A CASE REPORT OF 'RETROPERITONEAL FIBROSIS CAUSING RENOVASCULAR HYPERTENSION' ASSOCIATED WITH SARS-CoV2

Introduction: Retroperitoneal fibrosis (RPF) is a rare disease which can be primary (idiopathic) or secondary to drugs, tumors or infections. We are reporting the first case of RPF causing renal atrophy, renal artery stenosis and renovascular hypertension associated with SARS-CoV2. Method(s): A 37-year-old female nurse presented to her PCP with a new-onset of hypertension. She had recovered from severe SARS-CoV2 infection merely two months ago. Physical examination was remarkable for BP 170/110 mmHg, HR 88 beats/min, BMI of 31 alongside trace pitting edema. Initial lab data showed her creatinine to be 1.1mg/dl and ultrasound of her kidneys showed an atrophied right kidney with a size of 7.8 cm while the left kidney was 11.6 cm. An ultrasound KUB of that same time showed that the size of the right kidney was 10.4 cm and left 11.5 with normal renal parenchyma. She was started on amlodipine 10 mg and valsartan 160 mg per day. Two weeks later she was referred to a nephrologist when her creatinine was increased to 3.1 mg/dl. Renovascular hypertension secondary to right renal artery stenosis or thrombus was suspected. Autoimmune & hypercoagulable work up was negative. CT angiogram showed an ill-defined, poorly enhancing retroperitoneal soft tissue thickening draping the mid abdominal aorta, the origin of SMA, and bilateral renal arteries which terminated above the aortoiliac bifurcation. This, RPF, involved segment of 8.6 cm of the mid and lower abdominal aorta, causing moderate narrowing of proximal SMA, short segment narrowing of proximal left main and accessory renal artery, and diffuse long segmental narrowing of the right main renal artery. RPF encasement of right renal artery lead to poor right renal nephrogram and atrophic kidney. (Figure no A: Abdominal contrast-enhanced computed tomographic (CT) scan showing the encasement of the both renal arteries by the retroperitoneal fibrosis (RPF).Figure no B : Renal angiogram showing the renal artery stenosis on right side) Acute kidney injury (AKI) was initially thought to be due to angiotensin receptor blockade in the setting of bilateral renal artery stenosis. Valsartan was swapped for metoprolol and the serum creatinine levels decreased to 1.5 mg/dl in two weeks. Prednisone was started for RPF at a dose of 60 mg per day with a slow taper over 4 months. Over the next 8 weeks, creatinine became normal and blood pressure was controlled with amlodipine 2.5 mg/day. Subsequently at 4 months her creatinine was 1.0 mg/dl and she was off all anti-hypertensive drugs. A repeat CTA after 6 months showed that there was significant reduction in RPF. Atrophic right kidney was noted without any significant interval change. RPF, renal artery stenosis, renovascular hypertension and right renal atrophy was strongly suspected to be associated with SARS-Cov2 since none of these were identified prior to her suffering from SARS-CoV2. Result(s): [Formula presented] [Formula presented] Conclusion(s): To our knowledge, this is the first case of RPF associated with SARS-CoV-2 causing renovascular hypertension and renal atrophy. Local and systemic production of IL-6, TGF- beta and Th2 cytokines has been demonstrated in idiopathic RPF and pulmonary fibrosis due to SARS-CoV2. The presumptive pathogenesis could involve SARS-Cov2 induced release of IL-6 and other cytokines which can activate B cells and fibroblasts. No conflict of interestCopyright © 2023

Acute Mesenteric Thrombosis, Small Intestine Necrosis and Peritonitis as a Complication of Covid-19 - a Case Report

Introduction. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to a family of ribonucleic acid (RNA) viruses, causing novel coronavirus disease 2019 (COVID-19). Because of a global inflammatory response and endothelial damage, COVID-19 may predispose to coagulation disorders and severe thrombotic events. Case presentation. A 62-year-old man patient was admitted for COVID-19 pneumonia and abdominal pain for 10 days. Because of the rapid deterioration of the clinical status, shock and evidence of peritoneal irritation, the patient was consulted by a surgeon. The native spiral computed tomography (CT) of the abdomen detected enlarged colon filled with air collections and hydro-aeric levels. The surgical intervention revealed diffuse peritonitis with necrosis of the distal ileum secondary to mesenteric thrombosis. A partial resection of the ileum was done. The histological examination showed an infarcted small bowel, with hemorrhage, vascular thrombosis, and signs of necrotizing endovasculitis. Conclusions. SARS-CoV-2 binds to ACE2 receptor, which results in increased signalling by thrombin receptors on platelet and endothelial cells, leading to coagulopathy. In older patients presenting with abdominal pain, shock and peritonitis, the most common underlying cause is mesenteric thrombosis which could be a complication of COVID-19.Copyright © 2022 Balkan Medical Union.

