Thrombotic microangiopathy in patients with sickle cell disease / Microangiopatia trombótica em pacientes com doença falciforme

ABSTRACT Objective: To describe two cases of patients who had thrombotic microangiopathy (TMA) associated with sickle cell disease (SCD). Case description: Both patients started with a painful crisis and had acute chest syndrome during hospitalization. They showed significant worsening of hemolytic anemia, with very high levels of lactate dehydrogenase, thrombocytopenia, lowered level of consciousness, organ damage and the presence of schistocytes in peripheral blood. Due to the possibility of TMA, despite the very rare association with SCD, they were treated with fresh frozen plasma replacement and plasmapheresis, with good response. Comments: TMA is a serious, life-threatening disease, characterized by microangiopathic hemolytic anemia, thrombocytopenia, and organ damage. The association of SCD and TMA is difficult to diagnose, since they can share a similar clinical presentation. Recognizing this association and promptly instituting treatment may impact the survival of these patients.

RESUMO Objetivo: Descrever dois casos de pacientes que apresentaram microangiopatia trombótica (MAT) associada à doença falciforme (DF). Descrição do caso: Ambos os pacientes iniciaram com crise dolorosa e apresentaram síndrome torácica aguda durante a internação. Eles apresentaram piora significativa da anemia hemolítica, com níveis muito elevados de lactato desidrogenase, trombocitopenia, rebaixamento do nível de consciência, lesão de órgãos e presença de esquistócitos no sangue periférico. Diante da possibilidade de MAT, apesar da associação muito rara com DF, eles foram tratados com reposição de plasma fresco congelado e plasmaférese, com boa resposta. Comentários: A MAT é uma doença grave e com risco de vida, caracterizada por anemia hemolítica microangiopática, trombocitopenia e danos a órgãos. A associação de DF e MAT é de difícil diagnóstico, pois as duas podem ter apresentação clínica semelhante, portanto reconhecer essa associação e instituir o tratamento prontamente pode ter grande impacto na sobrevida desses pacientes.

Microangiopatías trombóticas en niños críticamente enfermos. Registro español MATUCIP / Thrombotic microangiopathies in critically ill children: The MATUCIP registry in Spain

Introducción: Las microangiopatías trombóticas (MAT) son entidades infrecuentes que suelen causar afectación renal, hematológica, neurológica y cardiovascular, con síntomas inespecíficos pero graves. Con la finalidad de mejorar el conocimiento de sus características clínicas, el proceso diagnóstico y el tratamiento en la fase aguda, se ha creado el registro de MAT en las unidades de cuidados intensivos pediátricos (UCIP) de España (Registro MATUCIP). Pacientes y métodos: Estudio observacional, multicéntrico, realizado en 20 UCIP españolas desde enero de 2017 hasta diciembre de 2021 que incluyó niños mayores de 1mes con diagnóstico de MAT y seguimiento hasta el alta de la UCIP. Resultados: Se incluyeron 97 pacientes (51,5% mujeres), con una mediana de edad de 2,6años (RIQ: 1,6-5,7). La clínica inicial fue de tipo gastrointestinal (74,2%), respiratoria (14,4%), cuadro febril (5,2%), neurológica (3,1%) y otras (3,1%). Al ingreso, el 75,3% presentaban anemia hemolítica microangiopática, el 95,9% trombocitopenia y el 94,8% daño renal agudo. Fueron diagnosticados de síndrome hemolítico urémico (SHU) asociado a Escherichia coli productora de toxina Shiga el 57,7%, SHU por Streptococcus pneumoniae el 14,4%, SHU atípico el 15,6%, MAT secundaria el 10,3% y púrpura trombótica trombocitopénica el 2,1%. Desarrollaron hipertensión arterial el 89,7%, manifestaciones digestivas el 49,5%, respiratorias el 22,7%, neurológicas el 25,8% y cardiacas el 12,4%. El 60,8% requirieron depuración extrarrenal y el 2,1%, plasmaféresis. Recibieron eculizumab 20 pacientes. La mediana de estancia en la UCIP fue de 8,5días (RIQ: 5-16,5). Dos niños fallecieron. (AU)

