Allogeneic Hematopoietic Stem Cell Transplantation for Paroxysmal Nocturnal Hemoglobinuria / 中国实验血液学杂志

OBJECTIVE@#To analyze the clinical efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for paroxysmal nocturnal hemoglobinuria (PNH), and preliminarily explore the role of an improved post-transplantation cyclophosphamide (PTCy) based conditioning regimen in PNH patients receiving transplantation.@*METHODS@#Clinical related data of PNH sufferers receiving allo-HSCT in Department of Hematology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology were collected, and hematopoietic reconstitution, chimerism, PNH cloning, graft-versus-host disease (GVHD), infection, and survival were analyzed.@*RESULTS@#Totally five PNH patients receiving allo-HSCT were enrolled, including 1 case with classic PNH, 3 cases with aplastic anemia-PNH syndrome, 1 case with myelodysplastic syndrome, three of them (case 1-3) received the improved PTCy based conditioning regimen before HSCT. All sufferers engrafted successfully within 28 days, the median time of neutrophil and platelet engraftment was 11 days and 12 days, respectively, no patient occurred acute or chronic GVHD, after a median follow-up of 16 months, all recipients survived and completely eliminated PNH cloning.@*CONCLUSION@#Allo-HSCT can completely clear PNH cloning and restore hematopoietic function with controllable complications, and the improved PTCy based conditioning regimen is proved to be effective in PNH transplantation.

Hemoglobinuria paroxística nocturna: revisión de la literatura / Paroxysmal nocturnal hemoglobinuria: literature Review

La hemoglobinuria paroxística nocturna (HPN) es una enfermedad clonal y adquirida causada por una mutación somática en el gen PIG-A que se encuentra en el cromosoma X y codifica una proteína involucrada en la síntesis del glicosilfosfatidilinositol (GPI), el cual le sirve como anclaje a muchas proteínas de la membrana celular produciendo mayor sensibilidad al complemento. Los distintos signos y síntomas que se presentan tienen gran impacto en la calidad de vida de los pacientes, por lo que un diagnóstico correcto es de vital importancia. Actualmente, la citometría de flujo multiparamétrica es la metodología de elección para detectar y seguir al paciente con HPN.

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal and acquired disease caused by a somatic mutation in the PIG-A gene found on the X chromosome and encoding a protein involved in the synthesis of glycosylphosphatidylinositol (GPI), which serves as anchoring to many proteins of the cell membrane producing greater sensitivity to complement. The different signs and symptoms that appear have a great impact on the quality of life of patients, so a correct diagnosis is of vital importance. Currently, multiparameter flow cytometry is the methodology of choice to detect and follow the patient with PNH.

Outcomes of allogeneic hematopoietic stem cell transplantation in patients with paroxysmal nocturnal hemoglobinuria compared to paroxysmal nocturnal hemoglobinuria-aplastic anemia syndrome / 中华血液学杂志

Objective: To compare the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for paroxysmal nocturnal hemoglobinuria (PNH) with paroxysmal nocturnal hemoglobinuria-aplastic anemia (PNH-AA) syndrome. Methods: The outcomes of 46 patients who received allo-HSCT (16 PNH patients, 30 PNH-AA patients) from July 10, 2007 to June 2, 2018 were analyzed retrospectively. The conditioning regimen was busulfan, cyclophosphoramide, and ATG in haploidentical donors and unrelated donors. Patients with matched sibling donors were treated with the fludarabine, cyclophosphamide, and ATG regimen. Results: There were no differences of baseline data between the 2 groups except gender distribution and the numbers of haploidentical donor transplantation. The median values of absolute nucleated cell counts were 10.58 (3.83-13.83) ×10(8)/kg in the PNH group and 10.81 (3.96-33.40) ×10(8)/kg in the PNH-AA group (P=0.668) . The median doses of CD34(+) cells infused were 5.00 (3.14-8.42) ×10(6)/kg and 3.57 (1.97-6.17) ×10(6)/kg (P=0.002) , respectively. All patients obtained complete engraftment. The median time for myeloid engraftment were 11 (7-14) days in the PNH group and 12 (10-26) days in the PNH-AA group (P=0.003) . The median time for platelet engraftment were 13 (11-16) days and 18 (12-75) days (P=0.002) , respectively, after a median follow-up of 36 (4-132) months in the PNH group and 26 (4-75) months in the PNH-AA group (P=0.428) . There were no differences of incidence rates of acute graft-versus-host disease (aGVHD) , chronic GVHD and infection between PNH and PNH-AA groups (P>0.05) . No patient occurred early death and relapse. The estimated 3-year overall survival (OS) of PNH and PNH-AA groups were (100.0±0.0) % and (85.7± 6.6) % (P=0.141) , GVHD-free and failure-free survival (GFFS) were (100.0±0.0) %, (78.7±7.7) % (P=0.067) . Conclusions: allo-HSCT is effective for patients with PNH and PNH-AA syndrome. The preliminary results indicate that myeloid and platelet engraftment in PNH group were faster than PNH-AA group. There were no differences in OS and GFFS between PNH group and PNH-AA group.

