Correlation of plasma lipidomic profiles with cardiometabolic disease in transfusion-dependent thalassemia patients with six-month N-acetylcysteine intervention: A prospective cohort study.

Investigations into the Mechanisms and Clinical Implications of Modulation of Hepcidin Levels By Luspatercept in TD MDS and TD b-Thalassemia

Background: Transfusion dependent thalassemia (TDT) patients require regular blood transfusion and iron chelator therapy to maintain their life. Iron chelator may alter serum zinc and copper level in TDT patients.
 Objective: To observe serum zinc and copper and ferritin levels in transfusion dependent thalassemic patients treated with iron chelator.
 Method: The present cross sectional study was carried out in the department of Physiology, BSMMU, Dhaka between September 2017 to February 2019. Thirty cases of TDT, aged 5-40 year were included in the study group. Age and sex matched 30 healthy subjects were also studied as control. All the TDT patients were selected from the outpatient Department of Hematology and Transfusion Medicine, BSMMU, Dhaka. Serum zinc was measured by Spectrophotometric method and serum copper and ferritin levels were measured by colorimetric method. For statistical analysis independent sample t test was used.
 Result: The mean serum zinc level was significantly (p<0.05) lower and serum ferritin level was significantly (p<0.001) higher in TDT compared to control. Again, mean serum copper level and Zn/Cu ratio were not significantly (p>0.05) different in study groups compared to that of control. In addition, 3.3 % TDT patients had hypozincemia and 13.3% TDT patients had hypercupremia.
 Conclusion: This study may conclude that low serum zinc level and high copper level may be associated with TDT patients treated by combined deferoxamine (DFO) & deferiprone (DFP) iron chelator.
 J Bangladesh Soc Physiol. 2019, June; 14(1): 38-42

Background: Studies showed that transfusion dependent thalassemia (TDT) patients may develop premature atherosclerosis due to chronic hemolysis, iron deposition in blood vessels and dyslipidemia. Serum lipids abnormalities have been reported in TDT increasing the risk for premature atherosclerosis and other cardiovascular complications. Iron overload and oxidative stress are the main contributing factors to dyslipidemia in TDT patients. Few studies revealed that vitamin D is associated with favorable lipid profile in children and had relation to total cholesterol, low-density lipoproteins (LDL), high-density lipoprotein (HDL) level and triglyceride (TG) levels. However, its role in patients with TDT needs to be determined. Aim: To investigate the correlation between serum lipid profile and dyslipidemia with serum vitamin D level in TDT patients. Methods: This cross-sectional observational study conducted at Pediatric Hematology Unit, Cairo University Children Hospital included 50 children aged 3-18 years diagnosed with TDT and 30 apparently healthy unrelated age and sex matched children as a control group. Subjects were enrolled after obtaining willingly informed consents from parents. Vitamin D (25-OHD) level was measured using HPLC-UV method and 10-12 hour overnight fasting serum lipid profile including total cholesterol, HDL, LDL, and triglyceride (TG) were performed using automated chemistry analyzer Cobas C 311. Atherogenic index of plasma (AIP), an index composed of TG and HDL-C, was measured. Results: TDT patients had significantly lower cholesterol, HDL and LDL and higher TG levels compared to control group (p=0.00 for all parameters respectively). The median AIP was significantly higher in TDT patients compared to control group (0.36 vs -0.08 respectively with p=0.00). Vitamin D deficiency and insufficiency (defined as 25-OH D3 level less than 20 ng/ml and 20-29 ng/ml respectively) were evident in 20% and 24% of TDT patients respectively. Mean Vitamin D level among TDT patients was 33.91 ng/ml. Vitamin D had a statistically significant negative correlation with total cholesterol (r = -0.288, p = 0.010), LDL (r = -0.287, p = 0.010), and HDL (r = -0.280, p = 0.012) but had no significant correlation with TG (p = 0.379). Lower hemoglobin and hematocrit levels were associated with lower total cholesterol, LDL and HDL levels (p=0.00 for all parameters respectively) and with higher TG (p=0.00). No correlation was evident between serum ferritin level and any of lipid profile parameters. Conclusion: Serum lipid abnormalities in TDT patients includes hypocholesterolemia, decreased HDL, LDL and increased TG levels Measurement of serum lipid profile may help in early detection of cardiovascular complications such as premature atherosclerosis among these patients. AIP may serve as an additional indicator of dyslipidemia. Our results reinforce previous reports of vitamin D deficiency in TDT patients and demonstrate its correlation with dyslipidemia. Key words: Thalassemia- Dyslipidemia- Lipid profile- Vitamin D.

