Hereditary hemolytic anemias are a group of disorders with a variety of causes, including red cell membrane defects, red blood cell enzyme disorders, congenital dyserythropoietic anemias, thalassemia ...syndromes and hemoglobinopathies. As damaged red blood cells passing through the red pulp of the spleen are removed by splenic macrophages, splenectomy is one possible therapeutic approach to the management of severely affected patients. However, except for hereditary spherocytosis for which the effectiveness of splenectomy has been well documented, the efficacy of splenectomy in other anemias within this group has yet to be determined and there are concerns regarding short- and long-term infectious and thrombotic complications. In light of the priorities identified by the European Hematology Association Roadmap we generated specific recommendations for each disorder, except thalassemia syndromes for which there are other, recent guidelines. Our recommendations are intended to enable clinicians to achieve better informed decisions on disease management by splenectomy, on the type of splenectomy and the possible consequences. As no randomized clinical trials, case control or cohort studies regarding splenectomy in these disorders were found in the literature, recommendations for each disease were based on expert opinion and were subsequently critically revised and modified by the Splenectomy in Rare Anemias Study Group, which includes hematologists caring for both adults and children.
β-thalassemia, a hereditary blood disorder caused by defective synthesis of hemoglobin β globin chains, leads to ineffective erythropoiesis and chronic anemia that may require blood transfusions. ...Sotatercept (ACE-011) acts as a ligand trap to inhibit negative regulators of late-stage erythropoiesis in the transforming growth factor β superfamily, correcting ineffective erythropoiesis. In this phase II, open-label, dose-finding study, 16 patients with transfusion-dependent β -thalassemia and 30 patients with non-transfusion-dependent β-thalassemia were enrolled at seven centers in four countries between November 2012 and November 2014. Patients were treated with sotatercept at doses of 0.1, 0.3, 0.5, 0.75, or 1.0 mg/kg to determine a safe and effective dose. Doses were administered by subcutaneous injection every 3 weeks. Patients were treated for ≤22 months. Response was assessed as a ≥20% reduction in transfusion burden sustained for 24 weeks in transfusion-dependent β-thalassemia patients, and an increase in hemoglobin level of ≥1.0 g/dL sustained for 12 weeks in non-transfusion-dependent β-thalassemia patients. Sotatercept was well tolerated. After a median treatment duration of 14.4 months (range 0.6-35.9), no severe life-threatening adverse events were observed. Thirteen percent of patients reported serious but manageable adverse events. The active dose of sotatercept was ≥0.3 mg/kg for patients with non-transfusion-dependent β-thalassemia and ≥0.5 mg/kg for those with transfusion-dependent β-thalassemia. Of 30 non-transfusion-dependent β-thalassemia patients treated with ≥0.1 mg/kg sotatercept, 18 (60%) achieved a mean hemoglobin increase ≥1.0 g/dL, and 11 (37%) an increase ≥1.5 g/dL, sustained for ≥12 weeks. Four (100%) transfusion-dependent β-thalassemia patients treated with 1.0 mg/kg sotatercept achieved a transfusion-burden reduction of ≥20%. Sotatercept was effective and well tolerated in patients with β-thalassemia. Most patients with non-transfusion-dependent β-thalassemia treated with higher doses achieved sustained increases in hemoglobin level. Transfusion-dependent β-thalassemia patients treated with higher doses of sotatercept achieved notable reductions in transfusion requirements. This trial was registered at ClinicalTrials.gov with the number NCT01571635.
Patients with β thalassemia intermedia can have substantial iron overload, irrespectively of their transfusion status, secondary to increased intestinal iron absorption. This study evaluates whether ...iron overload in patients with β thalassemia intermedia is associated with morbidity.
This was a cross-sectional study of 168 patients with β thalassemia intermedia treated at two centers in Lebanon and Italy. Data on demographics, splenectomy status, transfusion status, and presence of co-morbidities were retrieved. Laboratory values of serum ferritin, fetal and total hemoglobin levels, as well as platelet and nucleated red blood cell counts were also obtained. Iron burden was determined directly by measuring liver iron concentration using magnetic resonance imaging. Patients were subdivided according to transfusion and splenectomy status into groups with phenotypes of different severity.
The mean age of the patients was 35.2 ± 12.6 years and 42.9% of them were male. The mean liver iron concentration was 8.4 ± 6.7 mg Fe/g dry weight. On multivariate logistic regression analysis, after adjusting for age, gender, splenectomy status, transfusion status, and laboratory indices, an increase in 1 mg Fe/g dry weight liver iron concentration was independently and significantly associated with higher odds of thrombosis, pulmonary hypertension, hypothyroidism, osteoporosis, and hypogonadism. A liver iron concentration of at least 7 and at least 6 mg Fe/g dry weight were the best thresholds for discriminating the presence and absence of vascular and endocrine/bone morbidities, respectively (area under the receiver-operating characteristic curve: 0.72, P<0.001). Elevated liver iron concentration was associated with an increased rate of morbidity in patients with phenotypes of all severity, with a steeper increase in the rate of vascular morbidity being attributed to aging, and an earlier appearance of endocrine and bone disease.
