Reduction of extramedullary erythropoiesis and amelioration of anemia in a ß-thalassemia patient treated with thalidomide.

ß-thalassemia patient treated with thalidomide: dimensional reduction of EMH foci (MRI evaluation) and reduction of hematological responce at follow-up.

Thalassaemia is paradoxically associated with a reduced risk of in-hospital complications and mortality in COVID-19: Data from an international registry.

Although numerous patient-specific co-factors have been shown to be associated with worse outcomes in COVID-19, the prognostic value of thalassaemic syndromes in COVID-19 patients remains poorly understood. We studied the outcomes of 137 COVID-19 patients with a history of transfusion-dependent thalassaemia (TDT) and transfusion independent thalassaemia (TIT) extracted from a large international cohort and compared them with the outcomes from a matched cohort of COVID-19 patients with no history of thalassaemia. The mean age of thalassaemia patients included in our study was 41 ± 16 years (48.9% male). Almost 81% of these patients suffered from TDT requiring blood transfusions on a regular basis. 38.7% of patients were blood group O. Cardiac iron overload was documented in 6.8% of study patients, whereas liver iron overload was documented in 35% of study patients. 40% of thalassaemia patients had a history of splenectomy. 27.7% of study patients required hospitalization due to COVID-19 infection. Amongst the hospitalized patients, one patient died (0.7%) and one patient required intubation. Continuous positive airway pressure (CPAP) was required in almost 5% of study patients. After adjustment for age-, sex- and other known risk factors (cardiac disease, kidney disease and pulmonary disease), the rate of in-hospital complications (supplemental oxygen use, admission to an intensive care unit for CPAP therapy or intubation) and all-cause mortality was significantly lower in the thalassaemia group compared to the matched cohort with no history of thalassaemia. Amongst thalassaemia patients in general, the TIT group exhibited a higher rate of hospitalization compared to the TDT group (p = 0.001). In addition, the rate of complications such as acute kidney injury and need for supplemental oxygen was significantly higher in the TIT group compared to the TDT group. In the multivariable logistic regression analysis, age and history of heart or kidney disease were all found to be independent risk factors for increased in-hospital, all-cause mortality, whereas the presence of thalassaemia (either TDT or TIT) was found to be independently associated with reduced all-cause mortality. The presence of thalassaemia in COVID-19 patients was independently associated with lower in-hospital, all-cause mortality and few in-hospital complications in our study. The pathophysiology of this is unclear and needs to be studied in vitro and in animal models.

Development of Algorithm for Clinical Management of Sickle Cell Bone Disease: Evidence for a Role of Vertebral Fractures in Patient Follow-up.

Sickle-cell disease (SCD) is a worldwide distributed hemoglobinopathy, characterized by hemolytic anemia associated with vaso-occlusive events. These result in acute and chronic multiorgan damage. Bone is early involved, leading to long-term disability, chronic pain and fractures. Here, we carried out a retrospective study to evaluate sickle bone disease (SBD) in a cohort of adults with SCD. We assessed bone density, metabolism and turnover. We also evaluated the presence of fractures and the correlation between SCD severity and skeletal manifestations. A total of 71 patients with SCD were analyzed. The mean age of population was 39 ± 10 years, 56% of which were females. We found osteoporosis in a range between 7% and 18% with a high incidence of vertebral fractures. LDH and AST were predictive for the severity of vertebral fractures, while bone density was not. Noteworthy, we identified -1.4 Standard Deviations T-score as the cutoff for detecting the presence of fractures in patients with SCD. Collectively our data allowed us to develop an algorithm for the management of SBD, which may be useful in daily clinical practice to early intersect and treat SBD.

Sickle cell disease: a review for the internist.

Sickle cell disease (SCD) is the most important hemoglobinopathy worldwide in terms of frequency and social impact, recently recognized as a global public health problem by the World Health Organization. It is a monogenic but multisystem disorder with high morbidity and mortality. Vaso-occlusion, hemolytic anemia and vasculopathy are the hallmarks of SCD pathophysiology. This review focuses both on "time-dependent" acute clinical manifestations of SCD and chronic complications commonly described in adults with SCD. The review covers a broad spectrum of topics concerning current management of SCD targeted at the internists and emergency specialists who are increasingly involved in the care of acute and chronic complications of SCD patients.

Iron overload-related heart failure in a patient with transfusion-dependent myelodysplastic syndrome reversed by intensive combined chelation therapy.