Present study was carried out to analyze quantitatively the blood parameters of Transfusion Dependent Thalassemia (TDT) patients. A total number of seventy one (n=71) TDT patients aged 04 to 26 years were selected from Fatimid foundation center, Hyderabad from June 2015 to May 2016 and eighty four (n=84) control subjects (age, gender and locality matched persons with negative personal and family history of thalassemia) were included in this study. Blood sample of 5mL was collected from each participant to analyze white blood cells (WBC); total leukocytes counts (TLC); red blood cells (RBC); mean corpuscular value (MCV); mean corpuscular hemoglobin (MCH); mean corpuscular hemoglobin concentration (MCHC); hemoglobin (HB) and hematocrit (HCT). All the patients and control subjects were interviewed through a standard questionnaire specially developed to study their life style and dietary habits. The collected data from TDT patients and control subjects was statistically analyzed by using p<0.05 as statistically significant variation between two groups. Results revealed significantly decreased levels of HCT, MCV, MCH and platelets in TDT patients as compared to control subjects. All TDT patients were frequentlyundergoing blood transfusion within the age groups.

Regular blood transfusions in transfusion-dependent thalassemia (TDT) patients can lead to iron overload, causing oxidative stress and sympathovagal imbalance, resulting in increased cardiac complications. We hypothesized that administrating of N-acetylcysteine (NAC) prevents serious adverse events including cardiac complications in TDT patients by reducing systemic oxidative stress and balancing cardiac sympathovagal control. This study was double-blind, randomized control trial, investigating in 59 Thai TDT patients. After randomization, the participants were divided into two groups. The control group received standard care of TDT patient plus placebo, whereas the intervention group received 600 mg of NAC orally for six months. Serum 8-isoprostane, TNF-alpha, IL-10, 24-hour ECG monitoring, echocardiograms and the incidence of thalassemia-related complications were collected. At baseline, no significant difference in any parameters between the control and the intervention groups. At the end of intervention, the incidence of serious adverse events (i.e. infection, worsening thalassemia) was significantly higher in the control group when compared with the intervention group (24.1% vs. 3.3%, p=0.019) (Chi-square test; absolute risk reduction=20.8%, number needed to treat=4.8). The control group also had significantly lower time-dependent HRV parameters, compared with the intervention group (p=0.025 and 0.030, independent t-test). Treatment with NAC restored HRV and reduced serious adverse event in TDT patients, however, no difference in cardiac complications could be demonstrated. NAC could prevent serious adverse events in TDT patients. The proposed mechanism might be the balancing of sympathovagal control.