Comparison of haploidentical hematopoietic stem cell transplantation and matched-sibling donor transplantation for the treatment of paroxysmal nocturnal hemoglobinuria / 中华血液学杂志

Objective: To compare the outcomes between haploidentical donor hematopoietic stem cell transplantation (haplo-HSCT) and matched-sibling donor transplantation (MSD-HSCT) for paroxysmal nocturnal hemoglobinuria (PNH) . Methods: The clinical data of 40 PNH patients received HSCT (haplo-HSCT=25, MSD-HSCT=15) from July 2007 to May 2018 were analyzed retrospectively to compare the outcomes between haplo-HSCT and MSD-HSCT groups. Results: There were no differences in terms of gender, age, patients of PNH-AA and median time from diagnosis to transplantation between the 2 groups (P>0.05) . The median values of absolute mononuclear cell counts and CD34+ cells infused were 10.74 (4.80-22.86) ×108/kg and 12.19 (5.14-17.25) ×108/kg (P=0.866) , 3.57 (0.68-7.80) ×106/kg and 4.00 (3.02-8.42) ×106/kg (P=0.151) respectively, in haplo-HSCT and MSD-HSCT groups. All patients attained complete engraftment, no patient occurred graft failure. The median durations for myeloid and platelet engraftment were 12 (range, 9-26) and 11 (range, 7-15) days (P=0.065) , 19 (range, 11-75) and 13 (range, 11-25) days (P=0.027) respectively, in haplo-HSCT and MSD-HSCT groups. During a median follow-up of 26 (4-65) months in haplo-HSCT and 36 (4-132) months in MSD-HSCT groups (P=0.294) , the incidences of grade Ⅰ-Ⅳ acute graft-versus-host disease (aGVHD) were 32.0% and 20.0% (P=0.343) , grade Ⅱ-Ⅳ aGVHD were 16.0%, 13.3% (P=0.759) , chronic GVHD were 30.7% and 24.6% (P=0.418) , moderate-severe chronic GVHD were 12.7% and 7.1% (P=0.522) respectively, in haplo-HSCT and MSD-HSCT groups. The incidences of infection were 32.0% (8/25) and 26.7% (4/15) (P=1.000) respectively, in haplo-HSCT and MSD-HSCT groups. No patients occurred early death and relapse. Three-year estimated overall survival (OS) were (86.5±7.3) % and (93.3 ±6.4) % (P=0.520) , GVHD-free and failure-free survival (GFFS) were (78.3±8.6) % and (92.9±6.9) % (P=0.250) respectively, in haplo-HSCT and MSD-HSCT groups. Conclusion: The preliminary results indicated that haplo-HSCT was a feasible choice for PNH with favorable outcomes, haplo-HSCT and MSD-HSCT produced similar therapeutic efficacy.

Renal involvement in paroxysmal nocturnal haemoglobinuria: a brief review of the literature

SUMMARY INTRODUCTION: Paroxysmal Nocturnal Haemoglobinuria (PNH) is an acquired genetic disorder characterized by complement-mediated haemolysis, thrombosis and variable cytopenias. Renal involvement may occur and causes significant morbidity to these patients. OBJECTIVE: To review the literature about pathophysiology and provide recommendations on diagnosis and management of renal involvement in PNH. METHODS: Online research in the Medline database with compilation of the most relevant 26 studies found. RESULTS: PNH may present with acute kidney injury caused by massive haemolysis, which is usually very severe. In the chronic setting, PNH may develop insidious decline in renal function caused by tubular deposits of hemosiderin, renal micro-infarcts and interstitial fibrosis. Although hematopoietic stem cell transplantation remains the only curative treatment for PNH, the drug Eculizumab, a humanized anti-C5 monoclonal antibody is capable of improving renal function, among other outcomes, by inhibiting C5 cleavage with the subsequent inhibition of the terminal complement pathway which would ultimately give rise to the assembly of the membrane attack complex. CONCLUSION: There is a lack of information in literature regarding renal involvement in PNH, albeit it is possible to state that the pathophysiological mechanisms of acute and chronic impairment differ. Despite not being a curative therapy, Eculizumab is able to ease kidney lesions in these patients.

