History

Fact Explanation
An inherited hemoglobinopathy This is an autosomal recessively inherited condition. Alteration in the globin chain production of either alpha or Beta can cause Thalassemia and when the β chain production is low, it's called β thalassemia. b-like globin genes are arranged in chromosome 11. Symptoms may not be evident until the 6-8 months of life as Hemoglobin F production occurs with production of γ-globin instead of beta chains. [1] [4] [6] [8] [9] [10]
Asymptomatic [1] [4] [6] Silent carriers and most patients with thalassemia traits also have no signs or symptoms and usually diagnosed when RBC indices are low and when there's hypochromic microcytic anemia that does not respond to iron supplementation. [1] [4] [6]
Shortness of breath on exertion, increased fatigue, suggestive of anemia [1] [4] [6] [10] Accumulation of α chains in the deficiency of beta chains in the RBC precursors causes intramedullary destruction of these cells and red blood cells in the circulation with excess alpha chains undergo hemolysis. Anemia in the person with β thalassemia are caused by both hemolysis and ineffective erythropoiesis.[1] [4] [6] [10]
Yellowish discolration of the sclera [1] [4] [6] [10] This is due to hemolytic process which results in increased production of bilirubin which gets deposited in the sclera. [1] [4] [6] [10]
Slight enlargement of the abdomen [1] [2] [4] [6] [8] [9] Increased extramedullary hemopoiesis in the spleen cause splenic enlargement. [1] [2] [4] [6] [8] [9]
Frontal bossing and charesteristic facies [1] [2] [4] [6] ineffective erythropoiesis in the bone causes expansion of the marrow and these bone changes. [1] [2] [4] [6]
Fever and poor growth [1] [2] [4] [6] Poor growth in patients with thalassemia could be due to involvement of endocrine organs in iron overload as well as due to chronicity of the disease. [1] [2] [4] [6]
Acute loin to groin pain with hematuria [1] [2] [4] [6] Hyperuricemia can occur as there's increased cell turn over due to hemolysis and kidney stones can result. [1] [2] [4] [6]
Bleeding tendency [1] [2] [4] This complication results from iron overload due to increased iron absorption as well as due to multiple transfusions. Many internal organs are affected especially liver. Liver dysfunction results in reduced production of coagulation factors and low platelets with bleeding tendency. [1] [2] [4]
Slate grey discoloration of the skin [1] [2] [4] This is due to iron deposition in the skin [1] [2] [4]
Increased thirst, urination and weight loss [5] [7] These symptoms result from diabetes mellitus due to deposition of iron in the pancreas [5] [7]
Delayed puberty [7] This is due to iron deposition in the pitiutary and endocrine organs such as Thyroid gland. [7]
Chest pain, palpitations [3] This is due to iron deposition in the heart resulting in cardiomyopathy causing chest pain and rhythm disturbances. [3]
References
  1. GALANELLO RENZO, ORIGA RAFFAELLA. Beta-thalassemia. Array [online] 2010 December [viewed 30 August 2014] Available from: doi:10.1186/1750-1172-5-11
  2. PERISANO CARLO, MARZETTI EMANUELE, SPINELLI MARIA SILVIA, CALLà CINZIA ANNA MARIA, GRACI CALOGERO, MACCAURO GIULIO. Physiopathology of Bone Modifications in 𝜷-Thalassemia. Anemia [online] 2012 December, 2012:1-5 [viewed 30 August 2014] Available from: doi:10.1155/2012/320737
  3. KREMASTINOS D. T., FARMAKIS D., AESSOPOS A., HAHALIS G., HAMODRAKA E., TSIAPRAS D., KEREN A.. -Thalassemia Cardiomyopathy: History, Present Considerations, and Future Perspectives. Circulation: Heart Failure [online] December, 3(3):451-458 [viewed 30 August 2014] Available from: doi:10.1161/CIRCHEARTFAILURE.109.913863
  4. RIBEIL JEAN-ANTOINE, ARLET JEAN-BENOIT, DUSSIOT MICHAEL, CRUZ MOURA IVAN, COURTOIS GENEVIèVE, HERMINE OLIVIER. Ineffective Erythropoiesis in β-Thalassemia. The Scientific World Journal [online] 2013 December, 2013:1-11 [viewed 30 August 2014] Available from: doi:10.1155/2013/394295
  5. BAHAR ADELE, KASHI ZAHRA, SOHRAB MEHRNOUSH, KOSARYAN MEHRNOUSH, JANBABAI GHASEM. Relationship between beta-globin gene carrier state and insulin resistance. Array [online] 2012 December [viewed 30 August 2014] Available from: doi:10.1186/2251-6581-11-22
  6. ATANASOVSKA BILJANA, BOZHINOVSKI GEORGI, PLASESKA-KARANFILSKA DIJANA, CHAKALOVA LYUBOMIRA, PALAU FRANCESC. Efficient Detection of Mediterranean β-Thalassemia Mutations by Multiplex Single-Nucleotide Primer Extension. PLoS ONE [online] 2012 October [viewed 30 August 2014] Available from: doi:10.1371/journal.pone.0048167
  7. ABDOLLAH SHAMSHIRSAZ ALIREZA, BEKHEIRNIA MIR REZA, KAMGAR MOHAMMAD, POURZAHEDGILANI NIMA, BOUZARI NAVID, HABIBZADEH MOHAMMADREZA, HASHEMI REZA, ABDOLLAH SHAMSHIRSAZ AMIR HOOSHANG, AGHAKHANI SHAHRIAR, HOMAYOUN HOOMAN, LARIJANI BAGHER. . BMC Endocr Disord [online] 2003 December [viewed 30 August 2014] Available from: doi:10.1186/1472-6823-3-4
  8. THEIN SL. Genetic modifiers of beta-thalassemia. Haematologica [online] 2005 May, 90(5):649-60 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15921380
  9. HARTEVELD CORNELIS L, HIGGS DOUGLAS R. α-thalassaemia. Array [online] 2010 December [viewed 30 August 2014] Available from: doi:10.1186/1750-1172-5-13
  10. SHACKLEY B. S., DRAKE T. A., BUTCH A. W.. Chronic Microcytic Anemia and Jaundice in a 36-Year-Old Male of Burmese Descent. Laboratory Medicine [online] December, 41(2):78-82 [viewed 30 August 2014] Available from: doi:10.1309/LM73OLT7NPYEHHWR
  11. MANDAL PK, DOLAI TK. Intrathoracic extramedullary hematopoiesis in E-beta thalassemia. Indian J Pathol Microbiol [serial online] 2014 [cited 2014 Aug 30];57:497-8. Available from: http://www.ijpmonline.org/text.asp?2014/57/3/497/138800

