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thalassemia , management

Published in: Health & Medicine


  2. 2. OBJECTIVES To know : • Basic features of thalassemia syndromes • Transfusion protocols in thalassemia • Chelation therapy in thalassemia • Supportive care in thalassemic patients • Follow-up guidelines • Hemtopoitic Stem cell transplantation • Future aspects.
  3. 3. DEFINITION Thalassemia is a group of inherited disorders of hemoglobin synthesis characterized by a reduced or absent one or more of the globin chains of adult hemoglobin. They characterised by varying degrees of ineffective hematopoiesis and increased hemolysis ICD classification: D-56
  4. 4. HEMOGLOBIN A  Fetal Hemoglobin (2 alpha, 2 gamma)  Hemoglobin A2 (2 alpha, 2 delta)  Small amounts in body α αβ β
  5. 5. Copyright ©1997 BMJ Publishing Group Ltd.
  6. 6. NORMAL HUMAN HAEMOGLOBINS Haemoglobin Structural formula Adult Hb-A 2 2 97% Hb-A2 2 2 1.5-3.2% Fetal Hb-F 2 2 0.5-1% Embryonic Hb-Gower 1 2 2 Hb-Gower 2 2 2 Hb-Portland 2 2
  7. 7. GENETIC TYPES OF THALASSEMIA : There are two basic groups of thalassemia.  Alpha (  )Thalassemia In alpha-thalassemia, the alpha genes are deleted; loss of one gene (α-/α) or both genes (α-/α-) from each chromosome 16 may occur, in association with the production of some or no alpha globin chains  Beta (  )Thalassemia In beta-thalassemia defective production usually results from disabling point mutations causing no (β0) or reduced (β-) beta chain production.
  8. 8. CHROMOSOMES  Thalassemia is inherited as an autosmal recessive disease.
  9. 9. EPIDEMIOLOGY  Recent data indicate that about 7% of the world population is carrier of hemoglobin disorder.  About 100,000 children are born every year world over with the homozygous state for thalassemia. There are around 65,000 - 67,000 thalassemia patients in our country.  In India prevalence of this gene varies, 1-17 % (3.3%).  Common in certain Communities like sindhis, punjabis, khatris, khukrajas, bhanushalies, baniyas, lohanas, kuchies, mahars, kolies, agries, goudas, lingayats .
  10. 10. ALPHA THALASSEMIA  Alpha Thalassemia: deficient/absent alpha subunits  Excess beta subunits  Excess gamma subunits newborns  Tetramers formed:  Hemoglobin H adults  Hemoglobin Bart’s newborns  types:  Silent Carrier  Trait (Minor)  Hemoglobin H Disease  Hydrops fetalis(Hb Bart’s)
  11. 11. GENETIC BASIS OF ALPHA THALASSEMIA  Encoding genes on chromosome 16 (short arm)  Each cell has 4 copies of the alpha globin gene  Each gene responsible for ¼ production of alpha globin  4 possible mutation states:  Loss of ONE gene  silent carrier  Loss of TWO genes  thalassemia minor (trait)  Loss of THREE genes  Hemoglobin H  Accumulation of beta chains  Association of beta chains in groups of 4  Hemoglobin H  Loss of FOUR genes  Hemoglobin Barts  NO alpha chains produced ∴ only gamma chains present  Association of 4 gamma chains  Hemoglobin Barts
  12. 12. CLASSIFICATION & TERMINOLOGY ALPHA THALASSEMIA • Normal / • Silent carrier - / • Minor -/- --/ • Hb H disease --/- • Barts hydrops fetalis --/--
  13. 13. CLINICAL OUTCOMES OF ALPHA THALASSEMIA  Silent carriers • asymptomatic • “normal”  Alpha Thalassemia trait • no anemia /mild anemia • microcytosis -unusually small red blood cells due to fewer Hb in RBC  Hb H disease • microcytosis & hemolysis (breakdown of RBC) - results in severe anemia • bone deformities • splenomegaly (enlargement of spleen) • “severe and life threatening” • Golf ball inclusions on micrscopy
  14. 14. CLINICAL OUTCOMES OF ALPHA THALASSEMIA  Bart’s Hydrops fetalis • Hb Bart’s • fatal hydrops fetalis - fluid build-up in fetal compartments, leads to death occurs in utero
  15. 15. BETA THALASSEMIA  Beta Thalassemia: deficient/absent beta subunits  Commonly found in Mediterranean, Middle East, Asia, and Africa  Three types:  Minor  Intermedia  Major (Cooley anemia)  asymptomatic at birth as HbF functions
  16. 16. GENETIC BASIS OF BETA THALASSEMIA  Encoding genes on chromosome 11 (short arm)  Each cell contains 2 copies of beta globin gene  beta globin protein level = alpha globin protein level  Suppression of gene more likely than deletion  2 mutations: beta-+-thal / beta-0-thal  “Loss” of ONE gene  thalassemia minor (trait)  “Loss” of BOTH gene  complex picture  2 beta-+-thal  thalassemia intermedia / thalassemia major  2 beta-0-thal  thalassemia major  Excess of alpha globin chains
