A comprehensive study of the basics of Thalassemia

1. Thalassemia
By Fatima Farid Mir

2. Contents
ϟ Definition
ϟ Beta Thalassemia
ϟ Alpha Thalassemia
ϟ Pathogenesis
ϟ Clinical features
ϟ Diagnosis
ϟ Treatment and Disease Monitoring
ϟ References

3. Definition
ϟ Thalassemia is a diverse group of disorders, manifesting as anemia of
varying degrees.
ϟ Occurs as a result of defective/ abnormal rate of production of globin
portion of hemoglobin molecule.
ϟ The globin chains are structurally normal, but an imbalance is present.
This can lead to hemolysis.
ϟ The defect may be homozygous or heterozygous.
ϟ May contribute to protection against malaria.

4. Genetics
ϟ There are two major types of thalassemia:
ϟ Alpha: caused by defect in rate of synthesis of alpha chains.
ϟ Beta: caused by defect in rate of synthesis of beta chains.
ϟ Alpha thalassemia is caused by gene deletion on chromosome 16.
ϟ Beta thalassemia is caused by mutation on chromosome 11.
ϟ The end result is microcytic hypochromic anemia of varying degrees.

5. Beta Thalassemia

6. Beta Thalassemia
ϟ Classical syndromes:
ϟ Silent carrier state: mildest form of beta thalassemia
ϟ Beta thalassemia minor: heterozygous disorder resulting in mild
hypochromic microcytic hemolytic anemia
ϟ Beta thalassemia intermedia: severity lies between major and minor
ϟ Beta thalassemia major: homozygous disorder resulting in severe
transfusion dependent hemolytic anemia

7. Beta = normal
Beta+ = reduced function
Beta 0 = no function

8. Silent Carrier State of Beta Thalassemia
ϟ Various heterozygous beta mutations that produce only small decrease in
production of beta chains.
ϟ Patients have nearly normal beta/ alpha chain ratio and NO hematological
abnormalities.
ϟ Have normal levels of HbA2.

9. Beta Thalassemia Minor
ϟ Caused by heterogeneous mutations that affect beta globin synthesis
ϟ Usually presents as mild, asymptomatic hemolytic anemia unless the patient
is under stress (infection, pregnancy, folic acid deficiency)
ϟ Have one normal beta gene, and one mutated beta gene.
ϟ Hemoglobin level 10- 13 g/dl range, with normal or slightly elevated RBC
count.

10. Beta Thalassemia Minor
ϟ Anemia is usually hypochromic microcytic with target cells and elliptocytes.
May see basophilic stippling.
ϟ Rarely see hepatomegaly and splenomegaly.
ϟ Have high HbA2 levels (3.5- 8%), and normal/ slightly elevated HbF levels.
ϟ There are different variations of this form depending upon which gene has
mutated.
ϟ Normally requires no treatment
ϟ Make sure not the diagnose with only iron deficiency anemia.

13. Beta Thalassemia Intermedia
ϟ Patients are able to maintain minimum hemoglobin of 7 g/dl without
transfusions.
ϟ Expression of disorder may be either heterozygous for mutations (causing
mild decrease in beta chain production), or be homozygous (causing more
serious reduction in beta chain production).
ϟ Increased levels of both HbA2 and HbF.
ϟ Peripheral blood smear similar to Thalassemia minor.

14. Beta Thalassemia Intermedia
ϟ Have varying symptoms of anemia, jaundice, splenomegaly and
hepatomegaly.
ϟ Significantly increased bilirubin levels.
ϟ Anemia usually becomes worse with infections/ pregnancy
ϟ May become transfusion dependent as adults.
ϟ Tend to develop iron overload as a result of increased GI absorption.
ϟ Usually survive into adulthood.

15. Beta Thalassemia Major
ϟ Severe microcytic hypochromic anemia
ϟ Detected early in childhood:
ϟ Failure to thrive
ϟ Pallor, variable degrees of jaundice, Hepato/splenomegaly (enlarged
abdomen)
ϟ Hemoglobin levels between 4 and 8 g/dl
ϟ Severe anemia causes marked bone changes due to expansion of marrow
space for increased erythropoiesis.

16. Beta Thalassemia Major
ϟ There will be changes in skull, long bones and hand bones.
ϟ Protrusion of upper teeth. Mongoloid facial features.
ϟ Physical growth and developmental delay.
ϟ Peripheral blood shows markedly hypochromic microcytic erythrocytes with
extreme poikilocytosis (target cells, tear drop cells) and elliptocytosis.
ϟ MCV ranges from 50 to 60fl. Low retic count 2-8%.
ϟ Most hemoglobin present is HbF, with slight increase in HbA2.

