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.

Risk factors for endocrine complications in transfusion-dependent thalassemia patients on chelation therapy with deferasirox: a risk assessment study from a multi-center nation-wide cohort.

Transfusion-dependent patients typically develop iron-induced cardiomyopathy, liver disease, and endocrine complications. We aimed to estimate the incidence of endocrine disorders in transfusiondependent thalassemia (TDT) patients during long-term iron-chelation therapy with deferasirox (DFX). We developed a multi-center follow-up study of 426 TDT patients treated with once-daily DFX for a median duration of 8 years, up to 18.5 years. At baseline, 118, 121, and 187 patients had 0, 1, or ≥2 endocrine diseases respectively. 104 additional endocrine diseases were developed during the follow-up. The overall risk of developing a new endocrine complication within 5 years was 9.7% (95% Confidence Interval [CI]: 6.3-13.1). Multiple Cox regression analysis identified three key predictors: age showed a positive log-linear effect (adjusted hazard ratio [HR] for 50% increase 1.2, 95% CI: 1.1-1.3, P=0.005), the serum concentration of thyrotropin showed a positive linear effect (adjusted HR for 1 mIU/L increase 1.3, 95% CI: 1.1-1.4, P<0.001) regardless the kind of disease incident, while the number of previous endocrine diseases showed a negative linear effect: the higher the number of diseases at baseline the lower the chance of developing further diseasess (adjusted HR for unit increase 0.5, 95% CI: 0.4-0.7, P<0.001). Age and thyrotropin had similar effect sizes across the categories of baseline diseases. The administration of levothyroxine as a covariate did not change the estimates. Although in DFX-treated TDT patients the risk of developing an endocrine complication is generally lower than the previously reported risk, there is considerable risk variation and the burden of these complications remains high. We developed a simple risk score chart enabling clinicians to estimate their patients' risk. Future research will look at increasing the amount of variation explained from our model and testing further clinical and laboratory predictors, including the assessment of direct endocrine magnetic resonance imaging.

Epidemiological shift of glucose-6-phosphate dehydrogenase mutations in northern Italy in the last 15 years.

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.

Innovative Treatments for Rare Anemias.

Rare anemias (RA) are mostly hereditary disorders with low prevalence and a broad spectrum of clinical severity, affecting different stages of erythropoiesis or red blood cell components. RA often remains underdiagnosed or misdiagnosed, and treatment options have been limited to supportive care for many years. During the last decades, the elucidation of the molecular mechanisms underlying several RA paved the way for developing new treatments. Innovative treatments other than supportive care and allogeneic bone marrow transplantation are currently in clinical trials for ß-thalassemias, sickle cell disease (SCD), and congenital hemolytic anemias. Recently, luspatercept, an activin receptor ligand trap targeting ineffective erythropoiesis, has been approved as the first pharmacological treatment for transfusion-dependent ß-thalassemia. L-glutamine, voxelotor, and crizanlizumab are new drugs approved SCD, targeting different steps of the complex pathophysiological mechanism. Gene therapy represents an innovative and encouraging strategy currently under evaluation in several RA and recently approved for ß-thalassemia. Moreover, the advent of gene-editing technologies represents an additional option, mainly focused on correcting the defective gene or editing the expression of genes that regulate fetal hemoglobin synthesis. In this review, we aim to update the status of innovative treatments and the ongoing trials and discuss RA treatments' future directions. Interestingly, several molecules that showed promising results for treating one of these disorders are now under evaluation in the others. In the near future, the management of RA will probably consist of polypharmacotherapy tailored to patients' characteristics.

Management of age-associated medical complications in patients with ß-thalassemia.

Introduction: ß-Thalassemia syndromes are among the most common monogenic disorders worldwide. Clinically, on the basis of the severity of the phenotype, ß-thalassemias are classified into two groups: transfusion-dependent thalassemia (TDT) and non-transfusion-dependent thalassemia (NTDT). In the last few decades, considerable advances in understanding the pathophysiology of ß-thalassemia have significantly improve d patient management, which has led to an increase in the life span of these subjects. However, new complications associated with aging are emerging, and ß-thalassemias are becoming a growing concern for the health care systems.Areas covered: The present review focused on the age-related complications in adults with ß-thalassemia. Among the cardiovascular diseases, which remain a major cause of morbidity, pulmonary hypertension and arrhythmias are exhibiting increased prevalence. Adrenal insufficiency and bone disease are emerging as endocrinological complications that require proper treatment. Moreover, age-related complications observed in the general population, including cancers and renal disease, should not be neglected.Expert opinion: The present study reviews the management of above-stated complications in adults with ß-thalassemia based on the experience of a referral center. It is noteworthy that clinical trials in this context are limited, and the expert opinion offered in the present report stems mainly from direct clinical experience.