  17. 17. CLASSIFICATION & TERMINOLOGY BETA THALASSEMIA • Normal / • Minor /0 /+ • Intermedia 0/+ +/+ • Major 0/0 +/
  18. 18. CLINICAL OUTCOMES OF BETA THALASSEMIA  Beta Thalassemia minor (trait) • asymptomatic • microcytosis • minor anemia • Elevated HbA2 >3.4%  Beta Thalassemia intermedia . • symptoms similar to Cooley Anemia but less severe  Beta Thalassemia major (Cooley Anemia) • most severe form • moderate to severe anemia • intramedullary hemolysis (RBC die before full development) • peripheral hemolysis & splenomegaly • skeletal abnormalities (overcompensation by bone marrow) • congestive heart failure,pulmonary hypertension
  19. 19. PATHOPHYSIOLOGY Disturbance of ratio between Alpha & non alpha globin chain synthesis then absent or decrease production of one or more globin chains Formation of abnormal Hb structures Ineffective erythropoiesis Excessive RBCs Destruction Iron Overload Extra-medullary hematopoiesis
  21. 21. SIGNS & SYMPTOMS  Beta Thalassaemia Minor : Usually no signs or symptoms except for a mild persistent anemia not responding to hematinics.  BetaThalassaemia Major : manifests after 6 months 1. Pallor- fatigue, irritability 2. Growth retardation. 3. Recurrent infections 4. Bony abnormalities specially of the facial bones,hemolytic facies, caput quadtratum 5. Enlarged spleen and liver. 6. Delayed sexual development 7. Features of complications .
  22. 22. THALASSEMIA COMPLICATIONS  Complications can be grouped as (1) transfusion-transmitted infections, (2) transfusional iron overload, (3) toxicities of iron chelation therapy, and (4) bacterial infections
  23. 23. COMPLICTIONS ..CONT..  Cardiac complications  Liver complications  Endocrine complications  Bone complications  Other complications  Infections: yersinia,parvovirus B19  Dental Complications  Growth retardation  Leg ulcers
  24. 24. CARDIAC COMPLICATIONS  Cardiac dysfunction(both systolic and diastolic dysfuction)  Arrhythmias  Ferritin greater than 2500 mg/L or a liver iron concentration > 15 mg Fe/g dry weightis associated with high risk of cardiac death in thalassemia  ferritin and liver iron may not correlate with cardiac iron load, cardiac iron can be specifically and reproducibly measured using cardiac MRI T2*. Cardiac MRI T2* less than 20 ms correlates with a progressive and significant decline in LVEF
  25. 25. CARDIAC COMPLICATIONS CONT..  Monitoring: 6 monthly cardiac physical examination, cardiac function yearly starting at age of 10 years, if history suggestive of arrhythmias ECG, 24-hour Holter monitoring should be done.  Chelation therapy to reduce high iron load lowers the likelihood of developing cardiac dysfunction
  26. 26. CARDIAC COMPLICATIONS..CONT Cardiac MRI T2 Cardiac iron load Cardiac function intervention values greater than 20 ms not usually associated with significant iron load not usually associated with cardiac dysfunction compliance and importance of chelation stressed values between 10 and 20 ms significant cardiac iron deposition a risk of eventual cardiac decompensation more aggressive chelation program should be implemented values < 10 ms Very high cardiac iron load significant risk of more immediate cardiac decompensation without aggressive Aggressive chelation therapy should be started immediately and cardiac function
  27. 27. CARDIAC COMPLICATIONS..CONT  Where cardiac MRI T2* is not available, • chelation decisions should be based on ferritin, LIC and cardiac function assessment  Patients with ferritin > 2500 mg/ml and LIC >15g Fe/g dry weight should be chelated more aggressively.  those with ferritin < 2500 mg/ml and LIC 7 – 15 g Fe/g dry weight should have chelation adjusted accordingly and compliance encouraged.  Cardiologic intervention and management for heart failure and arrhythmia should follow cardiology standards apart from aggressive chelation
  28. 28. LIVER COMPLICATIONS  includes- transfusion-related viral hepatitis (Hepatitis B, C), iron overload, drug toxicity, and biliary disease due to gallstones.  Liver enzymes should be monitored routinely.  Liver iron concentration should be monitored routinely and chelation therapy initiated and adjusted to reduce complications of iron overload.  In the presence of elevated liver iron, liver fibrosis, and cirrhosis may be accelerated by alcohol, liver- toxic drugs, and untreated viral hepatitis, Limit such exposure.