Tumor Neuroectodermico Primitivo (Pnet) Com Invasao Macica Em Medula Ossea Simulando Leucemia Aguda: Relato De Caso

Objetivos: Sabe-se que os tumores neuroectodermicos primitivos (PNETs) sao tumores raros envolvendo o sistema nervoso central, ossos ou tecidos moles, com pico de incidencia na adolescencia. O PNET e um tumor extremamente agressivo cuja sobrevida livre de doenca em 2 a 3 anos varia de 25 a 60%. Cerca de 30% dos pacientes apresentam metastase no momento do diagnostico. O prognostico varia de acordo com sitio acometido e a extensao da doenca ao diagnostico. O objetivo e relatar um caso raro de PNET, avaliado pela hematologia, com hipotese diagnostica inicial de leucemia aguda. Materiais e metodos: Coleta dos dados clinicos da paciente nas Unidades de Clinica Medica e Hematologia do HUCAM, bem como o levantamento em prontuario dos resultados de provas laboratoriais e exames especializados. Resultado: Paciente do sexo feminino, 19 anos, admitida no hospital com plaquetopenia grave. A paciente relatava mialgia, cefaleia e calafrios que iniciaram apos a terceira dose da vacinacao para Covid, evoluindo 2 dias apos com o surgimento de equimoses em membros e metrorragia. Ao exame fisico apresentava-se levemente palida, afebril, com sangramento cutaneo, sem linfonodomegalias perifericas ou visceromegalia. Os exames iniciais revelaram uma anemia normocitica (Hb-10.5g/dl), leucocitos-8200/mm3, plaquetopenia (12000/mm3), aumento de desidrogenase latica (DHL-4550), beta HCG negativo. A morfologia inicial do sangue periferico nao revelou alteracoes leucocitarias, porem o mielograma mostrou uma infiltracao intensa da medula ossea por celulas com caracteristicas imaturas, compativel com celulas blasticas. A imunofenotipagem estas celulas eram negativas para CD45, e para os marcadores de linhagens mieloide, linfoides B e T, e celulas dendriticas, e positivas para CD56. O diagnostico final foi de um tumor neuroectodermico primitivo com base na histopatologia da biopsia de medula. Discussao: Apresentamos o caso de uma paciente jovem com o diagnostico de PNET avancado, com manifestacoes hemorragicas cutaneo-mucosas de evolucao aguda, associado a plaquetopenia grave e infiltracao da medula ossea por celulas imaturas com caracteristicas blasticas, que faziam suspeitar fortemente de uma leucemia aguda, portanto, uma apresentacao atipica para um tumor solido raro e de comportamento agressivo, cujo diagnostico so foi possivel atraves de exames especializados. Conclusao: O diagnostico de certas neoplasias pode ser desafiador devido a sua rara incidencia e, por vezes, apresentacao clinica atipica, que pode simular outras doencas. O envolvimento primario do sangue periferico e da medula ossea suscita a avaliacao inicial do hematologista que, com base nos conhecimentos clinico e laboratorial, e capaz de estabelecer um raciocinio amplo e diferencial, cuja confirmacao requer o conhecimento de um especialista experiente para diagnostico assertivo e precoce. Copyright © 2022

Sindrome Hemofagocitica Secundaria a Doenca De Coronavirus 2019: Relato De Caso

Objetivos: O objetivo deste estudo foi discutir a sindrome hemofagocitica, considerando a infeccao pelo SARS-CoV-2como fator desencadeador. Relato de caso: Paciente do sexo feminino, 60 anos, portadora de hipertensao arterial sistemica, hipotireoidismo e esquizofrenia, admitida por episodio de convulsao tonico-clonico generalizada secundaria a hiponatremia de etiologia medicamentosa. Apos 7degree dia de internacao, controlado o quadro inicial, evoluiu com febre e elevacao de provas inflamatorias. Nao houve deteccao de foco infeccioso em triagem infecto-metabolica, iniciado antibioticoterapia empirica e seguimento de investigacao com sorologias (HIV, hepatites, CMV, toxoplasmose, EBV, sifilis), e marcadores reumatologicos (FAN, FR), todos negativos. Em apenas tres dias, apresentou piora clinica com alteracao abrupta de exames laboratoriais, em especial pancitopenia e disfuncao renal. Evoluiu com choque presumido septico sem etiologia definida, instituido suporte ventilatorio e drogas vasoativas. A despeito de antibioticoterapia empirica, persiste com febre, insuficiencia renal e pancitopenia, com necessidade transfusional diaria. Prosseguimos investigacao de biopsia de medula ossea, evidenciando-se numerosos histiocitos volumosos fagocitando hemacias e mesmo elementos nucleados, sugestivo de sindrome hemofagocitica (SHF). Seguindo-se ao resultado da biopsia, a paciente apresentou RT-PCR covid positivo. Foi revisto todo o quadro clinico da paciente e levantada a hipotese diagnostica de sindrome hemofagocitica associada a COVID-19. O HScore do paciente foi calculado em 195, sendo que informacoes faltantes foram calculadas como zero, tendo assim uma sensibilidade 93% e especificidade 86% para SHF. Realizou terapeutica com altas doses de corticoide metilprednisolona, porem antes do inicio de tratamento com vincristina, evoluiu rapidamente com insuficiencia renal, hepatica, medular e respiratoria, indo a obito aproximadamente 20 dias apos inicio do quadro. Discussao: A SHF e um processo inflamatorio sistemico agudo grave e rapidamente progressivo. E uma complicacao rara de muitas condicoes comuns, incluindo infeccoes, especialmente de etiologia viral, doencas autoimunes e neoplasias, sobretudo oncohematologicas. Esta relacionada com defeito na citotoxicidade celular e no gene da perforina, causando ativacao sistemica de macrofagos com intensa atividade hemofagocitica. Tem caracteristicas clinico-patologicas semelhantes a sepse, manifestando-se com febre, hepatoesplenomegalia, hiperferritinemia e citopenia. A doenca de coronavirus 2019 (COVID-19) causada pelo SARS-CoV-2 contempla formas de evolucao critica com sintomas e sinais semelhantes em frequencia e intensidade as manifestacoes clinicas e laboratoriais exuberantes da SHF. O numero de relatos de casos de paciente com COVID-19 e suspeita ou diagnostico confirmado de SHF aumentou nos ultimos dois anos. Alguns autores sugerem rastreio para SHF em todos os pacientes COVID-19 graves, enquanto outros argumentam que a maioria dos pacientes desenvolvem sindrome com tempestade de citocinas similar a SHF. Conclusao: Sindrome hemofagocitica deve ser lembrada em pacientes com COVID-19 com rapida deterioracao, febre persistente, sintomas respiratorios e neurologicos, citopenias e niveis anormais de ferritina. Copyright © 2022

