Suppression of Growth Differentiation Factor 15 Gene Expression by Curcumin in Patients with Beta-Thalassemia Intermedia.

BACKGROUND: ß-thalassemia is an inherited disorder caused by defects in the synthesis of the beta-globin chain. One of the significant clinical complications in ß-thalassemia intermedia is iron overload toxicity, which may be attributed to reduced levels of hepcidin. This reduction in hepcidin leads to increased absorption of iron in the intestines, ultimately resulting in iron overload. The objective of this study was to assess the impact of curcumin on the expression of growth differentiating factor-15 (GDF-15) and hepcidin genes in patients with beta-thalassemia intermedia. METHODS: This study was designed as a randomized controlled double-blind clinical trial. Prior to and after the intervention period with curcumin, a blood sample of 5 mL was collected from both the placebo and curcumin-treated groups for the assessment of hepcidin and growth differentiating factor-15 gene expression. RESULTS: This study revealed a significant reduction in the expression of growth differentiating factor-15 in the curcumin group compared to the placebo group during the 3-month treatment period. Furthermore, curcumin supplementation led to a remarkable 10.1-fold increase in the levels of hepcidin in the curcumin group compared to the placebo group. CONCLUSIONS: The results of this study show that curcumin administration increases the mRNA levels of hepcidin in whole blood of thalassemia intermedia patients and supports the idea that curcumin could be a potential treatment to reduce suppression of hepcidin in thalassemias and other iron-loading anemias. CONCLUSIONS: The results of this study show that curcumin administration increases the mRNA levels of hepcidin in whole blood of thalassemia intermedia patients and supports the idea that curcumin could be a potential treatment to reduce suppression of hepcidin in thalassemias and other iron-loading anemias.

Pro-haemostatic effect of DDAVP is partially derived through non-classical (CD14dim /CD16++ ) monocytes residing the spleen.

The splenic endothelial Weibel-palade bodies are one of the most important candidate organelles to release von Willebrand factor upon stimulation with desmopressin. However, the presence of functional desmopressin-specific receptor has not yet been demonstrated on endothelial cells. Experimental evidences are in favour of an indirect pro-haemostatic effect of desmopressin, but the exact mediator and its cellular origin are largely elusive. Here, we report partially hampered desmopressin response in a splenectomised severe haemophilia A/Beta Thalassemia patient without any genetic variant relevant to his incomplete desmopressin response. To further investigate the role of the spleen in this phenomenon, the release of VWF from desmopressin-treated human splenic endothelial cells was assessed in vitro. As a result, desmopressin induced the release of VWF from endothelial cells when the cells were co-cultured with non-classical (CD14dim /CD16++ ), but not other subtypes of monocytes or PBMCs. This in vitro study which resembles close proximity of endothelial cells of sinusoids to monocyte reservoir reside in parenchyma of subcapsular red pulp of the spleen sheds a light upon the role of this highly vascularized VWF-producing organ in driving indirect effect of desmopressin.

Development of a Thalassemia International Prognostic Scoring System (TIPSS).

A prognostic scoring system that can differentiate ß-thalassemia patients based on mortality risk is lacking. We analysed data from 3145 ß-thalassemia patients followed through a retrospective cohort design for the outcome of death. An a priori list of prognostic variables was collected. ß Coefficients from a multivariate cox regression model were used from a development dataset (n = 2516) to construct a formula for a Thalassemia International Prognostic Scoring System (TIPSS) which was subsequently applied to a validation dataset (n = 629). The median duration of observation was 10.0 years. The TIPSS score formula was constructed as exp (1.4 × heart disease + 0.9 × liver disease + 0.9 × diabetes + 0.9 × sepsis + 0.6 × alanine aminotransferase ≥42 IU/L + 0.6 × hemoglobin ≤9 g/dL + 0.4 × serum ferritin ≥1850 ng/mL). TIPSS score thresholds of greatest differentiation were assigned as <2.0 (low-risk), 2.0 to <5.0 (intermediate-risk), and ≥5.0 (high-risk). The TIPSS score was a good predictor for the outcome of death in the validation dataset (AUC: 0.722, 95%CI: 0.641-0.804) and survival was significantly different between patients in the three risk categories (P < 0.001). Compared to low-risk patients, the hazard ratio for death was 2.778 (95%CI: 1.335-5.780) in patients with intermediate-risk and 6.431 (95%CI: 3.151-13.128) in patients with high-risk. This study provides a novel tool to support mortality risk categorization for patients with ß-thalassemia that could help management and research decisions.