Examination

Fact Explanation
No signs [1] [3] [4] [7] Silent carriers and most patients with thalassemia traits also have no signs or symptoms and usually diagnosed when RBC indices are low and when there's hypochromic microcytic anemia that does not respond to iron supplementation. [1] [4] [6]
Pallor, Icterus and Splenomegaly in infancy [1] [3] [4] [8] Symptoms usually appear when there's conversion of Hb F to Hb A (in which gamma chains are replaced with beta chains) at aroung 6-8 months of life. A thalassemic infant typically presents with pallor due to anemia, icterus and splenomegaly. [1] [3] [4] [8]
Pallor [1] [3] [4] [8] Accumulation of α chains in the deficiency of beta chains in the RBC precursors causes intramedullary destruction of these cells and red blood cells in the circulation with excess alpha chains undergo hemolysis. Anemia in the person with β thalassemia are caused by both hemolysis and ineffective erythropoiesis [1] [3] [4] [8]
Icterus [1] [3] [4] [8] This is due to hemolytic process which results in increased production of bilirubin which gets deposited in the sclera. [1] [3] [4] [8]
Charesteristic facies such as frontal bossing, prominent facial bones, and dental malocclusion [1] [2] [3] [4] [7] [8] [9] Increased erythropoiesis in the bone causes expansion of the marrow and these bone changes. [1] [2] [3] [4] [7] [8] [9]
Massive splenomegaly [1] [3] [4] [8] Increased extramedullary hemopoiesis in the spleen cause splenic enlargement. [1] [3] [4] [8]
Hepatomegaly [5] [11] [12] This results from iron overload due to increased iron absorption as well as due to multiple transfusions. Many internal organs are affected especially liver. Liver can be enlarged due to extramedullary hemopoiesis as well. [5] [11] [12]
Slate grey discoloration of the skin [5] [11] [12] This is due to iron deposition in the skin [5] [11] [12]
Growth retardation [5] [11] [12] Poor growth in patients with thalassemia could be due to involvement of endocrine organs in iron overload as well as due to chronicity of the disease.[5] [11] [12]
Heart murmer and Signs of heart failure such as Cardiomegaly, Gallop rhythm, Bilateral inspiratory crepiations [5] [6] [10] [11] This is due to iron deposition in the heart resulting in cardiomyopathy causing chest pain and rhythm disturbances abd subsequent heart failure [5] [6] [10] [11]
Paralysis, Neuropathy [9] Large extramedullary hematopoietic masses in the spine can compress the nerves and cause neuropathy [9]
Transfusion marks over the abdomen [12] This is due to iron chelation therapy with subcutaneous chelating agents. These injections are usually given around the umbilicus and can be seen as a feature of good compliance to chelation therapy. [12]
References
  1. GALANELLO RENZO, ORIGA RAFFAELLA. Beta-thalassemia. Array [online] 2010 December [viewed 30 August 2014] Available from: doi:10.1186/1750-1172-5-11
  2. PERISANO CARLO, MARZETTI EMANUELE, SPINELLI MARIA SILVIA, CALLà CINZIA ANNA MARIA, GRACI CALOGERO, MACCAURO GIULIO. Physiopathology of Bone Modifications in 𝜷-Thalassemia. Anemia [online] 2012 December, 2012:1-5 [viewed 30 August 2014] Available from: doi:10.1155/2012/320737
  3. RIBEIL JEAN-ANTOINE, ARLET JEAN-BENOIT, DUSSIOT MICHAEL, CRUZ MOURA IVAN, COURTOIS GENEVIèVE, HERMINE OLIVIER. Ineffective Erythropoiesis in β-Thalassemia. The Scientific World Journal [online] 2013 December, 2013:1-11 [viewed 30 August 2014] Available from: doi:10.1155/2013/394295
  4. ATANASOVSKA BILJANA, BOZHINOVSKI GEORGI, PLASESKA-KARANFILSKA DIJANA, CHAKALOVA LYUBOMIRA, PALAU FRANCESC. Efficient Detection of Mediterranean β-Thalassemia Mutations by Multiplex Single-Nucleotide Primer Extension. PLoS ONE [online] 2012 October [viewed 30 August 2014] Available from: doi:10.1371/journal.pone.0048167
  5. ABDOLLAH SHAMSHIRSAZ ALIREZA, BEKHEIRNIA MIR REZA, KAMGAR MOHAMMAD, POURZAHEDGILANI NIMA, BOUZARI NAVID, HABIBZADEH MOHAMMADREZA, HASHEMI REZA, ABDOLLAH SHAMSHIRSAZ AMIR HOOSHANG, AGHAKHANI SHAHRIAR, HOMAYOUN HOOMAN, LARIJANI BAGHER. . BMC Endocr Disord [online] 2003 December [viewed 30 August 2014] Available from: doi:10.1186/1472-6823-3-4
  6. KREMASTINOS D. T., FARMAKIS D., AESSOPOS A., HAHALIS G., HAMODRAKA E., TSIAPRAS D., KEREN A.. -Thalassemia Cardiomyopathy: History, Present Considerations, and Future Perspectives. Circulation: Heart Failure [online] December, 3(3):451-458 [viewed 30 August 2014] Available from: doi:10.1161/CIRCHEARTFAILURE.109.913863
  7. THEIN SL. Genetic modifiers of beta-thalassemia. Haematologica [online] 2005 May, 90(5):649-60 [viewed 30 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/15921380
  8. HOPPE C. C.. Newborn screening for non-sickling hemoglobinopathies. Hematology [online] December, 2009(1):19-25 [viewed 30 August 2014] Available from: doi:10.1182/asheducation-2009.1.19
  9. MANDAL PK, DOLAI TK. Intrathoracic extramedullary hematopoiesis in E-beta thalassemia. Indian J Pathol Microbiol [serial online] 2014 [cited 2014 Aug 30];57:497-8. Available from: http://www.ijpmonline.org/text.asp?2014/57/3/497/138800
  10. YANG GAOHUI, LIU RONGRONG, PENG PENG, LONG LILING, ZHANG XINHUA, YANG WEIJIA, TAN SHAOHONG, PAN HONGFEI, LONG XINGJIANG, HE TAIGANG, ANDERSON LISA, LAI YONGRONG, XU XIAOLEI. How Early Can Myocardial Iron Overload Occur in Beta Thalassemia Major?. PLoS ONE [online] 2014 January [viewed 30 August 2014] Available from: doi:10.1371/journal.pone.0085379
  11. MELCHIORI LUCA, GARDENGHI SARA, RIVELLA STEFANO. 𝛽-Thalassemia: HiJAKing Ineffective Erythropoiesis and Iron Overload. Advances in Hematology [online] 2010 December, 2010:1-7 [viewed 30 August 2014] Available from: doi:10.1155/2010/938640
  12. VICHINSKY E.. Oral Iron Chelators and the Treatment of Iron Overload in Pediatric Patients With Chronic Anemia. PEDIATRICS [online] 2008 June, 121(6):1253-1256 [viewed 30 August 2014] Available from: doi:10.1542/peds.2007-1824