Sacubitril/Valsartan and Ivabradine Attenuate Left Ventricular Remodelling and Dysfunction in Spontaneously Hypertensive Rats: Different Interactions with the Renin-Angiotensin-Aldosterone System.

This study investigated whether sacubitril/valsartan and ivabradine are able to prevent left ventricular (LV) fibrotic remodelling and dysfunction in a rat experimental model of spontaneous hypertension (spontaneously hypertensive rats, SHRs) and whether this potential protection is associated with RAAS alterations. Five groups of three-month-old male Wistar rats and SHRs were treated for six weeks as follows: untreated Wistar controls, Wistar plus sacubitril/valsartan, SHR, SHR plus sacubitril/valsartan, and SHR plus ivabradine. The SHRs developed a systolic blood pressure (SBP) increase, LV hypertrophy and fibrosis, and LV systolic and diastolic dysfunction. However, no changes in serum RAAS were observed in SHRs compared with the controls. Elevated SBP in SHRs was decreased by sacubitril/valsartan but not by ivabradine, and only sacubitril/valsartan attenuated LV hypertrophy. Both sacubitril/valsartan and ivabradine reduced LV collagen content and attenuated LV systolic and diastolic dysfunction. Sacubitril/valsartan increased the serum levels of angiotensin (Ang) II, Ang III, Ang IV, Ang 1-5, Ang 1-7, and aldosterone, while ivabradine did not affect the RAAS. We conclude that the SHR is a normal-to-low serum RAAS model of experimental hypertension. While the protection of the hypertensive heart in SHRs by sacubitril/valsartan may be related to an Ang II blockade and the protective Ang 1-7, the benefits of ivabradine were not associated with RAAS modulation.

CLASSCRAFT: UMA PLATAFORMA INTERATIVA PARA O ENSINO VIRTUAL

Objetivos: Descrever a experĩencia no ensino virtual da Hematologia utilizando a plataforma Classcraft. Material e métodos: Trata-se de um relato de experiência sobre o uso da plataforma virtual Classcraft no ensino remoto da Hematologia. Resultados: Para o ensino no semestre letivo 2021.1, em modo virtual, da disciplina de Hematologia da Universidade Federal da Paraíba foi utilizada a plataforma Classcraft. Os alunos foram cadastrados como personagens de um jogo de fantasia e precisavam vencer as missões afim de ganhar pontos de experiência. A plataforma foi usada como ferramenta complementar ás aulas teóricas tradicionais. A adesão dos alunos foi de 100%. Discussão: Com a pandemia da COVID 19 a educação teve que se adequar, mesmo que de forma transitória, aos modelos de ensino remoto. Na Universidade Federal da Paraíba, no semestre letivo 2021.1, as disciplinas tiveram que ser ofertadas apenas na forma virtual. O Classcraft é uma plataforma educativa interativa onde os alunos são cadastrados como personagens de fantasia em tr̃es formas: Guerreiro, Mago e Sacerdote. Cada tipo tem poderes especiais e, á medida que evoluem no jogo, vão acumulando pontos de experĩencia e adquirindo mais poderes. Os alunos tinham que cumprir missões com conteúdos especificos de Hematologia que, somadas ás aulas teóricas tradicoionais, objetivavam a consolidação do conhecimento. As missões consistiam em assistir vídeos, ler artigos e ao final comentar em fóruns de discussão. A cada missão completada o aluno poderia utilizar um poder de seu personagem que lhe garantiria um benefício (Ex.: Extensão de prazo de uma tarefa, momento exclusivo para tirar dúvidas, dentre outros). O professor ainda podia bonificar os alunos por bom comportamento ou descontar pontos de experĩencia por mau comportamento (Ex.: Não entegar uma tarefa, não abrir a cãmera na aula, etc). Todas a sregras eram estabelecidas no início do semestre. Com o classcraft o rendimento dos alunso ans aulas tradicionais online eram cada vez mais positivos, uma vez que criava uma expectativa de serem pontuados no jogo. O desempenho dos alunos nas três provas teóricas foi muito bom e, ao final, todos os alunos completaram os objetivos do jogo. Importante frisar que o uso da plataforma foi essencial para que o semestre letivo ficasse menos engessado e mais divertido durante o período de pandemia, permitindo que a ansiedade dos alunos, pelo menos na disicplina de Hematologia, fosse mínima. Conclusão: O uso do Classcraft permitiu associar ensino com diversão, sendo uma ferramente importante para melhorar a adesão e rendimento dos estudantes durante o ensino remoto.