Introduction: Thrombotic microangiopathies (TMA) are rare diseases usually presenting with renal, haematological, neurologic and cardiovascular involvement and nonspecific but severe symptoms. A registry of TMA cases managed in Spanish paediatric intensive care units (the MATUCIP registry) was established with the aim of gaining knowledge on their clinical characteristics, diagnosis and acute-phase treatment. Patients and methods: We conducted a prospective multicentre observational study in 20 paediatric intensive care units (PICUs) in Spain from January 2017 to December 2021 in children aged more than 1month with TMAs, who were followed up through the discharge from the PICU. Results: The sample included 97 patients (51.5% female) with a median age of 2.6years (interquartile range [IQR]: 1.6-5.7). The initial manifestations were gastrointestinal (74.2%), respiratory (14.4%), fever (5.2%), neurologic (3.1%) and other (3.1%). At admission, 75.3% of patients had microangiopathic haemolytic anaemia, 95.9% thrombocytopenia and 94.8% acute kidney injury. Of the total sample, 57.7% of patients received a diagnosis of Shiga toxin-associated haemolytic uraemic syndrome (HUS), 14.4% of Streptococcus pneumoniae-associated HUS, 15.6% of atypical HUS, 10.3% of secondary TMA and 2.1% of thrombotic thrombocytopenic purpura. Eighty-seven patients (89.7%) developed arterial hypertension, and 49.5% gastrointestinal, 22.7% respiratory, 25.8% neurologic and 12.4% cardiac manifestations. Also, 60.8% required renal replacement therapy and 2.1% plasma exchange. Twenty patients received eculizumab. The median PICU stay was 8.5days (IQR: 5-16.5). Two children died. (AU)

Thrombotic microangiopathies in critically ill children: The MATUCIP registry in Spain.

INTRODUCTION: Thrombotic microangiopathies (TMA) are rare diseases usually presenting with renal, haematological, neurologic and cardiovascular involvement and nonspecific but severe symptoms. A registry of TMA cases managed in Spanish paediatric intensive care units (the MATUCIP Registry) was established with the aim of gaining knowledge on their clinical characteristics, diagnosis and acute-phase treatment. METHODS: We conducted a prospective multicentre observational study in 20 paediatric intensive care units (PICUs) in Spain from January 2017 to December 2021 in children aged more than 1 month with TMAs, who were followed up through the discharge from the PICU. RESULTS: The sample included 97 patients (51.5% female) with a median age of 2.6 years (interquartile range [IQR], 1.6-5.7). The initial manifestations were gastrointestinal (74.2%), respiratory (14.4%), fever (5.2%), neurologic (3.1%) and other (3.1%). At admission, 75.3% of patients had microangiopathic haemolytic anaemia, 95.9% thrombocytopenia and 94.8% acute kidney injury. Of the total sample, 57.7% of patients received a diagnosis of Shiga toxin-associated haemolytic uraemic syndrome (HUS), 14.4% of Streptococcus pneumoniae-associated HUS, 15.6% of atypical HUS, 10.3% of secondary TMA and 2.1% of thrombotic thrombocytopenic purpura. Eighty-seven patients (89.7%) developed arterial hypertension, and 49.5% gastrointestinal, 22.7% respiratory, 25.8% neurologic and 12.4% cardiac manifestations. Also, 60.8% required renal replacement therapy and 2.1% plasma exchange. Twenty patients received eculizumab. The median PICU stay was 8.5 days (IQR, 5-16.5). Two children died. CONCLUSIONS: The MATUCIP registry demonstrates the clinical variability of TMA cases requiring admission to the PICU. Knowledge of the presentation and outcomes of TMAs can facilitate early aetiological diagnosis. This registry can help improve our understanding of the clinical spectrum of these diseases, for which there is a dearth of published data.

Claves diagnósticas en el síndrome hemolítico urémico atípico: apropósito de un caso / Diagnostic clues in atypical hemolytic uremic syndrome: a case report

El síndrome hemolítico urémico atípico (SHUa) es una entidad clínica caracterizada por anemia hemolítica no inmune, trombopenia y fallo renal, en la que las lesiones están mediadas por un proceso de microangiopatía trombótica (MAT) sistémica. Es una patología rara y cuyo origen es una desregulación del sistema del complemento debido a mutaciones en genes del mismo que llevan a una activación incontrolada de C5 y la formación del complejo de ataque de membrana. Su correcto diagnóstico permite prescribir el tratamiento basado en Eculizumab, inhibidor de C5.Se presenta el caso clínico de una paciente gestante con SHUa, con el objetivo de destacar la importancia del diagnóstico diferencial precoz para el establecimiento temprano de un tratamiento efectivo de esta patología. Se actualiza la fisiopatología, diagnóstico y estudio genético, así como el manejo terapéutico del SHUa. (AU)