Differential Diagnoses

Fact Explanation
Chronic iron deficiency anemia [1] Iron deficiency anemia develops there's severe iron deficiency which is an essential factor for formation of erythrocytes. Dietary iron deficiencies, iron absorption defects, chronic gasto-intestinal or genitourinary bleeding could be the causative factors. This also presents with microcytic hypochromic anemia. [1]
Pyruvate kinase deficiency [2] [3] Pyruvate kinase is an enzyme in the red blood cell and deficiency state causes a hemolytic anemia with normochromic and normocytic anemia with reticulocytosis. [2] [3]
Chronic malaria [4] [5] Malaria is caused by infection with Plasmodium protozoa and the infection is transmitted by an infective female Anopheles mosquito. Chronic malaria can result in massive splenomegaly, anemia and jaundice. [4] [5]
Hereditary spherocytosis [6] This is an autosomal dominant hemolytic disorder causing defects in red blood cell (RBC) membrane proteins and they present with anemia, reticulocytosis, spherocytes on the peripheral blood smear, and splenomegaly [6]
Sideroblastic anemia [7] [8] A sideroblast is a red blood cell with deposits of iron in cytoplasm and this stains with Prussian blue. This also produces a microcytic hypochromic anemia. [7] [8]
Lead poisoning [9] [10] [11] They also present with a microcytic hypochromic anemia. Clinical presentation is not very specific and toys in the children may contain lead and long term can cause lead poisoning [9] [10] [11]
References
  1. MILLER J. L.. Iron Deficiency Anemia: A Common and Curable Disease. Cold Spring Harbor Perspectives in Medicine [online] December, 3(7):a011866-a011866 [viewed 31 August 2014] Available from: doi:10.1101/cshperspect.a011866
  2. MACHADO PATRíCIA, et al. Pyruvate Kinase Deficiency in Sub-Saharan Africa: Identification of a Highly Frequent Missense Mutation (G829A;Glu277Lys) and Association with Malaria. PLoS ONE [online] 2012 October [viewed 31 August 2014] Available from: doi:10.1371/journal.pone.0047071
  3. JUVET FLORENCE, GIGER URS, BATTERSBY IAN, MENAUT PIERRE, SYME HARRIET M, MOONEY CARMEL T. Erythrocyte pyruvate kinase deficiency in three West Highland white terriers in Ireland and the UK. Array [online] 2013 December [viewed 31 August 2014] Available from: doi:10.1186/2046-0481-66-12
  4. HOMMEL BENJAMIN, et al. Chronic Malaria Revealed by a New Fluorescence Pattern on the Antinuclear Autoantibodies Test. PLoS ONE [online] 2014 February [viewed 31 August 2014] Available from: doi:10.1371/journal.pone.0088548
  5. STAUFFER W., FISCHER P. R.. Diagnosis and Treatment of Malaria in Children. Clinical Infectious Diseases [online] 2003 November, 37(10):1340-1348 [viewed 31 August 2014] Available from: doi:10.1086/379074
  6. BOLTON-MAGGS P H B. Hereditary spherocytosis; new guidelines. Archives of Disease in Childhood [online] 2004 September, 89(9):809-812 [viewed 31 August 2014] Available from: doi:10.1136/adc.2003.034587
  7. FLEMING M. D.. Congenital Sideroblastic Anemias: Iron and Heme Lost in Mitochondrial Translation. Hematology [online] December, 2011(1):525-531 [viewed 31 August 2014] Available from: doi:10.1182/asheducation-2011.1.525
  8. ISSA S., INGLEY K.. A case of refractory anemia with ring sideroblasts and associated thrombocytosis. Blood [online] December, 121(21):4256-4256 [viewed 31 August 2014] Available from: doi:10.1182/blood-2012-11-469189
  9. HOU SHUANGXING, YUAN LIANFANG, JIN PENGPENG, DING BOJUN, QIN NA, LI LI, LIU XUEDONG, WU ZHONGLIANG, ZHAO GANG, DENG YANCHUN. A clinical study of the effects of lead poisoning on the intelligence and neurobehavioral abilities of children. Array [online] 2013 December [viewed 31 August 2014] Available from: doi:10.1186/1742-4682-10-13
  10. BELLINGER D. C.. Childhood lead poisoning: the torturous path from science to policy. Journal of Clinical Investigation [online] 2006 March, 116(4):853-857 [viewed 31 August 2014] Available from: doi:10.1172/JCI28232
  11. Lead Exposure in Children: Prevention, Detection, and Management. PEDIATRICS [online] 2005 October, 116(4):1036-1046 [viewed 31 August 2014] Available from: doi:10.1542/peds.2005-1947