ANÁLISE DO TESTE DE MMA (MONOCYTE MONOLAYER ASSAY), SUBCLASSE DE ANTICORPOS E DESFECHO TRANSFUSIONAL EM PACIENTES COMPLEXOS ATENDIDOS NA FUNDAÇÃO HEMOCENTRO DE BRASÍLIA

Introdução: A técnica de monocamada de monócitos (Monocyte Monolayer Assay – MMA) é um ensaio celular funcional in vitro, capaz de prever a sobrevivência in vivo das hemácias transfundidas. É um teste utilizado para diferenciação entre anticorpos clinicamente significantes e não significantes, principalmente em pacientes complexos, para os quais não são encontrados hemocomponentes com provas de compatibilidade negativas. Objetivos: Analisar a relação entre os resultados dos testes de MMA, títulos e subclasses dos anticorpos envolvidos e o desfecho transfusional em pacientes complexos atendidos no Laboratório de Imuno-hematologia de Pacientes da Fundação Hemocentro de Brasília (LIHP-FHB). Materiais e métodos: As amostras dos pacientes foram coletadas nas agências transfusionais do DF e encaminhadas para os testes no LIHP-FHB. A monocamada dos monócitos foi obtida a partir de doadores saudáveis do sexo masculino (O RhD positivo), seguindo as etapas de isolamento (buffy-coat), separação (Ficoll) e cultivo (meio RPMI). A preparação das lâminas incluiu as fases de: aderência monocítica, adsorção do soro do paciente com as hemácias dos doadores, incubações, lavagens e coloração com Leishman. Os controles positivos (Control Cell, Immucor) e negativos (hemácias do doador) foram realizados nas mesmas condições. O Índice Monocitário (MI) foi calculado a partir da análise por microscopia óptica das hemácias fagocitadas ou aderidas, sendo considerados os resultados de MI ≤5%, 5,1%–20% e >20%, como baixo, moderado e alto risco de hemólise pós-transfusional, respectivamente. Foram realizados testes sorológicos em cartão gel-teste (Bio-Rad) para determinação da classe (IgG, IgM, IgA), subclasse (IgG1 e IgG3) e título dos anticorpos. Resultados: Foram avaliados 6 pacientes (13 a 51 anos), sendo 3 (50%) com múltiplos aloanticorpos e autoanticorpos, 2 (33,3%) com autoanticorpos e 1 (16,7%) com múltiplos aloanticorpos, autoanticorpos e anticorpos raros (anti-Hr, -hrs). Desses, 5 (83,3%) apresentavam anemia falciforme e 1 (16,7%) apresentava IRC e infecção por COVID-19. Metade dos pacientes apresentavam anticorpos IgG1 ou IgG3 com baixo risco hemolítico e a outra metade IgG1 ou IgG3 com alto risco. Foram testados 33 concentrados de hemácias (CHs) por meio do teste de MMA, sendo 8 (24,2%) com MI ≤5%, 20 (60,7%) com MI entre 5,1%–20% e 5 (15,1%) com MI >20%. Quatro pacientes receberam transfusões de CHs fenótipo-compatíveis para os sistemas Rh, Kell, Kidd, Duffy e MNS (MIs: 0%, 2%, 6% e 8%). Apenas o CH com MI de 8% resultou em redução dos índices de Hb (8,3 para 7,7 g/dL) e Ht (25 para 23,9%), após 1 hora da transfusão. Os demais CHs transfundidos promoveram incremento nos níveis de Hb e Ht, tanto após 1 hora (0,73 a 2,0 g/dL e 2,4 a 5,8%, respectivamente), quanto após 14 dias (0,8 a 1,2 g/dL e 2,9 a 4,2%, respectivamente). Discussão e conclusão: Nossos resultados revelaram que mais de 75% dos CHs testados apresentaram moderado ou alto risco de hemólise pós-transfusional. Das quatro unidades de CHs transfundidos, três (MIs: 0%, 2%, 6%) promoverem incremento e uma (MI: 8%) declínio, nos níveis de hemoglobina e hematócrito, indicando uma possível associação entre os índices de fagocitose e o risco de hemólise. Não foi evidenciado associação entre os resultados do MMA e as subclasses e títulos dos anticorpos. Apesar do pequeno número de amostras, nossos resultados revelam que o MMA pode ser uma importante ferramenta nas decisões transfusionais em pacientes complexos.

PESQUISA DE ANTÍGENOS C, E E KELL-1 POSITIVOS EM DOADORES D NEGATIVOS NO HEMOCENTRO REGIONAL DE SANTA MARIA DURANTE O PERÍODO DE PANDEMIA DA COVID-19 E A IMPORTÂNCIA NA SENSIBILIZAÇÃO EM RECEPTORES C, E E KELL-1 NEGATIVOS

