Survival and causes of death in 2,033 patients with non-transfusion-dependent β-thalassemia
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ABSTRACT:
SUBMITTER: Musallam KM
PROVIDER: S-EPMC8409024 | biostudies-literature | 2021 Sep
REPOSITORIES: biostudies-literature
Publications
Survival and causes of death in 2,033 patients with non-transfusion-dependent β-thalassemia
Musallam Khaled M KM Vitrano Angela A Meloni Antonella A Pollina Sebastiano Addario SA Karimi Mehran M El-Beshlawy Amal A Hajipour Mahmoud M Di Marco Vito V Ansari Saqib Hussain SH Filosa Aldo A Ricchi Paolo P Ceci Adriana A Daar Shahina S Vlachaki Efthymia E Singer Sylvia Titi ST Naserullah Zaki A ZA Pepe Alessia A Scondotto Salvatore S Dardanoni Gabriella G Bonifazi Fedele F Sankaran Vijay G VG Vichinsky Elliott E Taher Ali T AT Maggio Aurelio A
Haematologica 20210901 9
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Project description:The intricate interplay of anemia and iron overload under the pathophysiological umbrella of ineffective erythropoiesis in non-transfusion-dependent β-thalassemia (NTDT) results in a complex variety of clinical phenotypes that are challenging to diagnose and manage. In this article, we use a clinical framework rooted in pathophysiology to present 4 common scenarios of patients with NTDT. Starting from practical considerations in the diagnosis of NTDT, we delineate our strategy for the longitudinal care of patients who exhibit different constellations of symptoms and complications. We highlight the use of transfusion therapy and novel agents, such as luspatercept, in the patient with anemia-related complications. We also describe our approach to chelation therapy in the patient with iron overload. Although tackling every specific complication of NTDT is beyond the scope of this article, we touch on the management of the various morbidities and multisystem manifestations of the disease.
| S-EPMC10644094 | biostudies-literature
Project description:BackgroundThe finding of many Thai Hb E-β0-thalassemia patients with non-transfusion dependent thalassemia (NTDT) phenotype without co-inheritance of α-thalassemia has prompted us to investigate the existence of other genetic modifying factors.MethodsStudy was done on 122 adult Thai patients with NTDT Hb E-β-thalassemia patients without co-inheritance of α-thalassemia. Multiple single-nucleotide polymorphisms (SNPs) associated with γ-globin gene expression including the Gγ-XmnI of HBG2 gene, rs2297339, rs4895441, and rs9399137 of the HBS1L-MYB gene, rs4671393 in the BCL11A gene, and G176AfsX179, T334R, R238H and -154 (C-T) in the KLF1 gene were investigated using PCR and related techniques.ResultsHeterozygous and homozygous for Gγ-XmnI of HBG2 gene were detected at 70.5% and 7.4%, respectively. Further DNA analysis identified the rs2297339 (C-T), rs4895441 (A-G), and rs9399137 (T-C) of HBS1L-MYB gene in 86.9%, 25.4%, and 23.0%, respectively. The rs4671393 (G-A) of the BCL11A gene was found at 31.2%. For the KLF1 gene, only T334R was detected at 9.0%.ConclusionsIt was found that these SNPs, when analyzed in combination, could explain the mild phenotypic expression of all cases. These results underline the importance of these informative SNPs on phenotypic expression of Hb E-β-thalassemia patients.
| S-EPMC6613625 | biostudies-literature
Project description:Non-transfusion-dependent thalassemia (NTDT) has been considered less severe than its transfusion-dependent variants. The most common forms of NTDT include β-thalassemia intermedia, hemoglobin E/beta thalassemia, and hemoglobin H disease. Patients with NTDT develop several clinical complications, despite their regular transfusion independence. Ineffective erythropoiesis, iron overload, and hypercoagulability are pathophysiological factors that lead to morbidities in these patients. Therefore, an early and accurate diagnosis of NTDT is essential to ascertaining early interventions. Currently, several conventional management options are available, with guidelines suggested by the Thalassemia International Federation, and novel therapies are being developed in light of the advancement of the understanding of this disease. This review aimed to increase clinicians' awareness of NTDT, from its basic medical definition and genetics to its pathophysiology. Specific complications to NTDT were reviewed, along with the risk factors for its development. The indications of different therapeutic options were outlined, and recent advancements were reviewed.
