Conference Papers

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Elective cholecystectomy is associated with increased morbidity and mortality in patients with severe Thalassemia: A retrospective case control study.
(Ferrata Storti Foundation, 2015) Premawardhena, A.; Fernando, R.; Kumarage, S.; Nishad, N.; de Silva, I.
BACKGROUND: Haemoglobin disorders including thalassemia and sickle cell disease are often complicated with gall stone formation. The co-existence of Gilbert's syndrome together with these diseases further increases the risk of gall bladder disease. Some of these patients develop symptomatic disease which necessitates surgical intervention. At present the timing of cholecystectomy for thalassemia is no different from that of the general population with the exception of removal of the gall bladder at the time of splenectomy. This is no longer the case in sickle cell disease where, laparoscopic cholecystectomy is recommended even in asymptomatic patients. This practice however has not been extended to other types of haemoglobin disorders. AIM(S): 1.To assess the perioperative complications of patients with thalassaemia during cholecytetomy and to compare it with non thalassaemics who undergo the procedure. 2. To see if there is enough evidence to recommend elective cholecystectomy for thalassaemics. METHOD(S): We retrospectively studied case notes of thalassemia patients who had cholecystectomy (cases) in two of the biggest thalassaemia centres in Sri Lanka and also of 62 non-thalassaemics (controls) with gall bladder disease who had been scheduled to have gall bladder surgery in the same hospitals and looked at their peri-operative complications. RESULT(S): 98 out of 540 (18%) thalassaemics in the two centres had gall stones. Mean age of cases was 26.8 (SD 10.9) years and of controls 47.5 (SD 19.7) years. 19 (19%) thalassaemics with gall stones had undergone cholecystectomy. Ten patients had cholecystectomy simultaneously with splenectomy. The majority of non-thalassaemic "controls" had laparoscopic cholecystectomy 53/55 (96.3%) whilst the patients with thalassaemia were mostly operated with laparotomy 13/19 (68%). There was a significant excess complications occurring in both early (42.11 vs. 18.1%) and late (31.5 vs. 12.7%) phases in the thalassaemic patients compared with the controls. Among the early complications, sepsis (10.5% vs. 1.8%) and liver abscess formation (5.2 vs. 0%) was significantly different in the groups, adversely affecting the thalassaemics. Recurrent abdominal pain was more common among the thalassaemics as a late complication (P<0.05). Six thalassaemic patients with gall stone disease died during this study, 5(5%) while awaiting surgery and 1(1%) after surgery. There were no deaths among the controls. Out of the deaths, 3 (50%) were directly attributable to gallstone disease. In all three septicemia precipitated heart failure. We found a significant increase of both early and late post-surgical complications in the thalassemia group and also increased mortality most of which was related to severe sepsis. Higher perioperative mortality and morbidity were seen among symptomatic thalassaemic patients with gall stone disease undergoing cholecystectomy. This seems to suggest a strong case for supporting elective cholecystectomy in thalassemics before they develop symptoms. SUMMARY AND CONCLUSION(S): We suggest that laparoscopic elective cholecystectomy be considered for non-sickle, thalassemia patients too who have asymptomatic gall bladder disease, in an attempt to reduce this morbidity and mortality.
Genome editing of haemopoietic stem cells for treatment of thalassaemia
(Oxford University Press, 2019) Badat, M.; Mettananda, S.; Hua, P.; Schwessinger, R.; Hughes, J.; Higgs, D.; Davies, J.
AIM: Thalassaemia is commonly due to mutations at the beta globin (HBB) locus, and this causes transfusion dependent anaemia in severe cases. A key pathophysiological factor is the imbalance of alpha and beta globin production. This results in accumulation of excess alpha globin chains, which are toxic and cause cell death. Patients who co-inherit partial deletions of the alpha globin genes with beta thalassaemia usually have a mild phenotype and are transfusion independent. We aim to develop genome editing strategies of haemopoietic stem cells to exploit this for use as part of an autologous transplant to treat thalassaemia. METHODS: CRISPR-Cas9 was used to edit the most important enhancer of the alpha globin gene to elicit a controlled reduction in alpha globin expression. In silico methods were used to define the key sequences to delete to abrogate transcription factor binding. This allowed us to develop a strategy to disrupt single transcription factor binding sites using Cas9 ribonucleoprotein. RESULTS: Our in silico approaches allowed us to define three key transcription factor binding sites within the enhancer. We were able to achieve indel efficiencies in excess of 75% as measured by next generation sequencing. This resulted in a much more controlled reduction in alpha globin expression than was achieved by deletion of the whole enhancer. DISCUSSION: In silico prediction allows the identification of the sites within enhancers that allow genome editing to be used to reduce gene expression in a highly controlled manner.
Correlation of genotype with phenotype in beta thalassaemia intermedia in Sri lanka
(Thalassaemia International Federation, 2015) Perera, P.S.; Silva, D.P.S.I.; Hapugoda, M.; Wickramarathne, M.N.; Wijesiriwardena, I.; Efremov, D.G.; Fisher, C.A.; Weatherall, D.J.; Premawardhena, A.
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