Objetivos: Investigar, no Hemocentro Regional de Santa Maria (HEMOSM), os casos de doadores de sangue D negativos que apresentaram em sua fenotipagem resultados positivos para os antígenos (AG) C, E e Kell-1 na pesquisa de AG eritrocitários C.c,E,e e Kell-1. Material e métodos: Este é um estudo observacional retrospectivo realizado através da coleta de dados do Sistema HEMOVIDA (Sistema Nacional de Gerenciamento em Serviços de Hemoterapia) e dos arquivos do Laboratório de Imunohematologia do HEMOSM durante o período de fevereiro/2020 a julho/2021. As amostras utilizadas para o ensaio são amostras de sangue coletadas em tubo com anticoagulante EDTA, sendo centrifugadas e posteriormente tendo volume do concentrado de hemácias empregado na preparação de suspensões para realização dos testes conforme instruções dos fabricantes. A técnica empregada foi a aglutinação-centrifugação em cartão com gel. Anticorpos monoclonais dirigidos aos AG pesquisados encontram-se suspensos no gel em diferentes microtubos. Resultados: O total de doações com tipagem sanguínea D(-) foi de 2299 doações. Destas, 351 doadores (aproximadamente 15%) apresentaram um ou mais dos AG C, E ou Kell-1. Dentre estes, 139 doadores apresentaram fenótipo Rh Ccee, 29 apresentaram fenótipo ccEe, ainda 21 apresentaram ambos os AG, com fenótipo CcEe, enquanto o total de doadores com pesquisa positiva para o AG Kell-1 foi de 162. Discussão: Indivíduos que apresentam a tipagem sanguínea com resultado D(-), usualmente apresentam fenótipo Rh ccee com K(-), ou seja, sem a presença de AG C, E e Kell-1. Para doadores e para pacientes (pcte), a pesquisa destes AG em laboratórios de imunohematologia é importantíssima, isto porque C, E e Kell-1 apresentam elevada antigenicidade e, portanto, risco de sensibilização no caso de transfusão de hemácias com estes AG em pcte que não os apresentam. Sendo assim, concentrados de hemácias (CH) com D(-) que apresentem C, E e/ou Kell-1 devem ser direcionados para pcte que apresentem estes AG, na tentativa de utilização do hemocomponente, especialmente no período da pandemia de COVID-19, quando as doações de sangue reduziram aproximadamente 10% no HEMOSM durante o primeiro ano da pandemia (em comparação com o mesmo período do ano anterior). A destinação racional destes hemocomponentes no sentido de impedir a sensibilização dos pcte é essencial para que em futuras provas de compatibilização estes pcte não corram o risco de apresentar incompatibilidade decorrente da formação de anticorpos irregulares Anti-C, Anti-E e Anti-Kell-1. Conclusão: A utilização de CH D(-) com a presença de C, E e/ou Kell-1 só pode se dar no caso de os pcte apresentarem prova cruzada e configuração antigênica compatíveis com as hemácias do doador. Em razão disso, alguns desses CH podem permanecer represados nos estoques de sangue até seu vencimento e descarte. Uma alternativa para a utilização destes CH é a sua destinação para a compatibilização e uso em pcte D+, uma vez que estes apresentam AG C, E e/ou Kell-1 com maior frequência. Assim, são transfundidas hemácias com configuração antigênica compatível na tentativa de destinação desses CH para que não cheguem a ser desprezadas por validade, especialmente no contexto da redução das doações.

ANEMIA APLÁSTICA ADQUIRIDA SECUNDÁRIA À INFECÇÃO PELO SARS-COV-2

Introdução: A anemia aplástica adquirida (AAA) é uma condição rara, com alta morbidade. Em 70-80% dos casos é idiopática e ocorre por destruição das células tronco-hematopoiéticas por fenômeno autoimune. Com as terapias imunossupressoras e o transplante de medula óssea (TMO), a AAA teve excelentes resultados com taxas de sobrevida de 80% em 10 anos. Pode estar relacionada à outros mecanismos, como exposição a agentes tóxicos e infecções virais, especialmente vírus Epstein Barr, vírus de hepatite, HIV e parvovírus B19. A recente pandemia pelo vírus SARS-Cov-2 foi relacionada ao desenvolvimento de doenças autoimunes, corroborando a associação entre infecção viral e desbalanço imune. Apresentamos o caso de uma paciente, previamente hígida, que 60 dias após infecção pelo Sars-Cov-2 iniciou plaquetopenia, evoluindo para pancitopenia. Relato de caso: Paciente feminina, 29 anos, infecção pelo Sars-Cov-2 em agosto/20, quadro leve, sem necessidade de internação hospitalar. Em outubro/2020, apresentou equimoses persistentes, procurou atendimento médico, com os exames: Hb 11,5 g/dL;neutrófilos 1054/mm3 e 130.000/mm3 plaquetas, com conduta expectante nesse momento. Em janeiro/2021, com piora das equimoses e fadiga, retornou em atendimento com Hb 9,8 g/dL, neutrófilos 1278/mm3 e plaquetas 45.000/mm3. Iniciada investigação com sorologias para hepatites virais, HIV, sífilis, provas reumatológicas, vitamina B12, ácido fólico, função renal, hepática, tireoidiana e pesquisa de clone HPN, todos dentro da normalidade. Como tratamento, foi iniciado prednisona 1 mg/kg/dia e agendado retorno ambulatorial. Antes do previsto, procurou novamente atendimento por gengivorragia com plaquetas de 19.000/mm3, Hb 9,8 g/dL, neutrófilos 900/mm3 e Reticulócitos 46,536/mm3. Submetida a avaliação medular, com biópsia evidenciando hipocelularidade (cerca de 30%) com hipoplasia de todas as séries. O estudo imunofenotípico não mostrou proliferação de células imaturas, anômalas ou displásicas, cariótipo XX, FISH para síndrome mielodisplásica e DEB test negativos. Como pesquisas virais, citomegalovírus e parvovírus B19, além de RNA do vírus SARS-Cov-2 na extração de DNA em medula óssea, resultaram todos negativos. O diagnóstico de AAA foi estabelecido, evoluindo com piora progressiva da pancitopenia e necessidade de suporte transfusional recorrente. Apesar de candidata a transplante alogênico de medula óssea, a paciente não tinha irmãos e então, iniciado tratamento timoglobulina de coelho 3,5 mg/kg/dia por 5 dias, ciclosporina 10 mg/kg/dia e eltrombopag 150 mg/dia, além eritropoetina 40.000 UI/semana. O último exame de 29/06/2021 mostra resposta parcial a terapia estabelecida com Hb 11,7 g/dL, neutrófilos 1889/mm3 e 90.000/mm3 plaquetas. Conclusão: A AAA é uma condição que necessita de rápido diagnóstico e tratamento. O desbalanço imunológico, especialmente a hiperativação de linfócitos T citotóxicos CD8+, desencadeado por infecção viral pode ser gatilho para a condição em predispostos. Outros relatos semelhantes corroboram a associação temporal entre a infecção do SARS-Cov-2 e AAA. Sendo assim, consideramos importante compartilhar essa informação no meio científico.