Low-dose Synachten test with measurement of salivary cortisol in adult patients with ß-thalassemia major.

PURPOSE: Beta-thalassemia major is a severe, congenital hematological disorder and, if untreated, leads to early mortality. Progress in therapeutical strategies improved clinical outcomes and life expectancy; however, increased survival led to the development of new disorders, including endocrinopathies. Little is known on the possible impairment of adrenocortical function, a potentially life-threatening condition, in long-term thalassaemic survivors. We therefore decided to assess adrenal reserve and the value of salivary cortisol during ACTH stimulation in the diagnosis of adrenocortical insufficiency in adult patients with ß-thalassemia major. METHODS: Cross-sectional study including 72 adults with ß-thalassemia major. Patients were tested with 1 µg ACTH for serum and salivary cortisol. RESULTS: Subnormal serum cortisol responses to ACTH stimulation (i.e., <500 nmol/l) were registered in 15 out of 72 patients. Salivary cortisol increased in parallel with serum cortisol and a clear-cut positive correlation was detected at each timepoint. Moreover, peak salivary cortisol values after ACTH stimulation were significantly lower in patients with impaired adrenal reserve (513.6 ± 52.33 vs. 914.1 ± 44.04 nmol/l p < 0.0001). CONCLUSIONS: Our results attest to the need for testing for adrenal insufficiency among adult thalassaemic patients, as up to 20% presented impaired adrenal reserve. Salivary and serum cortisol levels during stimulation with ACTH were closely correlated and the use of salivary cortisol sampling during ACTH testing may represent a surrogate to serum cortisol in these patients.

Clinical Complications and Their Management.

The hallmarks of thalassemias are ineffective erythropoiesis and peripheral hemolysis leading to a cascade of events responsible for several clinical complications. This pathophysiologic mechanism can be partially controlled by blood transfusions or by correction of the severity of ineffective erythropoiesis. Thalassemias include a spectrum of phenotypes. Two main groups can be clinically distinguished: transfusion-dependent (TDT) and non-transfusion-dependent (NTDT) thalassemia. Both conditions are characterized by several clinical complications along life; some are shared, whereas some have higher prevalence in one group over the other. The authors present the most common clinical complications in TDT and NTDT and their management.

Pulmonary dysfunction in thalassaemia major: is there any relationship with body iron stores?

Although pulmonary function abnormalities in thalassaemia major (TM) were described in 1980, the pathogenetic mechanism is not clear and data are contradictory, probably because of study heterogeneity and the multifactorial nature of the pathogenesis. We retrospectively analysed 73 adult TM patients to evaluate the prevalence of pulmonary dysfunction in adult TM and investigate relationships with iron load. All patients underwent body plethysmography and carbon monoxide diffusion (DLCO) was assessed in 63, in addition to blood tests, echocardiogram and T2* myocardial and liver magnetic resonance imaging. Restrictive lung disease was present in 26 (35·6%) patients. Serum ferritin levels were higher in patients with restrictive pattern (1526 µg/l vs. 975 µg/l, P = 0·05). Restrictive lung disease did not correlate with cardiac or liver iron overload. However, considering only patients with serum ferritin >2500 µg/l, those with restrictive pattern also had heart (T2* 14·28 ± 9·99 ms vs. 31·59 ± 7·43 ms) and liver iron overload (LIC 16·02 ± 8·44 mg vs. 5·02 ± 2·69 mg Fe/g dry weight) compared to those without restrictive pattern. Twenty-five patients (39·7%) had decreased DLCO. No correlation was observed with iron parameters. In our data restrictive pattern was predominant; we observed a relationship with serum ferritin levels suggesting that iron, particularly its chronic effect, could play a role in the pathogenesis of pulmonary disease.

Priapism, an emerging complication in ß-thalassemia intermedia patients.

The increase in survival rate of ß-thalassemia (ß-thal) patients allowed for the appearance and manifestation of several complications in almost every organ system. Priapism in ß-thal patients is rarely reported in the literature. We herein report and investigate the occurrence of two cases of priapism in two young patients with ß-thal intermedia (ß-TI). The potential mechanisms are due to either a cellular mechanism involving a thrombus obstructing the efferent venules of the corpora cavernosa leading to priapism, or a recently elucidated functional mechanism that causes alteration of nitric oxide (NO) response of the penis, ultimately causing priapism. This should incite clinicians for a close follow-up and monitoring of high risk patients who are susceptible to developing priapism.

