there was an adequate response to rituximab. We also analyze the role of ADAMTS 13 levels for the management and diagnosis of this disease. (Acta Med Colomb 2012; 37: 201-206).

Microangiopatias trombóticas: púrpura trombocitopênica trombótica e síndrome hemolítico-urêmica / Thrombotic microangiopathies: thrombotic thrombocytopenic purpura / hemolytic uremic syndrome

As microangiopatias trombóticas (MATs) são condições caracterizadas por oclusão microvascular generalizada por trombos de plaquetas, trombocitopenia, e anemia hemolítica microangiopática. Duas manifestações fenotípicas típicas das MATs são a síndrome hemolítica urêmica (SHU) e a púrpura trombocitopênica trombótica (PTT). Outras doenças ocasionalmente apresentam manifestações similares. Na dependência de prevalecer a lesão renal ou a cerebral, duas entidades patologicamente indistinguíveis, mas de alguma forma clinicamente diferentes, têm sido descritas: a SHU e a PTT. Injúria das células endoteliais é o fator desencadeante central na sequência de eventos que levam a MAT. Perda da trombo resistência fisiológica, adesão de leucócitos no endotélio lesado, consumo de complemento, liberação e fragmentação anormais do fator de von Willebrand (FvW), e aumento do estresse de cisalhamento vascular podem sustentar e ampliar o processo microangiopático. Anormalidades intrínsecas do sistema do complemento e do FvW podem acompanhar a predisposição genética à doença, que pode ter um papel chave, em particular nas formas recorrentes e familiares. Nos casos de SHU associada à diarreia (SHU+D), o dano endotelial renal é mediado (pelo menos em parte) pela Shigatoxina (Stx) bacteriana, uma família de toxinas elaboradas por certas cepas da Escherichia coli e Shigella dysenteriae. A evolução é geralmente boa na criança, na SHU associada a Stx, enquanto sequelas renais e neurológicas são mais frequentemente encontradas em adultos, formas familiares e atípicas da SHU e na PTT. Estudos recentes têm demonstrado que a deficiência na clivagem do FvW pela proteinase ADAMTS13 pode ser genética ou mais comumente adquirida, resultante da produção de anticorpos inibidores da ADAMTS13, causando a PTT. Durante a última década, demonstrou-se que a SHU atípica (SHU-D) é uma doença de desregulação da via alternativa do complemento. Uma série de mutações e polimorfismo em genes que codificam proteínas reguladoras do complemento sozinhas ou em combinação podem levar a SHU atípica. Aproximadamente 60 por cento dos casos de SHU atípica têm mutações do tipo "perda da função" em genes que codificam as proteínas reguladoras do complemento, as quais protegem as células hospedeiras da ativação do complemento: fator H do complemento (FHC), fator I (FIC) e proteína cofator de membrana (PCM ou CD46), ou mutações do tipo "ganho da função" em genes que codificam o FHC ou C3. Além disso, aproximadamente 10 por cento dos pacientes com SHU atípica têm deficiência na função do FHC devido a anticorpos anti-FHC. Mesmo que as MATs sejam condições altamente heterogêneas, um terço dos pacientes tem deficiência severa da ADA-MTS13. Transfusões de plaquetas são contraindicadas nesses pacientes. Infusão de plasma ou plasma exchange (PE) é o único tratamento eficiente.

Thrombotic microangiopathies (TMAs) are pathological conditions characterized by generalized microvascular occlusion by platelet thrombi, thrombocytopenia, and microangiopathic hemolytic anemia. Two typical phenotypes of TMAs are hemolytic- uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). Other disorders occasionally present with similar manifestations. Depending on whether renal or brain lesions prevail, two pathologically indistinguishable but somehow clinically different disorders have been described: HUS and TTP. Injury to the endothelial cell is the central and likely inciting factor in the sequence of events leading to TMA. Loss of physiological thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, abnormal von Willebrand factor release and fragmentation, and increased vascular shear stress may then sustain and amplify the microangiopathic process. Intrinsic abnormalities of the complement system and of the von Willebrand factor pathway may account for a genetic predisposition to the disease that may play a paramount role in particular in familial and recurrent forms. In the case of diarrhea-associated HUS (D+HUS), renal endothelial damage is mediated (at least in large part) by the bacterial agent Shigatoxin (Stx), which is actually a family of toxins elaborated by certain strains of Escherichia coli and Shigella dysenteriae. Outcome is usually good in childhood, Shiga toxin-associated HUS, whereas renal and neurological sequelae are more frequently reported in adult, atypical, and familial forms of HUS and in TTP. Recent studies have demonstrated that deficiency in the von Willebrand factor cleaving protease ADAMTS13, due to deficiency of ADAMTS13 can be genetic or more common, acquired, resulting from autoimmune production of inhibitory anti-ADAMTS13 antibodies, that causes TTP. During the last decade, atypical HUS (aHUS) has been demonstrated to be a disorder of the complement alternative pathway dysregulation, as there is a growing list of mutations and polymorphisms in the genes encoding the complement regulatory proteins that alone or in combination may lead to aHUS. Approximately 60 percent of aHUS patients have so-called 'loss-of-function' mutations in the genes encoding the complement regulatory proteins, which normally protect host cells from complement activation: complement factor H (CFH), factor I (CFI) and membrane cofactor protein (MCP or CD46), or have 'gain-of-function' mutations in the genes encoding the complement factor B or C3. In addition, approximately 10 percent of aHUS patients have a functional CFH deficiency due to anti-CFH antibodies. Although TMAs are highly heterogeneous pathological conditions, one-third of TMA patients have severe deficiency of ADAMTS13. Platelet transfusions are contraindicated. Plasma infusion or exchange (PE) is the only treatment of proven efficacy.