21. Medullary
expansion +
Cortical thinning
Normal Hand

22. Normal Hand
Medullary
expansion +
Cortical thinning

24. Beta Thalassemia Major
ϟ Regular transfusions starting from one year of age, continuous throughout
life.
ϟ Excessive number of transfusions results in transfusional hemosiderosis.
Without iron chelation, the patient develops cardiac disease.
ϟ Dangers of continuous transfusion therapy:
ϟ Iron overload
ϟ Alloimmunization = development of antibodies against transfused RBCs
ϟ Transfusion- transmitted diseases (HIV, Hep B, Hep C).

25. Comparison
Genotype HbA HbA2 HbF
Normal Normal Normal Normal
Silent Carrier Normal Normal Normal
Minor Low
Normal/ slightly
high
Normal
Intermedia Low Little high High
Major Low High High

26. Delta Beta Thalassemia
ϟ Only alpha and gamma chains produced (delta and beta inactivated)
ϟ Growth and development nearly normal
ϟ Modest splenomegaly. Similar to beta thalassemia minor.

27. Hereditary Persistence of Fetal Hemoglobin (HPFH)
ϟ Rare condition. Continued synthesis of HbF into adult life.
ϟ Does not have usual symptoms of thalassemia.
ϟ Little significance unless combined with other hemoglobinopathies.
ϟ HbF is more resistant to denaturation than HbA- can be demonstrated using Kleihauer
Betke stain (stains cells with HbF).
ϟ Classified into 2 groups based on distribution of HbF among cells:
ϟ Pancellular: HbF uniformly distributed throughout all cells
ϟ Heterocellular: HbF only found in a small number of cells

30. Beta Thalassemia with HbS
ϟ Inherit gene for HbS from one parent, and gene for HbA from other parent
ϟ Great variety in clinical severity depending on amount of HbA produced.
ϟ If no HbA made, true sickle cell symptoms present.
If some HbA present, less symptoms appear.

32. Others
ϟ Beta Thalassemia with HbE: Very severe disease, transfusion dependent
patient
ϟ Beta Thalassemia with HbC: Usually asymptomatic.

33. Alpha Thalassemia

34. Alpha Thalassemia
ϟ Wide range of clinical expression
ϟ It is difficult to classify alpha thalassemia due to a wide variety of possible
genetic combinations
ϟ Absence of alpha chains will result in increase of gamma chains during fetal
life and excess beta chains later in life.
ϟ Molecules like Bart’s Hemoglobin (4 gamma chains) and HbH (4 beta chains)
form: they are stable molecules, but physiologically useless.

35. Alpha Thalassemia
ϟ The predominant cause is a large number of gene deletions in alpha- globin
gene.
ϟ There are 4 clinical syndromes present in alpha thalassemia:
ϟ Silent Carrier State
ϟ Alpha Thalassemia Trait (Alpha Thalassemia Minor)
ϟ Hemoglobin H disease
ϟ Bart’s Hydrops Fetalis Syndrome

37. Silent Carrier State
ϟ Deletion of one alpha gene, leaving 3 functional alpha genes
ϟ Alpha to beta chain ratio nearly normal
ϟ No hematologic abnormalities present. May have borderline low MCV (78-80
fl).
ϟ Diagnosis only possible by genetic mapping

38. Alpha Thalassemia Trait
ϟ Also called Alpha Thalassemia Minor
ϟ Caused by 2 missing alpha genes.
ϟ May be homozygous (-a/-a), or heterozygous (--/aa)
ϟ Exhibits mild microcytic hypochromic anemia. MCV 70- 75 fl.
ϟ May be confused with iron deficiency anemia.

39. Hemoglobin H Disease
ϟ Second most severe form of alpha thalassemia
ϟ Caused by presence of only one gene producing alpha chains (--/-a)
ϟ Results in accumulation of excess unpaired gamma or beta chains.
ϟ Born with 10- 40% Bart’s hemoglobin. Gradually replaced with HbH.
ϟ Adults have about 30- 50% HbH.

40. Hemoglobin H Disease
ϟ Live normal life, but infections/ pregnancy can trigger hemolysis
ϟ RBCs are MCHC with target cells.
ϟ HbH is vulnerable to oxidation. It gradually precipitates in vivo to form
Heinz- like bodies of denatured hemoglobin.
ϟ Cells have been described to have a golf- ball appearance, especially when
stained with Brilliant Cresyl Blue.