  29. 29. ENDOCRINE COMPLICATIONS  Iron overload is responsible for dysfunction of many of endocrine glands like thyroid, parathyroid pituitary gland, gonads and pancreas.  These include-  short stature (34%),  delayed puberty, hypogonadotropic hypogonadism (35 – 55%),  hypothyroidism (10%),  hypoparathyroidism (4%), and  diabetes mellitus (5.6 – 20%)
  30. 30. ENDOCRINE COMPLICATIONS - INTERVENTIONS  Short stature-  The diagnosis of growth hormone deficiency, other hormonal or nutritional deficiencies or deferoxamine toxicity should be considered  Growth hormone stimulation testing should be done and, if indicated, growth hormone therapy started  Hypothyroidism  TSH levels should be measured annually beginning at 12 years of age since hypothyroidism often develops after adolescence.  Hypothyroidism should be treated with thyroid hormone replacement.
  31. 31. ENDOCRINE COMPLICATIONS - INTERVENTIONS  Impaired Glucose Tolerance and Diabetes  Improvement of iron load with adequate combination chelation therapy may decrease insulin resistance and decrease glucose intolerance  Impaired glucose tolerance and diabetes should be managed as per diabetes protocols with emphasis on glycemic control, diet, exercise, and management of complications.
  32. 32. ENDOCRINE COMPLICATIONS - INTERVENTIONS  Delayed Puberty and Hypogonadism  most common endocrine complication  all children should be assessed yearly from the age of 10 years  All patients with delayed puberty or hypogonadism should receive appropriate investigations including bone age and hormonal assessments, hormonal replacement therapy, and subsequent follow-up by an endocrinologist  Hypoparathyroidism  All patients over the age of 12 years should have calcium and phosphate levels checked at least every 6 months.  If these are abnormal, parathyroid hormone level should be measured. Hypoparathyroidism should be managed as per endocrine standards
  33. 33. BONE COMPLICATIONS  Bone disorders are common and multifactorial in patients with thalassemia .  Related to inadequate transfusion, iron-overload, over-chelation, and other endocrine factors contribute to the development of osteopenia and osteoporosis  Interventions:  Adequate blood transfusions  Adequate chelation therapy should be maintained  No Over-chelation  Hormone replacement therapy  Calcitonin,bisphosphonates  Diet rich in calcium and vitamin D
  34. 34. HYPERSPLENISM- SPLENECTOMY  Indictions of splenectomy  An increase in the yearly requirement of packed cells more than 1.5 times the basal requirement, i.e. packed cell 200 to 220 cc per kg/ year.  Massive splenic enlargement posing risk of splenic rupture, or when it is associated with left upper quadrant pain or erly satiety  Presence of leukopenia or thrombocytopenia due to hyperspleenism  Splenectomy should be delayed till the patientis 5 years of age as there is risk of overwhleming sepsis below this age
  35. 35.  Risk of post-splenectomy serious infections can be reduced by:  Immunization against pneumococcal, meningococcal, and Hib and salmonella typhi infection atleast 3 weeks before splenectomy  Chemoprophylaxis with oral penicillin,  125 mg twice daily for children upto 2 years  250 mg twice daily for children 2 years and above  Post splenectomy there may be transient or persistent thrombocytosis. Aspirin 50-100 mg/day for patients if platelet count >8,00,000/mm3
  36. 36. IMMUNIZATION PRIOR TO SPLENECTOMY  Pneumcoccal vaccine. 0.5 ml SC  If child has received a complete primary course PLUS a single booster dose  Age<2 years: ( give one dose PCV13 Prevenar13 )  Age > 2years: ( give one dose PPV 23 Pneumovax 23 revaccinate after 3 years )  If child has not recieved primary course  Age 16 months – 5years : give two doses PCV13 Prevenar13 8 weeks apart  If aged 5-18 years - one dose  give one dose PPV 23 Pneumovax 23 at least 8 weeks after the last PCV13 dose , revaccinate after 3 years.
