Publications by authors named "Efthymia Vlachaki"

54 Publications

Total Annual Economic Burden of Patients with Sickle Cell Disease in Steady State in Greece.

Hemoglobin 2021 May 2;45(3):143-149. Epub 2021 Aug 2.

Faculty of Health Sciences, Department of Pharmacology, Medical School, Aristotle University of Medical Sciences Thessaloniki, Thessaloniki, Greece.

Sickle cell disease includes a group of congenital hemolytic anemias, all characterized by the predominance of Hb S (: c.20A>T). The population movement due to economic migration or escape from conflict zones will further affect the health systems of countries by either increasing the number of patients or forcing countries to create care units for sickle cell disease patients. This will probably also increase the incidence of the disease in areas where their incidence and prevalence were previously low. In the present study, an attempt has been made to estimate the total annual cost of the treatment of sickle cell disease in Greece. This was the first attempt to calculate the total annual cost of treating sickle cell disease patients in a steady state. The annual cost of sickle cell disease was estimated to be €21,152,340.00 (US$25,219,300.41), without calculating the cost of hospitalization for severe complications. Since 2013, in Greece, a pharmaceutical expenditure limit (decreasing with the years) has been budgeted at €1,945,000,000.00 (US$2,318,965,150.00), annually. It is therefore calculated that approximately 1.0% of the budget allocated to pharmaceutical spending is used to treat patients with sickle cell disease.
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http://dx.doi.org/10.1080/03630269.2021.1954944DOI Listing
May 2021

PTD-mediated delivery of α-globin chain into Κ-562 erythroleukemia cells and α-thalassemic (HBH) patients' RBCs ex vivo in the frame of Protein Replacement Therapy.

J Biol Res (Thessalon) 2021 Jul 20;28(1):16. Epub 2021 Jul 20.

Laboratory of Pharmacology, Department of Pharmacognosy - Pharmacology, School of Pharmacy, Faculty of Health Sciences, Aristotle University of Thessaloniki, 54124, Thessaloniki, Macedonia, Greece.

Background: α-Thalassemia, a congenital hemoglobinopathy, is characterized by deficiency and/or reduced levels of α-globin chains in serious forms of α-thalassemia (HbH disease/Hb Bart's). This research work deals with a Protein Replacement Therapy approach in order to manage α-thalassemia manifestations, caused by the excess of β-globin chain into HbH RBCs. The main goal was to produce the recombinant human α-globin chain in fusion with TAT, a Protein Transduction Domain, to ex vivo deliver it into HbH patients RBCs, to replace the endogenous missing α-globin chain.

Results: Cloning of the α-globin coding sequence, fused to the nucleotide sequence of TAT peptide was conducted and the human recombinant fusion proteins, 10xHis-Xa-α-globin-HA and 10xHis-Xa-TAT-α-globin-HA were produced. The ability of human recombinant 10xHis-Xa-α-globin-HA to interact in vitro with the previously produced 10xHis-Xa-TAT-β-globin-HA and form α-/β-globin heterodimers, was assessed and confirmed by size exclusion chromatography. The recombinant 10xHis-Xa-TAT-α-globin-HA was successfully delivered into human proerythroid K-562 cells, during the preliminary transduction evaluation experiments. Finally, the recombinant, TAT-fused α-globin was successfully transduced into RBCs, derived from HbH patients and reduced the formation of HbH-Inclusion Bodies, known to contain harmful β-globin chain tetramers.

Conclusions: Our data confirm the successful ex vivo transduction of recombinant α-globin chains in HbH RBCs to replace the missing a-globin chain and reduce the HbH-inclusion bodies, seen in α-thalassemias. These findings broaden the possibility of applying a Protein Replacement Therapy approach to module sever forms of α-thalassemia, using recombinant α-globin chains, through PTD technology.
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http://dx.doi.org/10.1186/s40709-021-00148-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290593PMC
July 2021

Complement in Sickle Cell Disease: Are We Ready for Prime Time?

J Blood Med 2021 23;12:177-187. Epub 2021 Mar 23.

Adults Thalassemia Unit, 2nd Department of Internal Medicine, Hippokration Hospital, Thessaloniki, Greece.

Sickle cell disease (SCD) is a widely spread inherited hemoglobinopathy that includes a group of congenital hemolytic anemias, all characterized by the predominance of sickle hemoglobin (HbS). Its features are anemia, predisposal to bacterial infections and complications such as vaso-occlusive crisis (VOC) or delayed hemolytic transfusion reaction (DHTR), which lead to increased rate of morbidity and mortality even in the era of hydroxyurea. The interaction between sickle cells, neutrophils, platelets or endothelial cells in small vessels results in hemolysis and has been considered the disease's main pathophysiological mechanism. Complement activation has been reported in small cohorts of SCD patients, but the governing mechanism has not been fully elucidated. This will be important to predict the patient group that would benefit from complement inhibition. Until now, eculizumab-mediated complement inhibition has shown beneficial effects in DHTR, with limited reports in patients with VOC. In the meantime, several innovative agents are under clinical development Our state-of-the-art review summarizes current data on 1) complement activation in SCD both in steady state and crisis, 2) underlying mechanisms of complement over-activation for the clinician in the context of SCD, 3) actions of hydroxyurea and new therapeutic approaches including indirect involvement in complement activation, and 4) novel paradigms in complement inhibition.
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http://dx.doi.org/10.2147/JBM.S287301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001680PMC
March 2021

Prediction of long-term survival in patients with transfusion-dependent hemoglobinopathies: Insights from cardiac imaging and ferritin.

Hellenic J Cardiol 2021 Jan 29. Epub 2021 Jan 29.

1st Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.

Aims: The current study evaluated the association of echocardiography, cardiac magnetic resonance (CMR), and ferritin data with 10-year survival in thalassemia patients.