Thromboprophylaxis Outcome in Childhood SARS-CoV-2 Infection: A Single-Center Experience.

BACKGROUND: The SARS-CoV-2 infection has been associated with potentially endothelial damage and coagulation cascade activation that cause thrombosis. There is limited information on thrombosis and anticoagulant therapy in children with coronavirus disease 2019 (COVID-19). AIMS: This study evaluates the outcome of thromboprophylaxis in children younger than 18-year old with COVID-19 infection. METHODS: A retrospective study was conducted on 184 hospitalized pediatric patients with confirmed COVID-19 infection. A designed questionnaire was made to collect all demographic, clinical, and laboratory data. According to World Health Organization, the patients were classified as asymptomatic/mild, moderate, severe, and critically ill. RESULTS: The mean age of the patients was 7.04±5.9 (1 wk to younger than 18 y). Overall, 33 patients received anticoagulant therapy. All patients who passed away (n=19) belonged to the critical group. One patient (1.28%) was complicated with deep vein thrombosis despite taking thromboprophylaxis, and 1 (1.28%) with pulmonary thromboembolism while the patient did not take an anticoagulant. CONCLUSIONS: Our data showed a lower rate of thrombosis (1.4%) than adult patients with COVID-19. It may underline the role of anticoagulants in moderate to severe/critically ill children with COVID-19 infection. Expert opinion and personal experience are necessary, while we have a significant knowledge gap in understanding COVID-19-associated coagulopathy and thrombotic risk in children.

Risk Factors for the Occurrence of Asymptomatic Brain Lesions in Patients with ß-Thalassemia: a Systematic Review and Meta-Analysis.

BACKGROUND: Several factors, including increased platelet aggregation, decreased platelet survival, decreased antithrombotic factors cause a hypercoagulable state in thalassemia patients. This is the first meta-analysis designed to summarize the association of age, splenectomy, gender, and serum ferritin and hemoglobin levels with the occurrence of asymptomatic brain lesions in thalassemia patients using MRI. METHODS: This systematic review and meta-analysis was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) checklist. We searched four major databases and included eight articles for this review. The quality of the included studies was assessed based on the Newcastle-Ottawa Scale checklist. Meta-analysis was performed using STATA 13. Odds ratio (OR) and standardized mean difference (SMD) were considered as effect sizes for comparing the categorical and continuous variables, respectively. RESULTS: The pooled OR for splenectomy in patients with brain lesions compared to those without lesions was 2.25 (95% CI 1.22 - 4.17, p = 0.01). The pooled analysis for SMD of age between patients with/without brain lesions was statistically significant, 0.4 (95% CI 0.07 - 0.73, p = 0.017). The pooled OR for the occurrence of silent brain lesions was not statistically significant in males compared to females, 1.08 (95% CI 0.62 - 1.87, p = 0.784). The pooled SMD of Hb and serum ferritin in positive brain lesions compared to negatives were 0.01 (95% CI -0.28, 0.35, p = 0.939) and 0.03 (95% CI -0.28, 0.22, p = 0.817), respectively, which were not statistically significant. CONCLUSIONS: Older age and splenectomy are risk factors for developing asymptomatic brain lesions in ß-thalassemia patients. Physicians should consider a careful assessment of high-risk patients for starting prophylactic treatment.

An Expert Overview on Therapies in Non-Transfusion-Dependent Thalassemia: Classical to Cutting Edge in Treatment.