  37. 37.  Meningococcal vaccine:  Quadravalent meningococcal (Menactra) 0.5 mL IM upper deltoid. o Children aged 2 through 6 years :Two doses of Menactra® at least 8 weeks apart, followed by a single booster dose 3 years later and then a single booster dose every 5 years  Children aged 7 years and over and adults through 55 years :Two doses of Menactra® at least 8 weeks apart, followed by a single booster dose every 5 years  Haemophilus b conjugate : One dose regardless of previous vaccination history
  40. 40. CAUSES OF DEATH  Congestive heart failure  Arrhythmia  Sepsis secondary to increased susceptability to infection post spleenectomy  Multiorgan failure due to hemochromatosis
  42. 42.  Complete Blood Count (CBC) with red cell indices and Peripheral Blood Film (PBF) Examination and reticulocyte count.  Hb low, total RBC count and Hct decreased  Thalassemics have uniform microcytosis with out increase in RDW  PS of Thalassemia Child Characteristic bizarre picture of red cells, which are microcytic, hypochromic, with poikilocytosis, polychromasia, moderate basophilic stippling, and fragmented erythrocytes, target cells, and large number of normoblasts
  43. 43. Thalassemia trait Iron deficiency anemia RDW Normal(11.5-14.5) high RBC count High relative to hematocrit,Hb levels low Thalassemia major Iron deficiency anemia serum Iron levels Serum iron high Sr.ferritin high TIBC decreased Transferrin saturation: increased Low Low Increased decreased
  44. 44.  The baseline serum ferritin and liver enzymes including ALT, AST, bilirubin, lactate dehydrogenase (LDH) should be measured.  Full red cell phenoptype [C, c, D, E, e, K, k, Jka, Jkb, Fya, Fyb, Kpa, Kpb, MNS, Lewis]  Serologic testing for hepatitis A, B, and C, and HIV should be performed as baseline measures.  All first-degree family members should undergo HLA-typing, if potential future allogeneic hematopoietic stem cell transplant is considered an option.
  46. 46. LAB DIAGNOSIS ..CONT.  Osmotic fragility test : decreased  Urinary urobilinogen: increased (Ehrlich test)  Stool examination: dark stools, increased stercobilinogen.  Radiological changes: seen after 1 year  X-ray of metacarpals,ribs, vertebra show thinning of cortex  X-ray of skull shows “hair on end appearance”  Generalised skeletal osteoporosis
  47. 47. MANAGEMENT OF THALASSEMIA MAJOR  Comprehensive management includes the following: • Confirmation of the diagnosis • Correction of anemia– Packed red cell transfusions • Removal of excess iron– Chelation Therapy • Management of complications – Endocrine and Cardiac complications • Pharmacological methods to increase gamma chain synthesis • Supportive care • Curative Treatment– Stem Cell Transplantation • Future treatment– Gene replacement therapy.
  48. 48.  A team approach includes: • Pediatric hematologist, • Pediatrician, • Blood transfusion specialist • Endocrinologist, • Psychologist and • Social worker, etc
  49. 49. TRANSFUSION THERAPY IN THALASSEMIA  Transfusion therapy in thalassemia has two goals: • To prevent anemia • To suppress endogenous erythropoiesis  Regular Blood Transfusions are Presently the Mainstay of Treatment of Thalassemia Major.  Concept of Neocyte transfusion
  50. 50. TRANSFUSION PROTOCOLS  Palliative– Pretransfusion - Hb level is around < 7 gm% and mean Hb maintained is < 8.5 gm/dl.  Hyper Transfusion– Pretransfusion Hb level is around > 10gm% and mean Hb. Maintained is > 12 gm%.  Super Transfusion– Pretransfusion Hb level is around > 12gm% and mean Hb. Maintained is >14gm%.  Moderate– Transfusion- Pretransfusion- Hb level is around 9-10.5 gm% and mean Hb. Maintained is >12gm %. Current recommendation?