New therapies for the treatment of heart failure with preserved ejection fraction.

PURPOSE: This review of chronic heart failure with preserved ejection fraction (HFpEF), including new and emerging evidence for treatment of patients with this condition, is intended to offer data supporting the use of specific agents for this patient population. SUMMARY: Chronic heart failure is a major health concern affecting millions of Americans annually and remains a significant burden on the healthcare system. Heart failure is divided into categories based on left ventricular ejection fraction (LVEF). Current treatments for heart failure with reduced ejection fraction, defined by an LVEF of less than 40%, involve a variety of agents with established morbidity and mortality benefits. This is in stark contrast to directed treatments for patients with HFpEF, defined by an LVEF of greater than 50%. Treatments for this form of heart failure have been elusive until recently, when studies were published with sacubitril/valsartan and empagliflozin. Results of the PARAGON-HF trial suggested benefit from sacubitril/valsartan in patients with an ejection fraction between 45% and 57%, leading to its approval in 2021 as the first medication indicated for treatment of patients with a preserved ejection fraction. Months later, the results of the EMPEROR-Preserved trial demonstrated a statistically significant benefit in the composite outcome of heart failure hospitalizations and cardiovascular death in patients with HFpEF taking empagliflozin. This medication has yet to gain approval for HFpEF; however, these data along with ongoing and future trials will likely impact standard treatment for these patients. CONCLUSION: The PARAGON-HF and EMPEROR-Preserved trials will serve as the foundation for a new era in the treatment of HFpEF.

Discovery of a new generation of angiotensin receptor blocking drugs: Receptor mechanisms and in silico binding to enzymes relevant to SARS-CoV-2.

The discovery and facile synthesis of a new class of sartan-like arterial antihypertensive drugs (angiotensin receptor blockers [ARBs]), subsequently referred to as "bisartans" is reported. In vivo results and complementary molecular modelling presented in this communication indicate bisartans may be beneficial for the treatment of not only heart disease, diabetes, renal dysfunction, and related illnesses, but possibly COVID-19. Bisartans are novel bis-alkylated imidazole sartan derivatives bearing dual symmetric anionic biphenyl tetrazole moieties. In silico docking and molecular dynamics studies revealed bisartans exhibited higher binding affinities for the ACE2/spike protein complex (PDB 6LZG) compared to all other known sartans. They also underwent stable docking to the Zn2 + domain of the ACE2 catalytic site as well as the critical interfacial region between ACE2 and the SARS-CoV-2 receptor binding domain. Additionally, semi-stable docking of bisartans at the arginine-rich furin-cleavage site of the SARS-CoV-2 spike protein (residues 681-686) required for virus entry into host cells, suggest bisartans may inhibit furin action thereby retarding viral entry into host cells. Bisartan tetrazole groups surpass nitrile, the pharmacophoric "warhead" of PF-07321332, in its ability to disrupt the cysteine charge relay system of 3CLpro. However, despite the apparent targeting of multifunctional sites, bisartans do not inhibit SARS-CoV-2 infection in bioassays as effectively as PF-07321332 (Paxlovid).

Impact of the COVID-19 pandemic on prescription of sacubitril/valsartan in Italy.

AIMS: The present study sought to examine the effect of the COVID-19 pandemic and lockdown measures on the prescription of sacubitril/valsartan in patients with heart failure (HF) in Italy. METHODS AND RESULTS: Data from Italian Medicines Agency (AIFA) monitoring registries were analysed. The sacubitril/valsartan monitoring registry is based on 6-month prescriptions. A monthly aggregation on new activations throughout the observational period was computed. From March to December 2020, the initiation of new HF patients on sacubitril/valsartan decreased by nearly 40% with prescriptions dropping to values similar to 2018 when the registry was still operated off-line. A slight increase in prescriptions was observed after the lockdown measures were lifted, but prescriptions remained constantly below the pre-lockdown period. CONCLUSION: A marked and worrisome decline during the COVID-19 pandemic in the activation of a life-saving treatment such as sacubitril/valsartan was observed. This decline was clearly linked to the lockdown measures instated to counteract the COVID-19 pandemic. Upcoming studies should analyse the occurrence of new cases of HF as well as the severity of patients admitted to hospitals and their mortality compared to pre-pandemic levels.

