scholarly journals A Prospective Randomized Multicenter Trial Using Either Deferiprone or Deferasirox after an Early Start of Deferiprone or Placebo in Young Children Newly Diagnosed with Transfusion-Dependent Beta-Thalassemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3071-3071
Author(s):  
Mohsen Saleh Elalfy ◽  
Amira Adly ◽  
Fatma Soliman Elsayed Ebeid ◽  
Amal El-Beshlawy ◽  
Neveen Salama ◽  
...  
Keyword(s):  
Young Children ◽  
Iron Overload ◽  
Growth Velocity ◽  
Chelation Therapy ◽  
Elevated Serum ◽  
Iron Chelation ◽  
Beta Thalassemia ◽  
P Value ◽  
Growth Enhancement ◽  
Early Start

Abstract Iron overload is a potentially preventable complication of blood transfusion dependency. The effectiveness and safety of early start of iron chelation therapy in young children with transfusion-dependent Beta-thalassemia (TDB-T) prior to development of iron overload have been recently demonstrated. The aim of this study was to evaluate the long term effectiveness and safety of continued iron chelation in these children. Methodology: This is a multi-center, investigator initiated, one year prospective randomized study of children with TDB-T who completed the randomized START study (NCT03591575), which had evaluated the safety and efficacy of the oral iron chelator (DFP) in children who did not yet meet the criteria for starting chelation therapy as per standard practice. Enrolment is shown in follow-up chart below; 48 children with TDBT from 3 centers were eligible to be enrolled and were randomized in 1:1 ratio to receive either DFP (n=23) or deferasirox (DFX) (n=25). Half of patients in this study were naïve to chelation (on placebo in START study); had received DFP at a dose; 75 mg/kg/ day or DFX in a dose; 20-25mg/kg/d in 2:1 ratio respectively, while those on DFP in START had continued on either DFP or DFX in 1:2 ratio with same doses. Patients were kept on regular transfusion to keep pre-transfusion Hb >8gm/dl. The primary endpoint was safety and secondary endpoints were changes in serum ferritin (SF) and growth enhancement (height, weight) both were assessed quarterly. An informed consent was signed by parents of all patients before start of the study. Statistical significance between DFP and DFX treated groups was calculated via t-test for continuous variables and Fisher's exact test for discrete variables. Results: In the current study; 66% of the children were males, at enrolment; their age ranged from 20-68 (median 38) months; those who were on DFP or placebo in START had received comparable transfusion units (median 11 and 9 respectively) and SF (880 and 1150 ng/ml respectively). At 12 month of continuation on iron chelation 22% and 60% of children on DFP vs 12% and 48% of those on DFX had SF<500 ng/ml or 500- <1000 ng/ml, respectively (p value <0.05);. TDB-T initiated and continued on DFP had the best growth velocity; all had annual growth velocity >5cm (p value <0.01), as well as a significant lower final SF (P value < 0.01). Adverse events were mild and uncommon in both groups. There were no episodes of arthralgia or agranulocytosis in either group. Elevated serum creatinine > 33% from baseline on 2 successive visits were observed in 0% in DFP vs. 12% in DFX. No unexpected, serious, or severe AEs were reported in both groups. Conclusion: Children with TDB-T whether on DFP or DFX showed uncommon mild AEs, with no serious or severe AEs. Patients on DFP after an early start of DFP showed adequate growth velocity and better control of iron-overload on serial measurement of SF; compared with those who were on placebo. Figure 1 Figure 1. Disclosures Hamdy: ApoPharma: Honoraria; Amgen: Honoraria; Bayer: Honoraria; Novartis: Honoraria; NovoNordisk: Honoraria; Roche: Honoraria; Takeda: Honoraria.

scholarly journals A Prospective Observational Multicenter Study on Deferiprone & Deferasirox in Clinical Practice of Pediatric Patients with Transfusion-Dependent B-Thalassemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 5044-5044
Author(s):  
Mohsen Saleh Elalfy ◽  
Amira Adly ◽  
Tamer Hassan ◽  
Mohamed Maebid ◽  
Rasha el Ashry ◽  
...  
Keyword(s):  
Young Children ◽  
Adverse Events ◽  
Serum Creatinine ◽  
Growth Velocity ◽  
Elevated Serum ◽  
Real Life ◽  
Iron Chelation ◽  
Liquid Solution ◽  
Published Data ◽  
Good Growth