43. Bart’s Hydrops Fetalis Syndrome
ϟ Most severe form. Incompatible with life.
ϟ Have no functioning alpha genes.
ϟ Baby born with hydrops fetalis: edema and ascites caused by accumulation
of fluid in fetal tissues as a result of severe anemia. Causes
hepatosplenomegaly and cardiomegaly.
ϟ Predominant hemoglobin is Hb Bart, along with Hb Portland.
ϟ Hb Bart has high oxygen affinity, so it cannot carry oxygen to tissues. Fetus
dies in utero or shortly after birth. Mother has increased risk of PPH.

44. Alpha Thalassemia with HbS
ϟ Common in populations of African descent
ϟ Asymptomatic patient
ϟ Have less HbS than in those with sickle cell trait.

45. Remember!

47. Pathogenesis

48. B

50. Clinical Features

58. Diagnosing Thalassemia

59. Diagnosis
ϟ History and physical exam (pallor, jaundice, hepatosplenomegaly, skeletal defects)
ϟ LAB:
ϟ Low hemoglobin. Hypochromic microcytic. Low hematocrit.
ϟ MCHC normal or slightly low.
ϟ Normal or HIGH RBC count.
ϟ MCV MUCH LOWER THAN EXPECTED FOR HEMOGLOBIN LEVEL.
ϟ High retics (depends on severity)
ϟ Raised indirect bilirubin (Thalassemia major and intermedia)

60. Diagnosis
ϟ HEMOGLOBIN ELECTROPHORESIS:
ϟ Can detect type of hemoglobin (HbA, HbA2, HbF and abnormal types)
ϟ Detects combinations of thalassemia and other hemoglobinopathies
ϟ HEMOGLOBIN QUANTIFICATION
ϟ Reduced osmotic fragility: easy screen for carriers
ϟ Brilliant Cresyl Blue stain for HbH disease and Acid Elution test (Kelihauer Betke
test) for HbF
ϟ Iron studies to detect/ rule out concurrent iron deficiency anemia

64. Howell Jolly bodies
are DNA clusters
(remnants) in
circulating RBCs:
asplenia = cannot
remove these
abnormal cells

65. Heinz Bodies are
fragments of
denatured
hemoglobin within
circulating RBCs:
Alpha Thalassemia
(Beta tetramers =
HbH) and Asplenia
(cannot remove
these abnormal cells)

67. Management

68. Blood Transfusion Programs
ϟ Three main Transfusion Programs:
ϟ Regular Transfusion Program: Corrects severe anemia to a safe hemoglobin
of 7- 9g/dl to avoid symptoms of anemia.
ϟ Hypertransfusion Program: Maintains hemoglobin between 10- 12g/dl to
decrease the effects of chronic anemia and prevent abnormal growth/
development.
ϟ Super-Transfusion Program: Hemoglobin is maintained at 12g/dl to
completely suppress hematopoiesis. This reduces transfusion requirements
and iron overload; less Hypersplenism; less damage to bones/ heart; better

69. Dose of Blood Transfusion
ϟ Ideally, RBCs should be 6 days old, leucocyte reduced.
ϟ 10- 20 ml/kg body weight every 3- 4 weeks. As body size increases, 1-2 units
every 3 weeks.
ϟ Pre-transfusion hemoglobin should be maintained at 10g/dl.
ϟ With each unit of transfused blood, 200mg of iron collects in the body.

70. Neocyte Transfusion- Not widely practiced
ϟ Younger red cells are selectively extracted from donor blood (found in the
upper portion of the layer of red cells after centrifugation).
ϟ Half life of neocytes is 90- 100 days (compared to 60 days of mature RBCs).
ϟ This leads to reduced transfusion requirements; longer intervals between
transfusions; reduced iron overload.
ϟ Procedure is very expensive and time consuming: not widely accepted.

71. Iron Overload Management
ϟ Desferrioxamine is currently the most effective iron chelating agent.
ϟ It is started as early as possible; usually when Ferritin >1,000 ng/ml. Must be
older than 5 years.
ϟ Daily subcutaneous infusion of Desferrioxamine 20- 40 mg/kg during sleep
(over 8- 12 hours) with a portable battery- operated infusion pump, 5 days a
week.
ϟ Vitamin C up to 200 mg/day is given alongside Desferrioxamine as it converts
the ferric form of iron into the ferrous form and mobilizes stored iron into free
form.