Methods: Demographics, ferritin, echocardiography, and CMR parameters of stable consecutive thalassemia patients were prospectively collected.

Results: In total, 75 patients (mean age 37 ± 11 years, 45% male) with thalassemia were included and dichotomized based on their survival status after a median follow-up period of 10.3 [9.6-10.9] years. Older age (HR: 1.071, p = 0.001), ferritin ≥2000 ng/ml (HR: 4.682, p = 0.007) and ≥1700 ng/ml (HR: 7.817, p = 0.002), elevated LV end-diastolic pressure (HR: 1.019, p = 0.044), TR Vmax >2.8 m/s (HR: 6.845, p = 0.005), and CMR T2∗ ≤20 msec (HR: 3.602, p = 0.043) and ≤34 msec (HR: 5.854, p = 0.026) were associated with increased all-cause mortality (primary endpoint). A baseline model including age was created and became more predictive of worse survival by adding TR Vmax >2.8 m/s instead of elevated LV end-diastolic pressure (C index 0.767 vs. 0.760, respectively), ferritin ≥1700 ng/ml instead of ≥2000 ng/ml (C index 0.890 vs. 0.807, respectively), or CMR T2∗≤34 msec instead of ≤20 msec (C index 0.845 vs. 0.839, respectively). Parameters associated with the combined endpoint of cardiac mortality/cardiac hospitalization (secondary endpoint) after adjusting for age were ferritin ≥1700 ng/ml (HR 3.770, p = 0.014), ratio E/A wave >2 (HR 3.565, p = 0.04), TR Vmax >2.8 m/s (HR 4.541, p = 0.049), CMR T2∗ ≤20 ms (HR 9.462, p = 0.001), and CMR T2∗ ≤34 ms (HR 11.735, p = 0.002). The model including age and T2∗ ≤34 ms instead of T2∗ ≤20 ms was more predictive of the secondary endpoint (C-index 0.844 vs 0.838, respectively).

Conclusions: In thalassemia patients, TR Vmax >2.8 m/s, ferritin ≥2000 ng/ml, and CMR T2∗ ≤20 ms were associated with worse long-term survival. In the current era of advanced chelation therapy, aiming for ferritin ≤1700 ng/ml and CMR T2∗ ≥34 ms may improve their prognosis.
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http://dx.doi.org/10.1016/j.hjc.2021.01.010DOI Listing
January 2021

Complement in sickle cell disease and targeted therapy: I know one thing, that I know nothing.

Blood Rev 2021 07 21;48:100805. Epub 2021 Jan 21.

Adults Thalassemia Unit, 2nd Department of Internal Medicine, Hippokration Hospital, Thessaloniki, Greece.

Sickle cell disease (SCD) is a common inherited clinical syndrome, characterized by the presence of hemoglobin S. Anemia, susceptibility to infections and episodes of vaso-occlusive crisis (VOC) are among its features. Since SCD complications (VOC or delayed hemolytic transfusion reaction/DHTR) lead to significant morbidity and mortality, a number of studies have addressed their pathophysiology Although SCD pathophysiology has been mainly attributed to the interaction between sickle cells and neutrophils, platelets or endothelial cells in small vessels leading to hemolysis, the role of complement activation has been increasingly investigated. Importantly, complement inhibition with eculizumab has shown beneficial effects in DHTR. Given the unmet clinical need of novel therapeutics in SCD, our review summarizes current understanding of (a) complement system for the clinician, (b) complement activation in SCD both in asymptomatic state and severe clinical manifestations, (c) probable underlying mechanisms of complement activation in SCD, and (d) new therapeutic perspective of complement inhibition.
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http://dx.doi.org/10.1016/j.blre.2021.100805DOI Listing
July 2021

Left Atrial Strain Identifies Increased Atrial Ectopy in Patients with Beta-Thalassemia Major.

Diagnostics (Basel) 2020 Dec 22;11(1). Epub 2020 Dec 22.

1st Cardiology Department, AHEPA Hospital, Aristotle University of Thessaloniki, Stilponos Kyriakidi 1, 54621 Thessaloniki, Greece.

Patients with beta-thalassemia major (β-ΤΜ) may develop cardiac arrhythmias through a multifactorial mechanism. The current study evaluated the association of cardiac structure and function on echocardiography with atrial ectopic burden on 24-hour tape recording in β-ΤΜ patients. This prospective study included consecutive β-ΤΜ patients. Demographic, laboratory, echocardiographic, cardiac magnetic resonance (CMR) T2* and 24-hour tape recording data were prospectively collected. The patients were classified according to the median value of premature atrial contractions (PACs) on 24-hour tape. In total, 50 β-TM patients (37.6 ± 9.1 years old, 50% male) were divided in 2 groups; PACs ≤ 24/day and > 24/day. Patients with PACs > 24/day were treated with blood transfusion for a longer period of time (39.0 ± 8.6 vs. 32.0 ± 8.9 years, < 0.007), compared to their counterparts. Older age (OR: 1.121, 95% CI: 1.032-1.217, = 0.007), longer duration of blood transfusion (OR:1.101, 95% CI:1.019-1.188, = 0.014), larger LV end-diastolic diameter (OR: 4.522, 95% CI:1.009-20.280, = 0.049), higher values of LA peak systolic strain (OR: 0.869, 95% CI: 0.783-0.964, = 0.008), higher MV E/E' average (OR: 1.407, 95% CI: 1.028-1.926, = 0.033) and higher right ventricular systolic pressure (OR: 1.147, 95% CI: 1.039-1.266, = 0.006) were univariably associated with PACs > 24/day. LA peak systolic strain remained significantly associated with PACs > 24/day after adjusting for the duration of blood transfusions or for CMR T2*. The multivariable model including blood transfusion duration and LA peak systolic strain was the most closely associated with PACs > 24/day. Receiver operating characteristic curve analysis identified a left atrial peak systolic strain of 31.5%, as the best cut-off value (83% sensitivity, 68% specificity) for prediction of PACs > 24/day. In β-TM patients, LA peak systolic strain was associated with the atrial arrhythmia burden independently to the duration of blood transfusions and CMR T2*.
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http://dx.doi.org/10.3390/diagnostics11010001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822012PMC
December 2020

Cutaneous manifestations of mantle cell lymphoma: an extensive literature review.

