RESUMO
Red blood cell (RBC) membrane disorders represent a significant category of hereditary hemolytic anemia; however, information from Southeast Asia is limited. We established a national registry aiming to characterize RBC membrane disorders and their molecular features in Thailand. A total of 100 patients (99 kindreds) diagnosed with RBC membrane disorders between 2011 and 2020 from seven university hospitals were enrolled. The most prevalent disorders observed were hereditary elliptocytosis (HE; n=33), hereditary pyropoikilocytosis (HPP; n=28), hereditary spherocytosis (HS; n=19), Southeast Asian ovalocytosis (SAO; n=10 of 9 kindreds), and two cases of homozygous SAO. The remaining cases were grouped as unclassified membrane disorder. Seventy-six patients (76%) were molecularly confirmed by PCR, direct DNA sequencing, or hi-throughput sequencing. The primary causative gene for HE and HPP was SPTB, accounting for 28 out of 29 studied alleles for HE and 56 of 56 studied alleles for HPP. In the case of HS, dominant sporadic mutations in the ANK1 gene (n=4) and SPTB gene (n=3) were identified as the underlying cause. Notably, the four most common variants causing HE and HPP were SPTB Providence (c.6055 T>C), SPTB Buffalo (c.6074 T>G), SPTB Chiang Mai (c.6224 A>G), and SPTB c.6171__82delins TGCCCAGCT. These recurrent SPTB mutations accounted for 79 out of 84 mutated SPTB alleles (94%). In summary, HE and hereditary HPP associated with recurrent SPTB mutations are the predominant types of RBC membrane disorders observed in Thailand. These findings have significant implications for the clinical management and future research of RBC membrane disorders in the region.
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Eliptocitose Hereditária , Esferocitose Hereditária , Humanos , Eliptocitose Hereditária/epidemiologia , Eliptocitose Hereditária/genética , Eliptocitose Hereditária/diagnóstico , Membrana Eritrocítica/genética , Membrana Eritrocítica/metabolismo , Mutação , Esferocitose Hereditária/epidemiologia , Esferocitose Hereditária/genética , Esferocitose Hereditária/diagnóstico , Tailândia/epidemiologia , Estudos Multicêntricos como Assunto , Sistema de RegistrosRESUMO
Patients with transfusion-dependent thalassemia (TDT) have an increased risk of osteoporosis and fractures. They also have several potential factors associated with sarcopenia. There has been currently no study on sarcopenia and its association with falls and fractures in TDT. This study aims to determine the prevalence of and factors associated with osteoporosis, fragility fractures, and sarcopenia in adults with TDT. A cross-sectional study was conducted at the hematologic clinic at King Chulalongkorn Memorial Hospital, Bangkok, Thailand. Clinical data and laboratory testing were collected. Bone mineral density and morphometric vertebral fracture were assessed. Sarcopenia was defined using the 2014 and 2019 Asian Working Group for Sarcopenia (AWGS) criteria. We included 112 TDT patients aged 35.1 ± 12.5 years. The prevalence of osteoporosis was 38.4%. Fragility fractures were found in 20.5% of patients. Lower BMI (OR 0.29; 95% CI 0.12-0.72, P = 0.007) and hypogonadal state (OR 3.72; 95% CI 1.09-12.74, P = 0.036) were independently associated with osteoporosis. According to the 2014 AWGS criteria, the prevalence of overall sarcopenia and severe sarcopenia was 44.6% and 13.4%, respectively. Severe sarcopenia was strongly associated with fragility fractures (OR 4.59, 95% CI 1.21-17.46, P = 0.025). In conclusion, osteoporosis, fragility fractures, and sarcopenia were prevalent in adults with TDT. Severe sarcopenia was associated with fragility fractures. Early osteoporosis and sarcopenia screening and prevention may reduce fracture risk and its complications in these patients.