The spectrum of ocular alterations in patients with ß-thalassemia syndromes suggests a pathology similar to pseudoxanthoma elasticum.

PURPOSE: To determine the prevalence and spectrum of ocular fundus abnormalities in patients with ß-thalassemia and to investigate risk factors for their development. DESIGN: Cross-sectional, observational study. PARTICIPANTS: A total of 255 patients with ß-thalassemia major (TM) and ß-thalassemia intermedia (TI) were consecutively recruited and investigated. METHODS: Patients underwent best correct visual acuity, indirect ophthalmoscopy, and fundus photography, including fundus autofluorescence (FAF) and near-infrared reflectance imaging using a confocal scanning laser ophthalmoscope (cSLO). Hematologic parameters were determined, including mean ferritin levels, aspartate amino transferase, alanine amino transferase, calcium, pre-transfusion hemoglobin, history of splenectomy, and liver iron concentration. Factors associated with the ocular phenotype were assessed using logistic regression. MAIN OUTCOME MEASURES: Ocular phenotype as determined by clinical examination and used multimodal imaging. RESULTS: A total of 153 patients (60.0%) affected by TM and 102 patients (40.0%) affected by TI participated, of whom 216 (84.7%) were receiving iron-chelating therapy. Ocular fundus abnormalities characteristic of pseudoxanthoma elasticum (PXE) were detected by cSLO in 70 of 255 patients (27.8%) and included peau d'orange (19.6%), angioid streaks (12.9%), pattern dystrophy-like changes (7.5%), and optic disc drusen (2.0%). Pseudoxanthoma elasticum-like changes were more frequent in patients with TI (P<0.001). Patients with PXE-like fundus changes were older than patients without these fundus changes (P<0.001). In both patients with TI and TM, age (P = 0.001) and splenectomy (P = 0.001) had the strongest association with presence of PXE-like fundus changes in multivariate analyses. A total of 43 of 255 patients (16.9%) showed increased retinal vascular tortuosity independently of the PXE-like fundus changes, which was associated with aspartate amino transferase (P = 0.036), hemoglobin (P = 0.008), and ferritin levels (P = 0.005). CONCLUSIONS: Pseudoxanthoma elasticum-like fundus changes are a frequent finding in patients with ß-thalassemia. In TI, these changes increase with duration or severity of the disease. This particular ocular phenotype suggests an ocular pathology similar to PXE. Retinal vascular tortuosity may be an additional disease manifestation independent of the PXE-like syndrome. Patients with long-standing disease requiring iron-chelating treatment and a history of splenectomy need regular ophthalmic checkups because they are at risk of developing PXE-like fundus changes and potentially of subsequent choroidal neovascularization.

Longitudinal changes in serum ferritin levels correlate with measures of hepatic stiffness in transfusion-independent patients with ß-thalassemia intermedia.

Despite evidence of considerable iron overload in transfusion-independent patients with ß-thalassemia intermedia, data on hepatic outcomes remain scarce. We analyzed data from a cohort of 42 ß-thalassemia intermedia adults followed for four years (median age 38years), and evaluated the association between longitudinal changes in serum ferritin levels and transient elastography values, a measure of hepatic stiffness predictive of fibrosis. We observed a significant increase in both serum ferritin levels (+81.2 [µg/l]/year) and transient elastography values in non-chelated patients (n=28) (+0.3kPa/year), with two patients worsening their fibrosis stage. Chelated patients (n=14) had a significant decrease in both measures (-42.0 [µg/l]/year and -0.9kPa/year, respectively), with two patients improving their fibrosis stage. There was a strong correlation between the rate of change in serum ferritin level and the rate of change in transient elastography value (R(2): 0.836, p<0.001) noted in both non-chelated and chelated patients. An association between iron overload status and hepatic disease merits further evaluation in this subset of transfusion-independent patients.

Endocrine and bone disease in appropriately treated adult patients with beta-thalassemia major.