PIH23 ECONOMIC BURDEN OF TRANSFUSION DEPENDENT THALASSAEMIA (TDT) PATIENT IN MALAYSIA: A SOCIETAL PERSPECTIVE

Madam, Thalassemia is an inherited blood disorder caused by ineffective erythropoiesis. Worldwide, it is among the most common genetic disorders. In Pakistan, around 5000 babies are born with this deadly disease every year.¹ Besides stem cell transplant the regular blood transfusion is the only treatment for thalassemia major. As one pint of blood contains 200-250 mg of iron, these transfusions ultimately lead to iron overload in the body. Consequently, excessive iron deposits in the internal organs such as the liver, heart, and endocrine organs.2 To forestall iron overload in TDT patients, ICT is mandatory. Currently, three drugs are recommended, deferoxamine, deferiprone, and deferasirox.3 Although these drugs are vital for iron excretion, it has been reported that 3-8 people out of 10 are non-compliant with these drugs.4 Besides social, economic, and behavioral factors, patient-related, medication-related, and socio-cultural barriers play vital roles in management through ICT. According to a survey conducted in Malaysia by Chong CC et.al, patients reported several factors affecting their compliance with ICT. Nescience, among patients regarding the application of intravenous chelators makes them reliant on paramedics. Furthermore, emotional stress due to this everlasting disorder drains them. Medication-related barriers include adverse drug reactions such as vomiting, burning skin sensation, dizziness and fear and discomfort among pediatric patients owing to intravenous infusing chelator. The poor doctor-patient relationship results in patient's negligence towards treatment.5 Poverty beingis a significant issue in Pakistan, has many negative impacts on the health system of its population, limiting access to medications. Considering the hazardous situation, effective approaches should be made on the national and personal levels. Enlightening patients to understand the treatment regimen and its advantages could be an integral approach. workshops, counseling sessions, and awareness campaigns must be put into place to educate the population. A social media approach will help provide the basic knowledge and preventive measures to the public. Government must ensure that patients are provided with essential medication and proper treatment. Actions including cost reduction of the medications, counseling session arrangements, and funding of TDT patients are required to reduce the burden of these patients. By adopting a multidisciplinary approach NGOs can play a vital role in fundraising and awareness through their drives and campaigns.

Implications of Low Zinc and Copper Levels As Well As Altered Iron Trafficking Proteins on Oxidant Stress in Patients with Transfusion Dependant Thalassemia

Background: The risk of heavy metal toxicity, including lead and cadmium, is high in individuals with diseases requiring multiple blood transfusions like thalassemia. Objectives: To evaluate blood lead levels and serum cadmium in transfusion-dependent thalassemia (TDT) patients and the impact of iron chelation therapy (ICT) on their levels. Materials and Methods: This case–control study involved 110 patients with TDT and 70 healthy individuals, their ages ranged from 4 to 37 years. Patients with TDT were subdivided into those on deferasirox (60 patients) and deferoxamine (50 patients). Blood samples were collected from all participants for complete blood counts of serum ferritin and iron. Serum cadmium and lead levels were estimated using an AA-7000 Atomic Absorption Spectrophotometer. Results: Mean hemoglobin level was significantly lower while serum iron and ferritin were significantly higher in TDT patients compared to the control group. Serum levels of lead and cadmium were not significantly different between healthy subjects and TDT patients, P &gt; 0.05. Serum lead and cadmium levels were also not significantly different between patients on different iron chelators, P &gt; 0.05. Pearson correlation did not reveal any significant correlation between lead (R* = 0.05 and 0.176) and cadmium (R* = -0.012 and -0.075) with each of serum iron and ferritin, respectively. Conclusions: Although serum levels of lead and cadmium were not significantly different between TDT patients and healthy individuals, the relatively high lead levels among studied participants need further studies to identify risk factors and to put an immediate action plan.

PurposeThere is a gap of information describing the health state utility values (HSUVs) of transfusion-dependent thalassemia (TDT) patients in Malaysia. These values are useful in the assessment of health-related quality of life (HRQoL), economic evaluations and provide guidance to disease management decisions. The objective of this study was to estimate and derive HSUVs associated with the treatment and complications of TDT patients in Malaysia using the EQ-5D-3L instrument.MethodsA cross-sectional survey using the EQ-5D-3L instrument was conducted between May to September 2018 across various public hospitals in Malaysia. Using a multi-stage sampling, patients diagnosed with TDT and receiving iron chelating therapy were sampled. The findings on the EQ-5D-3L survey were converted into utility values using local tariff values. A two-part model was used to examine and derive the HSUVs associated with the treatment and complications of iron overload in TDT.ResultsA total of 585 patients were surveyed. The unadjusted mean (SD) EQ-5D-3L utility value for TDT patients were 0.893 (0.167) while mean (SD) EQ VAS score was 81.22 (16.92). Patients who had more than two iron overload complications had a significant decline in HRQoL. Patients who were on oral monotherapy had a higher utility value of 0.9180 compared to other regimen combinations.ConclusionLower EQ-5D-3L utility values were associated with patients who developed iron overload complications and were on multiple iron chelating agents. Emphasizing compliance to iron chelating therapy to prevent the development of complications is crucial in the effort to preserve the HRQoL of TDT patients.