Investigations - for Diagnosis

Fact Explanation
Full blood count [2] [3] [4] [9] Hemoglobin count is low. Both MCV(Mean corpuscular volume) and MCH (mean corpuscular Hb) are very low. Remarkably RDW is very high due to presence of cells of various sizes and shapes. Platelet count is usually normal but splenomegaly can cause low counts. [2] [3] [4] [9]
Blood picture [2] [3] [4] This shows hypochromatic microcytic cells with reticulocytosis, nucleated RBCs and basophilic stippling. Occaional target cells can be seen as well. [2] [3] [4]
Hemoglobin electrophoresis [2] [3] [4] [6] This confirms the diagnosis of thalassemia. This shows elevated Hb F fraction in patients with β thalassemia. Hb A is not present and only Hb A2 and Hb F are seen. [2] [3] [4] [6]
High Performance Liquid Chromatography (HPLC) [1] [2] [3] [4] [7] This also confirms Thalassemia and it gives a quick diagnosis than Hb electrophoresis and only needs a small amount of blood. [1] [2] [3] [4] [7]
Serum iron studies- Serum iron, Serum Ferritin, Total iron binding capacity [5] [6] Are usually normal unless there's iron overload. This is usually done to exclude iron deficiency anemia. [5] [6]
Skeletal x-rays [8] The classic "hair on end" appearance of the skull x-ray with expansion of the marrow with marked thinning the cortex is seen.[8]
References
  1. HOPPE C. C.. Newborn screening for non-sickling hemoglobinopathies. Hematology [online] December, 2009(1):19-25 [viewed 31 August 2014] Available from: doi:10.1182/asheducation-2009.1.19
  2. GALANELLO RENZO, ORIGA RAFFAELLA. Beta-thalassemia. Array [online] 2010 December [viewed 31 August 2014] Available from: doi:10.1186/1750-1172-5-11
  3. BENZ E J, BERMAN B W, TONKONOW B L, COUPAL E, COATES T, BOXER L A, ALTMAN A, ADAMS J G. Molecular analysis of the beta-thalassemia phenotype associated with inheritance of hemoglobin E (alpha 2 beta2(26)Glu leads to Lys).. J. Clin. Invest. [online] 1981 July, 68(1):118-126 [viewed 31 August 2014] Available from: doi:10.1172/JCI110226
  4. RIBEIL JEAN-ANTOINE, ARLET JEAN-BENOIT, DUSSIOT MICHAEL, CRUZ MOURA IVAN, COURTOIS GENEVIèVE, HERMINE OLIVIER. Ineffective Erythropoiesis in β-Thalassemia. The Scientific World Journal [online] 2013 December, 2013:1-11 [viewed 31 August 2014] Available from: doi:10.1155/2013/394295
  5. VERMA SARIKA, GUPTA RUCHIKA, KUDESIA MADHUR, MATHUR ALKA, KRISHAN GOPAL, SINGH SOMPAL. Coexisting Iron Deficiency Anemia and Beta Thalassemia Trait: Effect of Iron Therapy on Red Cell Parameters and Hemoglobin Subtypes. ISRN Hematology [online] 2014 December, 2014:1-5 [viewed 31 August 2014] Available from: doi:10.1155/2014/293216
  6. BURDICK C. O., NTAIOS G., RATHOD D.. Separating Thalassemia Trait and Iron Deficiency by Simple Inspection. American Journal of Clinical Pathology [online] 2009 March, 131(3):444-444 [viewed 31 August 2014] Available from: doi:10.1309/AJCPC09VRAXEASMH
  7. YANG ZHAOHAI, CHAFFIN CAROLYN H., EASLEY PATTYE L., THIGPEN BEATRICE, REDDY VISHNU V. B.. Prevalence of Elevated Hemoglobin A2 Measured by the CAPILLARYS System. American Journal of Clinical Pathology [online] December, 131(1):42-48 [viewed 31 August 2014] Available from: doi:10.1309/AJCPD0PJGFT0SXMK
  8. TOUMBA MEROPI, SKORDIS NICOS. Osteoporosis Syndrome in Thalassaemia Major: An Overview. Journal of Osteoporosis [online] 2010 December, 2010:1-7 [viewed 31 August 2014] Available from: doi:10.4061/2010/537673
  9. VEHAPOGLU AYSEL, OZGURHAN GAMZE, DEMIR AYşEGUL DOGAN, UZUNER SELCUK, NURSOY MUSTAFA ATILLA, TURKMEN SERDAR, KACAN ARZU. Hematological Indices for Differential Diagnosis of Beta Thalassemia Trait and Iron Deficiency Anemia. Anemia [online] 2014 December, 2014:1-7 [viewed 31 August 2014] Available from: doi:10.1155/2014/576738

Investigations - Fitness for Management

Fact Explanation
phenotyping of RBC [2] [3] When multiple transfusions are carried out, antibodies can form against donor blood therefore this is done prior to starting transfusion therapy [2] [3]
Hepatitis screen [5] [6] Children affected with Thalassemia are dependent on blood transfusion, therefore Hepatitis is an infection that is likely to transmit from blood. Therefore the child is first screened against Hepatitis. Hepatitis vaccination is carried out before starting transfusion. [5] [6]
Folic acid level [4] Blood level maybe done prior to starting transfusion and folic acid is also administered. [4]
human leukocyte antigen (HLA) typing [1] [2] Stem cell transplantation is an emerging treatment method for thalassemia therefore to find a compatible donor, this is done. [1] [2]
Full blood count [7] [8] To exclude any significant anemia prior to surgery (Splenectomy) [7] [8]
Coagulation studies [7] [8] To exclude any coagulopathy prior to surgery (Splenectomy) [7] [8]
Renal function tests- Serum Creatinine, Blood urea nitrogen [7] [8] To exclude any renal dysfunction prior to anesthesia. [7] [8]
References
  1. ANGELUCCI E.. Hematopoietic Stem Cell Transplantation in Thalassemia. Hematology [online] December, 2010(1):456-462 [viewed 31 August 2014] Available from: doi:10.1182/asheducation-2010.1.456
  2. GALANELLO RENZO, ORIGA RAFFAELLA. Beta-thalassemia. Array [online] 2010 December [viewed 31 August 2014] Available from: doi:10.1186/1750-1172-5-11
  3. SINGER ST, WU V, MIGNACCA R, KUYPERS FA, MOREL P, VICHINSKY EP. Alloimmunization and erythrocyte autoimmunization in transfusion-dependent thalassemia patients of predominantly asian descent. Blood [online] 2000 Nov 15, 96(10):3369-73 [viewed 31 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/11071629
  4. SHERIEF LAILA M., ABD EL-SALAM SANAA M., KAMAL NAGLAA M., EL SAFY OSAMA, ALMALKY MOHAMED A. A., AZAB SEHAM F., MORSY HEMAT M., GHARIEB AMAL F.. Nutritional Biomarkers in Children and Adolescents with Beta-Thalassemia-Major: An Egyptian Center Experience. BioMed Research International [online] 2014 December, 2014:1-7 [viewed 31 August 2014] Available from: doi:10.1155/2014/261761
  5. ALI IJAZ, SIDDIQUE LUBNA, REHMAN LATIF U, KHAN NAJIB U, IQBAL AQIB, MUNIR IQBAL, RASHID FARZANA, KHAN SANA U, ATTACHE SAFIRA, SWATI ZAHOOR A, ASLAM MEHWISH S. Prevalence of HCV among the high risk groups in Khyber Pakhtunkhwa. Array [online] 2011 December [viewed 31 August 2014] Available from: doi:10.1186/1743-422X-8-296
  6. ARABABADI MK, NASIRI AHMADABADI B, YOUSEFI DAREDOR H, KENNEDY D. Epidemiology of occult hepatitis B infection among thalassemic, hemophilia, and hemodialysis patients. Hepat Mon [online] 2012 May, 12(5):315-9 [viewed 31 August 2014] Available from: doi:10.5812/hepatmon.5934
  7. SHULMAN M. A., THOMPSON B. R.. I. Not fit for a haircut ... how should we assess fitness and stratify risk for surgery?. British Journal of Anaesthesia [online] December, 112(6):955-957 [viewed 31 August 2014] Available from: doi:10.1093/bja/aeu003
  8. KUMAR A, SRIVASTAVA U. Role of routine laboratory investigations in preoperative evaluation J Anaesthesiol Clin Pharmacol [online] 2011, 27(2):174-179 [viewed 31 August 2014] Available from: doi:10.4103/0970-9185.81824