Elevated liver iron concentration in patients with β thalassemia intermedia is a marker of increased vascular, endocrine, and bone disease.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked recessive hemolytic anemia caused by mutations in G6PD gene. The distribution and frequency of genetic variants differ depending on ...ethnicity and geographical areas. Because of new migrations different variants are now present in Europe. This retrospective study aims to identify variants among the G6PD deficient subjects referred since 2004 to IRCCS Ca’ Granda Foundation Hospital in Milan. The subjects were divided into 3 groups: group 1 (2004–2008), group 2 (2009–2013), and group 3 (2014–2018). During 15 years a significant decrease of the Mediterranean and an important increase of the African, Asian, and uncommon variants (classified as Others) have been observed. Three new mutations were found: in group 2 heterozygosity for c.1454G > A (Gly485Asp) in an adult female with severe anemia, high bilirubin levels and G6PD activity of 0,69 (IU/gHb) and heterozygosity for c.584A > G (Gln195Arg) in an elderly woman of Italian origin showing only anemia and enzymatic activity of 1,54 (IU/gHb) were detected. In group 3 hemizygosity for c.670A > T (Ile224Phe) in an adult Chinese man without anemia but with total absence of G6PD activity was found. These data reflect the appearance of uncommon G6PD mutations in northern Italy, probably due to new migrations, as consequence G6PD characterization becomes a diagnostic issue.
Partial deficiency of the last enzyme of the heme biosynthetic pathway, namely, ferrochelatase (FECH), is responsible for erythropoietic protoporphyria (EPP) in humans. This disorder is characterized ...by painful skin photosensitivity, due to excessive protoporphyrin IX (PPIX) production in erythrocytes. Although several papers report the presence of iron deficiency anemia in about 50% of EPP patients, there is still no a conclusive explanation of the why this occurs. In the present work, we explored hematological indices and iron status in 20 unrelated Italian EPP patients in order to propose a new hypothesis. Our data show that microcytosis is present in EPP patients also in the absence of anemia and iron deficiency with a link between PPIX accumulation and reduced MCV, probably indicating an indirect condition of heme deficiency. Patients studied had a downward shift of iron parameters due to increased hepcidin concentrations only in a state of repleted iron stores. Interestingly, hemoglobin synthesis was not limited by iron supply except in cases with further iron loss, in which concomitantly increased soluble transferrin (Tf) receptor (sTfR) levels were detected. The mechanisms involved in the iron uptake downregulation in EPP remain unclear, and the role of PPIX accumulation in microcytosis.
Sickle cell disease (SCD) is an inherited red blood cell disorder caused by a structural abnormality of hemoglobin called sickle hemoglobin (HbS). Clinical manifestations of SCD are mainly ...characterized by chronic hemolysis and acute vaso-occlusive crisis, which are responsible for severe acute and chronic organ damage. SCD is widespread in sub-Saharan Africa, in the Middle East, Indian subcontinent, and some Mediterranean regions. With voluntary population migrations, people harboring the HbS gene have spread globally. In 2006, the World Health Organization recognized hemoglobinopathies, including SCD, as a global public health problem and urged national health systems worldwide to design and establish programs for the prevention and management of SCD. Herein we describe the historical experience of the network of hemoglobinopathy centers and their approach to SCD in Italy, a country where hemoglobinopathies have a high prevalence and where SCD, associated with different genotypes including ß-thalassemia, is present in the native population.
To identify systemic risk factors for sickle cell maculopathy, and to analyze the microstructure of the macula of Sickle Cell Disease (SCD) patients by using automated segmentation of individual ...retinal layers.
Thirty consecutive patients with SCD and 30 matched controls underwent spectral-domain optical coherence tomography (SD-OCT) and automated thickness measurement for each retinal layer; thicknesses for SCD patients were then compared to normal controls. Demographic data, systemic data, and lab results were collected for each SCD patient; multivariate logistic regression analysis was used to identify potential risk factors for sickle cell maculopathy.
Ongoing chelation treatment (p = 0.0187) was the most predictive factor for the presence of sickle cell maculopathy; the odds were 94.2% lower when chelation was present. HbF level tended to influence sickle cell maculopathy (p = 0.0775); the odds decreased by 12.9% when HbF increased by 1%. Sickle cell maculopathy was detected in 43% of SCD patients as patchy areas of retinal thinning on SD-OCT thickness map, mostly located temporally to the macula, especially in eyes with more advanced forms of sickle cell retinopathy (p = 0.003). In comparison to controls, SCD patients had a subtle thinning of the overall macula and temporal retina compared to controls (most p<0.0001), involving inner and outer retinal layers. Thickening of the retinal pigment epithelium was also detected in SCD eyes (p<0.0001).
Chronic chelation therapy and, potentially, high levels of HbF are possible protective factors for the presence of sickle cell maculopathy, especially for patients with more advanced forms of sickle cell retinopathy. A subtle thinning of the overall macula occurs in SCD patients and involves multiple retinal layers, suggesting that ischemic vasculopathy may happen in both superficial and deep capillary plexi. Thinning of the outer retinal layers suggests that an ischemic insult of the choriocapillaris may also occur in SCD patients.
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