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Fraturas Ósseas , Osteoporose , Sarcopenia , Talassemia , Humanos , Sarcopenia/complicações , Sarcopenia/epidemiologia , Sarcopenia/diagnóstico , Estudos Transversais , Tailândia/epidemiologia , Osteoporose/complicações , Osteoporose/epidemiologia , Fraturas Ósseas/epidemiologia , Densidade Óssea , Talassemia/complicações , Talassemia/terapia , Fatores de RiscoRESUMO
INTRODUCTION: Management of transfusion-dependent thalassemia (TDT) can be challenging due to numerous potential disease-related complications and comorbidities in particular age groups. The objective of this study was to report thalassemia-related complications and risk factors in pediatric, adolescent, and young adult patients with TDT. METHODS: A multicenter web-based registry was conducted in patients with TDT aged 25 years and younger from eight university hospitals covering all parts of Thailand. Factors significantly associated with each complication were analyzed by logistic regression methods. RESULTS: Of 605 patients, 267 thalassemia-related complications were reported from 231 pediatric, adolescent, and young adult patients with TDT patients (38.2%). The most common complications were infections, followed by cholelithiasis and growth failure. Splenectomy and elevated pre-transfusion hemoglobin were statistically significant risk factors for infections (adjusted odds ratio [AOR] = 2.3, 95% confidence interval [CI]: 1.2-4.5, p-value = .01 and AOR = 1.5, 95% CI: 1.2-1.7, p-value < .005, respectively). There were two statistically significant risk factors conferred endocrinopathies, including older age (AOR = 1.06, 95% CI: 1.01-1.1, p-value = .01) and being male (AOR = 2.4, 95% CI: 1.4-4.0, p-value = .002). CONCLUSION: Nearly 40% of the patients in this cohort had thalassemia-related complications. Periodic surveillance and optimal care for respective complications may minimize comorbidities in pediatric, adolescent, and young adult patients with TDT.
Assuntos
Doenças do Sistema Endócrino , Talassemia , Humanos , Criança , Masculino , Adolescente , Adulto Jovem , Feminino , Tailândia/epidemiologia , Talassemia/complicações , Talassemia/epidemiologia , Talassemia/terapia , Fatores de Risco , ComorbidadeRESUMO
OBJECTIVE: Hemoglobin Constant Spring (HbCS) is often missed by routine hemoglobin analysis. The aim of this research was to study HbCS stability as identified by capillary electrophoresis (CE) to determine the specimen storage time limit. METHODS: The EDTA blood of 29 HbCS samples were kept at 4°C and analyzed every workday until CE could not detect HbCS or until 7 weeks after blood collection. The genotypes were confirmed by multiplex polymerase chain reaction. RESULTS: The median subject age was 27 years and 10 subjects were male. The HbCS levels were stable during the first 7 days but became undetectable in 5 cases (17.2%) after 1 week. All of them were heterozygous HbCS. Longer detection times were correlated with the higher baseline HbCS levels, with a correlation coefficient of 0.582 (P â ≤â 0.001). CONCLUSION: Routine hemoglobin typing and quantitation should be performed within 1 week after blood collection to detect low HbCS levels, especially in heterozygous HbCS.
Assuntos
Hemoglobinas Anormais , Humanos , Masculino , Adulto , Feminino , Hemoglobinas Anormais/análise , Genótipo , Heterozigoto , Eletroforese CapilarRESUMO
Background: Hyperfunctional platelets play important roles in thromboembolism in patients with ß-thalassaemia/ haemoglobin E (ß-thal/HbE). Our previous study revealed ex vivo inhibitory effects of deferiprone on normal platelets. Herein, we aimed to investigate the in vivo effects on platelets in patients with ß-thal/HbE. Methods: A prospective, self-controlled clinical study on 30 patients with ß-thal/HbE who had received therapeutic deferiprone (20.8-94.5 mg/kg/day) was conducted. The study included a 4-week washout period followed by 4 and 12 weeks of deferiprone treatment. Platelet aggregation was performed by a turbidimetric method. Levels of deferiprone and soluble platelet (sP)-selectin in serum were measured by high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA) kit, respectively. Results: The washout period significantly enhanced platelet hyperactivity both in patients who had undergone splenectomy and in those who had not. At 2 hours following the administration of a single dose of deferiprone, platelet sensitivity to ADP and arachidonic acid was significantly reduced. The inhibitory effects of deferiprone were gradually increased over the period of 4 and 12 weeks. Deferiprone also depressed sP-selectin levels, but the effect was stable over longer follow-up periods. Correlation analysis demonstrated the relationship between serum levels of deferiprone, sP-selectin, and platelet activities induced by ADP and arachidonic acid. Conclusion: We first demonstrated the in vivo antiplatelet effect and benefit of short-term treatment of deferiprone in patients with ß-thal/HbE. The impact on thrombotic outcomes deserves further study.