Investigations - Followup

Fact Explanation
Full blood count [1] [2] [3] To assess the Hemoglobin count and to plan the transfusion and also to monitor the effects of deferoxamine (DFO) therapy such as agranulocytosis, neutropenia, thrombocytopenia and worsening anemia.[1] [2] [3]
Serum iron studies- Serum Ferritin, Serum Iron, Total iron binding capacity [1] [2] [3] [5] The serum ferritin level is frequently used to monitor the status of iron overload. [1] [2] [3] [5]
Thyroid function tests [8] [9] Hypothyroidism can occur due to deposition of iron in the thyroid gland therefore thyroid functions are monitored. [8] [9]
CT scan- abdomen [1] [2] [3] [5] As a non invasive method to assess the hepatomegaly for iron overload in patients receiving chelation therapy. [1] [2] [3] [5]
MRI scan- abdomen [1] [2] [3] [5] As a non invasive method to assess the hepatomegaly for iron overload in patients receiving chelation therapy. [1] [2] [3] [5]
Liver function tests [1] [2] [3] [5] To assess the liver finctions for iron overload [1] [2] [3] [5]
Per cutaneous liver biopsy [1] [2] [3] [5] Liver biopsy is used to measure the iron content in the liver per gram of tissue [1] [2] [3] [5]
Chest X-ray [1] [2] [3] [4] [5] [6] [7] Cardiac size and shape is evaluated as iron is deposited in the heart [1] [2] [3] [4] [5] [6] [7]
Cardiac T2-MRI [1] [2] [3] [4] [5] [6] [7] [10] This does not correlate well with serum ferritin or either echocardiography findings but this is non invasive method to detect iron deposition in the heart. [1] [2] [3] [4] [5] [6] [7] [10]
Electrocardiogram [1] [2] [3] [4] [5] [6] [7] To assess the cardiac function in a patient having cardiomyopathy due to iron over load [1] [2] [3] [4] [5] [6] [7]
Echocardiography [1] [2] [3] [4] [5] [6] [7] To assess the cardiac function in a patient having cardiomyopathy due to iron over load [1] [2] [3] [4] [5] [6] [7]
Eye examination by Ophthalmoscopy and slit lamp examination [1] [2] [3] [5] [11] To monitor the effects on the eye such as lens opacities, cataracts, elevations in intraocular pressure, and retinal disorders after deferoxamine (DFO) therapy and the administration of other chelating agents [1] [2] [3] [5] [11]
Hearing tests [1] [2] [3] [5] [11] To monitor the effects on hearing such as high frequency hearing loss after deferoxamine (DFO) therapy and the administration of other chelating agents [1] [2] [3] [5] [11]
Renal function tests [1] [2] [3] [5] [11] to monitor the effects of deferoxamine (DFO) therapy such as dose related increases in serum creatinine [1] [2] [3] [5] [11]
Fasting blood sugar [12] Iron deposition in the pancreas can cause diabetes and to detect, this is done.[12]
References
  1. CECI ADRIANA, MANGIARINI LAURA, FELISI MARIAGRAZIA, BARTOLONI FRANCO, CIANCIO ANGELA, CAPRA MARCELLO, D'ASCOLA DOMENICO, CIANCIULLI PAOLO, FILOSA ALDO. The Management of Iron Chelation Therapy: Preliminary Data from a National Registry of Thalassaemic Patients. Anemia [online] 2011 December, 2011:1-7 [viewed 31 August 2014] Available from: doi:10.1155/2011/435683
  2. VICHINSKY E.. Oral Iron Chelators and the Treatment of Iron Overload in Pediatric Patients With Chronic Anemia. PEDIATRICS [online] 2008 June, 121(6):1253-1256 [viewed 31 August 2014] Available from: doi:10.1542/peds.2007-1824
  3. TANNER MARK A, GALANELLO RENZO, DESSI CARLO, SMITH GILLIAN C, WESTWOOD MARK A, AGUS ANNALISA, PIBIRI MARTINA, NAIR SUNIL V, WALKER J MALCOLM, PENNELL DUDLEY J. Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction. Array [online] 2008 December [viewed 31 August 2014] Available from: doi:10.1186/1532-429X-10-12
  4. YANG GAOHUI, LIU RONGRONG, PENG PENG, LONG LILING, ZHANG XINHUA, YANG WEIJIA, TAN SHAOHONG, PAN HONGFEI, LONG XINGJIANG, HE TAIGANG, ANDERSON LISA, LAI YONGRONG, XU XIAOLEI. How Early Can Myocardial Iron Overload Occur in Beta Thalassemia Major?. PLoS ONE [online] 2014 January [viewed 31 August 2014] Available from: doi:10.1371/journal.pone.0085379
  5. MELCHIORI LUCA, GARDENGHI SARA, RIVELLA STEFANO. 𝛽-Thalassemia: HiJAKing Ineffective Erythropoiesis and Iron Overload. Advances in Hematology [online] 2010 December, 2010:1-7 [viewed 31 August 2014] Available from: doi:10.1155/2010/938640
  6. TRACHTENBERG FELICIA L, MEDNICK LAUREN, KWIATKOWSKI JANET L, NEUFELD ELLIS J, HAINES DRU, PAKBAZ ZAHRA, THOMPSON ALEXIS A, QUINN CHARLES T, GRADY ROBERT, SOBOTA AMY, OLIVIERI NANCY, HORNE ROBERT, YAMASHITA ROBERT. Beliefs about chelation among thalassemia patients. Array [online] 2012 December [viewed 31 August 2014] Available from: doi:10.1186/1477-7525-10-148
  7. KREMASTINOS D. T., FARMAKIS D., AESSOPOS A., HAHALIS G., HAMODRAKA E., TSIAPRAS D., KEREN A.. -Thalassemia Cardiomyopathy: History, Present Considerations, and Future Perspectives. Circulation: Heart Failure [online] December, 3(3):451-458 [viewed 30 August 2014] Available from: doi:10.1161/CIRCHEARTFAILURE.109.913863
  8. DE LUCA F, MELLUSO R, SOBBRIO G, CANFORA G, TRIMARCHI F. Thyroid function in thalassaemia major. Arch Dis Child [online] 1980 May, 55(5):389-392 [viewed 31 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1626864
  9. ZERVAS ATHANASIOS, KATOPODI ANNA, PROTONOTARIOU ANTHI, LIVADAS SARANTIS, KARAGIORGA MARKESIA, POLITIS CONSTANTINA, TOLIS GEORGE. Assessment of Thyroid Function in Two Hundred Patients with -Thalassemia Major . Thyroid [online] 2002 February, 12(2):151-154 [viewed 31 August 2014] Available from: doi:10.1089/105072502753522383
  10. ANDERSON L. Cardiovascular T2-star (T2*) magnetic resonance for the early diagnosis of myocardial iron overload. European Heart Journal [online] 2001 December, 22(23):2171-2179 [viewed 31 August 2014] Available from: doi:10.1053/euhj.2001.2822
  11. LEE J. W., YOON S.-S., XIANG SHEN Z., GANSER A., HSU H.-C., HABR D., DOMOKOS G., ROUBERT B., PORTER J. B.. Iron chelation therapy with deferasirox in patients with aplastic anemia: a subgroup analysis of 116 patients from the EPIC trial. Blood [online] December, 116(14):2448-2454 [viewed 31 August 2014] Available from: doi:10.1182/blood-2010-01-261289
  12. BAHAR ADELE, KASHI ZAHRA, SOHRAB MEHRNOUSH, KOSARYAN MEHRNOUSH, JANBABAI GHASEM. Relationship between beta-globin gene carrier state and insulin resistance. Array [online] 2012 December [viewed 30 August 2014] Available from: doi:10.1186/2251-6581-11-22

