Browsing by Author "Olivieri, N."

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Adaptation to anemia in hemoglobin E-beta thalassemia
(American Society of Hematology, 2010) Allen, A.; Fisher, C.; Premawardhena, A.; Peto, T.; Allen, S.J.; Arambepola, M.; Thayalsuthan, V.; Olivieri, N.; Weatherall, D.
Hemoglobin E beta thalassemia is the commonest form of severe thalassemia in many Asian countries. Its remarkably variable clinical phenotype presents a major challenge to determining its most appropriate management. In particular, it is not clear why some patients with this condition can develop and function well at very low hemoglobin levels. Here, we demonstrate that patients with hemoglobin E beta thalassemia have a significant decrease in the oxygen affinity of their hemoglobin, that is an increased P(50) value, in response to anemia. This may in part reflect the lower level of hemoglobin F in this condition compared with other forms of beta thalassemia intermedia. The ability to right-shift the oxygen dissociation curve was retained across the spectrum of mild and severe phenotypes, despite the significantly higher levels of hemoglobin F in the former, suggesting that efforts directed at producing a modest increase in the level of hemoglobin F in symptomatic patients with this disease should be of therapeutic value.
Alpha thalassaemia and extended alpha globin genes in Sri Lanka
(Elsevier-Academic Press, 2013) Suresh, S.; Fisher, C.; Ayyub, H.; Premawardhena, A.; Allen, A.; Perera, A.; Bandara, D.; Olivieri, N.; Weatherall, D.
The α-globin genes were studied in nine families with unexplained hypochromic anaemia and in 167 patients with HbE β thalassaemia in Sri Lanka. As well as the common deletion forms of α(+) thalassaemia three families from an ethnic minority were found to carry a novel form of α(0) thalassaemia, one family carried a previously reported form of α(0) thalassaemia, --(THAI), and five families had different forms of non-deletional thalassaemia. The patients with HbE β thalassaemia who had co-inherited α thalassaemia all showed an extremely mild phenotype and reduced levels of HbF and there was a highly significant paucity of α(+) thalassaemia in these patients compared with the normal population. Extended α gene arrangements, including ααα, αααα and ααααα, occurred at a low frequency and were commoner in the more severe phenotypes of HbE β thalassaemia. As well as emphasising the ameliorating effect of α thalassaemia on HbE β thalassaemia the finding of a novel form of α(0) thalassaemia in an ethnic minority, together with an unexpected diversity of forms of non-deletion α thalassaemia in Sri Lanka, further emphasises the critical importance of micro-mapping populations for determining the frequency of clinically important forms of the disease.
The Evolutionary and clinical implications of the uneven distribution of the frequency of the inherited haemoglobin variants over short geographical distances
(Wiley-Blackwell, 2017) Premawardhena, A.; Allen, A.; Piel, F.; Fisher, C.; Perera, L.; Rodrigo, R.; Goonathilaka, G.; Ramees, L.; Peto, T.; Olivieri, N.; Weatherall, D.
Studies of the frequency of heterozygous carriers for common inherited diseases of haemoglobin in over 7500 adolescent children in 25 districts in Sri Lanka have disclosed a highly significant variation over very short geographical distances. A further analysis of these findings, including their relationship to the past frequency and distribution of malaria, climatic variation, altitude, ethnic origin and consanguinity rates, have provided evidence regarding the evolutionary basis for the variable distribution of these conditions over short distances. It is likely that the complex interplay between malaria and the environment, together with related ethnic and social issues, exists in many countries across the tropical belt. Hence, these observations emphasise the importance of micromapping heterozygote distributions in high-frequency countries in order to define their true burden and the facilities required for the prevention and management of the homozygous and compound heterozygous disorders that result from their interaction.
Headache: an important symptom possibly linked to white matter lesions in thalassaemia.
(Wiley-Blackwell, 2019) Premawardhena, A.; Ranawaka, U.; Pilapitiya, T.; Weerasinghe, G.; Hapangama, A.; Hettiarachchi, S.; Salvin, K.; Silva, I.; Hameed, N.; Weatherall, M.; Olivieri, N.; Weatherall, D.