Microangiopatía trombótica en paciente con cáncer de origen desconocido / Thrombotic microangiopathy in a patient with cancer of unknown origin

Resumen La microangiopatía trombótica asociada a cáncer (MTAC) comprende la presencia de anemia hemolítica microangiopática, trombocitopenia y lesión isquémica de órganos en pacientes con neoplasia de origen conocido o desconocido. Su diagnóstico es desafiante pues suele ser confundido con la púrpura trombocitopénica trombótica, que es la causa más frecuente de microangiopatía trombótica en pacientes sanos. La MTAC puede ser manifestación de la neoplasia en sí misma o manifestación de complicación de la quimioterapia, por lo que tiene un pronóstico pobre. A continuación se presenta el caso de una paciente que desarrolló MTAC en el contexto de cáncer metastásico de origen primario desconocido.

Abstract Cancer-associated thrombotic microangiopathy (CATM) consists of microangiopathic haemolytic anaemia, thrombocytopenia, and ischaemic end organ-damage in patients with a known or unknown primary malignancy. Its diagnosis is challenging, as it is sometimes confused with thrombotic thrombocytopenic purpura, which is the most common cause of thrombotic microangiopathy in healthy patients. CATM can be a manifestation of the malignancy itself or a chemotherapy-related complication, with these patients having a poor prognosis. A case is presented of a patient who developed CATM in the context of metastatic cancer with an unknown primary site.

Síndrome hemolítico urémico atípico: papel del perfil genético / Atypical hemolytic uremic syndrome: role of the genetic profile

Resumen: El síndrome hemolítico urémico es una microangiopatía trombótica caracterizada por anemia hemolítica microangiopática, trombocitopenia y daño renal agudo. El síndrome hemolítico urémico típico (el más común) es ocasionado por bacterias productoras de la toxina Shiga, típicamente por cepas de Escherichia coli. El término síndrome hemolítico urémico atípico se usa para referirse a los pacientes que padecen este cuadro por causas diferentes. Las manifestaciones clínicas y paraclínicas no son suficientes para diferenciar el síndrome hemolítico urémico atípico de otras microangiopatías trombóticas, por lo que la determinación de la actividad de ADAMTS13 y la prueba de la toxina Shiga resultan esenciales para establecer el diagnóstico preciso. Aunque en la actualidad el diagnóstico definitivo requiere confirmación genética, las pruebas genéticas son costosas y poco útiles para el diagnóstico inicial; sin embargo, más que importancia diagnóstica, tiene gran valor pronóstico, permite prescribir el tratamiento adecuado disminuyendo significativamente la morbilidad y mortalidad atribuibles a esta enfermedad.

Abstract: The haemolytic uraemic syndrome is a thrombotic microangiopathy (TMA) characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal injury. The typical haemolytic uraemic syndrome (tHUS, the most common) is caused by bacteria that produce Shiga toxin, typically strains of Escherichia coli. On the other hand, the term atypical haemolytic uraemic syndrome (aHUS) is used to refer to those patients who develop this condition due to different etiologies. The clinical and paraclinical manifestations are not enough to differentiate the aHUS from other thrombotic microangiopathies, so the determination of the activity of ADAMTS13 and the Shiga toxin test are essential to establish the precise diagnosis. Although currently the diagnosis requires genetic confirmation, the genetic tests are expensive and not very useful for the initial diagnosis; however, more than diagnostic importance, it has a great prognostic value allowing establishing an adequate management and significantly reducing the morbidity and mortality attributable to this condition.

Where are we with haemolytic uremic syndrome? / Síndrome hemolítico urémico: estado actual.

Haemolytic uremic syndrome (HUS) is characterised by microangiopathic haemolytic anaemia with acute kidney injury. It is currently classified into two main categories: Shiga-toxin producing E. coli-hemolytic uremic syndrome (STEC-HUS) and atypical haemolytic uremic syndrome (aHUS). Endothelial cell damage is the common pathway in HUS to developing thrombotic microangiopathy. Atypical HUS includes primary, secondary and aHUS due to metabolic diseases. In the majority of aHUS cases, hyperactivity of the alternative complement pathway plays a central role. Therefore, treatment is based on complement inhibitors like eculizumab, a drug that has revolutionised the natural history of the disease. Relapses are frequent after kidney transplant and thus confer a poor prognosis.