  51. 51. TYPE OF TRANSFUSION  Leukoreduced packed red cell transfusion is desired type of blood for thalassemic children  Reduction of leukocytes to 5000000 is considered adequate.(reduced by 70%)  It helps in prevention of transfusion reactions and is achieved by centrifugation;/saline washing/filtration.
  52. 52. METHODS FOR LEUKODEPLETION  Centrifugation– Packed red cell transfusions  Saline-cell washing (Triple Saline Washed)  Deglycerolized–red cells.  Third generation leucocyte filters  Irradiated blood cells
  53. 53. BENEFITS OF BLOOD TRANFUSION- THALASSEMIA  Improves tissue oxygenation, and prevents chronic hypoxia  Improves normal growth and development  Prevents erythropoiesis thus avoiding expansion of the bone marrow and extra medullary erythropoiesis  Reduces hemolytic facies  Reduces hepatosplenomegaly and cardiomyopathy  Reduces gastro-intestinal absorption of iron.
  54. 54. WHEN TO START THE TRANSFUSION  Blood transfusion is started as soon as diagnosis firmly established (Except in children > 18 months of age).  If age is > 18 months, these children are observed to r/o Thalassemia Intermedia and if Hb drops < 7 gms%, regular transfusion started.  The most ideal way to transfuse thalassemics is using group and type specific saline washed packed red cells (HCT - 65 to 75%) that are compatible by direct antiglobulin test (Coomb’s crossmatched)
  55. 55. RATE AND FREQUENCY OF TRANSFUSIONS  10-15 ml/kg of saline washed packed red cells every 3 to 4 weeks.  Rate not more than 5 ml/kg/hr, however, in patients with cardiac dysfunction not more than 2-3 ml/kg/hr should be given.  Shorter intervals of 2 to 3 weeks are more physiological.  Average time taken is 3-4 hours  Approximately 180 ml/kg of red cells are required to be transfused per year in non-splenectomized, nonsensitized patients to maintain the hemoglobin above 10 gms%, whereas splenectomized patients require 133 ml/kg per year.  Even without hypersplenism, the requirement is 30% higher in non-splenectomized patients
  56. 56. COMPLICATIONS OF TRANSFUSION  NHFTR (Non hemolytic febrile transfusion reaction)  Allergic reactions  Acute hemolytic reactions  Delayed hemolytic reactions  TRALI-transfusion related acute lung injury  TACO- transfusion associated circulatory overload  Alloimmunizaton.  Transfusion transmitted infections  Iron overload  Steps to Prevent These Infections Include  Screening of blood products.  All thalassemic children should recieve hepatitis vaccination if not previously immunised  Leukodepletion can minimize CMV infection
  57. 57. IRON OVERLOAD AND CHELATION THERAPY  Iron Overload Occurs in Thalassemic Patients due to  Treatment with multiple transfusions  Ineffective erythropoiesis  Excessive dietary absorption of iron from gut, to compensate the large turnover of red cell mass  Lack of physiologic excretory mechanism for the excess iron  The goal of iron chelation is to reduce the iron store and subsequently maintain at low level (sr.ferritin less than 1000ng/ml).
  58. 58. INITIATION OF CHELATION THERAPY  Serum ferritin >1000ng/dl  Patient has received 15-20 transfusions  Hepatic iron concentration exceeds 3.2mg/ g dry weight
  59. 59. CHELATING AGENTS  Deferoxamine(DFO)  Route:SC/IV  Dose: 25-50 mg/kg/day  Schedule: over 8 to 10 hrs for 5-6 nights a week with the help of subcutaneous desferal infusion pump  MOA:chelates loosely bound iron, iron from ferritin,hemosiderin ,not from transferrin  Excretion :Urine(80%,urine red)/Feces  Plasma clearance t1/2: 20 minutes  Adverse effects Local skin reaction, ototoxicity, infections ,ophthalmic toxicity, skeletal impairment  Monitoring Long bone films in growing children, annual eye and ear check-up
  60. 60. CONSIDERATION OF AGGRESSIVE CHELATION THERAPY  Severe iron over load  Persistently very high ferritin value  Liver iron >15mg/ g dry weight  Significant cardiac disease  Cardiac arrhythmias  Evidence of falling left ventricular function  Evidence of very severe heart iron loading(MRI T2* <6 ms)  Prior to bone marrow transplantation when rapid reversal of iron loading may be desirable  tab Vitamin C 1hr prior to infusion .