RESUMO
BACKGROUND: Thalassemia is a common genetic disease in Southeast Asia. Red blood cell (RBC) transfusion is an essential treatment for severe forms of thalassemia. We performed a study to demonstrate RBC alloimmunization and other transfusion-related complications in patients with transfusion-dependent thalassemia (TDT). STUDY DESIGN AND METHODS: A multi-center web-based registry of TDT was conducted in eight medical centers across Thailand. Thalassemia information, transfusion therapy, and transfusion-related complications were collected. Factors associated with each complication were demonstrated using the logistic regression analysis. RESULTS: Of 1000 patients recruited for the study, 449 were males (44.9%). The mean age was 23.9 ± 15.4 years. The majority of patients, 738 (73.8%) had hemoglobin E/beta-thalassemia. In the study, 421 transfusion-related complications were reported from 357 patients (35.7%). Alloimmunization was the most common complication which was found in 156 patients (15.6%) with 284 positive antibody tests. The most frequent antibodies against RBC were anti-E (80/284, 28.2%) followed by anti-Mia (45/284, 15.8%) and anti-c (32/284, 11.3%). Age ≥3 years at initial blood transfusion, splenomegaly, higher frequencies, and volumes of transfusion were significant factors associated with alloimmunization. None of the patients had to terminate blood transfusion due to multiple alloantibodies. Other commonly seen complications were allergic reactions (130, 13.0%), autoimmune hemolytic anemia (70, 7.0%) and febrile non-hemolytic transfusion reaction (54, 5.4%). CONCLUSIONS: Transfusion-related complications, especially alloimmunization, were common among Thai patients with TDT. Extended RBC antigen-matching for the Rh system and Mia should be implemented to prevent the development of alloantibodies in multi-transfused patients.
Assuntos
Anemia Hemolítica Autoimune , Hemoglobina E , Talassemia , Reação Transfusional , Adolescente , Adulto , Criança , Pré-Escolar , Eritrócitos , Feminino , Hemoglobina E/análise , Humanos , Isoanticorpos , Masculino , Tailândia/epidemiologia , Talassemia/complicações , Talassemia/terapia , Adulto JovemAssuntos
Qualidade de Vida , Talassemia beta/psicologia , Adulto , Terapia por Quelação/psicologia , Transfusão de Eritrócitos/psicologia , Feminino , Grécia , Necessidades e Demandas de Serviços de Saúde , Humanos , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/psicologia , Itália , Líbano , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de Doença , Tailândia , Adulto Jovem , Talassemia beta/terapiaRESUMO
INTRODUCTION: Pulmonary hypertension (PH) is the commonest cardiac complication in ß-thalassemia intermedia, including ß-thalassemia/hemoglobin E (ß-thal/HbE), and is strongly associated with splenectomy. We aimed to define the prevalence and comprehensively explore mechanisms of PH in ß-thal/HbE patients receiving regular transfusion and iron chelation, which were reported to alleviate PH. MATERIALS AND METHODS: ß-Thal/HbE patients receiving regular transfusion and iron chelation over one year were enrolled. Patients at risk for PH were defined by tricuspid-regurgitant-jet-velocity (TRV)â¯≥â¯2.5â¯m/s. Laboratory and echocardiographic variables were compared with healthy controls. RESULTS: There were 68 ß-thal/HbE, including 31 (45.6%) splenectomized patients, and 38 controls included for analysis. PH was detected in 29 ß-thal/HbE (42.6%). ß-Thal/HbE with PH had a significant reduction in nitric oxide metabolites (NOx) but elevations in thrombin-antithrombin (TAT) complex, soluble thrombomodulin (sTM), endothelin-1 (ET-1) and flow-mediated dilation (FMD) values compared to those without PH (all, pâ¯<â¯0.05). TRV was significantly correlated with NOx, TAT, sTM, ET-1 and FMD values (râ¯=â¯-0.514, râ¯=â¯0.281, râ¯=â¯0.313, râ¯=â¯0.245 and râ¯=â¯-0.474; all pâ¯<â¯0.05). Erythropoietic activity, serum ferritin, circulating total tissue factor (TF) antigen, microparticle-associated TF activity, microparticle's procoagulant activity and soluble p-selectin levels were not different between PH and non-PH subgroups. Notably, there were no significant associations between splenectomy and PH. CONCLUSIONS: PH remains prevalent in ß-thal/HbE patients receiving long-term transfusion and iron chelation. PH is not associated with splenectomy status but correlated with NO depletion, TF-independent hypercoagulability and endothelial perturbation.