| S-EPMC9608723 | biostudies-literature
Project description:Patients with beta-thalassemia major (BTM) suffer from fatigue, poor physical fitness, muscle weakness, lethargy, and cardiac complications which are related to an energy crisis. Carnitine and acylcarnitine derivatives play important roles in fatty acid oxidation, and deregulation of carnitine and acylcarnitine metabolism may lead to an energy crisis. The present study aimed to investigate carnitine and acylcarnitine metabolites to gain an insight into the pathophysiology of BTM. Dried blood spots of 45 patients with BTM and 96 age-matched healthy controls were analyzed for free carnitine and 24 acylcarnitines by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Although medium chain acylcarnitine levels were similar in the patients with BTM and healthy controls, free carnitine, short chain acylcarnitines, long chain acylcarnitines, and total acylcarnitine levels were significantly lower in patients with BTM than in the healthy controls (P < 0.05). Moreover, an impaired fatty acid oxidation rate was observed in the patients with BTM, as manifested by decreased fatty acid oxidation indicator ratios, namely C2/C0 and (C2 + C3)/C0. Furthermore, an increase in the C0/(C16 + C18) ratio indicated reduced carnitine palmitoyltransferase-1 (CPT-1) activity in the patients with BTM compared with that in the healthy controls. Thus, a low level of free carnitine and acylcarnitines together with impaired CPT-1 activity contribute to energy crisis-related complications in the patients with BTM.
| S-EPMC6057484 | biostudies-literature
Project description:BackgroundIron overload is one of the main factors that increase morbidity and mortality in patients with non-transfusion dependent thalassemia (NTDT).AimThis study aimed at investigating the prevalence and severity of iron overload in Chinese NTDT patients.Methodswe analyzed serum ferritin (SF), liver iron concentration (LIC) and cardiac T2* in 178 Chinese NTDT in this cross-sectional study.ResultsThe median SF level was 996.00(27.15-19704.00) ng/ml and the median LIC value was 8.90(0.60-43.00) mg Fe/g dry weight (dw). The youngest patient with liver iron overload was 5 years old with 5.6 mg Fe/g dw in LIC. The median cardiac T2* was 33.06(7.46-75.08) ms. 6 patients had cardiac T2*⩽20ms. The patients with β thalassemia intermedia and HbE/β thalassemia showed a statistically significant lower Hb and higher values of SF and LIC than those of hemoglobin H disease patients. On multivariate logistic regression analysis, patients in ⩾ age 30-year old had a significant higher risk for iron overload (OR: 77.75, 95% CI: 8.76-690.49) in the age group. The detailed analysis of proportions of different LIC indicate in > 30-year old group, 76.8% patients suffered from moderate and severe LIC.ConclusionOur study provides a strong support for the novel findings that Chinese NTDT patients have a high prevalence of iron overload. The first assessment of MRI LIC should be performed as early as 5 years old. Then, NTDT patients > 30 years old may suffer with a high burden of iron overload.