The thalassemia issue is a growing worldwide health concern that anticipates the number of patients suffering from the disease will soon increase significantly. Patients with ß-thalassemia intermedia (ß-TI) manifest mild to intermediate levels of anemia, which is a reason for it to be clinically located between thalassemia minor and ß-thalassemia major (ß-TM). Notably, the determination of the actual rate of ß-TI is more complicated than ß-TM. The leading cause of this illness could be partial repression of ß-globin protein production; accordingly, the rate of ß-globin gene repression is different in patients, and the gene repression intensity creates a different clinical status. This review article provides an overview of functional mechanisms, advantages, and disadvantages of the classic to latest new treatments for this group of patients, depending on the disease severity divided into the typical management strategies for patients with ß-TI such as fetal hemoglobin (Hb) induction, splenectomy, bone marrow transplantation (BMT), transfusion therapy, and herbal and chemical iron chelators. Recently, novel erythropoiesis-stimulating agents have been added. Novel strategies are subclassified into molecular and cellular interventions. Genome editing is one of the efficient molecular therapies for improving hemoglobinopathies, especially ß-TI. It encompasses high-fidelity DNA repair (HDR), base and prime editing, clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 procedure, nuclease-free strategies, and epigenetic modulation. In cellular interventions, we mentioned the approach pattern to improve erythropoiesis impairments in translational models and patients with ß-TI that involve activin II receptor traps, Janus-associated kinase 2 (JAK2) inhibitors, and iron metabolism regulation.

Survival and Mortality in Hospitalized Children with COVID-19: A Referral Center Experience in Yazd, Iran.

Introduction: COVID-19 prognostic risk factors, therapeutic protocols, and clinical outcomes in pediatric cases are still under investigation. Materials and Methods: This historical cohort study evaluated the survival time of hospitalized children (1 month-18 years old) with COVID-19 admitted from March 2020 to August 2021 to an educational hospital in Yazd, Iran. The follow-up of patients was performed at least one month after discharge. Results: From 183 hospitalized cases, 24 children were deceased. The median age of patients was 5.41, and 54.2% were male. The survival rate after one-month follow-up was 0.88, and the most significant predictors associated with survival time were the male sex, positive history of hospitalization, lymphopenia, hypoxia, and length of stay more than two weeks using Bayesian Cox regression analysis. Conclusion: Accurate estimation of the impact of predictors on poor outcomes may help healthcare providers use therapeutic protocols based on risk factors and healthcare requirements of each patient to improve their survival.

Which Groups of Children Are at More Risk of Fatality during COVID-19 Pandemic? A Case-Control Study in Yazd, Iran.

Introduction: The study aims to investigate the characteristics, comorbidities, laboratory findings, and clinical manifestations of under 18-year-old patients who died with the diagnosis of COVID-19 and determination of the most prevalent risk factors. Method: This case-control study was performed at a referral hospital in Yazd from March 2020 to August 2021. All patients under 18 years who were diagnosed through real-time RT-PCR, chest computed tomography, and the World Health Organization definition were divided into deceased and survived groups. The characteristics (age and sex), disease severity, comorbidities, laboratory findings, and clinical manifestations of the two groups were compared and analyzed using SPSS, version 18 (SPSS Inc., Chicago, III., USA). Results: A total of 24 patients in the deceased group and 167 patients in the survived group were compared. The highest mortality rate was observed in the age group of 1 month to 5 years, although no statistically significant relationship was found between age groups and the risk of mortality. Disease severity, dyspnea, low oxygen saturation on admission, length of hospital stays, and hospitalization history before the last admission were significantly correlated with mortality (P < 0.05). Lymphopenia increased the probability of mortality by more than two times (OR: 2.568; 95% CI (0.962-6.852)), but this was not the case for D-dimer and C-reactive protein. Furthermore, 27.5% of survived patients had normal chest CT scans, which was a statistically significant difference compared to the deceased patients (P: 0.031). Conclusion: Based on the findings of this study, dyspnea, low oxygen saturation, and lymphopenia are critical indicators for identifying high-risk children with COVID-19 and triaging them for better care and treatment.

Primary HBB gene mutation severity and long-term outcomes in a global cohort of ß-thalassaemia.