Investigations - Screening/Staging

Fact Explanation
One tube osmotic fragility test [7] This is used as a screening test. Test is positive when there's increased hemolysis in thalassemia due to increased target cells. [7]
High performance liquid chromatography (HPLC) [1] Most newborn screening programs worldwide use high-performance liquid chromatography (HPLC) as the first-line investigation to confirm the diagnosis [1]
Echocardiogrpahy [2] [3] [4] [5] A staging system is present which takes the patient's symptoms, signs and echocardiogrpahic findings to stage thalessemia mainly to indicate the initiation of chelation therapy [2] [3] [4] [5]
radionuclide cineangiogram [2] [3] [4] [5] A staging system is present which takes the patient's symptoms, signs and this test findings to stage thalessemia mainly to indicate the initiation of chelation therapy [2] [3] [4] [5]
24-hour ECG [2] [3] [4] [5] A staging system is present which takes the patient's symptoms, signs and ECG findings to stage thalessemia mainly to indicate the initiation of chelation therapy [2] [3] [4] [5]
Percutaneous liver biopsy [6] Lucarelli classification, is used in patients who are about to undergo hematopoietic stem cell transplantation (HSCT) to assess hepatic iron content. [6]
References
  1. HOPPE C. C.. Newborn screening for non-sickling hemoglobinopathies. Hematology [online] December, 2009(1):19-25 [viewed 31 August 2014] Available from: doi:10.1182/asheducation-2009.1.19
  2. KREMASTINOS D. T., FARMAKIS D.. Iron Overload Cardiomyopathy in Clinical Practice. Circulation [online] December, 124(20):2253-2263 [viewed 31 August 2014] Available from: doi:10.1161/CIRCULATIONAHA.111.050773
  3. ABBASI MOHAMMADAMIN, KHAHESHI ISA, PAYDARY KOOSHA, FARAHANI BEHZAD. Evaluation of QT interval in β thalassemia major patients in comparison with control group. Heart Views [online] 2012 December [viewed 31 August 2014] Available from: doi:10.4103/1995-705X.99226
  4. VOGEL M. Tissue Doppler echocardiography in patients with thalassaemia detects early myocardial dysfunction related to myocardial iron overload. European Heart Journal [online] 2003 January, 24(1):113-119 [viewed 31 August 2014] Available from: doi:10.1016/S0195-668X(02)00381-0
  5. KAYRAK MEHMET, ACAR KADIR, GUL ENES ELVIN, ÖZBEK ORHAN, ABDULHALIKOV TURYAN, SONMEZ OSMAN, ALIBAşIç HAJRUDIN. The Association between Myocardial Iron Load and Ventricular Repolarization Parameters in Asymptomatic Beta-Thalassemia Patients. Advances in Hematology [online] 2012 December, 2012:1-6 [viewed 31 August 2014] Available from: doi:10.1155/2012/170510
  6. ANGELUCCI E.. Hematopoietic Stem Cell Transplantation in Thalassemia. Hematology [online] December, 2010(1):456-462 [viewed 31 August 2014] Available from: doi:10.1182/asheducation-2010.1.456
  7. PANYASAI S., SUKUNTHAMALA K., JAIPING K., WONGWIWATTHANANUKIT S., SINGBOOTTRA P., PORNPRASERT S.. Interference of Hemoglobin Hope on -Thalassemia Diagnosis by the Capillary Electrophoresis Method. American Journal of Clinical Pathology [online] December, 136(1):14-18 [viewed 31 August 2014] Available from: doi:10.1309/AJCP1BT2MGATKFHL