RESUMO INTRODUÇÃO: A hemoglobinúria paroxística noturna (HPN) é uma doença genética adquirida, caracterizada por hemólise mediada pelo sistema complemento, eventos trombóticos e citopenias variáveis. Envolvimento renal pode ocorrer, contribuindo com morbidade significativa nesses pacientes. OBJETIVO: Realização de revisão de literatura sobre o envolvimento renal na HPN. MÉTODOS: Pesquisa on-line na base de dados Medline, com compilação e análise dos 26 estudos encontrados de maior relevância. RESULTADOS: A HPN pode se apresentar com insuficiência renal aguda induzida por hemólise maciça, que geralmente tem apresentação grave. Em quadros crônicos, declínio insidioso da função renal pode ocorrer por depósitos tubulares de hemossiderina, microinfartos renais e fibrose intersticial. Apesar de o transplante de células-tronco hematopoiéticas permanecer como a única terapia curativa para a HPN, a droga Eculizumab é capaz de melhorar a função renal, entre outros desfechos, por meio da inibição de C5 e a subsequente ativação da cascata do complemento, que culminaria com a formação do complexo de ataque à membrana. CONCLUSÃO: Há poucas informações na literatura no que concerne ao envolvimento renal na HPN, apesar de ser possível estabelecer que os mecanismos fisiopatológicos das lesões agudas e crônicas são distintos. Apesar de não ser uma terapia curativa, Eculizumab é capaz de amenizar o comprometimento renal nesses pacientes.

Management of acquired thrombophilic disorders in 2011: focus on heparin-induced thrombocytopenia, antiphospholipid syndrome, myeloproliferative neoplasms and paroxysmal nocturnal hemoglobinuria

Arterial and venous thrombosis are interrelated disorders at the interplay of platelets and fibrin. Arterial thrombi are platelet-rich and occur at sites vulnerable to atherosclerotic plaque rupture where blood shear rates are high; on the contrary, venous thrombi occur in association with slow blood flow and shear rates. These differences may underlie why anti-platelet agents are more effective in prevention of arterial thrombosis, while anticoagulants are preferred for venous thrombosis. Although some common thrombophilic disorders [e.g., Factor V Leiden, prothrombin gene mutation, etc.] are almost exclusively associated with venous thromboembolism, there are several disorders that are important to consider when caring for patients with both arterial and venous thromboembolism. This article will review the evidence-based management of heparin induced thrombocytopenia with thrombosis, anti-phospholipid antibody syndrome and catastrophic anti-phospho-lipid antibody syndrome, thrombohemorrhagic manifestations of Philadelphia chromosome-negative chronic myeloproliferative neoplasms including polycythemia vera, essential thrombocythemia and primary myelofibrosis, as well as paroxysmal nocturnal hemoglobinuria

Hemoglobinúria paroxística noturna: da fisiopatologia ao tratamento / Paroxysmal nocturnal hemoglobinuria: from physiopathology to treatment