  61. 61.  Deferipone(Kelfer)  It mobilizes iron from transferrin, ferritin, and hemosiderin.  Dose: 75 to 100 mg/kg body weight/day in three to four divided doses  Excretion:Urine  Plasma clearance t1/2:53-166 minutes  Adverse effects: Agranulocytosis, GIT disturbances,transaminase elevation, arthralgias  Monitoring:Weekly CBC
  62. 62. DEFERIPONE ..CONT  Drug should be discontinued whenever  Total count drops to < 3000/mm 3  Absolute neutophil count drops to < 1000/mm 3  Zinc deficiency may develop, zinc supplementation may be necessary  It should be first line drug for patients not receiving DFO because of high cost, toxicity or poor compliance of the later.
  63. 63.  Deferasirox (exjade)  A novel chelating agent belongs to tridentate tiazole,with high affinity to iron as Fe+++ and chelates at a ratio of 2:1 (Deferasirox: Iron).  Dose :20-30 mg/kg/day  Schedule: daily ,OD  Excretion:Feces  Plasma clearance t1/2:1-16 hours  It should be given approximately same time each day on an empty stomach 30 minutes prior to food. Tablet should be dispersed in water/orange /apple juice.  It is available as 250/500 mg tablet for oral suspension dispersible tablets  Monitoring:Monthly RFT, LFT and urine analysis  Side effects: GI disturbances , rash, renal dysfunction
  64. 64. SHUTTLE HYPOTHESIS  Co-administration of ICL 670 (Deferasirox) with Inj DFO has synergic effect and helps in reducing dose of both the drugs thus improving the compliance and cost of the treatment as is done with oral chelation therapy with deriprone and inj. desferal.  Shuttle effect also seen with this combination, as ICL 670- Deferasirox acts as intracellular chelator and DFO as extracellular.
  65. 65. MANIPULATION OF HBF SWITCHING  Hydroxyurea  Histone Deacetylase Inhibitors  Butyric Acid Analogs  5-azacytidine,( risk of cancer –not used now)  Erythropoietin has been tried to induce HbF production with varying success
  66. 66. STEM CELL TRANSPLANTATION  This is only the curative therapy available today.  Sources of stem cells:Bone Marrow, Peripheral Blood, Cord Blood,Fetal Liver.  Though expensive, it is cost effective as compared to yearly cost of regular blood transfusion and chelation therapy.  cost 8-10 lakhs.  Umblical cord stem cells have good results(lower GVHD, longer engraftment)
  67. 67. GENE THERAPY Lenti Viral vector derived from Human Immunodeficiency Virus, where a large fragment of human beta gene and its locus control region, have been introduced, though experimental, more effectiv therapies will become available near future to cure the disease.
  68. 68. PREVENTION OF THALASSEMIA-CARRIER SCREENING  Thalassemia minor or carrier state can be easily detected in a person by doing simple blood test HbA2 by hemoglobin electrophoresis or variant machine or column chromatography  Prevention includes population education, mass screening, genetic counseling and antenatal diagnosis and therapeutic abortion of affected pregnancy  Carrier detection:The only confirmatory test is HbA2 estimation.  To conduct an effective mass screening program, the targeted population should belong to the premarital and newly married groups, i.e. before they have begun their families.
  69. 69. ANTENATAL DIAGNOSIS  When both partners, who are thalassemia minors, plan to have their baby, they are told to report to their hematologist as soon as possible after pregnancy is confirmed.  Chorionic villous sampling (CVS) done between 9th and 11th week of pregnancy.  amniocentesis or cordocentesis-16 to 18 weeks of pregnancy.  Test result:  ‘Affected’ which means the fetus has thalassemia major, or  ‘Unaffected’ meaning that the fetus is either thalassemia minor or normal.  Affected fetuses are advised to be terminated and unaffected fetuses to be continued
  70. 70. REFERENCES  IAP TEXT BOOK OF PEDIATRICS 5th Ed  Advances in pediatrics pedicon 2012  IAP Pediatric Hematology  Nelson Text Book Pediatrics  Standards for the Clinical Care of Children and Adults with Thalassaemia in the UK  Guidelines for the Clinical Care of Patients with Thalassemia in Canada
  71. 71. Thank you