Neurological manifestations are reported only occasionally in patients with thalassaemia and are given much less prominence than the complications related to anaemia and iron overload. White matter changes (WMCs) on magnetic resonance imaging (MRI) in patients with thalassaemia were first reported two decades ago but the significance of these lesions remains unclear. We studied the neurological and cognitive manifestations in 82 older patients with thalssaemia [25 Thalassaemia major (TM), 24 thalassaemia intermedia (TI) and 33 haemaglobin E β thalassaemia (EBT)] and 80 controls, and found that headaches were more common in thalassaemia patients (50/82, 61%) than in controls (18/80, 22·5%: P < 0·001). WMCs on MRI were found in 20/82 (24·3%) patients and 2/29 (6·9%) controls had (P = 0·078). WMC were more common among those with headaches (17/50: 34%) than in those without headache (3/32; 9·3%) (P = 0·023). WMCs were not associated with reduction of cognition. Nevertheless, cognition was lower in the TI and EBT groups compared with those with TM (P = 0·002). The association of headache with WMC in thalassaemia has not been reported before and warrants further study.
Methemoglobinemia and ascorbate deficiency in hemoglobin E β thalassemia: metabolic and clinical implications.
(American Society of Hematology., 2012) Allen, A.; Fisher, C.; Premawardhena, A.; Bandara, D.; Perera, A.; Allen, S.; St Pierre, T.; Olivieri, N.; Weatherall, D.
ABSTRACT: During investigations of the phenotypic diversity of hemoglobin (Hb) E β thalassemia, a patient was encountered with persistently high levels of methemoglobin associated with a left-shift in the oxygen dissociation curve, profound ascorbate deficiency, and clinical features of scurvy; these abnormalities were corrected by treatment with vitamin C. Studies of erythropoietin production before and after treatment suggested that, as in an ascorbate-deficient murine model, the human hypoxia induction factor pathway is not totally dependent on ascorbate levels. A follow-up study of 45 patients with HbE β thalassemia showed that methemoglobin levels were significantly increased and that there was also a significant reduction in plasma ascorbate levels. Haptoglobin levels were significantly reduced, and the high frequency of the 2.2 haptoglobin genotype may place an additional pressure on ascorbate as a free-radical scavenger in this population. There was, in addition, a highly significant correlation between methemoglobin levels, splenectomy, and factors that modify the degree of globin-chain imbalance. Because methemoglobin levels are modified by several mechanisms and may play a role in both adaptation to anemia and vascular damage, there is a strong case for its further study in other forms of thalassemia and sickle-cell anemia, particularly when splenic function is defective.
A "One-Stop" screening protocol for hemoglobinopathy traits and iron deficiency in Sri Lanka
(Lausanne : Frontiers Media S.A., 2019) Allen, A.; Perera, S.; Perera, L.; Rodrigo, R.; Mettananda, S.; Matope, A.; Silva, I.; Hameed, N.; Fisher, C. A.; Olivieri, N.; Weatherall, D. J.; Allen, S.; Premawardhena, A.
INTRODUCTION: The high frequencies of carriers of severe haemoglobinopathies and of iron deficiency in Southeast Asia require reliable and affordable tests to improve on current screening procedures. OBJECTIVES: We evaluate a "one stop" approach using the THALCON dichlorophenolindophenol (DCIP) and one-tube osmotic fragility (OF) tests and measurement of Zinc Protoporphyrin (ZPP) to detect and distinguish HbE and β-thalassaemia traits from iron deficiency. We compare findings with current screening practice in Sri Lanka that relies on the identification of low mean red cell volume and/or mean red cell hemoglobin for this purpose.METHODS: Between November 2017 and May 2018, we undertook a cross-sectional survey of secondary school students in Gampaha district, Sri Lanka. The THALCON-DCIP and OF tests were compared to capillary electrophoresis (CE), used as a gold standard to detect haemoglobinopathies. ZPP was measured in whole blood. Plasma ferritin and C-reactive protein (CRP) were measured in