Hemoglobinúria paroxística noturna (HPN) é uma anemia hemolítica crônica adquirida rara, de curso clínico extremamente variável. Apresenta-se frequentemente com infecções recorrentes, neutropenia e trombocitopenia, e surge em associação com outras doenças hematológicas, especialmente com síndromes de falência medular, como anemia aplásica e síndrome mielodisplásica. É considerada ainda um tipo de trombofilia adquirida, apresentando-se com tromboses venosas variadas, com especial predileção por trombose de veias hepáticas e intra-abdominais, sua maior causa de mortalidade. A tríade anemia hemolítica, pancitopenia e trombose faz da HPN uma síndrome clínica única, que deixou de ser encarada como simples anemia hemolítica adquirida para ser considerada um defeito mutacional clonal da célula-tronco hematopoética (CTH). A mutação ocorre no gene da fosfaditilinositolglicana classe-A, e resulta no bloqueio precoce da síntese de âncoras de glicosilfosfaditilinositol (GPI), responsáveis por manter aderidas à membrana plasmática dezenas de proteínas com funções específicas. A falência em sintetizar GPI madura gera redução de todas as proteínas de superfície normalmente ancoradas por ela. Dentre elas estão o CD55 e o CD59, que controlam a ativação da cascata do complemento. Assim, na HPN há aumento da susceptibilidade de eritrócitos ao complemento, gerando hemólise. Revisa-se aqui sua fisiopatologia, curso clínico, os tratamentos disponíveis com ênfase para o transplante de células-tronco hematopoéticas alogênicas e para o eculizumab, um anticorpo monoclonal humanizado que bloqueia a ativação do complemento terminal no nível C5 e previne a formação do complexo de ataque à membrana, a primeira droga a demonstrar eficácia no tratamento da HPN.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder, an acquired chronic hemolytic anemia, often associated with recurrent nocturnal exacerbations, recurrent infections, neutropenia, thrombocytopenia, and episodes of venous thrombosis. Its clinical course is highly variable. It frequently arises in association with bone marrow failure, particularly aplastic anemia and myelodysplastic syndrome. It is also an acquired thrombophilia, presenting with a variety of venous thrombosis, mainly manifested with intra-abdominal thrombosis, here the major cause of mortality. The triad of hemolytic anemia, pancytopenia, and thrombosis makes a truly unique clinical syndrome of PNH, which was reclassified from a purely acquired hemolytic anemia to a hematopoietic stem cell mutation defect of the phosphatidyl inositol glycanclass-A gene. This mutation results in an early block in the synthesis of glycosylphosphatidylinositol (GPI) anchors, responsible for binding membrane functional proteins. Among these proteins are the complement inhibitors, especially CD55 and CD59, that play a key role in protecting blood cells from complement cascade attack. Therefore, in PNH occurs an increased susceptibility of red cells to complement, and consequently, hemolysis. We here review PNH physiopathology, clinical course, and treatment options, especially eculizumab, a humanized monoclonal antibody that blocks the activation of terminal complement at C5 and prevents formation of the terminal complement complex, the first effective drug therapy for PNH.

Citologia vaginal a fresco na gravidez: correlação com a citologia corada pela técnica de Papanicolaou / Fresh wet mount in pregnancy: correlation with Pap smears

OBJETIVO: analisar o conteúdo vaginal utilizando o exame citológico a fresco na primeira consulta pré-natal em mulheres com ou sem queixas genitais e correlacionar os resultados com os encontrados na citologia corada pela técnica de Papanicolaou. A microscopia direta durante a gravidez deve ser valorizada e reconhecida como método propedêutico capaz de diagnosticar, de forma imediata, 90 por cento dos casos de vaginose bacteriana, candidose e tricomonose. MÉTODOS: estudo prospectivo em 216 gestantes, selecionadas em ambulatório de pré-natal no período de 30 de outubro de 2001 a 12 de novembro de 2002. Foram colhidas duas amostras do conteúdo existente no fundo de saco vaginal posterior e depositadas em lâminas de vidro para microscopia. Sobre a primeira e a segunda amostra eram colocadas uma gota de NaCl a 0,9 por cento e uma de KOH a 10 por cento, respectivamente. Adicionalmente, em todas as grávidas determinou-se o pH vaginal e realizaram-se os testes de produção das aminas com odores de pescado. O material era examinado ao microscópio em aumentos de 100 vezes, 400 vezes e excepcionalmente 1000 vezes. Foram realizados esfregaços cervicovaginais para citologia corada pelo método de Papanicolaou. A correlação entre os resultados dos métodos citológicos empregados foi realizada pelo cálculo do coeficiente kappa, que avalia a concordância para variáveis qualitativas. RESULTADOS: o encontro nos esfregaços a fresco de flora bacteriana normal foi de 51,8, representando o aspecto citológico mais observado e sem correspondência com os 3,7 por cento apurados na microscopia corada. No exame citológico direto foram observados 30,9 por cento de vaginose bacteriana e 7,9 por cento de candidose. Todavia, no Papanicolaou não foi encontrada tal equivalência, sendo as porcentagens de 0,7 e 24,3 por cento, respectivamente. A ausência de correlação no diagnóstico de colpite bacteriana inespecífica na microscopia direta (17,5 por cento) e corada (51,3 por cento) talvez deva-se ao subdiagnóstico de vaginose neste último método propedêutico. Os diagnósticos de tricomoníase observados em ambos os métodos citológicos (3,7 e 2,7 por cento) traduzem a baixa prevalência destes parasitas na gestação. O cálculo do índice kappa para avaliação da concordância entre os dois procedimentos citológicos nos diversos achados microbiológicos demonstrou baixa correlação nos diagnósticos da vaginose bacteriana e colpites bacterianas inespecíficas, bem como na identificação da flora...