Abstract Background: Iron overload is inevitable but a manageable complication of frequent blood transfusion, the effectiveness and safety of two iron chelation therapy in young children with transfusion-dependent B thalassemia (TDB-T) using either deferiprone (DFP) or deferasirox (DFX) were well studied in clinical trials. The primary objectives were; reporting efficacy and frequency of all adverse events (AEs) as compared with published data. Secondary objective was reporting deviation from guidelines, The analysis of clinical data is the first step to design new strategies Methodology: An investigator initiated 2-year multicenter prospective study enrolling over 6 months period; 302 children with TDB-T from 11 centers; keeping pre-transfusion Hb >8gm/dl. When serum ferritin (SF) reached around 1000 ng/ml; they had received according to availability; either DFP liquid solution in a dose; 75 mg/kg/day (n=62) or DFX (n=240); (dispersed tablet; 25% or film-coated tablet 75% in a dose; 20-25 mg/kg/d or its equivalent). CBC was done biweekly in DFP and pre-transfusion in DFX group. Liver transaminases, serum creatinine and (SF) were done /3 months. Changes in growth velocity over time were documented. Results: 66% were males, age at enrolment was; (11-19 and 14-26 months) in DFP and DFX respectively; they had received (6-8) and (7-11) transfusions prior to chelation in both groups respectively in addition to (16-21) during the study. 20% of patients did not achieve the target pre-transfusion Hb level. At initiation of DFP; SF median; 960 (IQR; 122 ng/ml) while those on DFX had SF; median 1070 (IQR 138 ng/ml) both groups had comparable transfusion iron input during the study. At 24 months of regular transfusion-chelation; SF < 1000 ng/ml was noticed in 65% and 60% of the patients respectively with good growth velocity in children using either chelator. Unnecessary over-dosing of DFX > 40 mg/kg was observed in 5%, meanwhile 3.2% had received DFP in a dose >75-100 mg/kg while SF was <1500 ng/ml. Under-reporting of adverse events in both groups was observed; 5% GIT upset, neither arthralgia nor agranulocytosis, neutropenia (3.2%) in DFP group and CBC was not checked biweekly; but only prior to transfusion. 4-5 % had elevated transaminases in both chelators, while patients on DFX reported; GIT upset in 4.2% and rash in 1.6%. Elevated serum creatinine > 33% from baseline on 2 successive visits was observed in 5% in DFX without reducing the dose or re-check. No unexpected, serious severe adverse events were reported in both groups. Poorly controlled patients with SF > 1500 ng /ml at 12 or 24 months were 12, 8% in DFP group; in contrast to 15%, 10% in DFX group respectively; with no statistical difference; (compliance was comparable). The total DFP and DFX discontinuation ratio was 5% in each group. Conclusion: infants and young children with TDB-T naïve to chelation were put on mono-therapy at younger age than reported before. Both chelators were effective, well tolerated and with no severe safety concerns; however deviation from guidelines was observed as; unnecessary over-dosing of DFX and under-reporting of AEs in both groups in real life practice. Disclosures Hamdy: ApoPharma: Honoraria; Amgen: Honoraria; Bayer: Honoraria; Novartis: Honoraria; NovoNordisk: Honoraria; Roche: Honoraria; Takeda: Honoraria.

Effective and Safe Deferasirox Treatment of Patients with Various anemia's and Transfusional Iron-Overload in the Medical Practice: Results From Two German Observational Studies

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5165-5165
Author(s):  
Christian Junghanss ◽  
Rudolf Schlag ◽  
Bernd Gaede ◽  
Matthias Moelle ◽  
Steffen Doerfel ◽  
...  
Keyword(s):  
Iron Overload ◽  
Serum Ferritin ◽  
Observational Studies ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Beta Thalassemia ◽  
Final Visit ◽  
Iron Chelation Therapy ◽  
The Mean