Practice guidelines for the emergency treatment of thrombotic microangiopathy. / Guía práctica de tratamiento urgente de la microangiopatía trombótica.

BACKGROUND AND AIM: The term thrombotic microangiopathy (TMA) involves a heterogeneous group of diseases that can be overwhelming or invalidating, with an acute development, characterised by microangiopathic haemolytic anaemia and thrombocytopaenia. Its management during its initial hours is essential to improving the prognostic of these patients. The aim of this review is to give recommendations about the optimisation of TMA initial treatment and to accelerate the aetiological diagnosis. PATIENTS AND METHODS: We provide a practice guideline based on four steps for the initial management of TMA: diagnosis of suspicion, syndromic confirmation, emergent treatment and complementary tests. RESULTS: The detection of microangiopathic haemolytic anaemia (characterised by elevated reticulocytes, LDH and indirect bilirubin, negative direct Coombs test and schistocytes in peripheral blood), and thrombocytopaenia not explained by other secondary aetiologies confirm the syndromic diagnosis of microangiopathic haemolytic anaemia and thrombocytopaenia (MAHAT). These patients require admission to an Intensive Care Unit to initiate plasma exchange therapy as soon as possible, ideally within the first 4-8hours. Prior to this, samples for ADAMTS13 and complement study should be obtained. Finally, it is important to request the complementary tests necessary to have a correct aetiological diagnosis. CONCLUSIONS: Adherence to the agreed recommendations in this guideline will improve therapeutic results by facilitating cooperation between different specialists involved in TMA management.

Hemoglobinuria paroxística nocturna / Paroxysmal nocturnal hemoglobinuria

ResumenLa hemoglobinuria paroxística nocturna es una anemia hemolítica crónica, adquirida, poco común, que afecta con igual frecuencia ambos sexos. Se manifiesta a cualquier edad y con mayor incidencia en países del sudeste asiático. Es el resultado de la expansión clonal no maligna de células progenitoras hematopoyéticas. Se caracteriza por anemia hemolítica intravascular, tendencia a la trombosis y un componente variable de insuficiencia medular.Se asocia a otras patologías hematológicas como anemia aplásica y síndrome mielodisplásico. La citometría de flujo es el método de elección para diagnóstico. El eculizumab y el trasplante de médula ósea alogénico son las únicas terapias efectivas.

Abstract:Paroxysmal nocturnal hemoglobinuria is a rare acquired chronic hemolytic anemia, which affects both sexes with equal frequency. It occurs at any age and more frequently in Southeast Asian countries. It is the result of non malignant clonal expansion of hematopoietic progenitor cells. It is characterized by intravascular hemolytic anemia, recurrent thrombosis and a variable component of bone marrow failure. It is associated with other hematologic disorders such as aplastic anemia and myelodysplastic syndrome. Flow cytometry is the method of choice for diagnosis. Eculizumab and allogeneic bone marrow transplantation is the only effective therapies.

Systemic lupus erythematosus and thrombotic thrombocytopenia purpura: a refractory case without lupus activity.

The association between systemic lupus erythematosus (SLE) and thrombotic thrombocytopenic purpura (TTP) has been infrequently reported. Usually, patients with TTP have more SLE activity and frequent renal involvement. Here we present a case of TTP associated to low-activity SLE. The absence of renal and major organ involvement increased the difficulty in making the initial diagnosis. ADAMTS13 activity in plasma in this patient was very low, as seen in other similar cases. The evolution of the patient was poor, needing plasma exchanges and immunosuppressive therapy, including the use of rituximab.

Anemia hemolítica microangiopática induzida por tacrolimus e ciclosporina A / Microangiopathic hemolytic anemia induced by tacrolimus and ciclosporine A

Relatamos caso raro de anemia hemolítica microangiopática em paciente após transplante hepático por cirrose Child B causada por deficiência de alfa1-antitripsina. Após análise clínica e laboratorial extensa, concluiu-se que o quadro de hemólise foi causado pela medicação imunossupressora utilizada após transplante. Inicialmente foi utilizado tacrolimus que, posteriormente, foi substituído por ciclosporina A, entretanto não houve melhora da hemólise. Após suspensão das duas drogas, houve melhora importante clínica do paciente, com normalização dos parâmetros hematológicos.