In ß-thalassaemia, the severity of inherited ß-globin gene mutations determines the severity of the clinical phenotype at presentation and subsequent transfusion requirements. However, data on associated long-term outcomes remain limited. We analysed data from 2109 ß-thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as ß0 /ß0 , ß0 /ß+ , ß+ /ß+ , ß0 /ß++ , ß+ /ß++ , and ß++ /ß++ . Patients were followed from birth until death or loss to follow-up. The median follow-up time was 34·1 years. Mortality and multiple morbidity outcomes were analyzed through five different stratification models of genotype severity groups. Interestingly, ß0 and ß+ mutations showed similar risk profiles. Upon adjustment for demographics and receipt of conventional therapy, patients with ß0 /ß0 , ß0 /ß+ , or ß+ /ß+ had a 2·104-increased risk of death [95% confidence interval (CI): 1·176-3·763, P = 0·011] and 2·956-increased odds of multiple morbidity (95% CI: 2·310-3·784, P < 0·001) compared to patients in lower genotype severity groups. Cumulative survival estimates by age 65 years were 36·8% for this subgroup compared with 90·2% for patients in lower genotype severity groups (P < 0·001). Our study identified mortality and morbidity risk estimates across various genotype severity groups in patients with ß-thalassaemia and suggests inclusion of both ß+ and ß0 mutations in strata of greatest severity.

The Effect of Curcumin on Iron Overload in Patients with Beta-Thalassemia Intermedia.

BACKGROUND: ß-thalassemia is an inherited disorder that stems from a defect in beta-globin chain synthesis. Iron overload toxicity is one of the major clinical complications in ß-thalassemia that may be due to a reduction in the hepcidin level. As a result, intestinal iron absorption increases and finally iron overload occurs. The current study aimed to investigate the effect of curcumin on serum iron status, ferritin, and transferrin in patients with ß-thalas-semia intermedia. METHODS: This study was a randomized, controlled, double-blind clinical trial. Before and after the intervention period with curcumin, 5 ml blood was taken for the measurement of the entire index related to iron status. RESULTS: Our results demonstrated the levels of serum iron (p-value < 0.001), ferritin (p-value = 0.002), and transferrin saturation (p-value < 0.001) significantly decreased in the curcumin group compared to placebo. CONCLUSIONS: The data presented in this article show that curcumin supplementation would be effective in alleviating iron overload in patients with ß-thalassemia intermedia.

Oncogenic and tumor suppressor genes expression in myeloproliferative neoplasms: The hidden side of a complex pathology.

BACKGROUND: The present study aimed to explore the changes in the expressions of six tumor-related genes in myeloproliferative neoplasms (MPNs). The study population included 130 patients with MPNs (52 with chronic myeloid leukemia (CML), 49 with essential thrombocythemia (ET), 20 with polycythemia vera (PV), and 9 with primary myelofibrosis (PMF)) and 51 healthy individuals. METHODS: The expression profiling of six genes (ADAMTS18, CMTM5, CDKN2B, DCC, FHIT, and WNT5B) in the peripheral blood granulocyte cells was explored by real-time quantitative reverse transcription polymerase chain reaction. RESULTS: The patients with MPNs showed significant downregulation of CMTM5 (EFC = 0.66) and DCC (EFC = 0.65) genes in contrast to a non-significant upregulation of ADAMTS18, CDKN2B, FHIT, and WNT5B genes. Downregulation of DCC was consistent in all subtypes of MPN (EFC range: 0.591-0.860). However, CMTM5 had a 1.22-fold upregulation in PMF in contrast to downregulation in other MPN subtypes (EFC range: 0.599-0.775). The results revealed a significant downregulation in CMTM5 and DCC at below 60-years of age. Furthermore, female patients showed a clear-cut downregulation in both CMTM5 and DCC (EFC DCC: 0.436 and CMTM5: 0.570), while male patients presented a less prominent downregulation with a borderline p-value only in DCC (EFC: 0.69; p = 0.05). CONCLUSIONS: Chronic myeloid leukemia cases showed a significant upregulation of WNT5B, as a known oncogenesis gene. Two tumor suppressor genes, namely DCC and CMTM5, were downregulated in the patients with MPNs, especially in females and patients below 60 years of age.

