Large deletions and small insertions and deletions in the factor VIII gene predict unfavorable immune tolerance induction outcome in people with severe hemophilia A and high-responding inhibitors.

INTRODUCTION: Hemophilia A is an inherited bleeding disorder caused by pathogenic variants in the factor VIII gene (F8), which leads to factor VIII (FVIII) deficiency. Immune tolerance induction (ITI) is a therapeutic approach to eradicate alloantibodies (inhibitors) against exogenous FVIII in people with inherited hemophilia A. Few studies have evaluated the role of F8 variants on ITI outcome. MATERIAL AND METHODS: We included people with severe hemophilia A (FVIII ˂ 1 international units/dL) and high-responding inhibitors (≥ 5 Bethesda units/mL lifelong) who underwent a first course of ITI. Socio-demographic, clinical and laboratory data were collected. ITI outcomes were defined as total, partial successes, and failure. Detection of intron 1 and 22 inversions was performed by polymerase-chain reaction, followed by F8 sequencing. RESULTS: We included 168 people with inherited hemophilia A and high-responding inhibitors, median age 6 years at ITI start. Intron 22 inversion was the most prevalent variant (53.6 %), followed by nonsense (16.1 %), small insertion/deletion (11.3 %), and large deletion (10.7 %). In comparison with intron 22 inversion, the odds of ITI failure were 15.5 times higher (odds ratio [OR] 15.50; 95 % confidence interval [95 % CI] 4.59-71.30) and 4.25 times higher (95 % CI, 1.53-12.3) among carriers of F8 large deletions and small insertions and deletions, respectively. CONCLUSION: F8 large deletions and small insertions/deletions predicted ITI failure after a first course of ITI in patients with severe hemophilia A and high-responding inhibitors. This is the first study to show F8 large deletions and small insertions/deletions as predictors of ITI failure.

Effect of the First Factor VIII Infusions on Immunological Biomarkers in Previously Untreated Patients with Hemophilia A from the HEMFIL Study.

Hemophilia A (HA) is an inherited bleeding disorder which requires continuous replacement with factor (F) VIII concentrate. The main complication of HA is the development of neutralizing alloantibodies which inhibit FVIII activity (inhibitors). The objective of this study was to investigate the effect of the first FVIII infusions on immunological biomarkers in previously untreated patients with HA. Plasma samples were collected at enrollment before any FVIII infusion (T0) and at inhibitor development (INB +/T1) or up to 35 exposure days without inhibitors (INB -/T1). Anti-FVIII antibodies (immunoglobulin M, immunoglobulin G [IgG] 1, IgG3, and IgG4), chemokines (CCL2, CCL5, CXCL8, CXCL9, and CXCL10), and cytokines (interleukin [IL]-2, IL-4, IL-6, IL-10, interferon-γ, tumor necrosis factor, and IL-17) were assessed. A total of 71 children with severe HA were included, of whom 28 (39.4%) developed inhibitors. Plasma levels of anti-FVIII IgG4, IL-6, and CXCL8 were higher at INB +/T1 when compared with INB -/T1. This group presented a mixed cytokine profile and higher plasma levels of CXCL9 and CXL10 when compared with INB +/T1. We conclude that exposure to FVIII triggers a proinflammatory response mediated by IL-6 and CXCL8 in patients with HA who developed inhibitors. Regardless of inhibitor status, the immune system of all HA patients is stimulated after infusions of FVIII.