Assuntos
Transfusão de Sangue/métodos , Hipertensão Pulmonar/etiologia , Quelantes de Ferro/uso terapêutico , Talassemia beta/complicações , Adulto , Idoso , Estudos Transversais , Feminino , Hemoglobina E , Hemostáticos , Humanos , Hipertensão Pulmonar/patologia , Quelantes de Ferro/farmacologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem , Talassemia beta/patologiaRESUMO
This study demonstrates the quantitative characteristics of the first patient-reported outcome (PRO) tool developed for patients with nontransfusion-dependent ß-thalassemia (NTDT), the NTDT-PRO© . A multicenter validation study was performed over 24 weeks, involving 48 patients from Italy, Lebanon, Greece, and Thailand. Most patients were female (68.8%), with a median age of 34.5 years (range, 18-52); 66.7% were diagnosed with ß-thalassemia intermedia, and median time since diagnosis was 22 years (range, 0-43). The NTDT-PRO comprises 6 items across 2 domains (Tiredness/Weakness and Shortness of Breath [SoB]), and was valid and reliable, with good consistency. At baseline, most patients reported symptoms as present via the NTDT-PRO, and were highly compliant, ≥90% completing the NTDT-PRO tool. In a pairwise correlation analysis, all items were positively correlated. Correlations between NTDT-PRO and existing tools-36-Item Short Form Health Survey version 2 (SF-36v2) and Functional Assessment of Cancer Therapy-Anemia (FACT-An)-were assessed at weeks 1, 3, and 12; robust correlations were seen between SoB and SF-36v2-Vitality (rs = -0.53), and between SoB and Fact-An-Fatigue Experience (rs = -0.66) at week 1. Internal consistency was high for both Tiredness/Weakness (Cronbach alpha, 0.91) and SoB (Spearman-Brown coefficient, 0.78); intraclass correlation coefficients were high (Tiredness/Weakness, 0.88 and 0.97; SoB, 0.92 and 0.98), demonstrating stability. Further studies are required to fully support the validity of this tool, this study demonstrated the usefulness of the NTDT-PRO in the clinical setting and for longitudinal clinical research, particularly in trials where patient health-related quality of life is expected to change.
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Medidas de Resultados Relatados pelo Paciente , Talassemia beta/patologia , Adolescente , Adulto , Dispneia , Fadiga , Feminino , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Adulto JovemRESUMO
ß-Thalassemia, a hereditary blood disorder caused by reduced or absent synthesis of the ß-globin chain of hemoglobin, is characterized by ineffective erythropoiesis, and can manifest as nontransfusion-dependent thalassemia (NTDT) or transfusion-dependent thalassemia (TDT). Many patients with NTDT develop a wide range of serious complications that affect survival and quality of life (QoL). Patient-reported outcomes (PRO), including health-related QoL (HRQoL), are important tools for determining patient health impairment and selecting appropriate treatment. However, there are currently no disease-specific PRO tools available to assess symptoms related to chronic anemia experienced by patients with NTDT. This study aimed to develop a new, US Food and Drug Administration (FDA)-compliant PRO of chronic anemia symptoms, the NTDT-PRO© tool, for use in patients with NTDT. Participants had a median age of 36 years (range, 18-47) and 60% were female. The initial development of the NTDT-PRO tool involved concept-elicitation interviews with 25 patients from 3 centers (in Lebanon, Greece, and Canada); subsequent interview discussions and clinical input resulted in the generation of 9 items for inclusion in the draft NTDT-PRO. Following a round of cognitive interviews involving 21 patients from 2 centers (in Lebanon and Greece), 4 items (Pain, Headaches, Ability to Concentrate, and Paleness) were removed from the draft NTDT-PRO. The final NTDT-PRO comprises 6 items that measure Tiredness, Weakness, and Shortness of Breath, with or without Physical Activity. The NTDT-PRO is a new disease-specific HRQoL tool for patients with NTDT, developed using a thorough methodology based on FDA 2009 PRO development guidelines.