Management - General Measures

Fact Explanation
Parent and patient education [1] [2] [3] [8] Parental education plays a major role in the management of thalassemia. This is a disease needs life long management with regular blood transfusions and regular follow up for complications is also important. sometimes psychiatric referral may be needed as it's a life long disease. Genetic counseling regarding the disease, and the screening of siblings is also needed [1] [2] [3] [8]
Regular follow up [3] [4] [5] Patient should be regularly followed up for blood transfusions and it's of much importance to follow up for complications of iron over load. [3] [4] [5]
Diet and activity [3] [6] A diet rich in folic acid, vitamin C is important as well as avoidance of iron rich food. Reduction in the level of activity is not needed unless the child is suffering from heart failure due to iron overload and cardiomyopathy in which restriction of activity is needed. [3] [6]
Folic acid therapy [4] [6] Daily 5mg is given if the diet is poor. [4] [6]
Vitamin C therapy [6] 200 mg/day is given and is thought to increase iron excretion [6]
Vaccination [4] [7] Immunization against Hepatitis B and C prior to blood transfusion is needed. Also vaccination against Pneumococcal, Hemopilus, Meningococcal is needed prior to splenectomy. [4] [7]
Screening [8] [9] Screening of parents and siblings is carried out when a child is diagnosed with thalassemia [8] [9]
Prenatal diagnosis [10] [11] When two carriers are expecting a baby, prenatal diagnosis of the fetus for thalassemia is also available. [10] [11]
References
  1. AZIZ KASHIF, SADAF BREERA, KANWAL SADIA. Psychosocial problems of Pakistani parents of Thalassemic children: a cross sectional study done in Bahawalpur, Pakistan. Array [online] 2012 December [viewed 31 August 2014] Available from: doi:10.1186/1751-0759-6-15
  2. SHARGHI AFSHAN, KARBAKHSH MOJGAN, NABAEI BEHROOZ, MEYSAMIE ALIPASHA, FARROKHI ALIREZA. . Clin Pract Epidemiol Ment Health [online] 2006 December [viewed 31 August 2014] Available from: doi:10.1186/1745-0179-2-27
  3. TRACHTENBERG FELICIA L, MEDNICK LAUREN, KWIATKOWSKI JANET L, NEUFELD ELLIS J, HAINES DRU, PAKBAZ ZAHRA, THOMPSON ALEXIS A, QUINN CHARLES T, GRADY ROBERT, SOBOTA AMY, OLIVIERI NANCY, HORNE ROBERT, YAMASHITA ROBERT. Beliefs about chelation among thalassemia patients. Array [online] 2012 December [viewed 31 August 2014] Available from: doi:10.1186/1477-7525-10-148
  4. GALANELLO RENZO, ORIGA RAFFAELLA. Beta-thalassemia. Array [online] 2010 December [viewed 31 August 2014] Available from: doi:10.1186/1750-1172-5-11
  5. BAHAR ADELE, KASHI ZAHRA, SOHRAB MEHRNOUSH, KOSARYAN MEHRNOUSH, JANBABAI GHASEM. Relationship between beta-globin gene carrier state and insulin resistance. Array [online] 2012 December [viewed 31 August 2014] Available from: doi:10.1186/2251-6581-11-22
  6. SHERIEF LAILA M., ABD EL-SALAM SANAA M., KAMAL NAGLAA M., EL SAFY OSAMA, ALMALKY MOHAMED A. A., AZAB SEHAM F., MORSY HEMAT M., GHARIEB AMAL F.. Nutritional Biomarkers in Children and Adolescents with Beta-Thalassemia-Major: An Egyptian Center Experience. BioMed Research International [online] 2014 December, 2014:1-7 [viewed 31 August 2014] Available from: doi:10.1155/2014/261761
  7. CIMAZ ROLANDO, MENSI CAROLINA, D'ANGELO EMANUELA, FANTOLA ELISABETTA, MILONE VITTORIA, BIASIO LUIGI R., CARNELLI VITTORIO, ZANETTI ALESSANDRO R.. Safety and Immunogenicity of a Conjugate Vaccine against Type b in Splenectomized and Nonsplenectomized Patients with Cooley Anemia . J INFECT DIS [online] 2001 June, 183(12):1819-1821 [viewed 31 August 2014] Available from: doi:10.1086/320727
  8. WONG LI PING, GEORGE ELIZABETH, TAN JIN-AI. Public perceptions and attitudes toward thalassaemia: Influencing factors in a multi-racial population. Array [online] 2011 December [viewed 31 August 2014] Available from: doi:10.1186/1471-2458-11-193
  9. PREMAWARDHENA A.. Thalassemia in Sri Lanka: a progress report. Human Molecular Genetics [online] 2004 October, 13(suppl_2):R203-R206 [viewed 31 August 2014] Available from: doi:10.1093/hmg/ddh250
  10. ATANASOVSKA BILJANA, BOZHINOVSKI GEORGI, PLASESKA-KARANFILSKA DIJANA, CHAKALOVA LYUBOMIRA, PALAU FRANCESC. Efficient Detection of Mediterranean β-Thalassemia Mutations by Multiplex Single-Nucleotide Primer Extension. PLoS ONE [online] 2012 October [viewed 31 August 2014] Available from: doi:10.1371/journal.pone.0048167
  11. CAI SP, CHANG CA, ZHANG JZ, SAIKI RK, ERLICH HA, KAN YW. Rapid prenatal diagnosis of beta thalassemia using DNA amplification and nonradioactive probes. Blood [online] 1989 Feb, 73(2):372-4 [viewed 31 August 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/2917180