Acta Dermatovenerol Alp Pannonica Adriat 2020 Dec;29(4):185-191

Second Propedeutical Department of Surgery, Aristotle University of Thessaloniki, Ippokrateio General Hospital of Thessaloniki, Thessaloniki, Greece.

Mantle cell lymphomas account for about 2 to 10% of non-Hodgkin B-cell lymphomas. Despite the cellular maturity of B-cell lymphomas, the disease is aggressive in the majority of cases and its course is unpredictable. The clinical presentation is variable, and multiple nodal and extranodal manifestations have been described. Cutaneous infiltration is an uncommon (2-6%) location of the disease. An extensive review of the literature was performed, and 24 case reports and five case series were found describing cutaneous locations. These data were thoroughly studied in order to present their clinical and laboratory characteristics in this review.
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December 2020

First Report of a Coincidental Discovery of Hb Antibes-Juan-Les-Pins (: c.349_350insGTGTGCTGGCCC) in a Greek Woman.

Hemoglobin 2020 Sep 2;44(5):361-363. Epub 2020 Dec 2.

Adult Thalassaemia Unit, Aristotle University of Thessaloniki, Thessaloniki, Greece.

The rare Hb Antibes-Juan-Les-Pins (: c.349_350insGTGTGCTGGCCC) was first reported in France. Hb Antibes-Juan-Les-Pins seems to be an innocuous variant and few published data are available. Heterozygous carriers have mild clinical or hematological findings. The abnormal hemoglobin (Hb) is detected by high performance liquid chromatography (HPLC) or capillary zone electrophoresis (CZE), but confirmation of the variant requires molecular analysis. This is the first description of Hb Antibes-Juan-Les-Pins heterozygosity in a woman of Greek origin.
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http://dx.doi.org/10.1080/03630269.2020.1813160DOI Listing
September 2020

Necrobiosis Lipoidica in a Patient with β-Thalassemia Major: A Case Report and Review of the Literature.

Hemoglobin 2020 May 1;44(3):221-223. Epub 2020 Jul 1.

Adult Thalassemia Unit, Second Department of Internal Medicine, Hippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece.

Necrobiosis lipoidica (NL) is a rare granulomatous disease that predominantly affects middle-aged women and is often associated with diabetes mellitus (DM), rheumatoid arthritis (RA) and other metabolic disorders. Thalassemias are the most common hereditary hemoglobin (Hb) disorders worldwide. A few studies investigated dermatologic problems that coexist with β-thalassemia major (β-TM). The most common skin disorders in patients with β-TM are xerosis, urticaria, pseudoxanthoma, hyperpigmentation, leg ulcers and small-vessel vasculitis. Necrobiosis lipoidica has only been occasionally reported in patients with β-TM. Herein, we present a female with β-TM and NL. Furthermore, a brief review of the literature was performed.
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http://dx.doi.org/10.1080/03630269.2020.1783287DOI Listing
May 2020

Biochemical and imaging markers in patients with thalassaemia.

Hellenic J Cardiol 2021 Jan-Feb;62(1):4-12. Epub 2020 May 6.

1(st) Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece.

Beta-thalassaemia is a genetic disease with different clinical aspects, which can lead to heart failure with a multifactorial mechanism. Over the last years, growing interest has been reported for biomarkers that may help in the diagnosis, staging and prognosis of heart disease at an early stage, in patients with beta-thalassaemia. This review will highlight the current clinical value of cardiac biomarkers in patients with beta-thalassaemia and the ongoing research for a possible expanded future use.
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http://dx.doi.org/10.1016/j.hjc.2020.04.012DOI Listing
August 2021

A Phase 3 Trial of Luspatercept in Patients with Transfusion-Dependent β-Thalassemia.

N Engl J Med 2020 03;382(13):1219-1231

From the Department of Clinical Sciences and Community, University of Milan, IRCCS Ca' Granda Foundation Maggiore Policlinico Hospital, Milan (M.D.C.), Centro della Microcitemia e Anemie Congenite e del Dismetabolismo del Ferro, E.O. Ospedali Galliera, Genoa (G.L.F.), Ospedale Pediatrico Microcitemico A. Cao, Azienda Ospedaliera G. Brotzu, Cagliari (R.O.), Ematologia e Oncologia Pediatrica, Università della Campania L. Vanvitelli, Caserta (S.P.), and the Department of Clinical and Biological Sciences, University of Turin, Turin (A.P.) - all in Italy; Siriraj Hospital, Mahidol University, Bangkok (V.V.), and the Division of Hematology, Department of Internal Medicine, Chiang Mai University, Chiang Mai (A. Tantiworawit) - both in Thailand; the Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon (A.T.T.); St. George University Hospital for Active Treatment and Medical University of Plovdiv, Plovdiv (P. Georgiev), University Specialized Hospital for Active Treatment in Oncology, Sofia (P. Ganeva), and University Hospital St. Marina, Varna (L.G.) - all in Bulgaria; the Division of Medical Oncology and Hematology, Department of Medicine, University Health Network and Division of Hematology, Department of Medicine, University of Toronto, Toronto (K.H.M.K.); the Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, and Keck School of Medicine of the University of Southern California, Los Angeles (T.C.), and the University of California San Francisco Benioff Children's Hospital, Oakland (A. Lal) - all in California; the Thalassemia and Sickle Cell Center, Laiko General Hospital (E. Voskaridou), and the First Department of Pediatrics, National and Kapodistrian University of Athens (A. Kattamis), Athens, and the Adult Thalassemia Unit, Hippokration Hospital, Thessaloniki (E. Vlachaki) - all in Greece; Hospital Sultanah Bahiyah, Alor Setar (H.K.L.), Hospital Umum, Sarawak, Kuching (L.P.C.), the University of Malaya Medical Center, Kuala Lumpur (P.C.B.), and Hospital Sultanah Aminah, Johor Bahru (S.M.L.) - all in Malaysia; the Comprehensive Center of Thalassemia, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel (I.P.-K.); Farhat Hached University Hospital, Sousse (A. Khelif), and the National Bone Marrow Transplant Center and Faculty of Medicine, University of Tunis El Manar, Tunis (M.B.) - both in Tunisia; the Department of Pediatric Hematology and Oncology, Ege University Hospital, Izmir, Turkey (Y.A.); Royal Prince Alfred Hospital and the University of Sydney, Sydney (P.J.H.); National Taiwan University, Taipei, Taiwan (M.-Y. L.); the Department of Haematology, Whittington Health NHS Trust (F.S.), and the Department of Haematology, University College London and University College London Hospitals NHS Foundation Trust (J.P.) - all in London; St. Jude Children's Research Hospital, Memphis, TN (E.J.N.); Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago (A. Thompson); Celgene, Summit, NJ (A. Laadem, J. Zou, J. Zhang); Celgene, Boudry, Switzerland (J.K.S., D.M., T.Z.); Acceleron Pharma, Cambridge, MA (P.G.L., M.L.S.); and the Department of Hematology, Necker Hospital, Assistance Publique-Hôpitaux de Paris (O.H.), and Imagine Institute, INSERM Unité 1163, University of Paris (O.H.) - both in Paris.

