Speckle tracking echocardiography and ß-thalassemia major. A systematic review.

Heart disease is among the primary causes of morbidity and mortality in ß-thalassemia major (ß-TM). Conventional echocardiography has failed to identify myocardial dysfunction at an early stage among these patients, thus speckle tracking echocardiography (STE) has been lately used. The objectives of this review were to 1) identify all published studies having evaluated myocardial strain among ß-TM patients, 2) gather their results, 3) compare their findings and 4) propose recommendations based on these data. Literature search was conducted in PubMed, SCOPUS and Cohrane Library. Data regarding left ventricular global longitudinal (LV-GLS), circumferential (LV-GCS) and radial strain (LV-GRS), right ventricular longitudinal strain (RV-GLS), left and right atrial strain were extracted. Thirty-five studies (34 original articles and 1 meta-analysis) have met the inclusion criteria. LV-GLS has been reported being worse in patients compared to controls in 13 of 21 studies, LV-GCS in 7 of 11 studies, LV-GRS in 6 of 7 studies, RV-GLS in 2 of 3 studies and left atrial strain in all case-control studies. Myocardial iron overload (MIO) patient subgroups had worse LV-GLS in 6 of 15 studies, LV-GCS in 2 of 7 studies and LV-GRS in none of 7 studies. A small number of studies suggest left atrial strain correlation with electrical atrial ectopy and atrial fibrillation. It is suggested that STE should be applied supplementary to conventional echocardiography for early identification of myocardial dysfunction among ß-TM patients. Potential myocardial strain utilities could be screening for myocardial iron overload, left ventricular diastolic dysfunction and atrial fibrillation.

Real-world complication burden and disease management paradigms in transfusion-related ß-thalassaemia in Greece: Results from ULYSSES, an epidemiological, multicentre, retrospective cross-sectional study.

Patients with transfusion-dependent beta (ß)-thalassaemia experience a broad range of complications. ULYSSES, an epidemiological, multicentre, retrospective cross-sectional study, aimed to assess the prevalence and severity of treatment and disease complications, capture disease management and identify predictors of complications in patients with transfusion-dependent ß-thalassaemia, treated in routine settings in Greece. Eligible patients were adults diagnosed with ß-thalassaemia ≥12 months before enrolment and having received ≥6 red blood cell (RBC) units (excluding elective surgery) with no transfusion-free period ≥35 days in the 24 weeks before enrolment. Primary data were collected at a single visit and through chart review. Between Oct 21, 2019, and Jun 15, 2020, 201 eligible patients [median (interquartile range, IQR) age 45.7 (40.2-50.5) years; 75.6% > 40 years old; 64.2% female] were enrolled, a mean (standard deviation) of 42.9 (7.8) years after diagnosis. Median (IQR) age at diagnosis and RBC transfusion initiation were 0.8 (0.4-2.8) and 1.3 (1.0-5.0) years, respectively. From diagnosis to enrolment, patients had developed a median of six (range: 1-55) complications; 19.6% were grade ≥3. The most represented complications were endocrine/metabolic/nutrition disorders (91.5%), surgical/medical procedures (67.7%) and blood/lymphatic system disorders (64.7%). Real-world data generated by ULYSSES underscore the substantial complication burden of transfusion-dependent ß-thalassaemia patients, routinely managed in Greece.

Predisposing factors for advanced liver fibrosis in patients with sickle cell disease.

Sickle cell disease (SCD) is one of the most common monogenic disorders worldwide and liver complications are common in this group of patients. Our study aims to highlight the prevalence of chronic liver complications and the main predisposing factors for advanced liver fibrosis in SCD patients. For this purpose, 219 patients from eight Thalassemia and Sickle Cell Units across Greece enrolled in our study and history of liver related disease complications was recorded, as well as a full laboratory and imaging analysis concerning their liver function. 13.6% of the patients had advanced liver fibrosis. The presence of liver fibrosis was significantly correlated with advanced age, male gender, cholelithiasis and higher LDH, γ-GT, INR, direct and indirect bilirubin levels. These patients had exhibited significantly more episodes of liver crises and acute intrahepatic cholestasis. No correlation was observed with right heart failure or previous viral hepatitis. Patients with advanced liver fibrosis were receiving a more intensive transfusion therapy for a longer period of time and had higher Liver Iron Concentration levels. Our study shows that liver complications and cirrhosis is a significant cause of morbidity in patients with SCD and it is primarily associated with intravascular hemolysis and vaso-occlusive phenomena and secondarily with iron overload.