Clinical and genetic characteristics of hemoglobin H disease in Iran.

Hemoglobin H (Hb H) disease is a subtype of α-thalassemia caused by deletional and/or non-deletional mutations in three alpha-globin genes in which the various genotypes determine the disease severity. This study was aimed to investigate the frequency of alpha gene mutations and genotypes and their correlation with hematological and clinical characteristics in Iran. Among 202 patients diagnosed with Hb H disease through a national study in Iran according to standard methods, we had access to the hematologic and clinical findings and genetic data of 101 patients in whom genetic study was performed. Genomic DNA from peripheral blood was extracted and analyzed for identification of α-globin gene mutations using Multiplex Gap Polymerase Chain Reaction, Reverse Hybridization Assay, and finally Direct DNA Sequencing method. Twenty-one different mutations and thirty genotypes were detected in 101 patients with Hb H disease. In total, 39 patients (38.6%) were deletional and 62 patients (61.4%) were non-deletional type of the disease. The --MED mutation was highly prevalent in almost half of the patients (56.4%). Among various genotypes, -MED/-a3.7 (29.7%) and -α20.5/-α5NT (6.9%) were the most prevalent genotypes found in the studied group. Patients with non-deletional type presented with more severe hematological and clinical findings. Hb H percentage and serum ferritin levels were significantly higher in non-deletional patients in comparison to the deletional group (p < 0.05). 12 (11.9%) and 40 (39.6%) out of 101 patients were on regular and occasional transfusions, respectively. 83% of those with regular transfusion belonged to the non-deletional group. Among transfusion-dependent patients, -MED/αCSα and α20.5/-α5NT were the most common genotypes. In this study, two patients with -α20.5/αCSα and -MED/α-5NT genotypes experienced thrombotic events. This study indicated that although non-deletional genotypes of Hb H disease were responsible for more clinical severity of the disease, due to the presence of severe phenotypes even in deletional types, no definite correlation was found between genotype and phenotype.

Prediction of Heart and Liver Iron Overload in ß-Thalassemia Major Patients Using Machine Learning Methods.

Patients with ß-thalassemia major (ß-TM) face a wide range of complications as a result of excess iron in vital organs, including the heart and liver. Our aim was to find the best predictive machine learning (ML) model for assessing heart and liver iron overload in patients with ß-TM. Data from 624 ß-TM patients were entered into three ML models using random forest (RF), gradient boost model (GBM), and logistic regression (LR). The data were classified and analyzed by R software. Four evaluation metrics of predictive performance were measured: sensitivity, specificity, accuracy, and area under the curve (AUC), operating characteristic curve. For heart iron overload, the LR had the highest predictive performance based on AUC: 0.68 [95% CI (95% confidence interval): 0.60, 0.75]. The GBM also had the highest specificity (69.0%) and accuracy (67.0%). Most sensitivity is also acquired with LR (75.0%). For liver iron overload, the highest performance based on AUC was observed with RF, AUC: 0.68 (95% CI: 0.59, 0.76). The RF showed the highest accuracy (66.0%) and specificity (66.0%), while the LR had the highest sensitivity (84.0%). Ferritin, duration of transfusion, and age were determined as the most effective predictors of iron overload in both heart and liver. Logistic regression LR was determined to be the strongest method to predict cardiac and RF values for liver iron overload in patients with ß-TM. Older thalassemia patients with a high serum ferritin (SF) level and a longer duration of transfusion therapy were more prone to heart and liver iron overload.

A complication risk score to evaluate clinical severity of thalassaemia syndromes.

The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion-dependent thalassaemia (TDT)], Group B [transfused non-TDT (NTDT)] and Group C (non-transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left-ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients' treatment.

Long-term safety and efficacy of hydroxyurea in patients with non-transfusion-dependent ß-thalassemia: a comprehensive single-center experience.