Background: Patients with transfusion-dependent β-thalassemia need regular red-cell transfusions. Luspatercept, a recombinant fusion protein that binds to select transforming growth factor β superfamily ligands, may enhance erythroid maturation and reduce the transfusion burden (the total number of red-cell units transfused) in such patients.

Methods: In this randomized, double-blind, phase 3 trial, we assigned, in a 2:1 ratio, adults with transfusion-dependent β-thalassemia to receive best supportive care plus luspatercept (at a dose of 1.00 to 1.25 mg per kilogram of body weight) or placebo for at least 48 weeks. The primary end point was the percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval. Other efficacy end points included reductions in the transfusion burden during any 12-week interval and results of iron studies.

Results: A total of 224 patients were assigned to the luspatercept group and 112 to the placebo group. Luspatercept or placebo was administered for a median of approximately 64 weeks in both groups. The percentage of patients who had a reduction in the transfusion burden of at least 33% from baseline during weeks 13 through 24 plus a reduction of at least 2 red-cell units over this 12-week interval was significantly greater in the luspatercept group than in the placebo group (21.4% vs. 4.5%, P<0.001). During any 12-week interval, the percentage of patients who had a reduction in transfusion burden of at least 33% was greater in the luspatercept group than in the placebo group (70.5% vs. 29.5%), as was the percentage of those who had a reduction of at least 50% (40.2% vs. 6.3%). The least-squares mean difference between the groups in serum ferritin levels at week 48 was -348 μg per liter (95% confidence interval, -517 to -179) in favor of luspatercept. Adverse events of transient bone pain, arthralgia, dizziness, hypertension, and hyperuricemia were more common with luspatercept than placebo.

Conclusions: The percentage of patients with transfusion-dependent β-thalassemia who had a reduction in transfusion burden was significantly greater in the luspatercept group than in the placebo group, and few adverse events led to the discontinuation of treatment. (Funded by Celgene and Acceleron Pharma; BELIEVE ClinicalTrials.gov number, NCT02604433; EudraCT number, 2015-003224-31.).
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http://dx.doi.org/10.1056/NEJMoa1910182DOI Listing
March 2020

Coinheritance of Triplicated Alpha-Globin Gene and Beta-Thalassemia Mutations in Adulthood: Ten Years of Referrals in Northern Greece.

J Pediatr Hematol Oncol 2020 11;42(8):e762-e764

Adult Thalassaemia Unit, Hippokration Hospital.

Greece is a country of ~11 million people, where hemoglobinopathies are the most common genetic diseases. The reported data describe the clinical phenotype of cases with coinheritance of triplicated α-globin (anti-α3.7 kb) and β-globin gene mutations in Northern Greece, that were referred within the last 10 years, in The Adult Thalassemia Unit of "Hippokration" Hospital, Thessaloniki, Northern Greece. The description of specific genotypes of the β-globin gene mutations in coinheritance with the triplicated α-globin gene (anti-α3.7 kb) and correlation with the hematologic and clinical data in adulthood may be useful in the evaluation of pediatric patients' prognosis and in genetic counseling of couples at risk.
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http://dx.doi.org/10.1097/MPH.0000000000001730DOI Listing
November 2020

Role of Genomic Biomarkers in Increasing Fetal Hemoglobin Levels Upon Hydroxyurea Therapy and in β-Thalassemia Intermedia: A Validation Cohort Study.

Hemoglobin 2019 Jan 30;43(1):27-33. Epub 2019 Apr 30.

a University of Patras , Medical Faculty, Laboratory of General Biology , Patras , Greece.