Clinical significance of mutational variants in beta and alpha genes in patients with hemoglobinopathies from two large Greek centers: a complex interplay between genotype and phenotype.

Hemoglobinopathies affect patients in the wider Mediterranean area consisting of 4 distinct subgroups: beta thalassemia major (TM), beta thalassemia intermedia (TI), sickle cell disease (SCD) and hemoglobin H disease (alpha thalassemia). The clinical spectrum varies from mild to severe. Complex interactions between genes and environmental factors form the clinical manifestations. There is an unmet need to clarify these multifactorial mechanisms. This is the first Greek study describing mutational alleles (HBB and HBA1/HBA2 gene variants) in 217 patients with hemoglobinopathies of two large centers in Greece (Larissa and Athens) and associating particular genotypes or gene variants with clinical manifestations (transfusion frequency, complications). Thus, the complex interplay between corresponding genotypes and phenotypes was investigated. Our results are in accordance with previous national studies with limited variations, due to regional prevalence of specific gene variants, as expected. It is also a description of the prevalence of hemoglobinopathies in the Greek population. The type and prevalence of beta and alpha globin gene variants differ significantly among countries. We also confirm the well-known observation of many studies that in our beta thalassemic or SCD patients, co-inheritance of variants in the alpha globin genes, leading to absence or reduction of alpha globin synthesis were associated with milder clinical course, whereas the inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype. In cases in whom the genotype and phenotype did not correlate, factors like the function or modification of possible regulatory genes or additional nutritional-environmental effects should be investigated. KEY MESSAGES: • This is the first Greek study, fully molecularly defining the beta and alpha mutational alleles in 217 patients with hemoglobinopathies of two large centers in Greece and correlating particular genotypes or gene variants with clinical manifestations (transfusion frequency, complications). • In the beta thalassemic or SCD patients of our cohort, co-inheritance of variants in the alpha globin genes, leading to absence or reduction of alpha globin synthesis were associated with milder clinical course (confirmation of a well-known previous observation). • The inheritance of additional alpha genes (triplication) led to a more severe clinical phenotype (confirmation of a well known previous observation). • The function or modification of possible regulatory genes should be investigated in cases in whom the genotype and phenotype did not correlate.

Iron Chelators, Such as Deferasirox, When Combined With Hydroxyurea, Provide an Additional Benefit of Iron Chelation in Patients Receiving Chronic Transfusion Therapy.

Red blood cell (RBC) transfusions have been established as one of the primary therapies in treating sickle cell anemia. However, they are not free of side effects, with overloading the body with iron being one of the most important. Iron chelation therapy greatly reduces the iron load of the body. In addition, hydroxyurea (HU), an oral chemotherapeutic drug also has a significant role in the treatment of the disease with beneficial effects on many of the clinical problems that arise, mainly in reducing painful crises. The aim of this study was to investigate the effect of synergistic transfusion therapy and HU on the response to deferasirox (DFX) chelation therapy. Eighteen patients with sickle cell disease were divided into two groups based on their treatment, either with simple transfusions and DFX or with a combination of transfusion therapy, DFX and HU, and were evaluated with magnetic resonance imaging (MRI) for liver iron concentration (LIC) and biochemistry. All patients completed the study. The results of the study showed improvement in serum ferritin (FER) levels and LIC after 12 months of therapy in both groups, especially in the group receiving the combination therapy with HU. In addition, there was a noteworthy improvement in serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic pyruvic transaminase (SGPT) and lactate dehydrogenase (LDH) levels with serum creatinine (Cr) levels remaining stable during the study in both groups. Hydroxyurea, when combined with iron chelators such as DFX, provides an additional benefit of iron chelation in patients receiving chronic transfusion therapy.

Left atrial deformation indices in ß-thalassemia major patients.