Púrpura trombocitopênica trombótica: o papel do fator von Willebrand e da ADAMTS13 / Thrombotic thrombocytopenic purpura: the role of von Willebrand factor and ADAMTS13

A púrpura trombocitopênica trombótica (PTT) instala-se de modo abrupto e é caracterizada pela oclusão difusa de arteríolas e capilares da microcirculação, levando à isquemia de tecidos. A oclusão é causada por microtrombos compostos basicamente de plaquetas e fator von Willebrand (FvW). O FvW é uma glicoproteína de estrutura multimérica sintetizada exclusivamente por células endoteliais e megacariócitos. Este fator promove a adesão das plaquetas ao endotélio lesado, participa do processo de agregação plaquetária e é a proteína carreadora do fator VIII na circulação. Em condições fisiológicas, os grandes multímeros do FvW encontram-se dentro das células endoteliais e nas plaquetas e não estão presentes no plasma. Tão logo estes grandes multímeros são liberados da célula endotelial, são clivados e removidos da circulação pela enzima ADAMTS13 (A Desintegrin And Metalloprotease with eight Thrombo Spondin-1-like). A deficiência funcional ou quantitativa de ADAMTS13 resulta no acúmulo de grandes multímeros de FvW no plasma, propiciando a agregação das plaquetas e oclusão difusa das arteríolas e capilares. A maioria dos casos de PTT está associada à deficiência da ADAMTS13 e já estão disponíveis no mercado internacional conjuntos diagnósticos para a determinação dos níveis de antígenos desta enzima, da de sua atividade e dos anticorpos anti-ADAMTS13. A avaliação laboratorial da ADAMTS13 parece constituir um avanço para o diagnóstico precoce da PTT. No entanto, a interpretação dos resultados exige cautela e um conhecimento do princípio do método, bem como das etapas das reações envolvidas.

Thrombotic thrombocytopenic purpura (TTP) starts abruptly and is characterized by diffuse occlusion of microcirculation arterioles and capillaries, leading to ischemia of tissues. Occlusion is caused by microscopic clots primarily composed of platelets and von Willebrand factor (VWF). VWF is a multimeric glycoprotein synthesized exclusively by endothelial cells and megakaryocytes. This factor promotes adhesion of platelets to injured endothelium, participates in the process of platelet aggregation and is the carrier protein of factor VIII in the circulation. In physiological conditions, large VWF multimers are present in endothelial cells and platelets and are not present in plasma. As soon as these large multimers are released from the endothelial cell, they are cleaved and removed from circulation by the ADAMTS13 enzyme. A quantitative or functional deficiency of ADAMTS13 results in the accumulation of large VWF multimers in the plasma and may result in the aggregation of platelets and diffuse occlusion of arterioles and capillaries. Most cases of PTT are associated with ADAMTS13 deficiency. The levels of antigens, activity and antibodies of MTS13 can be evaluated using internationally manufactured kits. The laboratory evaluation of ADAMTS13 appears to be a useful tool for the early diagnosis of PTT. However, interpretation of the results requires caution, as well as knowledge of the principles of the method and the steps of the reactions involved.

Púrpura trombocitopênica trombótica associada à gravidez: relato de caso / Thrombotic thrombocytopenic purpura associated with pregnancy: case report

A púrpura trombocitopênica trombótica (PTT) é uma entidade rara em pacientes críticos. Relatamos um caso clínico de paciente gestante admitida em unidade de terapia intensiva obstétrica com quadro de alteração de sensório, atribuído inicialmente à doença hipertensiva da gravidez. Evoluiu com piora do quadro geral caracterizada por anemia e plaquetopenia grave, suscitando a investigação diagnóstica de púrpura trombocitopênica trombótica após o reconhecimento do perfil hematológico. Os autores enfatizam a importância do conhecimento da doença como marcador de prognóstico para pacientes obstétricas, em vista da semelhança com outras patologias comuns ao ciclo gravídico-puerperal e o fato do diagnóstico e tratamento precoce serem determinantes para o desfecho.

Case report of a patient with 37-week gestational age admitted to an obstetric intensive care unit with an altered level of consciousness, related primarily to the pregnancy-induced hypertension. The patient presented a worsening clinical course characterized by, anemia and severe thrombocytopenia, Investigation led to a diagnostic of thrombotic thrombocytopenic purpura after the hematological profile was assessed. The authors emphasize the importance of the disease recognition as a prognostic marker for obstetric patients, in view of the similarity with other common morbidities during pregnancy and the importance of timely diagnosis and early treatment as determinant factors for the outcome.