Hemoglobinopathies exhibit a remarkable phenotypic diversity in terms of disease severity, while individual genetic background plays a key role in differential response to drug treatment. In the last decade, genomic variants in genes located within, as well as outside the human β-globin cluster have been shown to be significantly associated with Hb F increase, in relation to hydroxyurea (HU) therapy in patients with these diseases. Here, we aim to determine the effect of genomic variants located in genes, such as , , , , , and , previously shown to modulate fetal hemoglobin (Hb F) levels in patients with β type hemoglobinopathies and reflecting disease severity and response to HU therapy in an independent cohort of Greek patients with these diseases. We recruited and genotyped 45 β-thalassemia patients (β-thal), either transfusion-dependent (TDT) or non transfusion-dependent (NTDT), 42 Hb S (: c.20A>T)-β-thal compound heterozygotes, who were treated with HU, as well as 53 healthy individuals, all of Hellenic origin. Our study showed that genomic variants of the , and gene are associated with HU therapy efficacy in Hb S-β-thal compound heterozygotes. We have also shown that and genomic variants are associated with the mild phenotype of NTDT patients. Our findings provide evidence that , , genomic variants could be considered as genomic biomarkers to predict HU therapy efficacy in Hb S-β-thal compound heterozygotes and also to describe disease severity in patients with β type hemoglobinopathies.
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http://dx.doi.org/10.1080/03630269.2019.1597732DOI Listing
January 2019

Beta-thalassemia: renal complications and mechanisms: a narrative review.

Hematology 2019 Dec;24(1):426-438

f Department of Nephrology , Hippokration Hospital, Aristotle University of Thessaloniki , Thessaloniki , Greece.

Objectives: Beta-thalassemias are a group of recessively autosomal inherited disorders of hemoglobin synthesis, which, due to mutations of the beta-globin gene, lead to various degrees of defective beta-chain production, an imbalance in alpha/beta-globin chain synthesis, ineffective erythropoiesis, and anemia. Improved survival in thalassemic patients has led to the emergence of previously unrecognized complications, such as renal disease.

Methods: A comprehensive literature review through PubMed was undertaken to summarize the published evidence on the epidemiology and pathophysiology of renal disease in thalassemia. Literature sources published in English since 1990 were searched, using the terms beta-thalassemia, renal disease.

Results: Renal disease is considered to be the 4th cause of morbidity among patients with transfusion dependent thalassemia. Chronic anemia, hypoxia and iron overload are the main mechanisms implicated in development of renal injury, whereas several studies also suggested a contributive role of iron chelators.

Discussion And Conclusion: Kidney disease may develop through progressive renal tubular and glomerular damage; thus, its early recognition is important in order to prevent and/or reverse deterioration. This review will provide an insight on the involved mechanisms implicated in kidney disease in thalassemic patients and will discuss the updates on diagnosis and prevention of renal complications in thalassemia.
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http://dx.doi.org/10.1080/16078454.2019.1599096DOI Listing
December 2019

Pre- and Post-transfusion Complement Activation in Transfusion-dependent β-thalassaemia.

Hemasphere 2018 10 2;2(5):e58. Epub 2018 Oct 2.

Adults Thalassaemia Unit, 2nd Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece.

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http://dx.doi.org/10.1097/HS9.0000000000000058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407797PMC
October 2018

Successful Outcome of Hyperhemolysis in Sickle Cell Disease following Multiple Lines of Treatment: The Role of Complement Inhibition.

Hemoglobin 2018 Sep - Nov;42(5-6):339-341. Epub 2019 Jan 9.

a Adult Thalassaemia Unit, 2nd Department of Internal Medicine , Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki , Thessaloniki , Greece.

Delayed hemolytic transfusion reaction (DHTR) is a life-threatening complication in patients with sickle cell disease, characterized by difficulties in diagnosis and management. Certain reports have suggested successful salvage treatment with the terminal complement inhibitor, eculizumab. We here report evidence of complement activation and successful complement inhibition with one dose of eculizumab in an adult sickle cell disease patient presenting DHTR with hyperhemolysis. A 21-year old female sickle cell disease patient [Hb S (HBB: c.20A>T)/β-thalassemia (β-thal)] presented at our Adult Thalassaemia Unit, Hippokration General Hospital of Thessaloniki, Thessaloniki, Greece, with headaches, perioral numbness and pain in both antibrachia. The patient was admitted with the diagnosis of vaso-occlussive crisis (VOC) and treated symptomatically. On her third day of admission, due to hemoglobin (Hb) value of 6.9 g/dL with increase in reticulocytes, the patient was transfused with one unit of compatible leukodepleted red blood cells (RBC). The following day, hemolytic parameters increased, although Coombs, panel antibodies and screening tests were negative. Five days later, she again received a unit of RBCs, resulting in another increase of hemolytic parameters. During the following 2 days, there was a dramatic decrease of Hb levels to 5.4 g/dL with reticulocytes at 6.0%, negative Coombs testing and negative alloantibodies. Based on these findings, we recognized the syndrome of DHTR with hyperhemolysis. Given the lack of immediate access to other treatment, we administered intravenous rituximab, immunoglobulins and corticosteroids. As there was no response, one dose of eculizumab (900 mg) was then administered with ciprofloxacin as prophylaxis. The patient remains well 6 months post treatment.
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http://dx.doi.org/10.1080/03630269.2018.1540353DOI Listing
May 2019

Production and Transduction of a Human Recombinant β-Globin Chain into Proerythroid K-562 Cells To Replace Missing Endogenous β-Globin.

Mol Pharm 2018 12 12;15(12):5665-5677. Epub 2018 Nov 12.

Laboratory of Pharmacology, School of Pharmacy, Faculty of Health Sciences , Aristotle University of Thessaloniki , Thessaloniki 54124 , Macedonia , Greece.