Assuntos
Medidas de Resultados Relatados pelo Paciente , Talassemia/patologia , Adolescente , Adulto , Feminino , Humanos , Entrevistas como Assunto , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estados Unidos , United States Food and Drug Administration , Adulto JovemRESUMO
Despite aggressive treatment, vascular pythiosis has a mortality rate of 40%. This is due to delays in diagnosis and a lack of effective monitoring tools. To overcome this drawback, serum beta-d-glucan (BG) and P. insidiosum-specific antibody (Pi-Ab) were examined as potential monitoring markers in vascular pythiosis. A prospective cohort study of vascular pythiosis patients was carried out from January 2010 to July 2016. Clinical information and blood samples were collected and evaluated by the BG and Pi-Ab assays. Linear mixed-effect models were used to compare BG and Pi-Ab levels. The in vitro susceptibility test was performed with all P. insidiosum isolates from culture-positive cases. A total of 50 patients were enrolled: 45 survived and 5 died during follow-up. The survivors had a significantly shorter time to medical care (P < 0.0001) and a significantly shorter waiting time to the first surgery (P < 0.0001). There were no differences in BG levels among the groups at diagnosis (P = 0.33); however, BG levels among survivors were significantly lower than those of the deceased group at 0.5 months (P < 0.0001) and became undetectable after 3 months. Survivors were able to maintain an enzyme-linked immunosorbent assay (ELISA) value (EV) of Pi-Ab above 8, whereas the EV among deceased patients was less than 4. In vitro susceptibility results revealed no synergistic effects between itraconazole and terbinafine. This study showed that BG and Pi-Ab are potentially valuable markers to monitor the disease after treatment initiation. An unchanged BG level at 2 weeks after surgery should prompt an evaluation for residual disease.
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Anticorpos Antibacterianos/sangue , Imunoglobulina G/sangue , Pitiose/sangue , Pythium/imunologia , beta-Glucanas/sangue , Adulto , Idoso , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Biomarcadores/sangue , Feminino , Seguimentos , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Prospectivos , Pitiose/diagnóstico , Pitiose/mortalidade , Pitiose/terapia , Pythium/efeitos dos fármacos , Pythium/isolamento & purificação , Adulto JovemRESUMO
Mechanisms of vascular disorders in ß-thalassemia/HbE patients remain poorly understood. In the present study, we aimed to determine the presence of endothelial dysfunction and its association with altered vascular mediators in this population. Forty-three ß-thalassemia/HbE patients without clinically documented vascular symptoms and 43 age-sex-matched healthy controls were enrolled. Endothelial function was assessed using flow-mediated dilatation (FMD) before and after administration of nitroglycerine (NTG). ß-Thalassemia/HbE patients showed a significant endothelial dysfunction using FMD. The percentage change in the brachial artery diameter before NTG was significantly lower in the thalassemia group compared to the control (5.0 ± 5.9 vs. 9.0 ± 4.0%, p < 0.01) while no significant differences after NTG (18.4 ± 8.3 vs. 17.8 ± 6.3%, p = 0.71). Plasma nitric oxide metabolites (NO x ) and prostaglandin E2 (PGE2) levels were significantly decreased in ß-thalassemia/HbE (117.2 ± 27.3 vs. 135.8 ± 11.3 µmol/L, p < 0.01) and (701.9 ± 676.0 vs. 1374.7 ± 716.5 pg/mL, p < 0.01), respectively, while a significant elevation in soluble thrombomodulin levels in ß-thalassemia/HbE (3587.7 ± 1310.0 vs. 3093.9 ± 583.8 pg/mL, p = 0.028). NO x and PGE2 levels were significantly correlated with FMD (r = 0.27, p = 0.025) and (r = 0.35, p = 0.003), respectively. These findings suggest roles for endothelial mediators and a new mechanism underlying endothelial dysfunction in ß-thalassemia/HbE patients.