Over the past 20 years, hydroxyurea (HU) has emerged as an effective therapeutic agent in thalassemic patients to improve anemia and decrease the transfusion dependency. We evaluated long-term safety and clinical response to HU in patients with non-transfusion-dependent ß-thalassemia (NTDT). In this retrospective study, medical records of 181 patients with NTDT were evaluated during October to December 2020 in Southern Iran. No requirement to blood transfusion was considered as sustained transfusion independence response. All patients were regularly examined and monitored for the occurrence of any adverse event (AE) of HU. The mean duration of HU consumption ± SD was 18.2 ± 4.0 (8-22) years. Overall, 149 patients (82.3%) had sustained transfusion independence response. ß-globin gene mutations and XmnI polymorphisms were not significantly associated with clinical response (P > 0.05). Mild and transient AEs were reported in 60 patients (33%) with no requirement to drug interruption. Hydroxyurea with the dose of 8-15 mg/kg can be used as a safe and effective treatment in NTDT patients. It was well tolerated in long term without any serious complication or secondary malignancy. No relationship between XmnI or ß-globin gene mutations with HU response was observed in this geographic area of the world.

Expression of the immune checkpoint receptors CTLA-4, LAG-3, and TIM-3 in ß-thalassemia major patients: correlation with alloantibody production and regulatory T cells (Tregs) phenotype.

Alloimmunization is a serious complication in ß-thalassemia major patients as a result of repeated blood transfusion. The immune checkpoint receptors play an important role in regulating immune system homeostasis and the function of the immune cells. This study aimed to evaluate the expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) immune checkpoint molecules in ß-thalassemia major patients with and without alloantibody. For this purpose, 68 ß-thalassemia major patients with (34 patients) and without (34 patients) alloantibody as well as 20 healthy controls were enrolled. The expression of these genes was evaluated in different groups of patients by SYBR Green real-time PCR method. Our results showed that the mean expression of LAG-3 was significantly increased in thalassemia patients compared to the control group (*P < 0.001). However, there was no significant difference in expression of the CTLA-4 and TIM-3 as well as LAG-3 genes between patients with and without alloantibody (P > 0.05). A positive correlation was observed between the level of LAG-3 expression with markers associated with Treg function including FOXP3 and GDF-15 genes in ß-thalassemia major patients. Taken together, the LAG-3 molecule might have a more prominent role in the abnormality of the immune system in thalassemia patients especially the function of regulatory T cells (Tregs), prior to the CTLA-4 and TIM-3 genes.

The effect of curcumin on serum copper, zinc, and zinc/copper ratio in patients with ß-thalassemia intermedia: a randomized double-blind clinical trial.

Thalassemia intermedia is a subgroup of ß-thalassemia which originates from mutations in the beta-globin gene. Zinc and copper play important roles in the metabolism. Due to its significant therapeutic effects, curcumin has led many studies to focus on curcumin. In a double-blind clinical trial study, 30 patients with beta-thalassemia intermedia with an age range of 20 to 35 years were randomly selected 1:1 to receive either curcumin or placebo for 3 months. Before and after the intervention period, 5 ml of blood was taken to determine the serum levels of zinc and copper. The laboratory tests were checked at baseline and at the end of the treatment. While the serum levels of zinc and zinc/copper significantly increased, the serum levels of copper decreased after 3 months of curcumin intake. In addition, on the basis of baseline characteristics, a negative correlation was found between zinc and body mass index and positive correlations were identified between copper with triglyceride and high-density lipoprotein. Also, the level of ferritin protein in the curcumin group compared to the placebo group showed a significant decrease after 3 months of curcumin use. Therefore, it could be concluded that curcumin might exert a net protective effect on copper toxicity in thalassemia intermedia patients. The investigation also implicated that curcumin represents an approach to regulating zinc homeostasis and may be useful as a complementary treatment of patients with thalassemia intermedia, especially in patients with zinc deficiency or low serum zinc/copper ratio. Clinical Trial Registration Number: IRCT20190902044668N1.