Abstract Abstract 5165 Background: Progressive anaemia is highly prevalent amongst many malignant diseases leading to RBC transfusion-dependency. Therefore transfusion-related iron overload (IOL) is common in these patients (pts) and can result in multiple organ failure. Iron chelation therapy prevents organ failure, reduces the risk of infections and can improve hematopoesis in some diseases. The once-daily oral iron chelator deferasirox has been shown to reduce iron overload in pts with various transfusion-dependent anaemias assessed by serum ferritin (SF). Despite extensive knowledge of iron chelation in MDS or beta-thalassemia pts, data in pts with other anaemias is limited. Here, we present data from a subgroup of transfusion-related IOL pts that were included two non-interventional studies (EXTEND, EXJANGE) performed in Germany and who suffered from diseases other than MDS or beta thalassemia. Methods: 130 pts with various malignant diseases such as myeloproliferative disorders (43 pts, including 31 pts particular specified as myelofibrosis), acute myeloid leukaemia (14 pts), sickle cell anaemia (6 pts), aplastic anaemia (11), congenital aplastic anaemia (5) or Non-Hodgkin's lymphoma (6 pts) were treated with deferasirox in the daily-routine setting of office-based physicians and included in either the EXTEND or EXJANGE study. Patient with MDS or beta-thalassemia were also included in the studies, but are excluded from this analysis. Analysis is based on 1-year pooled data of these two, multicenter, non-interventional observational studies. Transfusion-dependent pts with IOL with or without prior chelation were enrolled and received the iron chelator deferasirox. Prescription of deferasirox, just as inclusion and exclusion criteria was in accordance with the terms of Exjade marketing authorization in the EU. Efficacy and safety parameters, including serum ferritin and adverse events (AEs), were collected in 2-monthly intervals. Results: 98 pts had no prior chelation therapy (51 M, 45 F, 2 missing; mean age 63.3, range 3.2–91.9 yrs) and a median baseline SF of 2,968 (range 561–11, 423) ng/mL. 32 pts had prior received prior chelation therapy (mainly with desferal; 17 M, 15 F; mean age 50.1, range 3.5–80.9 yrs) and a median baseline SF of 2,635 (range 539–19, 540) ng/mL. The mean number of prior red blood cell transfusions was 55. The mean prescribed daily dose of deferasirox at the first visit was 16.3 mg/kg/d rising up to 18.1 mg/kg/d after 12 months. During treatment, median SF levels clearly decreased from first to final visit [-806 ng/mL; p<0.0001 (explorative analysis)] in the chelation-naïve and also in the pre-chelated population [-300 ng/ml; p = 0.1705 (explorative analysis)]. The median observation period and days on therapy was 349 and 343 days, respectively. At final visit 74 pts (56.9%) were still on deferasirox therapy. Reasons for discontinuation by the final visit included 19 AEs (35.2%). 45 pts (34.6%) experienced an investigator assessed drug-related AE. The most common drug-related AEs were diarrhea (n=17; 37.8%), nausea (n=11; 24.4%) and blood creatinine increased (n=6; 13.3%). As in previous clinical trials, serum creatinine clearances showed a minor decrease over the study period (median decrease until final visit: 4 ml/min). Conclusion: Our analysis confirmed that deferasirox is effective and well tolerated in chelation-naïve as well as in previously chelated pts with transfusion-related IOL and diseases other than MDS or beta thalassemia. As baseline serum ferritin values were >2,500 ng/mL even in pts with prior chelation therapy, adequate chelation treatment should be considered earlier at a serum ferritin >1,000 ng/mL in pts with transfusion-dependent IOL for adequate iron chelation therapy. Disclosures: Junghanss: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Haus:Novartis Pharma: Employment. Junkes:Novartis: Employment. Leismann:Novartis: Employment.

Supportive care and chelation therapy in MDS: are we saving lives or just lowering iron?

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 664-672 ◽  
Author(s):  
Heather A. Leitch ◽  
Linda M. Vickars
Keyword(s):  
Iron Overload ◽  
Supportive Care ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Left Ventricular ◽  
Left Ventricular Ejection ◽  
Beta Thalassemia ◽  
Ventricular Ejection Fraction ◽  
The Impact

AbstractThe myelodysplastic syndromes (MDS) are characterized by cytopenias and risk of transformation to acute myeloid leukemia (AML). Although new treatments are available, a mainstay in MDS remains supportive care, which aims to minimize the impact of cytopenias and transfusion of blood products. Red blood cell (RBC) transfusions place patients at risk of iron overload (IOL). In beta-thalassemia major (BTM), IOL from chronic RBC transfusions inevitably leads to organ dysfunction and death. With iron chelation therapy (ICT), survival in BTM improved from the second decade to near normal and correlated with ICT compliance. Effects of ICT in BTM include reversal of cardiac arrhythmias, improvement in left ventricular ejection fraction, arrest of hepatic fibrosis, and reduction of glucose intolerance.It is not clear whether these specific outcomes are applicable to MDS. Although retrospective, recent studies in MDS suggest an adverse effect of transfusion dependence and IOL on survival and AML transformation, and that lowering iron minimizes this impact. These data raise important points that warrant further study. ICT is potentially toxic and cumbersome, is costly, and in MDS patients should be initiated only after weighing potential risks against benefits until further data are available to better justify its use. Since most MDS patients eventually require RBC transfusions, the public health implications both of transfusion dependence and ICT in MDS are considerable. This paper summarizes the impact of cytopenias in MDS and treatment approaches to minimize their impact, with a focus on RBC transfusions and their complications, particularly with respect to iron overload.