Protein replacement therapy (PRT) has been applied to treat severe monogenetic/metabolic disorders characterized by a protein deficiency. In disorders where an intracellular protein is missing, PRT is not easily feasible due to the inability of proteins to cross the cell membrane. Instead, gene therapy has been applied, although still with limited success. β-Thalassemias are severe congenital hemoglobinopathies, characterized by deficiency or reduced production of the adult β-globin chain. The resulting imbalance of α-/β-globin chains of adult hemoglobin (αβ) leads to precipitation of unpaired α-globin chains and, eventually, to defective erythropoiesis. Since protein transduction domain (PTD) technology has emerged as a promising therapeutic approach, we produced a human recombinant β-globin chain in fusion with the TAT peptide and successfully transduced it into human proerythroid K-562 cells, deficient in mature β-globin chain. Notably, the produced human recombinant β-globin chain without the TAT peptide, used as internal negative control, failed to be transduced into K-562 cells under similar conditions. In silico studies complemented by SDS-PAGE, Western blotting, co-immunoprecipitation and LC-MS/MS analysis indicated that the transduced recombinant fusion TAT-β-globin protein interacts with the endogenous native α-like globins to form hemoglobin αβ-like tetramers to a limited extent. Our findings provide evidence that recombinant TAT-β-globin is transmissible into proerythroid K-562 cells and can be potentially considered as an alternative protein therapeutic approach for β-thalassemias.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b00857DOI Listing
December 2018

Impact of ZBTB7A hypomethylation and expression patterns on treatment response to hydroxyurea.

Hum Genomics 2018 10 1;12(1):45. Epub 2018 Oct 1.

School of Science and Technology, Biology Laboratory, Hellenic Open University, Patras, Greece.

Background: We aimed to clarify the emerging epigenetic landscape in a group of genes classified as "modifier genes" of the β-type globin genes (HBB cluster), known to operate in trans to accomplish the two natural developmental switches in globin expression, from embryonic to fetal during the first trimester of conception and from fetal to adult around the time of birth. The epigenetic alterations were determined in adult sickle cell anemia (SCA) homozygotes and SCA/β-thalassemia compound heterozygotes of Greek origin, who are under hydroxyurea (HU) treatment. Patients were distinguished in HU responders and HU non-responders (those not benefited from the HU) and both, and in vivo and in vitro approaches were implemented.

Results: We examined the CpG islands' DNA methylation profile of BCL11A, KLF1, MYB, MAP3K5, SIN3A, ZBTB7A, and GATA2, along with γ-globin and LRF/ZBTB7A expression levels. In vitro treatment of hematopoietic stem cells (HSCs) with HU induced a significant DNA hypomethylation pattern in ZBTB7A (p*, 0.04) and GATA2 (p*, 0.03) CpGs exclusively in the HU non-responders. Also, this group of patients exhibited significantly elevated baseline methylation patterns in ZBTB7A, before the HU treatment, compared to HU responders (p*, 0.019) and to control group of healthy individuals (p*, 0.021), which resembles a potential epigenetic barrier for the γ-globin expression. γ-Globin expression in vitro matched with detected HbF levels during patients' monitoring tests (in vivo) under HU treatment, implying a good reproducibility of the in vitro HU epigenetic effect. LRF/ZBTB7A expression was elevated only in the HU non-responders under the influence of HU.

Conclusions: This is one of the very first pharmacoepigenomic studies indicating that the hypomethylation of ZBTB7A during HU treatment enhances the LRF expression, which by its turn suppresses the HbF resumption in the HU non-responders. Its role as an epigenetic regulator of hemoglobin switching is also supported by the wide distribution of ZBTB7A-binding sites within the 5' CpG sequences of all studied human HBB cluster "modifier genes." Also, the baseline methylation level of selective CpGs in ZBTB7A and GATA2 could be an indicator of the negative HU response among the β-type hemoglobinopathy patients.
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http://dx.doi.org/10.1186/s40246-018-0177-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167880PMC
October 2018

Compound Heterozygosity for Silent Cap +1570 (T>C) (HBB: c*96T>C), Codon 39 (C>T) (HBB: c.118C>T) and the Presence of ααα/αα in Greece. A Case Presentation.

Hemoglobin 2018 May 12;42(3):194-195. Epub 2018 Sep 12.

c Adult Thalassemia Unit, Second Department of Internal Medicine , Aristotle University of Thessaloniki , Thessaloniki , Greece.

The rare point mutation Cap +1570 (T>C) (HBB: c*96T>C) has been reported in families of Czech, Greek, Turkish and Italian origin. The mutation contributes to a reduction of the β-globin chain synthesis, and in heterozygous carriers, it causes a silent phenotype, while in compound heterozygosity with severe β-thalassemia (β-thal) mutations, it leads to a non transfusion dependent β-thal intermedia (β-TI) state. We report a case of compound heterozygosity for codon 39 (C>T) (HBB: c.118C>T) and Cap +1570, in addition to the presence of ααα/αα.
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http://dx.doi.org/10.1080/03630269.2018.1495648DOI Listing
May 2018

National registry of hemoglobinopathies in Greece: updated demographics, current trends in affected births, and causes of mortality.

Ann Hematol 2019 Jan 8;98(1):55-66. Epub 2018 Sep 8.

General Hospital of Piraeus "Tzaneio", Piraeus, Greece.

National registries constitute an invaluable source of information and contribute to the improvement of hemoglobinopathy management. Herein, we present the second updated report of the National Registry for Haemoglobinopathies in Greece (NRHG) and critically discuss the time trends in demographics, affected births, and causes of mortality. Thirty-eight Greek hemoglobinopathy units reported data from diagnosis to the last follow-up or death by retrospectively completing an electronic form. Four thousand thirty-two patients were eligible for inclusion; more than half of them had thalassaemia major. Compared to the previous report, a reduction in the total number of all hemoglobinopathies except for hemoglobinopathy "Η" was evident. The total number of affected births was also reduced; most of them were attributable to diagnostic errors and lack of awareness. Importantly, data on iron overload are reported for the first time; although most patients had low or moderate liver iron concentration (LIC) values, a non-negligible proportion of patients had high LIC. The burden due to heart iron overload was less prominent. Cardiac- and liver-related complications are the major causes of morbidity and mortality. From 2000 to 2015, a decrease in heart-related deaths along with an increase in liver-associated fatalities was observed. The Hellenic Prevention Program along with advances in chelation regimens and iron status monitoring have resulted in improved patient outcomes. The NRHG gives insight into the effectiveness of prevention programs, the therapeutic management of hemoglobinopathies and associated outcomes. NRHG may contribute to the formulation of a roadmap for hemoglobinopathies in Europe and promote the implementation of effective public health policies.
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http://dx.doi.org/10.1007/s00277-018-3493-4DOI Listing
January 2019

A man with fever and haemoglobinuria after blood transfusion.