Assuntos
Dinoprostona/deficiência , Endotélio Vascular/fisiopatologia , Óxido Nítrico/deficiência , Talassemia beta/fisiopatologia , Adulto , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/terapia , Dinoprostona/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Óxido Nítrico/sangue , Nitroglicerina , Talassemia beta/sangue , Talassemia beta/complicaçõesRESUMO
No well-defined phenotypes that distinguish between unknown α- and ß-globin mutations have been reported to date. Direct DNA sequencing of α-globin genes can be technically challenging, as α1- and α2-globin genes are nearly indistinguishable. To detect hemoglobin variants (HbXs) on Hb analysis, the entire ß- and α-globin genes were directly sequenced using a newly developed sequencing protocol for α-globin genes. An algorithm to distinguish between α- and ß-HbXs was constructed and subsequently validated in the independent validation group. Distinctive characteristics that can distinguish 39 α-HbXs from 24 ß-HbXs were the presence of unidentifiable variants of HbA2 and/or HbX of <37% on isoelectric focusing and <31% on high-performance liquid chromatography. Another set of 67 HbXs was employed to validate our algorithm. This accurately predicted 33 α-HbXs with 100% sensitivity and 97.1% specificity. Our sequencing protocol for α-globin genes was able to identify 11 rare mutations among all exons of both α-globin genes from 72 subjects. Six of these variants were first discovered in Thais. This is the first well-characterized algorithm for distinguishing unknown Hb variants in a large cohort. Our validated criteria and DNA sequencing procedure are highly efficient for molecular characterization of rare Hb mutations.
Assuntos
Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , alfa-Globinas/genética , Cromatografia Líquida de Alta Pressão , Análise Mutacional de DNA , Feminino , Humanos , Focalização Isoelétrica , MasculinoRESUMO
BACKGROUND: In transfusion-dependent anaemias, while absolute serum ferritin levels broadly correlate with liver iron concentration (LIC), relationships between trends in these variables are unclear. These relationships are important because serum ferritin changes are often used to adjust or switch chelation regimens when liver magnetic resonance imaging (MRI) is unavailable. OBJECTIVES AND METHODS: This post hoc analysis of the EPIC study compared serum ferritin and LIC in 317 patients with transfusion-dependent thalassaemia before and after 1 yr of deferasirox. RESULTS: Serum ferritin responses (decreases) occurred in 73% of patients, 80% of whom also have decreased LIC. However, 52% of patients without a serum ferritin response did decrease LIC and by >1 mg Fe/g dw (median 3.9) in 77% of cases. Absolute serum ferritin and LIC values correlated significantly only when serum ferritin was <4000 ng/mL (r = 0.59; P < 0.0001) and not at higher levels (≥4000 ng/mL; r = 0.19). Serum ferritin response was accompanied by decreased LIC in 89% and 70% of cases when serum ferritin was <4000 or ≥4000 ng/mL, respectively. CONCLUSIONS: As serum ferritin non-response was associated with LIC decrease in over half of patients, use of liver MRI may be particularly useful for differentiating true from apparent non-responders to deferasirox based on serum ferritin trends alone.