The presence of atrial cardiomyopathy in ß-thalassemia major (ß-TM) patients complicates their clinical condition. The diagnosis is challenging even with cardiac magnetic resonance (CMR) imaging. Novel echocardiographic techniques are applied to increase the diagnostic yield. Fifty-six ß-TM patients and thirty age and sex-matched controls were included in the present cross-sectional study. Heart rate, PR duration, and P axis were measured by electrocardiography, left ventricular ejection fraction (LVEF) and end-diastolic diameter (LVEDD), ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e'), left atrial volume index (LAVI), left atrial strain at reservoir (LASr), conduit (LAScd) and contraction (LASct) phases respectively, left ventricular global longitudinal strain (GLS) by echocardiography, and T2* calculation in patient group by CMR. PR duration, LVEF, LAVI, E/e', GLS, and left atrial deformation parameters differed between patients and controls (p <0.05). In patient group, left atrial strain was correlated with PR duration, LAVI, E/e', GLS, and T2* (p <0.05). T2* was correlated only with left atrial deformation indices (p <0.05). Patients with a history of atrial fibrillation were older, had lower heart rate, prolonged PR, increased E/e' and LAVI, and impaired left atrial strain (p <0.05). LASct differed relative to the presence of atrial fibrillation and myocardial iron overload. Atrial strain could be of clinical use in the early detection of atrial cardiomyopathy. An impaired LASct could identify ß-TM patients with undetected episodes of atrial fibrillation. Finally, left atrial strain may be helpful in myocardial iron load estimation.

Acute Chest Syndrome in Sickle Cell Disease: Clinical Presentation and Outcomes. The Experience of a Single Thalassemia and Sickle Cell Unit in a University Hospital.

Acute chest syndrome (ACS) is a common cause of death for sickle cell disease patients. This syndrome is defined as: respiratory symptoms, new X-ray findings developed and/or fever; ACS requires prompt treatment to avoid clinical deterioration and death in adults with sickle cell disease. Sixteen episodes of acute chest syndrome were studied in 16 adults with sickle cell disease. The clinical and radiological findings, treatment, response and outcome of the episode were evaluated respectively. The patient's past history and comorbidities were taken into account in the outcome and days of hospitalization. Fourteen patients recovered with no sequelae; one patient who required mechanical ventilation also recovered; one patient died due to pulmonary emboli. The mean hospitalization days were 7.43.

Stroke and presence of patent foramen ovale in sickle cell disease.

Sickle cell disease (SCD) is an inherited monogenic hemoglobinopathy characterized by formation of sickle erythrocytes under conditions of deoxygenation. Sickle erythrocytes can lead to thrombus formation and vaso-occlusive episodes that may result in hemolytic anemia, pain crisis and multiple organ damage. Moreover, SCD is characterized by endothelial damage, increased inflammatory response, platelet activation and aggravation, and activation of both the intrinsic and the extrinsic coagulation pathways. Cerebrovascular events constitute an important clinical complication of SCD. Children with SCD have a 300-fold higher risk of acute stroke and by the age of 45 about 25% of patients have suffered an overt stoke. Management and prevention of stroke in patients with SCD is not well defined. Moreover, the presence of patent foramen ovale (PFO) increases the risk of the occurrence of an embolic cerebrovascular event. The role of PFO closure and antiplatelet or anticoagulation therapy has not been well investigated. Moreover, during COVID-19 pandemic and taking into account the increased rates of thrombotic events and the difficulties in blood transfusion, management of SCD patients is even more challenging and difficult, since data are scarce regarding stroke occurrence and management in this specific population in the COVID-19 era. This review focuses on pathophysiology of stroke in patients with SCD and possible treatment strategies in the presence of PFO.

Twelve-lead and signal-averaged electrocardiographic parameters among beta-thalassemia major patients.