BMJ 2018 Sep 6;362:k3138. Epub 2018 Sep 6.

Haemoglobinopathy Service, Homerton University Hospital NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1136/bmj.k3138DOI Listing
September 2018

Potential impact of Helicobacter pylori-related metabolic syndrome on upper and lower gastrointestinal tract oncogenesis.

Metabolism 2018 10 21;87:18-24. Epub 2018 Jun 21.

Division of Endocrinology, Diabetes and Metabolism, Department of Internal Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Both Helicobacter pylori infection and metabolic syndrome present significant global public health burdens. Metabolic syndrome is closely related to insulin resistance, the major underlying mechanism responsible for metabolic abnormalities, and Helicobacter pylori infection has been proposed to be a contributing factor. There is growing evidence for a potential association between Helicobacter pylori infection and insulin resistance, metabolic syndrome and related morbidity, including abdominal obesity, type 2 diabetes mellitus, dyslipidemia, hypertension, all of which increase mortality related to cardio-cerebrovascular disease, neurodegenerative disorders, nonalcoholic fatty liver disease and malignancies. More specifically, insulin resistance, metabolic syndrome and hyperinsulinemia have been associated with upper and lower gastrointestinal tract oncogenesis. Apart from cardio-cerebrovascular, degenerative diseases and nonalcoholic fatty liver disease, a number of studies claim that Helicobacter pylori infection is implicated in metabolic syndrome-related Barrett's esophagus and esophageal adenocarcinoma development, gastric and duodenal ulcers and gastric oncogenesis as well as lower gastrointestinal tract oncogenesis. This review summarizes evidence on the potential impact of Helicobacter pylori-related metabolic syndrome on gastroesophageal reflux disease-Barrett's esophagus-esophageal adenocarcinoma, gastric atrophy-intestinal metaplasia-dysplasia-gastric cancer and colorectal adenoma-dysplasia-colorectal cancer sequences. Helicobacter pylori eradication might inhibit these oncogenic processes, and thus further studies are warranted.
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http://dx.doi.org/10.1016/j.metabol.2018.06.008DOI Listing
October 2018

Safety and efficacy of intravenous iron administration for uterine bleeding or postpartum anaemia: a narrative review.

J Obstet Gynaecol 2018 May 23;38(4):443-447. Epub 2017 Oct 23.

a 2nd University Clinic of Obstetrics and Gynaecology , Aristotle University of Thessaloniki , Thessaloniki , Greece.

The management of iron deficiency anaemia (IDA) consists of oral or intravenous administration of iron supplements. The aim of this narrative review is to summarise information regarding the treatment of IDA in women who have postpartum anaemia or uterine bleeding with intravenous (IV) or oral iron supplements. Fourteen randomised control studies comparing IV to oral iron treatment for IDA in 2913 women with uterine bleeding or postpartum haemorrhage are included. All reviewed studies suggest that IV iron administration is important in treating the IDA in such women and in improving their physical performance and quality of life. Comparisons among intravenous iron supplements show advantages of ferric carboxymaltose over others in time of reaching desired haemoglobin and ferritin values and in adverse reactions. Despite the limitation that the above evidence emerges from not systematically collected data, our review highlights that new forms of IV iron supplements seem safe and efficient in treating IDA.
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http://dx.doi.org/10.1080/01443615.2017.1363170DOI Listing
May 2018

Rivaroxaban Use in Patients with Hemoglobinopathies.

Hemoglobin 2017 May;41(3):223-224

a Adult Thalassemia Unit, Second Department of Internal Medicine , Aristotle University, Hippokration Hospital , Thessaloniki , Greece.

The use of rivaroxaban in patients with hemoglobinopathies and thrombotic events has not been studied extensively. Here we present eight cases of such patients, five receiving rivaroxaban for stroke and systemic embolism prevention due to non-valvular atrial fibrillation and three for deep vein thrombosis treatment. The follow-up period ranged from 6 to 34 months. During this period none of the patients experienced any thrombotic or bleeding event.There were no other adverse events reported. Further studies with larger numbers of patients with hemoglobinopathies are needed to determine the use of rivaroxaban and ensure its safety in this patient setting.
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http://dx.doi.org/10.1080/03630269.2017.1374969DOI Listing
May 2017

evidence of complement activation in patients with sickle cell disease.

Haematologica 2017 12 14;102(12):e481-e482. Epub 2017 Sep 14.

Adults Thalassaemia Unit, 2 Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, Greece.

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http://dx.doi.org/10.3324/haematol.2017.174201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5709116PMC
December 2017

Successful Outcome of Severe Intra-cerebral Bleeding Associated with Acquired Factor V Inhibition: Utilization of Multiple Therapeutic Agents.

Balkan Med J 2018 01 13;35(1):112-115. Epub 2017 Sep 13.

Clinic of Internal Medicine, Ippokrateio General Hospital of Thessaloniki, Thessaloniki, Greece.

Background: Acquired coagulation factor inhibitors are antibodies that either inhibit activity or increase the clearance of a clotting factor and lead to an increased risk of bleeding. Most of the time, the disorder is attributed to factor VIII inhibition (acquired haemophilia A); however, other coagulation factors could also be implicated.

Case Report: Herein, we report an interesting case of a patient who underwent coronary artery bypass grafting and received antibiotic treatment after surgery with third generation cephalosporin. A month later, he presented with extreme bleeding diathesis and cerebral haemorrhage. Following a thorough clinical and laboratory investigation, an acquired factor V inhibitor was diagnosed. The patient received treatment with corticosteroids, intravenous immunoglobulins, anti-CD20 monoclonal antibodies (rituximab), cyclophosphamide and recombinant factor VIIa. Finally, despite the poor initial prognosis, the patient managed to achieve a full recovery.