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Benzoatos/uso terapêutico , Ferritinas/sangue , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Sobrecarga de Ferro/etiologia , Ferro/metabolismo , Fígado/metabolismo , Talassemia/sangue , Talassemia/complicações , Triazóis/uso terapêutico , Adolescente , Adulto , Biomarcadores , Terapia por Quelação , Criança , Pré-Escolar , Deferasirox , Feminino , Humanos , Sobrecarga de Ferro/diagnóstico , Masculino , Pessoa de Meia-Idade , Prognóstico , Curva ROC , Talassemia/terapia , Reação Transfusional , Resultado do Tratamento , Adulto JovemRESUMO
Liver iron concentration (LIC) assessment by magnetic resonance imaging (MRI) remains the gold standard to diagnose iron overload and guide iron chelation therapy in patients with non-transfusion-dependent thalassaemia (NTDT). However, limited access to MRI technology and expertise worldwide makes it practical to also use serum ferritin assessments. The THALASSA (assessment of Exjade(®) in non-transfusion-dependent THALASSemiA patients) study assessed the efficacy and safety of deferasirox in iron-overloaded NTDT patients and provided a large data set to allow exploration of the relationship between LIC and serum ferritin. Using data from screened patients and those treated with deferasirox for up to 2 years, we identified clinically relevant serum ferritin thresholds (for when MRI is unavailable) for the initiation of chelation therapy (>800 µg/l), as well as thresholds to guide chelator dose interruption (<300 µg/l) and dose escalation (>2000 µg/l). (clinicaltrials.gov identifier: NCT00873041).
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Benzoatos/administração & dosagem , Ferritinas/sangue , Quelantes de Ferro/administração & dosagem , Ferro/metabolismo , Fígado/metabolismo , Talassemia/tratamento farmacológico , Triazóis/administração & dosagem , Adolescente , Adulto , Deferasirox , Método Duplo-Cego , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Talassemia/sangue , Adulto JovemRESUMO
OBJECTIVE: Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload and related complications, and may require iron chelation. However, the risk of over-chelation emerges as patients reach low, near-normal body iron levels and dose adjustments may be needed. In the THALASSA study, the threshold for chelation interruption was LIC <3 mg Fe/g dw (LIC<3); 24 patients receiving deferasirox for up to 2 yr reached this target. A post hoc analysis was performed to characterize the safety profile of deferasirox as these patients approached LIC<3. METHODS: THALASSA was a randomized, double-blind, placebo-controlled study of two deferasirox regimens (5 and 10 mg/kg/d) versus placebo in patients with NTDT. Patients randomized to deferasirox or placebo in the core could enter a 1-yr extension, with all patients receiving deferasirox (extension starting doses based on LIC at end-of-core and prior chelation response). The deferasirox safety profile was assessed between baseline and 6 months before reaching LIC<3 (Period 1), and the 6 months immediately before achieving LIC<3 (Period 2). RESULTS: Mean ± SD deferasirox treatment duration up to reaching LIC<3 was 476 ± 207 d, and deferasirox dose was 9.7 ± 3.0 mg/kg/d. The exposure-adjusted AE incidence regardless of causality was similar in periods 1 (1.026) and 2 (1.012). There were no clinically relevant differences in renal and hepatic laboratory parameters measured close to the time of LIC<3 compared with measurements near the previous LIC assessment. CONCLUSIONS: The deferasirox safety profile remained consistent as patients approached the chelation interruption target, indicating that, with appropriate monitoring and dose adjustments in relation to iron load, low iron burdens may be reached with deferasirox with minimal risk of over-chelation.
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Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/metabolismo , Ferro/metabolismo , Fígado/metabolismo , Talassemia/complicações , Benzoatos/efeitos adversos , Benzoatos/uso terapêutico , Deferasirox , Humanos , Quelantes de Ferro/efeitos adversos , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Fígado/patologia , Reação Transfusional , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/uso terapêuticoRESUMO
BACKGROUND: Thalassemia syndromes are highly prevalent in Southeast Asia. In Thailand, high performance liquid chromatography (HPLC) is the most common technique routinely performed in diagnosis of thalassemia and hemoglobinopathies, while isoelectric focusing (IEF) is rarely employed. We compared the diagnostic utility of IEF and HPLC in neonatal screening for thalassemia and non-sickling hemoglobinopathies. METHODS: Two-hundred and forty-one cord blood samples were analyzed using IEF and HPLC, ß-thalassemia short program. The results were correlated with red cell indices and molecular analyses. Hemoglobin (Hb) Bart's was quantified only on IEF. RESULTS: Of 241 newborns, IEF and HPLC yielded 85.4% and 76.4% sensitivity to identify α-thalassemia syndrome, respectively. HbBart's≥2% yielded 100% sensitivity to identify 2 α-globin gene deletions and/or mutations, while MCV≤95fl and MCH≤30pg yielded 100% sensitivity to identify 2 α-globin gene deletions. DNA analysis revealed HbE mutation in all 61 subjects with HbA2>1% on both IEF and HPLC. CONCLUSION: IEF is an effective method in neonatal screening for thalassemia and non-sickling hemoglobinopathies. The HbBart's level, MCV and MCH are helpful for identifying α-thalassemia. The presence of HbA2 higher than 1% in cord blood indicates HbE carriers in Southeast Asian newborns.