We report a rare case of acute hemolysis in a patient after liver transplant for Child B cirrhosis caused by alfa1-antitripsine deficiency. History and laboratorial examinations indicated that the most probable cause of the hemolysis was the use of the immunosupressor tacrolimus and later Cyclosporine A. After the discontinuation of these drugs, there was improvement in the clinical condition of the patient, with a compensated hemolytic anemia.

Síndrome hemolítico-urêmica esporádica pós-parto / Sporadic postpartum hemolytic uremic syndrome

Anemia hemolítica microangiopática associado à trombocitopenia participa de um grupo de doenças que freqüentemente apresentam suas características clínicas muito semelhantes, sendo difícil distingui-las. A síndrome hemolítico-urêmica é dividida em duas apresentações: a forma não esporádica, que acomete comumente crianças após infecção bacteriana causando diarréia sanguinolenta, possui bom prognóstico; e a forma esporádica, que acomete adultos, sendo bem descritos casos em mulheres pósparto, é a forma sistêmica de trombocitopenia microangiopática de pior prognóstico com alta morbidade e mortalidade, cuja falência renal é o distúrbio predominante. Relatamos um caso de síndrome hemolítico-urêmica pós-parto em paciente previamente sadia, que apresentou quadro de insuficiência renal, anemia hemolítica e trombocitopenia. Instituída a terapêutica de suporte adequada e precocemente, a paciente evoluiu satisfatoriamente com normalização dos níveis pressóricos e recuperação da função renal.

Microangiopathic hemolytic associated with thrombocytopenia is part of a disease group that frequently show likeness and that's why become difficult to separate them. There are two types of hemolytic uremic syndrome (HUS); the non sporadic type and the epidemic or "typical" type that is common on childreen that is associated with diarrhea and infection caused by verotoxinaproducing E. coli with a good prognostic; and the sporadic postpartum period. It is the systemic type of mocroangiophatic thrombocytopenia of poor prognostic with high morbidity and mortality which renal failure is the main disturb. We reported a case of HUS occuring in postpartum previously healthy, that showed abrupt renal failure, hemolytic anemia and thrombocytopenia. After proper therapy the patient developed a normal blood pressure and recovery renal function.

Algunas consideraciones acerca de la púrpura trombocitopénica trombótica / Some considerations about the thrombocytopenic thrombotic purpura

La púrpura trombocitopénica trombótica (PTT) es una enfermedad caracterizada por anemia hemolítica microangiopática, trombocitopenia, manifestaciones neurológicas fluctuantes y trastornos renales. La oclusión de arteriolas y capilares por microtrombos compuestos fundamentalmente por plaquetas, es típica de este trastorno, y consecuencia de la presencia de grandes multímeros de factor von Willebrand (Fv W), presumiblemente debido a la disminución de la actividad de la enzima ADAMTS13, encargada de escindir estos multímeros. El diagnóstico precoz de la PTT permite un tratamiento rápido y eficaz de este trastorno, elemento decisivo para evitar la evolución fatal de estos enfermos. La presencia de anemia y trombocitopenia no explicada por otros procesos patológicos, debe hacer sospechar el diagnóstico. El recambio plasmático es la terapéutica más efectiva y se considera el tratamiento de elección de la PTT. El uso de inmunosupresores asociados con el recambio plasmático ha sido recomendado en algunos casos. En la actualidad, el Rituximab se considera un tratamiento adicional de la PTT.

The thrombocytopenic thrombotic purpura is a disease characterized by microangiopathic hemolytic anemia, thombocytopenia , fluctuating neurological manifestations, and renal disorders. The occlusion of arterioles and capillars by microthrombi mainly composed of platelets is typical of this disorder and a consequence of the presence of large von Willebrand factor multimers, due presumptively to the reduction of the activity of the enzyme ADAMTS13 that is in charge of splitting these multimers.The early diagnosis of TTP allows a fast and efficient treatment of this disorder, a decisive element to prevent the fatal evolution of these patients. The presence of anemia and thrombocytopenia nonexplained by other pathological processes makes us suspect the diagnosis. The plasmatic turnover is the most effective therapeutics, and it should be considered the elective treatment of TTP. The use of immunosuppressors associated with the plasmatic turnover has been recommended in some cases. Nowadays, rituximab is regarded as an additional treatment of TTP.