students with a raised ZPP concentration. RESULTS: We collected venous blood samples from 1,324/1,332 (99.4%) students. The median age of the students was 17 (IQR 16-18) years, all were Sinhalese and 814/1,324 (61.5%) were female. CE identified 3 students with HbE trait and 26 students with β-thalassaemia trait. The THALCON-DCIP test was positive only in the 3 students with HbE (sensitivity 100%, 95% CI 29.2-100.0; specificity 100%, 95% CI 99.7-100.0). The THALCON-OF test identified all 26 students with β-thalassaemia trait (sensitivity = 100%, 95% CI 86.8-100.0) and 287 students with a normal CE result (specificity = 77.9%; 95% CI 75.5-80.1). It was also positive in 2/3 (66.7%) students with HbE trait. Iron deficiency (ZPP > 70 μmol/mol heme) was present in 118/1,240 (9.5%) students with a normal hemoglobin genotype, all of whom had plasma ferritin <15 ng/ml and CRP <5 mg/L. CONCLUSION: This one-stop approach offers reliable and affordable population screening for both haemoglobinopathy traits and iron deficiency in resource-limited settings where these conditions are common and ensures that iron supplements are targeted only to those who require them. Further work is warranted to refine the OF test to reduce the number of false positive results
Oxidative status in the β-thalassemia syndromes in Sri Lanka; a cross-sectional survey
(Elsevier Science-Pergamon Press, 2021) Allen, A.; Perera, S.; Mettananda, S.; Rodrigo, R.; Perera, L.; Darshana, T.; Moggach, F.; Crawford, A.J.; Heirene, L.; Fisher, C.; Olivieri, N.; Rees, D.; Premawardhena, A.; Allen, S.
ABSTRACT: In the β-thalassemias, oxidative stress, resulting from chronic hemolysis, globin chain imbalance, iron overload and depleted antioxidant defences, likely contributes to cell death, organ damage, anemia, hypoxia and inflammation. We assessed variations in these parameters in β-thalassemia syndromes in Sri Lanka. Between November 2017 and June 2018, we assessed children and adults attending two thalassemia centres in Sri Lanka: 59 patients with HbE β-thalassemia, 50 β-thalassemia major, 40 β-thalassemia intermedia and 13 HbS β-thalassemia. Median age was 26.0 years (IQR 15.3-38.8), 101 (62.3%) were female and 152 (93.8%) of Sinhalese ethnicity. Methemoglobin, plasma hemoglobin, heme and ferritin were measured as sources of oxidants; plasma total antioxidant capacity, haptoglobin, hemopexin and vitamins C and E assessed antioxidant status; plasma thiobarbituric acid reactive substances and 8-hydroxy-2'-deoxyguanosine assessed oxidative damage; hemoglobin, plasma erythropoietin and transferrin receptor assessed anemia and hypoxia and plasma interleukin-6 and C-reactive protein assessed inflammation. Fruit and vegetable intake was determined by dietary recall. Physical fitness was investigated using the six-minute walk test and measurement of handgrip strength. Oxidant sources were frequently increased and antioxidants depleted, with consequent oxidative damage, anemia, hypoxia and inflammation. Biomarkers were generally most abnormal in HbE β-thalassemia and least abnormal in β-thalassemia intermedia but also varied markedly between individuals with the same thalassemia syndrome. Oxidative stress and damage were also more severe in splenectomized patients and/or those receiving iron chelation therapy. Less than 15% of patients ate fresh fruits or raw vegetables frequently, and plasma vitamins C and E were deficient in 132/160 (82.5%) and 140/160 (87.5%) patients respectively. Overall, physical fitness was poor in all syndromes and was likely due to anemic hypoxia. Studies of antioxidant supplements to improve outcomes in patients with thalassemia should consider individual patient variation in oxidative status both between and within the thalassemia syndromes. KEYWORDS: antioxidants; oxidative damage; oxidative stress; thalassemia; vitamins C and E.
Oxidative stress and antioxidant deficiency in the β-thalassaemia in Sri Lanka
(Sri Lanka Medical Association, 2021) Perera, S.; Allen, A.; Mettananda, S.; Rodrigo, R.; Perera, L.; Darshana, T.; Moggach, F.; Jackson-Crawford, A.; Heirene, L.; Fisher, C.; Olivieri, N.; Rees, D.; Allen, S.; Premawardhena, A.
