Clinical, laboratory, and molecular characteristics of a cohort of children with hemoglobinopathy S/beta-thalassemia.

INTRODUCTION: Hemoglobinopathy Sß-thalassemia (HbSß-thal) has a wide range of clinical and laboratory severity. There is limited information on the natural history of HbSß-thal and its modulating factors. We described the molecular, hematological, and clinical characteristics of a cohort of children with HbSß-thal and estimated its incidence in Minas Gerais, Brazil. METHODS: Laboratory and clinical data were retrieved from medical records. Molecular analysis was performed by HBB gene sequencing, PCR-RFLP, gap-PCR, and MLPA. RESULTS: Eighty-nine children were included in the study. Fourteen alleles of ß-thal mutations were identified. The incidence of HbSß-thal in the state was 1 per 22,250 newborns. The most common ßS-haplotypes were CAR and Benin. The most frequent ßthal-haplotypes were V, II, and I. Coexistence of 3.7 kb HBA1/HBA2 deletion was present in 21.3 % of children. ß-thalassemia mutations were associated with several clinical and laboratory features. In general, the incidence of clinical events per 100 patient-years was similar for children with HbSß0-thal, IVS-I-5 G>A, and IVS-I-110 G>A. Children with HbSß+-intermediate phenotypes had a more severe laboratory and clinical profile when compared with those with HbSß+-mild ones. ßS-haplotypes and α-thalassemia did not meaningfully influence the phenotype of children with HbSß-thal. CONCLUSION: The early identification of ß-thalassemia alleles may help the clinical management of these children.

Phenotypic variation in severe hemophilia A is related to endogenous thrombin potential and plasma levels of factor VII.

Hemophilia A is a bleeding disorder caused by deficiency or low activity of circulating factor VIII characterized by prolonged blood coagulation time and often spontaneous bleeding. Patients with the severe form of the disease may present considerable heterogeneity in the occurrence of bleeding episodes and some of them have a mild hemophilia A phenotype. This study aimed to evaluate the association of biomarkers and coagulation parameters to the differential hemorrhagic profile of severe hemophilia A patients. Polymorphisms in the genes of proteins C and S, factors V and VII and prothrombin were evaluated in a group of severe hemophilia A patients with a broad spectrum of bleeding profile. Plasma levels of coagulation factors and thrombin generation were also analyzed. This study included 59 Brazilian hemophilia A patients who were allocated into low bleeding profile (LBP; n = 33) and high bleeding profile (HBP; n = 26) groups based on their joint and muscle bleeding episodes requiring treatment in the 5 years before inclusion in the study. Results evidenced that endogenous thrombin potential (ETP) and plasma factor VII levels were significantly higher in the LBP group. Results indicate a prominent importance of FVII plasma activity and endogenous thrombin potential on the differential bleeding phenotype of hemophilia A patients.

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.