Late-Breaking Basic Science Abstracts From the American Heart Association's Scientific Sessions 2021

The proceedings contain 34 papers. The topics discussed include: combinatorial maturation of patient stem cell-derived atrial cardiomyocytes unmasks mechanism of atrial fibrillation induced by NPPA gene mutation;the pathogenesis of Covid-19 myocardial injury: an immunohistochemical study of postmortem biopsies;mitochondrial optogenetic-mediated preconditioning protects cardiomyocytes from stress-induced injury;the aldose reductase inhibitor At-001 improves cardiac efficiency and decreases diastolic dysfunction in an animal model of diabetic cardiomyopathy: comparative and add-on studies versus SGLT-2 inhibition;cardiomyocyte specific deletion Of Trpv4 offers cardio-protection independent of cardiac fibrosis following pressure overload-induced hypertrophy;and sacubitril-valsartan protects against aortic aneurysm progression via regulating neprilysin-induced vascular smooth muscle cell apoptosis.

Valsartan protects both cardiac and lung cells from sars-cov-2 infection

Background: Severe Acute Respiratory Syndrome-Coronavirus 2 (SARS-CoV-2) disease (COVID19) mainly affects the respiratory system, but cardiac complications occur very often. SARS-CoV-2 entry in host cells is mediated by the interaction between the viral Spike (S) glycoprotein and the host angiotensin-converting enzyme 2 (ACE2). The use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II type 1 receptor blockers (ARBs) might influence the expression of ACE2 and viral infection, but not much is known about these interactions. Aim: To evaluate the effects of ACEIs and ARBs during active viraemia. Methods: We tested the ACEI Lisinopril (at 100nM and 500nM) and the ARB Valsartan (at 10uM and 50uM) for one week on two cell types: cardiomyocytes derived from hiPSC (hiPSC-CMs) as heart model and a lung epithelial cancer cell line (16HBE) as pulmonary model. The SARS-CoV-2 wild strain was inoculated in the two treated cell types for one hour. Cell viability was measured 72 hours after infection. Supernatants were collected and titrated to verify the presence of infectious virus using a micro-neutralization assay on VERO-E6 cells. Levels of ACE2 mRNA and protein content on cell lysates were quantified after each treatment by RT-qPCR and western blot, respectively. Results: ACEI and ARB at both concentrations affected the viability of neither hiPSC-CMs nor 16HBE cells in the absence of virus. Vice versa, viral infection significantly decreased viability of both hiPSC-CMs (-46%;p<0,01) and 16HBE (-19%;p<0,05). Viral titration revealed that SARSCoV-2 replicated in both cell lines and was actively released in supernatants. Importantly, pretreatment with Valsartan 50uM increased the viability of both hiPSC-CMs and 16HBE after infection, while Lisinopril and the lower dose of Valsartan had neutral effect. Of note, Valsartan 50uM treatment decrease ACE2 mRNA level in both hiPSC-CMs (-47%, p<0,01) and 16HBE (-37%, p<0,01). Also ACE2 protein levels were reduced in cell lysates of hiPSC-CMs and 16HBE treated with Valsartan 50uM. Conclusion: These data suggest that ACEIs and ARBs do not worsen the SARS-CoV-2 infection. On the contrary, Valsartan seems to be protective against SARS-CoV-2 infection, possibly by reducing ACE2 expression.

ANMCO POSITION PAPER: Use of sacubitril/valsartan in hospitalized patients with acute heart failure.

Sacubitril/valsartan (S/V) has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms in chronic heart failure with reduced ejection fraction compared with enalapril. After 7 years since the publication of the results of PARADIGM-HF, further insight has been gained with potential new indications. Two prospective randomized multicentre studies (PIONEER-HF and TRANSITION) in patients hospitalized for acute heart failure (AHF) have shown an improved clinical outcome and biomarker profile as compared with enalapril, and good tolerability, safety, and feasibility of initiating in-hospital administration of S/V. Furthermore, some studies have highlighted the favourable effects of S/V in attenuating adverse myocardial remodelling, supporting an early benefit after treatment. Observational data from non-randomized studies in AHF report that in-hospital and pre-discharge prescription of evidence-based drugs associated with better survival still remain suboptimal. Additionally, the COVID-19 pandemic has also negatively impacted on outpatient activities. Therefore, hospitalization, a real crossroad in the history of heart failure, must become a management and therapeutic opportunity for our patients. The objective of this ANMCO position paper is to encourage and facilitate early S/V administration in stabilized patients during hospitalization after an AHF episode, with the aim of improving care efficiency and clinical outcome.

Angiotensin Receptor Blockers for COVID-19: Pathophysiological and Pharmacological Considerations About Ongoing and Future Prospective Clinical Trials.

COVID-19 pandemic demands a swift response to find therapeutic tools that effectively reduce morbidity and mortality. Despite initial fears, evidence from retrospective observational studies supports the inhibition of the renin-angiotensin system as an emerging pathway to delay or moderate angiotensin II-driven lung inflammation. This has triggered several prospective clinical trials. In this commentary we provide an overview and analysis of current ongoing clinical trials aimed at evaluating the therapeutic efficacy of angiotensin receptor blocker (ARB) use in COVID-19. The relevance of the results of these trials will have to be interpreted depending on the stage and severity of the disease and in light of the start time of their prescription related to the time of diagnosis of COVID-19 as well as the administered doses.