Management - Specific Treatments

Fact Explanation
Regular blood transfusion [7] 2-3 units of fresh leukocyte depleted blood is given every 4-6 weeks in transfusion dependent anemia. Antipyretics, Antihistamines are adminisered before blood transfusion to prevent or decrease febrile reactions. [7]
Endocrine therapy [7] [9] [10] [11] [12] Insulin is given when there's diabetes mellitus, Calcium, Vitamin D and Bisphosphanates for osteoporosis. Iron deposition in the pituitary, and Deferoxamine therapy may cause growth retardation therefore growth hormone may be helpful. [7] [9] [10] [11] [12]
Iron chelation therapy [2] [3] [4] [5] [6] [7] In iron overloaded patients iron chelation therapy is initiated and Deferoxamine is a parenteral drug that is used and Deferasirox, Deferiprone are oral iron chelators [2] [3] [4] [5] [6] [7]
Corticosteroids [7] Local reactions may occur at Deferoxamine injection sites. Hydrocortisone may help to reduce the reaction. [7]
Antibiotics [7] [13] [14] Yersinia enterocolitica is one such organism that occurs in increased frequency in pateints on iron chelation therapy and they are treated with Trimethoprim-sulfamethoxazole (TMP/SMX) and gentamicin. Patients undergoing splenectomy need to receive prophylactic antibiotics as well [7] [13] [14]
Chemotherapeutic agents [7] [8] Chemotherapeutic agents such as Hydroxyurea have shown to reduce transfusion requirement in some patients [7] [8]
Splenectomy [7] [13] [14] The spleen is responsible for red blood cell destruction, therefore splenectomy may be considered if there's severe disease .[7] [13] [14]
Allogenic stem cell transplantation [1] [7] This is now the definitive treatment for Thalassemia which has a high success rate in well chelated, young patients without liver fibrosis or hepatomegaly. [1] [7]
References
  1. ANGELUCCI E.. Hematopoietic Stem Cell Transplantation in Thalassemia. Hematology [online] December, 2010(1):456-462 [viewed 31 August 2014] Available from: doi:10.1182/asheducation-2010.1.456
  2. LEE J. W., YOON S.-S., XIANG SHEN Z., GANSER A., HSU H.-C., HABR D., DOMOKOS G., ROUBERT B., PORTER J. B.. Iron chelation therapy with deferasirox in patients with aplastic anemia: a subgroup analysis of 116 patients from the EPIC trial. Blood [online] December, 116(14):2448-2454 [viewed 31 August 2014] Available from: doi:10.1182/blood-2010-01-261289
  3. CECI ADRIANA, MANGIARINI LAURA, FELISI MARIAGRAZIA, BARTOLONI FRANCO, CIANCIO ANGELA, CAPRA MARCELLO, D'ASCOLA DOMENICO, CIANCIULLI PAOLO, FILOSA ALDO. The Management of Iron Chelation Therapy: Preliminary Data from a National Registry of Thalassaemic Patients. Anemia [online] 2011 December, 2011:1-7 [viewed 31 August 2014] Available from: doi:10.1155/2011/435683
  4. VICHINSKY E.. Oral Iron Chelators and the Treatment of Iron Overload in Pediatric Patients With Chronic Anemia. PEDIATRICS [online] 2008 June, 121(6):1253-1256 [viewed 31 August 2014] Available from: doi:10.1542/peds.2007-1824
  5. TANNER MARK A, GALANELLO RENZO, DESSI CARLO, SMITH GILLIAN C, WESTWOOD MARK A, AGUS ANNALISA, PIBIRI MARTINA, NAIR SUNIL V, WALKER J MALCOLM, PENNELL DUDLEY J. Combined chelation therapy in thalassemia major for the treatment of severe myocardial siderosis with left ventricular dysfunction. Array [online] 2008 December [viewed 31 August 2014] Available from: doi:10.1186/1532-429X-10-12
  6. MELCHIORI LUCA, GARDENGHI SARA, RIVELLA STEFANO. 𝛽-Thalassemia: HiJAKing Ineffective Erythropoiesis and Iron Overload. Advances in Hematology [online] 2010 December, 2010:1-7 [viewed 31 August 2014] Available from: doi:10.1155/2010/938640
  7. RACHMILEWITZ E. A., GIARDINA P. J.. How I treat thalassemia. Blood [online] December, 118(13):3479-3488 [viewed 31 August 2014] Available from: doi:10.1182/blood-2010-08-300335
  8. POURFARZAD F, VON LINDERN M, AZARKEIVAN A, HOU J, KIA SK, ESTEGHAMAT F, VAN IJCKEN W, PHILIPSEN S, NAJMABADI H, GROSVELD F. Hydroxyurea responsiveness in ?-thalassemic patients is determined by the stress response adaptation of erythroid progenitors and their differentiation propensity Haematologica [online] 2013 May, 98(5):696-704 [viewed 31 August 2014] Available from: doi:10.3324/haematol.2012.074492
  9. TOUMBA MEROPI, SKORDIS NICOS. Osteoporosis Syndrome in Thalassaemia Major: An Overview. Journal of Osteoporosis [online] 2010 December, 2010:1-7 [viewed 31 August 2014] Available from: doi:10.4061/2010/537673
  10. PERISANO CARLO, MARZETTI EMANUELE, SPINELLI MARIA SILVIA, CALLà CINZIA ANNA MARIA, GRACI CALOGERO, MACCAURO GIULIO. Physiopathology of Bone Modifications in 𝜷-Thalassemia. Anemia [online] 2012 December, 2012:1-5 [viewed 31 August 2014] Available from: doi:10.1155/2012/320737
  11. GALANELLO RENZO, ORIGA RAFFAELLA. Beta-thalassemia. Array [online] 2010 December [viewed 31 August 2014] Available from: doi:10.1186/1750-1172-5-11
  12. ABDOLLAH SHAMSHIRSAZ ALIREZA, BEKHEIRNIA MIR REZA, KAMGAR MOHAMMAD, POURZAHEDGILANI NIMA, BOUZARI NAVID, HABIBZADEH MOHAMMADREZA, HASHEMI REZA, ABDOLLAH SHAMSHIRSAZ AMIR HOOSHANG, AGHAKHANI SHAHRIAR, HOMAYOUN HOOMAN, LARIJANI BAGHER. . BMC Endocr Disord [online] 2003 December [viewed 31 August 2014] Available from: doi:10.1186/1472-6823-3-4
  13. BAHADOR ALI, BANANI SEYEDABBASS, FOROUTAN HAMIDREZA, HOSSEINI SEYEDMOHAMMAD VAHID, DAVANI SAMZERAATIAN NEJAD. A comparative study of partial vs total splenectomy in thalassemia major patients. J Indian Assoc Pediatr Surg [online] 2007 December [viewed 31 August 2014] Available from: doi:10.4103/0971-9261.34951
  14. WANG S.-C., LIN K.-H., CHERN J. P. S., LU M.-Y., JOU S.-T., LIN D.-T., LIN K.-S.. Severe Bacterial Infection in Transfusion-Dependent Patients with Thalassemia Major. Clinical Infectious Diseases [online] 2003 October, 37(7):984-988 [viewed 31 August 2014] Available from: doi:10.1086/378062