Assuntos
Sangue Fetal/química , Hemoglobinopatias/diagnóstico , Focalização Isoelétrica , Triagem Neonatal , Talassemia/diagnóstico , Contagem de Células Sanguíneas , Cromatografia Líquida de Alta Pressão , Genótipo , Hemoglobinopatias/sangue , Hemoglobinopatias/genética , Humanos , Recém-Nascido , Talassemia/sangue , Talassemia/genéticaRESUMO
Patients with non-transfusion-dependent thalassemia (NTDT) often develop iron overload that requires chelation to levels below the threshold associated with complications. This can take several years in patients with high iron burden, highlighting the value of long-term chelation data. Here, we report the 1-year extension of the THALASSA trial assessing deferasirox in NTDT; patients continued with deferasirox or crossed from placebo to deferasirox. Of 133 patients entering extension, 130 completed. Liver iron concentration (LIC) continued to decrease with deferasirox over 2 years; mean change was -7.14 mg Fe/g dry weight (dw) (mean dose 9.8 ± 3.6 mg/kg/day). In patients originally randomized to placebo, whose LIC had increased by the end of the core study, LIC decreased in the extension with deferasirox with a mean change of -6.66 mg Fe/g dw (baseline to month 24; mean dose in extension 13.7 ± 4.6 mg/kg/day). Of 166 patients enrolled, 64 (38.6 %) and 24 (14.5 %) patients achieved LIC <5 and <3 mg Fe/g dw by the end of the study, respectively. Mean LIC reduction was greatest in patients with the highest pretreatment LIC. Deferasirox progressively decreases iron overload over 2 years in NTDT patients with both low and high LIC. Safety profile of deferasirox over 2 years was consistent with that in the core study.
Assuntos
Benzoatos/uso terapêutico , Transfusão de Sangue , Quelantes de Ferro/uso terapêutico , Sobrecarga de Ferro/tratamento farmacológico , Talassemia/tratamento farmacológico , Triazóis/uso terapêutico , Estudos Cross-Over , Deferasirox , Método Duplo-Cego , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/epidemiologia , Estudos Prospectivos , Talassemia/sangue , Talassemia/epidemiologia , Fatores de Tempo , Resultado do TratamentoRESUMO
The 1-year THALASSA study enrolled 166 patients with various non-transfusion-dependent thalassemia (NTDT) syndromes, degrees of iron burden and patient characteristics, and demonstrated the overall efficacy and safety of deferasirox in reducing liver iron concentration (LIC) in these patients. Here, reduction in LIC with deferasirox 5 and 10 mg/kg/day starting dose groups is shown to be consistent across the following patient subgroups-baseline LIC/serum ferritin, age, gender, race, splenectomy (yes/no), and underlying NTDT syndrome (ß-thalassemia intermedia, HbE/ß-thalassemia or α-thalassemia). These analyses also evaluated deferasirox dosing strategies for patients with NTDT. Greater reductions in LIC were achieved in patients dose-escalated at Week 24 from deferasirox 10 mg/kg/day starting dose to 20 mg/kg/day. Patients who received an average actual dose of deferasirox >12.5-≤17.5 mg/kg/day achieved a greater LIC decrease compared with the ≥7.5-≤12.5 mg/kg/day and >0-<7.5 mg/kg/day subgroups, demonstrating a dose-response efficacy. LIC reduction across patient subgroups was generally consistent with the primary efficacy analysis with a similar safety profile.