scholarly journals PATTERN AND CLINICAL PROFILE OF PATIENTS WITH Β- THALASSEMIA IN REPEATED BLOOD TRANSFUSION

2020 ◽  
pp. 32-34
Author(s):  
Ashok Badakali ◽  
Deepti Shetty ◽  
Manohar MR
Keyword(s):  
Blood Transfusion ◽  
Iron Overload ◽  
Serum Calcium ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Serum Phosphate ◽  
Clinical Profile ◽  
Beta Thalassemia ◽  
Serum Phosphate Level ◽  
The Mean

Chronic transfusions inevitably lead to iron overload as humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. The combination of transfusion and chelation therapy has dramatically extended the life expectancy of thalassemia patients, but with complications like hypocalcaemia. Hence, present study was undertaken to determine pattern and clinical profile of patients with β- thalassemia who are receiving repeated blood transfusion Methods: Hospital based study conducted at S. Nijalingappa Medical College and Hanagal Shri Kumareshwar hospital, Bagalkot. The study period was one and half year from 2015 to 2016. 53 beta thalassemia major cases fulfilling inclusion criteria were investigated after an informed consent, for serum calcium, serum phosphorous, serum ALP and paratharmone levels. Result: Among 53 transfusion dependent children studied, the mean age is 5.249 years. The study consisted of 32 (60.4%) males and 21 (39.6%) females. Maximum number of cases i.e. 29 (54.7%) were diagnosed at the age of 4-6 months. 50 (94.3%) were on iron chelation therapy. The mean serum calcium is 8.28 + 0.89 mg/dl. The mean serum phosphate is 6.40 + 0.80mg/dl, mean PTH is 14.96 + 15.49ng/L. The mean value of serum phosphate level is 14.96 + 15.49 ng/L. The mean ALP is 166.789 U/L. Conclusion: To get better results, regular testing is needed to detect the complications of the early stages with proper treatment of the factors and complications. Therefore, should be monitored to avoid complication related to hypocalcemia.

scholarly journals Iron Chelation Therapy with Deferasirox Results in Improvement of Liver Enzyme Level in Patients with Iron Overload-Associated Liver Dysfunction

2010 ◽  
Vol 2010 ◽  
pp. 1-3 ◽  
Author(s):  
Yasuo Miura ◽  
Yusuke Matsui ◽  
Hitomi Kaneko ◽  
Mitsumasa Watanabe ◽  
Mitsuru Tsudo
Keyword(s):  
Iron Overload ◽  
Liver Dysfunction ◽  
Chelation Therapy ◽  
Enzyme Level ◽  
Elevated Serum ◽  
Iron Chelation ◽  
Iron Chelator ◽  
Similar Efficacy ◽  
Iron Chelation Therapy ◽  
Red Blood Cell Transfusions

Iron chelation therapy (ICT) has been applied for the patients with iron overload-associated liver dysfunction since it is one of the causes of death in patients with intractable hematological diseases requiring multiple red blood cell transfusions. Recently, deferasirox (DSX), a novel, once-daily oral iron chelator, was demonstrated to have similar efficacy to the conventional continuous infusion of deferoxamine on a decrease in serum ferritin (SF) level in heavily transfused patients. We show three cases of transfusion-mediated iron-overloaded patients with an elevated serum alanine aminotransaminase (ALT). All three patients who received the ICT with DSX showed a decrease in ALT level in association with a decrease in SF level. It is suggested that DSX therapy could be considered to expect the improvement of liver damage for iron-overloaded patients with an abnormal ALT level.

scholarly journals Some aspects of thyroid dysfunction in thalassemia major patients with severe iron overload

2011 ◽  
Vol 51 (2) ◽  
pp. 66
Author(s):  
Cynthia Rindang ◽  
Jose R. L. Batubara ◽  
Pustika Amalia ◽  
Hindra Satari
Keyword(s):  
Iron Overload ◽  
Chelation Therapy ◽  
Elevated Serum ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Primary Hypothyroidism ◽  
Iron Chelation Therapy ◽  
Free T4 ◽  
Cross Sectional ◽  
Female Ratio