Evidence That Platelets from Transfusion-Dependent Thalassemia Patients Induce T Cell Activation

Background Growth impairment is a serious concern in Transfusion dependent thalassemia (TDT) patients. Decreased height/length in these patients is a result of multiple factors such as nutrition, recurrent infections, iron overload, chronic anemia, multiple vitamin and mineral deficiency. Zinc is one such micronutrient which is deficient in TDT patients and has a role in enhancing growth. Objectives To determine the effect of oral zinc supplementation on linear growth of transfusion dependent thalassemia patients. To study the immuno-modulator role of zinc in respiratory infections and the adverse effects of zinc. Methods Forty TDT patients whose heights were &lt; 50th centile were randomly divided into two groups, each group consisted of 20 patients: Group I received oral zinc sulphate (40 mg per day) and Group II served as control group and received placebo (lactose) supplementation. Patients were followed for 12 months and mean of height and frequency of respiratory infections was compared in both the groups at the end of 12 months. Adverse effects of zinc were studied in Group1. Results TDT patients who had their height/length below 3rd centile and between 3rd and 50th centile were 32.5% and 67.5% respectively No statistically significant difference in height was noted between the two groups. There was no statistically significant difference in frequency of respiratory infections in both the groups (P = 1.00). Most common adverse effects of zinc reported was metallic/distortion of taste followed by nausea/vomiting and abdominal discomfort, while mouth sores was the least common adverse effect. Conclusion Oral Zinc supplementation had no effect on linear growth and in prevention of respiratory infections in TDT patients.

Transfusion-dependent thalassemia (TDT) patients require regular blood transfusions. The unavoidable consequence is iron overload. Iron chelation therapy is the mainstay of treatment, of which the favorable outcome depends mainly on adherence level. The aim of this study was to assess adherence to iron chelation therapy of TDT patients. A cross-sectional cohort of TDT patients were evaluated on their adherence to chelation therapy using the Thai version of Morisky Medication Adherence Scales (MMAS-8). A total of 70 patients (38 males, 32 females), with a median age of 10 years, were enrolled in the study. Sixteen patients (22.9%) and 54 patients (77.1%) were classified as high and medium-low adherence level groups. The raised serum ferritin value for 6 months previous to enrollment in the high adherence level group is lower than the medium-low adherence level group (276.4 vs. 413.0 ng/mL, p = 0.034, respectively). Factors impacted high adherence to iron chelation including younger age (p = 0.015) and deferasirox (DFX) administration (p = 0.025). The body weight and height in both groups were not statistically different. The most common obstacle to adherence was forgetfulness. The Thai version of MMAS-8 is a practical tool for evaluating adherence to chelation therapy in TDT patients. High adherence level of patients correlates with more controlled serum ferritin level. The younger age and once-daily dose chelation therapy are associated with better adherence.

Iron Chelation and Ferritin below 500 Mcg/L in Transfusion Dependent Thalassemia: Beyond the Limits of Clinical Trials

BACKGROUND: Although frequently diagnosed in our region, transfusion-dependent thalassemia (TDT) often remains a poorly managed disease. This is due to a lack of awareness of the long-term effect of iron overload among thalassemic patients. This study aimed to examine the unmet needs of TDT patients and provide insight into achieving better care. METHODS: We conducted a cross-sectional study of 50 caregivers of heavily transfused thalassemia and sickle cell anemia (SCA) patients. The participants were recruited during their visit to the pediatric hematology clinic or daycare unit between September 2018 and May 2019. The researchers administered a questionnaire to assess the awareness of iron overload and compliance with its management in TDT and SCA. RESULTS: Most participant caregivers of children with TDT and SCA had a low level of awareness about the most critical complication of TDT and SCA, which is iron overload. Furthermore, two-thirds of the participants did not appreciate the seriousness of iron overload nor its potential complications. Moreover, the participants reported that their health-care providers rarely or occasionally discuss iron overload or its management. Furthermore, they reported that compliance with health-care appointments and iron chelation therapy was suboptimal. CONCLUSION: Caregivers of TDT and SCA patients reported a low level of knowledge of the magnitude of iron overload, its management, and expected complications if not treated appropriately. Health education on iron overload is critical to ensure appropriate compliance and consequently, control of such disease. The focus must be shifted from giving blood to eliminating excess iron among TDT patients.