| S-EPMC8935562 | biostudies-literature
Project description:The rheological properties of blood play an important role in regulating blood flow in micro and macro circulation. In thalassemia syndromes red blood cells exhibit altered hemodynamic properties that facilitate microcirculatory diseases: increased aggregation and reduced deformability, as well as a marked increase in adherence to the vascular endothelial cells. A personalized approach to treating thalassemia patients (transfusions, iron chelation, and splenectomy), has increased patients' life expectancy, however they generally present many complications and several studies have demonstrated the presence of high incidence of thromboembolic events. In this study the hemorheological profiles of thalassemia patients have been characterized to point out new indices of vascular impairment in thalassemia. Plasma viscosity, blood viscosities at low and high shear rates (η1 and η200, respectively), erythrocyte aggregation index (η1/η200), and the erythrocyte viscoelastic profile (elastic modulus G', and viscous modulus G") have been studied in transfusion-dependent and non-transfusion-dependent thalassemia patients. Moreover, the levels of inflammation biomarkers in thalassemia have been evaluated to investigate a relationship between the biomarkers, the disease severity and the rheological parameters. The biomarkers studied are the main components of the immune and endothelial systems or are related to vascular inflammation: cytokines (IL-2, IL-6, IL-10, IL-17A, TNF-alpha), chemokines (IL-8, MIP-1alpha), adipocytokines (leptin and adiponectin), growth factors (VEGF, angiopoietin-1), adhesion molecules (ICAM-1, VCAM-1, E-selectin, L-selectin), and a monocyte/macrophage activation marker (CD163). This study shows that transfusion-dependent thalassemia patients, both major and intermedia, have blood viscosities comparable to those of healthy subjects. Non-transfusion-dependent thalassemia intermedia patients show high blood viscosities at low shear rates (η1), corresponding to the flow conditions of the microcirculation, an increase in erythrocyte aggregation, and high values of the elastic G' and viscous G" modules that reflect a reduced erythrocyte deformability and an increase in blood viscosity. Levels of cytokines, chemokines and adhesion molecules are different in transfusion- and non-transfusion dependent patients and positive correlations between η1 or η1/η200 and the cytokines IL-6 and IL-10 have been observed. The evaluation of the hemorheological profiles in thalassemia can provide new indicators of vascular impairment and disease severity in thalassemia in order to prevent the onset of thromboembolic events.
| S-EPMC9868635 | biostudies-literature
Project description:A preclinical humanized mouse model of beta thalassemia major or Cooley anemia (CA) was generated by targeted gene replacement of the mouse adult globin genes in embryonic stem cells. The mouse adult alpha and beta globin genes were replaced with adult human alpha globin genes (alpha2alpha1) and a human fetal to adult hemoglobin (Hb)-switching cassette (gamma(HPFH)deltabeta(0)), respectively. Similar to human infants with CA, fully humanized mice survived postnatally by synthesizing predominantly human fetal Hb, HbF (alpha(2)gamma(2)), with a small amount of human minor adult Hb, HbA2 (alpha(2)delta(2)). Completion of the human fetal to adult Hb switch after birth resulted in severe anemia marked by erythroid hyperplasia, ineffective erythropoiesis, hemolysis, and death. Similar to human patients, CA mice were rescued from lethal anemia by regular blood transfusion. Transfusion corrected the anemia and effectively suppressed the ineffective erythropoiesis, but led to iron overload. This preclinical humanized animal model of CA will be useful for the development of new transfusion and iron chelation regimens, the study of iron homeostasis in disease, and testing of cellular and genetic therapies for the correction of thalassemia.
| S-EPMC2680376 | biostudies-literature
Project description: Not available
| S-EPMC10460678 | biostudies-literature
Project description: Not available
| S-EPMC11880825 | biostudies-literature
Project description:BackgroundExtramedullary hematopoiesis (EMH) is common in non-transfusion-dependent thalassemia (NTDT) patients. Clinical presentations of EMH vary as MRI screening is not feasible. Hence, serum biomarkers are used to predict the risk of EMH.Materials and methods52 NTDT patients, including 26 EMH (+) and 26 EMH (-), together with 26 healthy controls, were enrolled in this case-control study from 2013 to 2016. EMH was confirmed by computed tomography or MRI. Demographic, transfusion, genetic, laboratory, and liver iron concentration (LIC) data, as well as clinical complications, were analyzed.ResultsEMH (+) patients had significantly higher serum ferritin (SF), growth differentiation factor 15 (GDF15), and erythropoietin (EPO) levels compared with EMH (-) patients and controls. The levels of erythroferrone (ERFE), hepcidin, and sTfR did not differ significantly between EMH (+) and EMH (-) patients (p>0.05). In NTDT patients, serum ERFE was not related to SF, LIC, hepcidin, sTfR, EPO, GDF15, and Hb levels. GDF15, EPO concentrations, and GDF15 to sTfR and GDF15 to EPO ratios are able to determine the presence of EMH with considerable sensitivity and specificity.ConclusionsGDF15, EPO, and GDF15 to EPO and GDF15 to sTfR ratios are potential biomarkers for the early prediction of NTDT in patients who are at risk for EMH.
| S-EPMC6374788 | biostudies-literature