Background Severe iron overload due to recurrent transfusions for chronic anemia and inadequate iron chelation therapy in thalassemia major patients result in various complications, including hypothyroidism. Currently, there has been no data on the prevalence of hypothyroidism in thalassemia major patients at the Thalassemia Centers, Department of Child Health, CiptoMangunkusumo Hospital (DCH CMH).Objective To study the prevalence of primary hypothyroidism in thalassemia major patients in the Thalassemia Center, DCH MCH.Methods We performed a cross-sectional, descriptive study. All thalassemia major subjects aged O􀁬18 years with severe iron overload underwent thyroid functionexamination. Primary hypothyroidism was defined as either normal (compensated) or decreased (decompensated) free T4 (FT4) levels, along with elevated sensitive thyroid􀁬stimulatinghonnone (TSH)levels. Results 179 subjects enrolled this study Mth male: female ratio of 1: 1.6. The prevalence of primary hypothyroidism in thalassemia majorpatients Mth severe iron overloadws26.8% (48/179). Of those 48,45 had compensated hypothyroidism and 3 had decompensated hypothyroidism, 25.1% and 1.7% of the total subjects, respectively. Compensated hypothyroidism was observed in 17 subjects aged ≤1O years and in 28 subjects aged> 10 years. All 3 decompensated hypothyroidism cases were> 10 years of age. No relationship was found between the occurrence of primary hypothyroidism and mean pre-tr811sfusion Hb levels (P=0.481, OR 1.30; 95% CI 0.63 to 2.68), elevated serum ferritin levels (P=0.74, OR 0.89; 95% CI 0.46 to 1.75), and compliance to iron chelation therapy (P=0.570, OR 0.76; 95% CI 035 to 1.65). Based on multivariate analysis, only age of <10 year-old (P=O.029, OR 0.469; 95% CI 0.23 to 0.93) was significantly associated Mth primary hypJthyroidism. Further analysis using receiver operator curve (ROC) technique found that age of 8.5 year-old was the cutoff value to predict the risk of hypothyroidism. Conclusion The prevalence of primary hypothyroidism in our study is high. The occurrence of hypothyroidism is associated with age.

scholarly journals Reduction of cardiac iron overload by optimising iron chelation therapy in transfusion dependent thalassaemia using cardiac T2* MRI: a quality improvement project from Pakistan

2020 ◽  
Vol 105 (11) ◽  
pp. 1041-1048
Author(s):  
Shabneez Hussain ◽  
Zahra Hoodbhoy ◽  
Fatima Ali ◽  
Erum Hasan ◽  
Najveen Alvi ◽  
...  
Keyword(s):  
Iron Overload ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Accurate Estimation ◽  
P Value ◽  
Improvement Project ◽  
Implementation Phase ◽  
Cardiac Morbidity ◽  
The Impact ◽  
T2 Mri

ObjectivesCardiac T2* MRI (T2*CMR), for accurate estimation of myocardial siderosis, was introduced as part of a QI collaborative to optimise chelation therapy in order to improve cardiac morbidity in transfusion dependent thalassaemia (TDT) patients. We report the impact of this QI initiative from two thalassaemia centres from this collaborative.Design and settingA key driver based quality initiative was implemented to improve chelation in TDT patients registered at these two centres in Karachi, Pakistan. Protocol optimisation and compliance to treatment through training, communication and feedback were used as the drivers for QI intervention. Preintervention variables (demographics, chelation history, T2*CMR, echocardiography and holters) were collected from January 2015 to December 2016) and compared with variables in the post implementation phase (January to December 2019). A standardised adverse event severity for chelators and its management was devised for safe drug therapy as well as ensuring compliance to the regimen. Preintervention and postintervention variables were compared using non-parametric test. P value<0.05 was statistically significant.Results100 patients with TDT, median age 17 (9–34) years, were included. An increase or stabilisation of T2*CMR was documented in 82% patients in the postintervention phase especially in patients with severe myocardial iron overload (5.5 vs 5.3 ms, p <0.01). Significantly fewer patients had abnormal echocardiographic findings (3.5% vs 26%, p <0.05) in the postintervention versus preintervention period.ConclusionThis QI initiative improved the chelation therapy leading to improved cardiac status in TDT patients at the participating centres.