Effects of three months of treatment with vitamin E and N-acetyl cysteine on the oxidative balance in patients with transfusion-dependent ß-thalassemia.

Oxidative stress is a major mechanism contributing to the progression of ß-thalassemia. To assess the effect of vitamin E and N-acetyl cysteine (NAC) as antioxidant agents on total oxidative stress (TOS) status and total antioxidant capacity (TAC) in patients with transfusion-dependent ß-thalassemia (TDT). In this open-label randomized controlled trial, from May to August 2019, 78 eligible patients with TDT over the age of 18 were enrolled. All patients were registered at the Thalassemia Clinic of Shiraz University of Medical Sciences in Southern Iran. Patients were randomly allocated to the NAC group (10 mg/kg/day, orally), vitamin E group (10 U/kg/day, orally), and control group. The duration of the study was 3 months. The mean age of the participants was 28.5 ± 5.1 (range: 18-41) years. At the end of the study, TOS significantly decreased only in the vitamin E group (mean difference (MD), 95% confidence interval (CI): 0.27 (0.03-0.50), P = 0.026). TAC significantly decreased in both supplemented groups at the 3rd month of treatment (NAC group: MD (95% CI): 0.11 (0.04-0.18), P = 0.002 and vitamin E group: 0.09 (0.01-0.16), P = 0.022 respectively). Hemoglobin did not significantly change at the end of the study in each group (P > 0.05). Mild transient adverse events occurred in 4 patients of the NAC group and 5 patients of the vitamin E group with no need to discontinue the treatment. Vitamin E can be a safe and effective supplement in improving oxidative stress in patients with TDT. Moreover, it seems that a longer duration of using antioxidant supplements needs to make clinical hematologic improvement in TDT patients.

Performance of a clinical risk prediction model for inhibitor formation in severe haemophilia A.

BACKGROUND: There is a need to identify patients with haemophilia who have a very low or high risk of developing inhibitors. These patients could be candidates for personalized treatment strategies. AIMS: The aim of this study was to externally validate a previously published prediction model for inhibitor development and to develop a new prediction model that incorporates novel predictors. METHODS: The population consisted of 251 previously untreated or minimally treated patients with severe haemophilia A enrolled in the SIPPET study. The outcome was inhibitor formation. Model discrimination was measured using the C-statistic, and model calibration was assessed with a calibration plot. The new model was internally validated using bootstrap resampling. RESULTS: Firstly, the previously published prediction model was validated. It consisted of three variables: family history of inhibitor development, F8 gene mutation and intensity of first treatment with factor VIII (FVIII). The C-statistic was 0.53 (95% CI: 0.46-0.60), and calibration was limited. Furthermore, a new prediction model was developed that consisted of four predictors: F8 gene mutation, intensity of first treatment with FVIII, the presence of factor VIII non-neutralizing antibodies before treatment initiation and lastly FVIII product type (recombinant vs. plasma-derived). The C-statistic was 0.66 (95 CI: 0.57-0.75), and calibration was moderate. Using a model cut-off point of 10%, positive- and negative predictive values were 0.22 and 0.95, respectively. CONCLUSION: Performance of all prediction models was limited. However, the new model with all predictors may be useful for identifying a small number of patients with a low risk of inhibitor formation.

Sickle cell disease and COVID-19: Susceptibility and severity.

We surveyed published papers and an international sickle cell disease (SCD) registry to detect susceptibility and clinical course of coronavirus disease 2019 (COVID-19) in SCD patients. COVID-19 presentation was mild in children and moderate in many SCD adults. Regarding increased comorbidities with age, it seems severe COVID-19 to be more common in older SCD patients. Although the overall outcome of COVID-19 was favorable in SCD children, a high rate of pediatric intensive care unit admission should be considered in managing these patients. To explain COVID-19 outcome in SCD patients, the possible benefits of hydroxyurea therapy could be considered. The obtained results should be interpreted, considering low cases from sub-Saharan people, younger age of SCD patients compared to general population, a bias toward registry of the more severe form of disease, the effect of pre-existing comorbidities with multisystem organ damage, and the role of health socio-economic determinants.