Introduction In the β thalassaemias oxidative stress is potentially high and this could be further exacerbated in the absence of robust antioxidant defences, such as nutritional vitamin C and E deficiencies. We undertook a comprehensive assessment of oxidant, antioxidant and inflammatory status in patients with subtypes of β-thalassaemia to study these factors in detail. Methods Consenting patients attending the thalassaemia centre in Ragama, (between November 2017 and June 2018) were assessed for the following: methaemoglobin, plasma haemoglobin, heme and ferritin as sources of oxidants, plasma haptoglobin, hemopexin and vitamins C and E as markers of antioxidants, plasma interleukin-6 and C-reactive protein for inflammation. Fruit and vegetable intake was determined by dietary recall. Results 162 patients were recruited. (59 HbE β-thalassaemia, 50 β-thalassaemia major, 40 β-thalassaemia intermedia, 13 HbS β-thalassaemia. Median age was 26.0 years (IQR 15.3-38.8), 101 (62.3%) were female. Oxidants were frequently increased and antioxidants depleted with high levels of oxidant damage, hypoxia and inflammation. Abnormalities were most severe in HbE-β thalassaemia and least severe in β thalassaemia intermedia. Oxidative stress was also more severe in splenectomised patients. Plasma vitamin C concentration was below the lower level of quantitation in 86/160 (53.8%) patients and vitamin E in 130/160 (81.3%) patients. Less than 15% of patients ate fresh fruits or raw vegetables frequently. Conclusion Markedly increased oxidative stress and antioxidant deficiency were observed in this study group, especially in those with HbE β-thalassaemia. Vitamin C & E supplementation may have a role in the long-term management of thalassaemia syndromes.
Paraspinal extramcduallry erythropoiesis- a rare cause of spinal cord compression: two case reports
(Sri Lanka Medical Association, 2004) Arambepola, M.; Premawardhena, A.P.; de Silva, S.; Olivieri, N.; Weatherall, D.J.
INTRODUCTION: Extrameduallry erythropoiesis (EME) is characterized by the appearance of haemopoietic tissue outside the bone marrow. When EME occurs, albeit rarely, outside the liver and spleen problems may occur. We describe two patients with haemoglobin E- [β thalassaemia who had spinal cord compression, due to EME masses which was reversed with treatment with hydroxyurea and hypertransfusion. PATIENT A: Was a 27year old with HbE -(β thalassaemia. His mean pre transfusion haemoglobin level was 5.5 g/dl. He presented with a six-month history of progressive numbness of his legs. On examination he was found to be paraparetic. The magnetic resonance scan (MRI) showed external compression of the spinal cord between the 4th and 8th thoracic vertebrae. Patient was put on a hypertransfusion regimen and hydroxyurea and made a complete recovery within 4 weeks. Patient B: Was a 9 year old boy with a diagnosis of Haemoglobin E [β thalassaemia who presented with paraplegia which had developed over 3 months. His spinal MRI showed two masses one in the upper thoracic vertebrae and the other at the 1st lumbar level. He was commenced on hydroxyurea and hypertransfusiion to maintain pre-transfusion haemoglobin at >9.5g/dl) and his neurological recover was remarkable. Six months later he had no neurological deficit. DISCUSSION: The above cases highlight the potentially dangerous complications of EME when it involves the spinal cord. They also highlight that even lesions which are sufficiently large to cause complete paraplegia are potentially reversible. Hypertransfusion, hydroxyurea, surgery and previously been used with varying success. The problem remains in deciding the optimal method of management.
Thalassemia in Sri Lanka: a progress report
(Oxford University Press, 2004) Premawardhena, A.P.; de Silva, S.; Arambepola, M.; Olivieri, N.; Merson, L.; Muraco, J.; Allen, A.; Fisher, C.A.; Peto, T.; Vichinsky, E.; Weatherall, D.J.
The thalassemias pose an increasing burden for health-care services in many Asian countries. In order to conserve rare resources, it is essential to determine the reasons for the remarkable phenotypic heterogeneity and natural history of these disorders so that the most cost-effective methods for their control and management can be established. A long-term observational study of patients with different forms of thalassemia in Sri Lanka suggests that in addition to the well-defined primary, secondary and tertiary genetic modifiers, environmental factors, particularly malaria, and variation in the ability to adapt to the profound anaemia which characterizes these conditions, may play a significant role in determining their clinical severity. These findings may have important implications for the control and management of thalassemia in Asian populations