Patients with transfusion-dependent myelodysplastic syndromes (MDS) have an increased risk of cardiac events, due to both chronic anemia and iron overload. Here, we report the recovery of cardiac function after an intensive iron chelation therapy in a MDS patient who had developed heart failure due to iron overload.

Characterization of ferromagnetic or conductive properties of metallic foreign objects embedded within the human body with magnetic iron detector (MID): Screening patients for MRI.

PURPOSE: A preliminary assessment of the MRI-compatibility of metallic object possibly embedded within the patient is required before conducting the MRI examination. The Magnetic Iron Detector (MID) is a highly sensitive susceptometer that uses a weak magnetic field to measure iron overload in the liver. MID might be used to perform a screening procedure for MRI by determining the ferromagnetic/conductive properties of embedded metallic objects. METHODS: The study was composed by: (i) definition of MID sensitivity threshold; (ii) application of MID in a procedure to characterize the ferromagnetic/conductive properties of metallic foreign objects in 958 patients scheduled for MID examination. RESULTS: The detection threshold for ferromagnetic objects was found to be the equivalent of a piece of wire of length 2 mm and gauge 0.8 mm(2) and, representing purely conductive objects, an aluminum sheet of area 2 × 2 cm(2) . Of 958 patients, 165 had foreign bodies of unknown nature. MID was able to detect those with ferromagnetic and/or conducting properties based on fluctuations in the magnetic and eddy current signals versus control. CONCLUSION: The high sensitivity of MID makes it suitable for assessing the ferromagnetic/conductive properties of metallic foreign objects embedded within the body of patients scheduled for MRI.

Development of interactive algorithm for clinical management of acute events related to sickle cell disease in emergency department.

Sickle cell disease (SCD ORPHA232; OMIM 603903) is a rare hereditary red cell disorder, which global distribution is changed in the last decade due to immigration-fluxes from endemic areas to Western-countries. One of the main clinical manifestations of SCD are the acute painful vaso-occlusive crisis, which cause frequent accesses of SCD patients to the emergency departments (EDs). This has generated the requirement of feasible tools for emergency givers. In the context of the scientific-Italian-Society for the study of Thalassemias and Hemoglobinopathies (SITE), we developed an algorithm with interactive windows to guide physicians in managing SCD patients in EDs.

Efficacy and safety of deferiprone for the treatment of pantothenate kinase-associated neurodegeneration (PKAN) and neurodegeneration with brain iron accumulation (NBIA): results from a four years follow-up.

OBJECTIVE: To evaluate the long-term effect of Deferiprone (DFP) in reducing brain iron overload and improving neurological manifestations in patients with NBIA. METHODS: 6 NBIA patients (5 with genetically confirmed PKAN), received DFP solution at 15 mg/kg po bid. They were assessed by UPDRS/III and UDRS scales and blinded video rating, performed at baseline and every six months. All patients underwent brain MRI at baseline and during follow up. Quantitative assessment of brain iron was performed with T2* relaxometry, using a gradient multi-echo T2* sequence. RESULTS: After 48 months of treatment clinical rating scales and blinded video rating indicated a stabilization in motor symptoms in 5/6 Pts. In the same subjects MRI evaluation showed reduced hypointensity in the globus pallidus (GP); quantitative assessment confirmed a significant increment in the T2* value, and hence reduction of the iron content of the GP. CONCLUSION: The data from our 4-years follow-up study confirm the safety of DFP as a chelator agent for iron accumulation. The clinical stabilization observed in 5/6 of our patients suggests that DFP may be a reasonable therapeutic option for the treatment of the neurological manifestations linked with iron accumulation and neurodegeneration, especially in adult patients at early stage of the disease. (Clinicaltrials.gov identifier: NTC00907283).

Diagnostic value of real-time elastography in the assessment of hepatic fibrosis in patients with liver iron overload.