Role of Hydrogen Bonds in Formation of Co-amorphous Valsartan/Nicotinamide Compositions of High Solubility and Durability with Anti-hypertension and Anti-COVID-19 Potential.

Physicochemical properties, in particular solubility and the associated bioavailability, are key factors in determining efficacy of poorly water-soluble drugs, which constitute 40% of new drugs in the market, and improving them is an important challenge for modern pharmacy. A recent strategy to achieve this goal is formation of stable co-amorphous solid dispersions with co-formers of low molecular weight. Here, the amorphization strategy was applied for low-soluble anti-hypertensive valsartan (VAL), an angiotensin II receptor blocker, and nicotinamide, which exhibits lung- and cardio-protective effects. Through interactions with the renin-angiotensin-aldosteron system, VAL may be used to treat both hypertension and the current pandemic coronavirus SARS-CoV-2 infection. Using mechanochemical and liquid- and solid-state approaches, solvated co-amorphous solid dispersions of VAL with nicotinamide were obtained. They were characterized by spectroscopic, thermal, and X-ray analyses. The density functional theory, quantum theory of atoms in molecules, and non-covalent interaction index calculations revealed the presence of two types of hydrogen bonds between VAL and NIC (i.e., N-H···O and O-H···O). One of them had a partially covalent character, which caused conformational changes in the flexible VAL molecule, restricting contribution of the tetrazolyl N-H donor and thus limiting the possibility of co-crystal formation. The recognized VAL/NIC1- and VAL/NIC2-type heterodimeric interactions were responsible for the excellent durability of the solid compositions and up to 24-fold better solubility than VAL alone. The synthesized dispersions constitute a new class of dually acting drugs, containing an active pharmaceutical ingredient (VAL) and supporting nutraceutical (nicotinamide).

The Rationale for Angiotensin Receptor Neprilysin Inhibitors in a Multi-Targeted Therapeutic Approach to COVID-19.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) determines the angiotensin converting enzyme 2 (ACE2) down-regulation and related decrease in angiotensin II degradation. Both these events trigger "cytokine storm" leading to acute lung and cardiovascular injury. A selective therapy for COVID-19 has not yet been identified. Clinical trials with remdesivir gave discordant results. Thus, healthcare systems have focused on "multi-targeted" therapeutic strategies aiming at relieving systemic inflammation and thrombotic complications. No randomized clinical trial has demonstrated the efficacy of renin angiotensin system antagonists in reducing inflammation related to COVID-19. Dexamethasone and tocilizumab showed encouraging data, but their use needs to be further validated. The still-controversial efficacy of these treatments highlighted the importance of organ injury prevention in COVID-19. Neprilysin (NEP) might be an interesting target for this purpose. NEP expression is increased by cytokines on lung fibroblasts surface. NEP activity is elevated in acute respiratory distress syndrome and it is conceivable that it is also high in COVID-19. NEP is implicated in the degradation of natriuretic peptides, bradykinin, substance P, adrenomedullin, and apelin that account for prevention of organ injury. Thus, NEP/angiotensin receptor type 1 (AT1R) inhibitor sacubitril/valsartan (SAC/VAL) may increase levels of these molecules and block AT1Rs required for ACE2 endocytosis in SARS-CoV-2 infection. Moreover, SAC/VAL has a positive impact on acute heart failure that is very frequently observed in deceased COVID-19 patients. The current review aims to summarize actual therapeutic strategies for COVID-19 and to examine the data supporting the potential benefits of SAC/VAL in COVID-19 treatment.

Sacubitril/Valsartan in Advanced Heart Failure With Reduced Ejection Fraction: Rationale and Design of the LIFE Trial.

The PARADIGM-HF (Prospective Comparison of Angiotensin II Receptor Blocker Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial reported that sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, significantly reduced mortality and heart failure (HF) hospitalization in HF patients with a reduced ejection fraction (HFrEF). However, fewer than 1% of patients in the PARADIGM-HF study had New York Heart Association (NYHA) functional class IV symptoms. Accordingly, data that informed the use of S/V among patients with advanced HF were limited. The LIFE (LCZ696 in Hospitalized Advanced Heart Failure) study was a 24-week prospective, multicenter, double-blinded, double-dummy, active comparator trial that compared the safety, efficacy, and tolerability of S/V with those of valsartan in patients with advanced HFrEF. The trial planned to randomize 400 patients ≥18 years of age with advanced HF, defined as an EF ≤35%, New York Heart Association functional class IV symptoms, elevated natriuretic peptide concentration (B-type natriuretic peptide [BNP] ≥250 pg/ml or N-terminal pro-B-type natriuretic peptide [NT-proBNP] ≥800 pg/ml), and ≥1 objective finding of advanced HF. Following a 3- to 7-day open label run-in period with S/V (24 mg/26 mg twice daily), patients were randomized 1:1 to S/V titrated to 97 mg/103 mg twice daily versus 160 mg of V twice daily. The primary endpoint was the proportional change from baseline in the area under the curve for NT-proBNP levels measured through week 24. Secondary and tertiary endpoints included clinical outcomes and safety and tolerability. Because of the COVID-19 pandemic, enrollment in the LIFE trial was stopped prematurely to ensure patient safety and data integrity. The primary analysis consists of the first 335 randomized patients whose clinical follow-up examination results were not severely impacted by COVID-19. (Entresto [LCZ696] in Advanced Heart Failure [LIFE STUDY] [HFN-LIFE]; NCT02816736).