scholarly journals Systemic Heme and Iron Overload Results in Depletion of Serum Hemopexin, Haptoglobin and Transferrin and Correlates with Markers of Endothelial Activation and Lipid Oxidation in Beta Thalassemia Major and Intermedia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2469-2469
Author(s):  
Francesca Vinchi ◽  
Gregory M Vercellotti ◽  
John D. Belcher ◽  
Eitan Fibach ◽  
Hala Zreid ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Iron Overload ◽  
Research Funding ◽  
Chelation Therapy ◽  
Iron Chelation ◽  
Thalassemia Major ◽  
Endothelial Activation ◽  
Beta Thalassemia ◽  
Iron Chelation Therapy ◽  
Cell Disease

Abstract Beta thalassemia is an inherited hemoglobinopathy due to reduced synthesis of Beta globin chains and, consequently, of hemoglobin A (a2b2). The clinical manifestations are mainly the result of chronic anemia and iron overload. The latter is due to increased iron absorption, induced by accelerated but ineffective erythropoiesis, and recurrent red blood cell transfusions. Alfa-chains and iron excess promote oxidative damage of red blood cell membrane, resulting in macrophage sequestration and extravascular hemolysis, and to a lower extent, in intravascular hemolysis, with consequent release of hemoglobin (Hb), heme and iron. Increasing evidence suggests that free heme exerts vasculotoxic, pro-inflammatory and procoagulant effects due to its ability to trigger endothelial and immune cells activation. In addition, a role for heme and iron has been postulated in the pathogenesis of other vascular diseases, including atherosclerosis. In mouse models of Beta thalassemia and sickle cell disease, circulating heme levels are elevated and correlate with the exhaustion of systemic scavengers for hemoglobin and heme, haptoglobin and hemopexin, respectively, as well as with severe endothelial dysfunction and inflammation. Hemopexin-based therapies significantly improve endothelial damage, vascular oxidative stress and inflammation in these mice (Vinchi et al., Circulation 2013, Blood 2016; Vercellotti GM. et al., Mol Med 2016). Whereas more data are reported on sickle patients in this regard, few data are available in patients with Beta thalassemia. In the present study, we examined serum samples from a cohort of 60 patients with Beta thalassemia major (age 11.5 ± 6.8, 44% males-56% females, Hb 7.69 ± 1.22 mg/dl, transfused every 3-4 weeks) and 7 patients with Beta thalassemia intermedia (age 14 ± 12 , 70% males-30% females, Hb 8.4 ± 0.74 mg/dl, transfused every 4-5 weeks). 10% of the patients received inconsistent iron chelation therapy. Serum from 10 healthy subjects (age 22.7±15.3, 50% males-50% females, Hb 13.12±1.15 mg/dl) served as control. Both groups of patients show high systemic heme and iron levels, which associate with a severe drop in serum haptoglobin, hemopexin and transferrin. Consistently, transferrin saturation (12.4±2 vs 79.6±24 %) and serum ferritin (55.14 ±0.23 vs 4919.2 ±2657.4 ng/ml) are elevated. Interestingly, these patients present with high systemic levels of the soluble adhesion molecules sVCAM-1 and sICAM-1, markers of enhanced endothelial activation. In addition, they show increased levels of serum malondialdehyde, a well-known marker of lipid peroxidation and oxidative stress, and high levels of circulating oxidized low density lipoproteins (oxLDL). All parameters significantly correlate with increased systemic heme and iron indices as well as decreased haptoglobin, hemopexin and transferrin levels. In conclusion, Beta thalassemia patients show a strong correlation between systemic heme and iron overload, depletion of the respective scavengers, and markers of oxidative stress and endothelial dysfunction, thus confirming studies in animal models. These results emphasize the involvement of serum hemoglobin, heme and iron in the pathophysiology of Beta thalassemia, including vascular dysfunction, and the key protective role of their carriers. These findings are relevant for disorders hallmarked by vasculopathy, such as sickle cell disease and Beta thalassemia, as well as cardiovascular diseases, such as atherosclerosis. Our data support the potential therapeutic benefit of the administration of hemoglobin/heme scavengers along with efficient iron chelation therapy to counteract heme- and iron-driven toxicity. (The last three authors equally contributed to the work) ****P<0.0001 Disclosures Vercellotti: CSL-Behring: Research Funding; Imara: Research Funding. Belcher:Cydan/Imara: Research Funding; CSL-Behring: Research Funding.

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