Conclusion: As there are no clear guidelines on acquired coagulation inhibitor treatment, reports of such cases could offer insight for future therapy choices. The case was unique because the treatment regimen included a combination of multiple therapeutic agents including rituximab.
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http://dx.doi.org/10.4274/balkanmedj.2017.0158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820439PMC
January 2018

Evaluation of the Greek TranQol: a novel questionnaire for measuring quality of life in transfusion-dependent thalassemia patients.

Ann Hematol 2017 Nov 7;96(11):1937-1944. Epub 2017 Sep 7.

Adults Thalassemia Unit, 2nd Department of Internal Medicine, Aristotle University of Thessaloniki, Hippokration General Hospital of Thessaloniki, 49, Konstantinoupoleos Street, 54642, Thessaloniki, Greece.

The aim of our study was to evaluate the Greek version of the transfusion-dependent quality of life (TranQol) questionnaire and report our experience of using this novel disease-specific quality of life (QoL) measure in patients with transfusion-dependent thalassemia (TDT). The TranQol and SF-36v2 questionnaires were administered to 94 adult TDT patients with a mean age of 32.1 years (SD = 7, range = 19-58), recruited from the Adult Thalassemia Unit of Hippokration General Hospital of Thessaloniki, Greece. The TranQol was evaluated in terms of construct validity, reliability, and responsiveness. There was a moderately strong correlation between the TranQol summary and both the SF-36v2 physical and mental component summaries (r = 0.4, p < 0.001 and r = 0.5, p < 0.001, respectively). There was also a moderately strong correlation between the physical health scale of TranQol and the relevant SF-36v2 scales, including physical functioning (r = 0.4, p < 0.001), role-physical (r = 0.6, p < 0.001), and bodily pain (r = 0.5, p < 0.001). TranQol also exhibited good internal consistency (Cronbach's alpha coefficient = 0.9) and excellent test-retest reliability (intra-class correlation coefficient = 0.9). The subgroup of patients that reported a better QoL 1 week after transfusion also demonstrated a significant improvement in their TranQol score. These are the first data regarding the administration of the Greek TranQol in a single thalassemia unit. The psychometric properties of the Greek TranQol confirmed it is a valid, reliable, and responsive to change questionnaire, which can be incorporated into future clinical trials.
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http://dx.doi.org/10.1007/s00277-017-3122-7DOI Listing
November 2017

A Time Course of Bevacizumab (Anti-VEGF) Effect on Rat Peritoneum: Relations Between Antiadhesive Action and Fibrin Regulation Enzymes.

Surg Innov 2017 Dec 7;24(6):543-551. Epub 2017 Sep 7.

1 Aristotle University School of Medicine, Thessaloniki, Greece.

Background: To investigate the early and late antiadhesive effect and any changes of fibrin matrix regulation enzymes on rat peritoneum, after local administration of bevacizumab.

Methods: Rats were subjected to cecal abrasion. Bevacizumab (5 mg/kg) against placebo was given intraperitoneally. On the 2nd, 14th, and 28th postoperative days adhesions were scored, and tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-9 (MMP-9), degree of fibrosis, and angiogenesis were measured in abrased cecum and in intact parietal peritoneum.

Results: Bevacizumab significantly reduced adhesions up to 15% on the 2nd, 52.5% on the 14th, and 55% on the 28th postoperative day, and significantly increased tPA concentrations in peritoneum. PAI-1 was decreased, and a significantly higher tPA/PAI-1 ratio along with an increase of MMP-9 was measured at all time points. Fibrosis and angiogenesis were significantly lower on the 14th and 28th postoperative days.

Conclusions: Local bevacizumab administration has a strong early and late antiadhesive action on rat peritoneum, mediated by changes in the tPA/PAI-1 and MMP balance in favor of fibrinolysis up to 28 days after operations.
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http://dx.doi.org/10.1177/1553350617729510DOI Listing
December 2017

Treatment of chronic hepatitis C with direct-acting antivirals in patients with β-thalassaemia major and advanced liver disease.

Br J Haematol 2017 07 25;178(1):130-136. Epub 2017 Apr 25.

Department of Gastroenterology, National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.

Interferon-based regimens for chronic hepatitis C (CHC) were often deferred in patients with β-thalasaemia major (β-TM) due to poor efficacy and tolerance. Current guidelines recommend direct-acting antivirals (DAAs) for these patients. The aim of this study was to assess the safety and efficacy of DAAs in patients with β-TM and advanced liver disease due to CHC. Patients were recruited from eight liver units in Greece. The stage of liver disease was assessed using transient elastography and/or liver histology. Five regimens were used: sofosbuvir (SOF) + ribavirin (RBV); SOF + simeprevir ± RBV; SOF + daclatasvir ± RBV; ledipasvir/SOF ± RBV and ombitasvir/paritaprevir-ritonavir + dasabuvir ± RBV. Sixty-one patients (median age 43 years) were included. The majority of patients was previously treated for hepatitis C (75%) and had cirrhosis (79%). Viral genotype distribution was: G1a: n = 10 (16%); G1b: n = 22 (36%); G2: n = 2 (3%); G3: n = 14 (23%); G4: n = 13 (22%). The predominant chelation therapy was a combination of deferoxamine and deferiprone (35%). Overall sustained virological response rates were 90%. All treatment regimens were well tolerated and no major adverse events or drug-drug interactions were observed. Approximately half of the patients who received RBV (7/16, 44%) had increased needs for blood transfusion. Treatment of CHC with DAAs in patients with β-TM and advanced liver disease was highly effective and safe.
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http://dx.doi.org/10.1111/bjh.14640DOI Listing
July 2017
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