Deficiência de ferro: ainda a principal etiologia entre crianças encaminhadas por motivo de anemia para serviço especializado de hematologia / Iron deficiency: still the main cause of referral of children to hematology services for reason of anemia

OBJETIVOS: determinar os motivos de encaminhamento e diagnósticos de crianças com anemia para serviço especializado. MÉTODOS: coorte histórico e concorrente de crianças com anemia encaminhadas ao Serviço de Hematologia do Hospital das Clínicas da Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brasil, entre maio de 1999 e dezembro de 2001. RESULTADOS: foram avaliadas 153 crianças menores de 16 anos, sendo 83 por cento procedentes de Centros de Saúde. Aproximadamente um terço das crianças não recebeu qualquer terapêutica no serviço de origem. Cento e onze (71,3 por cento) tiveram diagnóstico de anemia ferropriva. Treze crianças (8,6 por cento) tiveram diagnóstico de talassemia minor; outras treze crianças apresentaram outros diagnósticos de anemias e 11,5 por cento das crianças não apresentavam anemia. Os valores médios de hemoglobina na abordagem pelo hematologista foram significativamente maiores que os dos serviços de origem (9,7±1,9 vs. 8,9±2,0); p=0,001. Somente 16,2 por cento crianças não responderam ao primeiro tratamento com sais de ferro oral, sendo o sulfato ferroso o principal medicamento prescrito (79,3 por cento). CONCLUSÕES: A deficiência de ferro foi a principal etiologia das crianças encaminhadas por motivo de anemia para serviço especializado. Encaminhamentos desnecessários de indivíduos com anemia ferropriva para serviços especializados representam prejuízo aos pacientes e ônus excedente para o sistema de saúde.

OBJECTIVES: to determine the reasons for diagnosis of anemia among children and referral to specialized services. METHODS: an historical and concurrent cohort study was carried out among anemic children referred to the Hematology Service of the Federal University of Minas Gerais's Clinical Hospital, Belo Horizonte, in the State of Minas Gerais, Brazil, between May 1999 and December 2001. RESULTS: 153 children aged under 16 were evalua-ted, 83 percent of whom had been referred by Health Centers. Approximately one third of the children did not receive any treatment at the referring service. One hundred and eleven (71.3 percent) were diagnosed as having iron-deficiency anemia. Thirteen children (8.6 percent) received a diagnosis of thalassemia minor; and a further thirteen other anemia-related diagnoses. 11.5 percent had no kind of anemia. The mean hemoglobin levels were significantly higher when tested by a hematologist than at the referring services (9.7±1.9 vs. 8.9±2.0); p=0.001. Only 16.2 percent of children did not respond to initial treatment with oral iron salts, with iron (II) sulfate being the medication usually prescribed (79.3 percent). CONCLUSIONS: iron deficiency was the main cause of children being referred to a specialized service for reason of anemia. Unnecessary referral of individuals with iron-deficiency anemia is potentially harmful to patients and puts an excessive burden on the health system.

Mieloma múltiplo: diagnóstico e tratamento / Multiple myeloma: diagnosis and treatment

Esta revisão aborda os principais métodos de diagnóticos do mieloma múltiplo e analisar os tratamentos mais indicados para essa neoplasia. A revisão da literatura foi realizada a partir de artigos publicados após o ano 2000. O mieloma múltiplo é um tumor m aligno de células linfóides medulares, sendo o segundo câncer onco-hematológico mais frequente no mundo.É doença causada pela proliferação de um linfócito B clonal neoplásico, formando células produtoras de imunoglobinas anômalas. As manifestações clínicas surgem devido à infiltração, principalmente nos ossos, de plasmócitos neoplásicos, de produção de imunoglobulinas em excesso e de supressão da imunidade humoral normal. Com o resultado observa-se anemia grave, lesão óssea, insuficiência renal e infecção recorrente. A taxa de sobrevida dos pacientes pode variar de alguns meses a vários anos e depende da precocidade do diagnóstico e de tratamento adequado. Podem ser usados exames laboratoriais e de imagem de forma a auxiliar na identificação da neoplasia. O tratamento pode ser realizado através do transplante autogênico de células-tronco ou heterogênico. Medidas suportivas podemser adotadas, demonstrando melhora significativa da qualidade de vida do paciente. O mieloma múltiplo requer diagnóstico precoce, que pode ser feito utilizando-se exames laboratoriais e de imagem relativamente simples. O tratamento mais eficiente é o transplante autólogo de células- tronco.