BACKGROUND: The majority of beta thalassemia major (ß-TM) patients suffer from cardiac disease, while a significant proportion of them die suddenly. Twelve-lead and signal-averaged electrocardiography (SAECG) are simple, inexpensive, readily available tools for identifying an unfavorable arrhythmiological substrate by detecting the presence of arrhythmias, conduction abnormalities, and late potentials (LPs) in these patients. METHODS: A total of 47 ß-TM patients and 30 healthy controls were submitted to 12-lead and signal-averaged electrocardiography. Basic electrocardiographic parameters and prevalence of LPs were recorded. Basic echocardiographic parameters were estimated by transthoracic echocardiography. T2* was calculated by cardiac magnetic resonance imaging wherever available. RESULTS: ß-TM patients demonstrated a more prolonged PR interval (167.74 msec vs 147.07 msec) (P = .043), a higher prevalence of PR prolongation (21.05% vs 0%) (P = .013), and a higher prevalence of LPs (18/47, 38.3% vs 2/30, 6.7%) (P = .002) compared with controls. The prevalence of atrial fibrillation among b-TM patients was estimated at 10.64%. Patients had also greater E/e' ratio (8.35, SD = 2.2 vs 7, SD = 2.07) (P = .012) and LAVI (30.7 mL/m2, SD = 8.76 vs 24.6 mL/m2, SD = 6.57) (P = .002) than controls. Regression analysis showed that QTc and LAVI could correctly predict the presence of LPs in the 80.9% of the patients. CONCLUSIONS: ß-TM patients have a higher prevalence of a prolonged PR interval, atrial fibrillation, and LPs. Twelve-lead and SAECG performance was feasible in all subjects and constitutes a readily available tool for assessing myocardial electrophysiological alterations in this patient group.

Severity of heart failure and health-related quality of life in beta-thalassemia patients: a cross-sectional study.

Cardiovascular complications account for a substantial increase in morbidity and mortality in beta-thalassemia patients. Many patients have structural heart disease, and some of them present with symptomatic heart failure (HF). Quality of life (QOL) of beta-thalassemia patients is lower than that of the general population. The aim of our study was to explore the relationship between HF stages and QOL in beta-thalassemia patients. Seventy-three consecutive adult beta-thalassemia patients took part in this cross-sectional study. Stages of HF, classified with increasing severity as A, B, and C, were determined based on ACC/AHA guidelines. QOL was assessed using the SF-36 questionnaire. Fifteen patients had stage C HF, twenty-eight had stage B HF, and the remaining were considered stage A patients, as beta thalassemia is a predisposing factor for HF. All QOL domains except for bodily pain were significantly lower in stage C patients than in stage A patients. Stage C patients had significantly lower QOL scores for physical functioning, role physical, and social functioning domains than stage B patients. Stage B patients' QOL differed from stage A patients only in the vitality domain. In the multiple regression analysis which took several demographic and clinical factors into account, stage of HF was the most important factor associated with QOL, and negatively and significantly related to five QOL domains, namely physical functioning, role physical, general health, social functioning, and vitality. In conclusion, QOL is negatively affected by the severity of heart failure in beta-thalassemia patients.

Transient Elastography (TE) is a Useful Tool for Assessing the Response of Liver Iron Chelation in Sickle Cell Disease Patients.

Sickle cell disease patients often need regular blood transfusions to improve both the quality of life and survival from the veno-occlusive complications of the disease. Deferasirox, a convenient long acting oral agent, has recently been introduced in clinical practice with promising efficacy. This study aims to evaluate the association of liver stiffness and possible fibrosis with iron deposition and confirm the use of elastography as a validated test of responding to chelation with low cost and easy access. 15 patients with sickle cell disease and systemic or occasional transfusions were evaluated with MRI, transient elastography and biochemistry, for liver iron(LIC) and liver stiffness(LSM) before onset and one year after taking Deferasirox. All patients completed the study. Our results showed improvement in hepatic iron and hepatic stiffness after chelation therapy; Furthermore ALT, AST, LDH and ferritin levels have improved after 12 months of therapy with deferasirox. During the study no serious adverse events were encountered indicating the safety of the drug. Transient liver elastography findings correlate with serum ferritin and LIC in patients with sickle cell disease and it is a useful tool for assessing the response of liver iron chelation therapy.

Successful HLA-identical hematopoietic stem cell transplantation in a patient with purine nucleoside phosphorylase deficiency.

PNP deficiency is an autosomal recessive metabolic disorder characterized by severe combined immunodeficiency, autoimmune hemolytic anemia, and by a complex of neurologic manifestations including ataxia, developmental delay, and spasticity. PNP protein catalyzes the phosphorolysis of deoxyinosine and deoxyguanosine. It is found in most tissues of the body but is expressed at the highest levels in lymphoid tissues. This tissue distribution explains why the lymphoid system is predominantly affected in PNP deficiency. We describe a five-yr-old boy with muscular hypertonia, impaired growth, autoimmune hemolytic anemia, and neutropenia who underwent HSCT from his HLA-identical sister. One yr post-HSCT, the boy developed normal immunological functions, and his neurological status improved.