Membranous Glomerulopathy as a Manifestation of Chronic Graft-versus-Host-Disease After Non-myeloablative Stem Cell Transplantation in a Patient with Paroxysmal Nocturnal Hemoglobinuria

Allogeneic stem cell transplantation (allo-SCT) using related or unrelated donor could eradicate paroxysmal nocturnal hemoglobinuria (PNH) clones and may cure the disease. Chronic graft-versus host disease (GVHD) is a major complication of patients who have undergone allo-SCT. Nephrotic syndrome has been described as one of the rare manifestations of chronic GVHD following the usual myeloablative allo-SCT. We report a case of nephrotic syndrome that developed 25 months after non-myeloablative allo-SCT for PNH. The patient had grade II acute GVHD and extensive chronic GVHD after non-myeloablative allo-SCT. Typically the patient presented with preserved renal function and full nephrotic syndrome including generalized edema, proteinuria, hypoalbuminemia, and hypercholesterolemia. Renal biopsy revealed findings of membranous glomerulopathy (MG). The patient is alive with a stable engraftment and full donor chimerism under the administration of tacrolimus for control of chronic GVHD and MG without refractory hemolysis and cytopenia.

Hemoglobinúria paroxística noturna na gestação / Paroxysmal noctural hemoglobinuria: a case report

Hemoglobinúria Paroxística Noturna (HPN) é uma doença resultante da alteração clonal da célula tronco da medula óssea, que se manifesta por episódios de hemólise intravascular, seguida de hemoglobinúria. A gestação é relatada como fator desencadeante dos episódios hemolíticos. Relata-se um caso de paciente branca, 35 anos, portadora de HPN há 11 anos que, no decorrer da terceira gestação, necessitou realizar repetidas transfusões de hemácias lavadas. Cêrca de um mês após o parto retornou à emergência do hospital, em estado toxêmico. Transferida para a UTI, apresentou acidente vascular encefálico, evoluindo para óbito

Cerebral sinovenous thrombosis in a patient with paroxysmal nocturnal haemoglobinuria

Paroxysmal nocturnal haemoglobinuria may be complicated by life-threatening thrombosis. A patient who presented with the classical clinical picture of cerebral sinus thrombosis is described. Management of the condition is discussed.

Hemoglobinúria paroxística noturna (HPN) / Paroxysmal nocturnal hemoglobinuria (PNH)

hemoglobinúria Paroxistica Noturna (HPN) é uma doença hemolítica crônica adquirida. Depende de uma mutaçäo somática que ocorre na célula progenitora hemopoética (Stem cell). Essa anormalidade expressa-se por uma interaçäo anômala de membrana celular com os componentes do complemento plasmática provocando a disfunçäo ou destruiçäo celular. Aspectos novos da fisiopatogenia säo apresentados. manifesta-se, na maioria dos pacientes, por hemólise intravascular crônica sem um padräo noturmo clássico, por pancitopenia, deficiencia de ferro, ou episódios trombóticos recorrentes. O diagnóstico é baseado numa série de testes que avaliam a sensibilidade à lise por fraçöes do sistema do complemento. Tratamento consiste basicamente em medidas de suporte como transfusöes sangüíneas e anticoagulantes. Atualmente duas novas técnicas como transplante de medula e terapêutica fibrinolítica têm melhorado o prognóstico

Hemoglobinuria paroxística nocturna: fisiopatalogía y manejo terapéutico / Hemoglobinuria paroxysmal nocturnal: physioapathology and therapeutics handling

Se hace la revisión de la fisiopatología y el manejo terapéutico de los pacientes con hemoglobinuria paroxística nocturna (HPN), de acuerdo con la información bibliográfica que se menciona; y se refiere al hallazgo de siete casos, dos mujeres y cinco hombres, entre 26 y 76 años de edad, con HPN y sintomatología que iba desde moderada anemia hemolítica crónica y orina acolúrica, hasta severa pancitopenia, con sangramientos, infecciones y requerimiento de transfusiones, antibióticos, corticoides, andrógenos y otras medidas de soporte. La mayoría presentó agrandamiento del bazo y del hígado, especialmente durante las crisis hemolíticas

Transplante de médula ósea de trilliza idéntica a paciente con hemoglobinuria paroxística nocturna (HPN) y anemia aplástica / Transplantation of bone marrow from triplet of patient with paroxysmal nocturnal hemoglobin (PNH) and aplastic anemia

Una paciente con hemoglobinuria paroxística nocturna y aplasia severa de la médula ósea fue tratada con transplante de la médula ósea de su hermana trilliza idéntica. La paciente fue preparada con ciclofosfamida y ha tenido recuperación medular completa y constante. Las pruebas que identifican la hemoglobinuria paroxística nocturna han sido persistentemente negativas. La paciente ha estado clínica y hematológicamente normal durante más de 8 años sin ninguna medicación