OBJECTIVE: The objective of our prospective monocentric work was to determine the diagnostic value of real-time elastography (RTE) in the assessment of liver fibrosis in patients with iron overload, using transient elastography (TE) as reference standard. METHODS: Sixty-seven consecutive patients with MRI detectable iron overload (T2*<6.3 ms) were enrolled. TE and RTE were performed on the same day as MRI. Elastograms were acquired by an experienced operator and analyzed by calculating the elastic ratio between perihepatic soft tissues and liver parenchyma. An elliptical ROI of 1cm(2) (Z1) was positioned in the liver parenchyma and a smaller elliptical ROI of 2mm(2) (Z2) was positioned in a homogeneously soft (red) region of the diaphragm, which was considered as internal control to calculate the elastic ratio Z2/Z1. RESULTS: Seven patients were excluded because of invalid TE or RTE examinations. The remaining 60 patients were 57% males and 43% females (mean age: 42 [21-76] years), including 37 homozygous-ß-thalassemics, 13 patients with ß-thalassemia intermedia, 6 with primary hemochromatosis, and 4 with myelodysplastic syndrome. Increasing elastic ratios were significantly correlated with increasing TE values (r=0.645, 95% CI 0.468-0.772, P<0.0001). The mean elastic ratios for each METAVIR group were as follows: F0/1 = 1.9 ± 0.4; F2 = 2.2 ± 0.4; F3 = 2.9 ± 0.5; F4 = 3.2 ± 0.4. The diagnostic accuracy of RTE for F ≥ 2 evaluated by AUC-ROC analysis was 0.798 (95% CI 0.674-0.890). The diagnostic accuracy of RTE for F ≥ 3 was 0.909 (95% CI 0.806-0.968). At a cut-off ≥ 2.75, RTE showed a sensitivity of 70% (95% CI 45.7-88.1) and a specificity of 97.5% (95% CI 86.8-99.9). CONCLUSIONS: In patients with MRI-detectable liver iron-overload RTE allows to discriminate between F0/1-F2 and F3-F4 with a reasonable diagnostic accuracy.

Changes in the quality of life of people with thalassemia major between 2001 and 2009.

BACKGROUND: The prolonged survival of patients with thalassemia major as a result of the novel therapeutic strategies introduced in the last decade makes patient quality of life an important issue. This study investigated the changes occurring in overall quality of life in patients with thalassemia in the last decade. METHODS: This was a population-based cross-sectional survey of quality of life in the entire population with thalassemia major resident in the Liguria region of Italy from 2001 to 2009. The self-administered Short Form-36 (SF-36) questionnaire was used to measure quality of life in patients with thalassemia. RESULTS: Forty-nine and 52 eligible patients were assessed in 2001 and 2009, respectively. A total of 43 patients were assessed in both 2001 and 2009. Almost 40% of these 43 patients received deferasirox in 2009, a drug which was not available in 2001. The distribution of ferritin levels was lower in 2009 (median 730) as compared with 2001 (median 1107). Analysis of the raw differences between the two years did not show a significant difference. An improvement was observed in most SF-36 scales in 2009 as compared with 2001, particularly in the Mental Health scale (mean difference in Z score +4.0; 95% confidence interval 0.4-7.5; P = 0.030) and in the Mental Component Summary scale (mean difference in Z score +3.2; 95% confidence interval 0.2-6.2; P = 0.039). CONCLUSION: The challenge associated with new therapies and improvement in mental quality of life dimensions indicates that implementation of effective interventions for screening and evaluation of quality of life is now urgent.

Differential effects of the type of iron chelator on the absolute number of hematopoietic peripheral progenitors in patients with ß-thalassemia major.

Several studies have established an association between iron chelation therapy with deferasirox and hematopoietic improvement in patients with myelodysplastic syndromes. There are no data from patients with ß-thalassemia major. In a cross-sectional study, we evaluated the absolute number of several hematopoietic peripheral progenitors (colony-forming unit-granulocyte/macrophage, erythroid burst-forming units, colony-forming unit-granulocyte/erythrocyte/macrophage/megakaryocyte, and long-term culture-initiating cells) in 30 patients with ß-thalassemia major (median age 29.5 years, 40% males) and 12 age-matched controls. For the ß-thalassemia major patients, data on splenectomy status, the type of iron chelator used, and serum ferritin levels reflecting changes in iron status on the chelator were also retrieved. All patients had to be using the same iron chelator for at least 6 months with >80% compliance. The absolute number of all hematopoietic peripheral progenitors was higher in ß-thalassemia major patients than in controls, and varied between splenectomized and non-splenectomized patients (lower number of erythroid burst-forming units and higher numbers of colony-forming unit-granulocyte/macrophage, colony-forming unit-granulocyte/erythrocyte/macrophage/megakaryocyte, and long-term culture-initiating cells). The number of erythroid burst-forming units was significantly higher in patients taking deferasirox (n=10) than in those taking either deferoxamine (n=10) or deferiprone (n=10) (P<0.05). After adjusting for age, sex, splenectomy status, and serum ferritin changes, the association between a higher absolute number of erythroid burst-forming units in deferasirox-treated patients than in patients taking deferoxamine or deferiprone remained statistically significant (P=0.011). In conclusion, in ß-thalassemia major patients, compared with other iron chelators, deferasirox therapy is associated with higher levels of circulating erythroid burst-forming units. This variation is independent of iron status changes and is more likely to be due to the type of chelator.