With the optimization of transfusional and chelation regimens, beta-thalassemia has changed from a pediatric disease with poor life expectancy into a chronic disease. Bone demineralization is an important cause of morbidity in older patients; the etiology is multifactorial and partially unknown. We examined, cross-sectionally, 111 adult patients with beta-thalassemia major (66 females and 45 males, 32.6 ± 6 years) who were regularly transfused, sufficiently chelated and replaced for endocrine defects. Bone demineralization was detected in 92.7% of patients with different severity according to gender and site: osteopenia was the prominent finding at the femur, osteoporosis at the lumbar spine (p < 0.001), more evident in males. The femoral site was more influenced by biochemical and clinical factors; despite adequate replacement, the femoral T-score was lower in the hypogonadic group than in the eugonadic group (p = 0.047). A significant correlation was found between the bone mass and body mass index (BMI), alkaline phosphatase (ALP), and pre-transfusional Hb levels. The multivariate analysis indicated as significant regressors ALP, BMI and hypoparathyroidism (T-score, p = 0.005, 0.035, and 0.002; Z-score, 0.002, 0.009, and 0.003, respectively) at the femoral site; whereas, only ALP at the lumbar spine (p = 0.008 and 0.045 for T-and Z-scores, respectively). The statistical significance was reached more frequently by the T-score, while the Z-score seemed to be a less sensitive parameter. Despite best care facilities, bone demineralization in thalassemic patients remains a challenge. Further exploration of the relationships between bone loss and endocrine, biochemical and hematologic parameters is warranted to find effective measures to reduce the risk of fracture in this disease.

Pregnant women affected by thalassemia major: a controlled study of traits and personality.

BACKGROUND: The reproductive and sexual health issues concerning persons affected by thalassemia major are complex. The study was planned to investigate the psychological attitudes and expectations in a group of thalassemic pregnant women attending hospital for regular blood transfusion. METHODS: This is a preliminary cross-sectional study involving 20 consecutive thalassemic patients and a control group of 42 healthy pregnant volunteers. The personality structure was evaluated by Rorschach's test and the presence of psychic symptoms by SCL-90-R and STAI. RESULTS: Narcissism and sexual traumas are significantly higher in thalassemic women with respects to the control group. Also the percent of anxiety and depression observed with the SCL-90-R was significantly higher than in control group (45% vs. 3%, p < 0.001, mean and SD values are 1.65 ± 0.15 vs. 0.43 ± 0.18 for anxiety; 55% vs. 12%, p < 0.001, mean and SD values are 1.76 ± 0.18 vs. 0.85 ± 0.25 for depression). The score observed with the STAI shows that the trait of anxiety differed between thalassemic pregnant women and the control group, even though the score values aren't pathologic in neither group (87% vs. 42%, p < 0.05, mean and SD values are 33 ± 0.8 vs. 22 ± 0.2). CONCLUSIONS: This study addresses the need for developing, implementing and evaluating proper psychological support for thalassemic pregnant patients. Moreover, psychological screening and support prior to, during and following pregnancy would be indicated.

Hypercoagulability in splenectomized thalassemic patients detected by whole-blood thromboelastometry, but not by thrombin generation in platelet-poor plasma.

BACKGROUND: The mechanisms responsible for the increased thrombotic risk associated with thalassemia are still unclear. They might be related to the effects of red blood cell or endothelial cell derangements, increased numbers of platelets as well as abnormal plasma coagulation. DESIGN AND METHODS: To evaluate the relative role played by cells and plasma we investigated 169 patients with thalassemia by means of thromboelastometry and thrombin generation tests. Thromboelastometry measures indices of the viscoelastic properties of whole blood after activation of coagulation and is characterized by the clotting time, which may be considered as a conventional coagulation time, clot formation time, defined as the time needed for the clot to reach a fixed firmness, and the maximum clot firmness, defined as the maximal amplitude of the tracing. RESULTS: All the thromboelastometry parameters determined in whole blood (including shortened clotting time and clot formation time, and increased maximum clot firmness), were consistent with hypercoagulability, especially in splenectomized patients. Conversely, thrombin generation as determined in platelet-poor plasma was not. CONCLUSIONS: These findings point to blood cells and/or platelets rather than to plasma abnormalities as the most important determinants of the thrombotic risk observed in thalassemic patients who had been splenectomized. These results might have important diagnostic and therapeutic implications.

Coagulopathy in Beta-thalassemia: current understanding and future perspectives.

As the life expectancy of ß-thalassemia patients has markedly improved over the last decade, several new complications are being recognized. The presence of a high incidence of thromboembolic events, mainly in thalassemia intermedia patients, has led to the identification of a hypercoagulable state in thalassemia. In this review, the molecular and cellular mechanisms leading to hypercoagulability in thalassemia are highlighted, and the current clinical experience is summarized. Recommendations for thrombosis prophylaxis are also discussed.