A pilot trial of deferiprone for neurodegeneration with brain iron accumulation.

Deferiprone was shown to reverse iron deposition in Friedreich's ataxia. This multi-center, unblinded, single-arm pilot study evaluated safety and efficacy of deferiprone for reducing cerebral iron accumulation in neurodegeneration with brain iron accumulation. Four patients with genetically-confirmed pantothenate kinase-associated neurodegeneration, and 2 with parkinsonism and focal dystonia, but inconclusive genetic tests, received 15 mg/kg deferiprone bid. Magnetic resonance imaging and neurological examinations were conducted at baseline, six and 12 months. Chelation treatment caused no apparent hematologic or neurological side effects. Magnetic resonance imaging revealed decreased iron accumulation in the globus pallidus of 2 patients (one with pantothenate kinase-associated neurodegeneration). Clinical rating scales and blinded video rating evaluations documented mild-to-moderate motor improvement in 3 patients (2 with pantothenate kinase-associated neurodegeneration). These results underline the safety and tolerability of deferiprone, and suggest that chelating treatment might be effective in improving neurological manifestations associated with iron accumulation. (Clinicaltrials.gov Identifier: NTC00907283).

Musculoskeletal manifestations of chronic anemias.

This article provides an overview of the current use of diagnostic imaging modalities in the evaluation of a heterogeneous group of disorders causing chronic anemias by impaired blood cell production (inherited bone marrow failure syndromes of childhood, aplastic anemia and myelodysplastic syndromes, ß-thalassemia) or increased blood cell destruction (sickle cell disease). During the course of these disorders, various musculoskeletal abnormalities can be encountered, including marrow hyperplasia, reversion of yellow marrow to red marrow, growth disturbances, and, occasionally, extramedullary hematopoiesis. Diagnostic imaging may help the clinician to identify specific complications related to either the disease (e.g., bone infarction and acute osteomyelitis in sickle cell disease) or transfusion (e.g., iron overload due to increased hemolysis) and iron chelation (e.g., desferrioxamine-related dysplastic bone changes and deferiprone-related degenerative arthritis) treatments. In this field, magnetic resonance imaging plays a pivotal role because of its high tissue contrast that enables early assessment of bone marrow changes before they become apparent on plain films or computed tomography or metabolic changes occur on bone scintigraphy or positron emission tomography scan. Overall, familiarity with the range of radiological appearances in chronic anemias is important to diagnose complications and establish appropriate therapy.

Clinical management of cardiovascular complications in patients with thalassaemia major: a large observational multicenter study.

AIMS: To determine the clinical management of cardiovascular complications, and the extent of cardiac left ventricular (LV) involvement, in a large cohort of homogenously treated patients with thalassaemia major. METHODS AND RESULTS: Participants were ≥ 16 years of age and diagnosed with thalassaemia major requiring regular blood transfusions since the age of 2. Patient characteristics, clinical and echocardiography data for 524 patients were extracted from Webthal®, an Internet-shared database. Patients were considered to have evidence of cardiovascular disease if at least one cardiovascular drug was recorded in their file. The majority of patients (422 of 524; 80.5%) had not taken any cardiovascular drug. Among those who had angiotensin-converting enzyme-inhibitors were the most commonly used (81 patients) and these were used by significantly more males than females (P < 0.01). Patients in whom cardiovascular drugs were prescribed showed evidence of cardiac structural and/or functional abnormalities, inasmuch as fractional shortening and ejection fraction were significantly lower (31.3 vs. 35% and 54.4 vs. 60.6; both P < 0.001) and LV end-diastolic diameter index was significantly higher (32.9 vs. 31.8; P = 0.004). Interestingly, when compared with patients in whom cardiovascular drug therapy was not deemed necessary, transfusion period was longer in treated patients (26.2 vs. 24.5 years; P= 0.002). CONCLUSION: Approximately 19% of regularly transfused and chelated thalassaemia major patients need cardiovascular drug therapy. This subgroup is characterized by a dilated and mildly hypokinetic left ventricle when compared with the majority of thalassaemia major patients, who do not need any cardioactive drug. These data underscore the importance of careful evaluation of cardiac functional status in patients with thalassaemia major. Moreover, this database may serve as a clinically useful reference grid for echocardiograph values in this patient population.