72. Desferal
ϟ There are only 2 doses available: 500 mg/vial and 2 g/vial.
ϟ Subcutaneous Administration: 1-2 g over 8- 24 hours via pump
ϟ IV Administration: 40- 50mg/kg/ day over 8- 12 hours for 5- 7 days via PICC
line

73. Desferrioxamine Therapy

78. Desferal Usage Technique
ϟ Requirements:
ϟ 1. Sterile Water for Injection (around 20 ml)
ϟ 2. Desferal Medicine (around 2 g)
ϟ 3. 10 cc Syringe
ϟ 4. Micro-needle with tubing
ϟ 5. Desferal Infusion Pump
ϟ 6. Alcohol solution to sterilize work place
ϟ 7. Alcohol and iodine skin prep wipes
ϟ 8. Tegaderm (adhesive for skin)
ϟ 9. Emla cream

79. Steps for Desferal Usage
ϟ 1. Apply Emla cream 30 mins before starting. Clean work place with alcohol
solution.
ϟ 2. Gather all equipment needed
ϟ 3. Wash hands with sterile soap
ϟ 4. Open sterile water for injection and also the Desferal medicine bottles
ϟ 5. Sterilize the top of both bottles
ϟ 6. Using the syringe, pull out 20 ml of sterile water
ϟ 7. Add the sterile water to the Desferal medicine bottle

80. ϟ 8. Shake the Desferal medicine bottle well until it is a clear solution
ϟ 9. Attach the same syringe to the Desferal bottle, and pull out all the medicine
ϟ 10. Make sure there is no air in the syringe
ϟ 11. Remove the micro- needle off the syringe, and keep aside
ϟ 12. Put the Desferal syringe into the Desferal pump.
ϟ 13. Sterilize skin with alcohol wipe, then with the iodine wipe (make sure no iodine
allergy)
ϟ 14. Prick skin with the needle (attached to tubing), place the tegaderm on top
ϟ 14. Switch the pump on
ϟ 15. Continue with daily activities.

82. Deferasirox Oral Suspension= Exjade
ϟ Oral chelation agent. Used above the age of 2 years.
ϟ Tablet dissolved in water/ orange juice/ apple juice. Drank right away.
Should be taken on an empty stomach 30 minutes before food.
ϟ Should not be used with other iron chelators (Desferal).
ϟ Three tablets exist: 125 mg; 250 mg; 500 mg.
ϟ Dose: 20 mg/kg/day QID. May increase gradually based on serum ferritin
levels.
ϟ The average adult weighing 70kg will require 1,400 mg = 3 tablets of 500mg
QID = 12 tablets daily

84. Deferasirox Oral Tablet/ Oral Granules = Jadenu
ϟ New form of Deferasirox.
ϟ Three tablet forms exist: 90 mg; 180 mg; 360 mg.
ϟ Dose: 14- 28 mg/kg/day QID.
ϟ The average adult weighing 70kg requires a minimum of 980 mg = 3 tablets
of 360 mg QID = 12 tablets daily (minimum)
ϟ The highest dose possible for 70 kg is 1,960 mg = 5 tablets of 360 mg QID =
20 tablets daily (maximum)

88. Deferasirox Side Effects
ϟ Abdominal pain, nausea, vomiting, diarrhea
ϟ Proteinuria, dose- related increase in serum creatinine
ϟ Cough, nasopharyngitis, pharyngolaryngeal pain
ϟ Headache
ϟ Rash
ϟ Fever
ϟ Agranulocytosis: needs monitoring of absolute neutrophil count

89. Deferiprone = Ferriprox
ϟ Oral chelation agent
ϟ Dose: 25 mg/kg TDS
ϟ Only one tablet available: 500 mg
ϟ Average adult 70kg needs 1,750 mg = 4 tablets TDS = 12 tablets daily
ϟ Used above the age of 2 years

90. Deferiprone = Ferriprox
ϟ Side effects:
ϟ Agranulocytosis
ϟ Drug- induced lupus
ϟ Reversible arthropathy

91. Additional Supportive Medications
ϟ Folic Acid 5 mg once a week
ϟ Vitamin C 100 mg daily (if on Desferal)
ϟ Calcium Carbonate 600 mg BD or 1,200
mg BD depending on levels
ϟ Vitamin D 1,000 IU daily or 50,000 IU
weekly/ monthly: depending on levels
ϟ Osteocare Syrup 12 ml BD
ϟ Progyluton tablets for menstrual cycle
(Estradiol valerate + Norgestrel)
ϟ Sustanon injection IM 250 mg every 3
weeks (testosterone)
ϟ Insulin/ Metformin
ϟ Thyroxine
ϟ Growth Hormone injections every 3
weeks
ϟ Lisinopril, Bisoprolol for cardiac disease
ϟ Penicillin 250 mg BD (if splenectomized)

93. Splenectomy
ϟ Performed after 5 years of age
ϟ Patient must receive pneumococcal vaccine 2- 4 weeks in advance
ϟ Indications:
ϟ Severe hepatosplenomegaly causing abdominal discomfort
ϟ Transfusion requirements exceeding 200- 250 ml/kg/ year
ϟ Following splenectomy, all patients must be given a prophylactic antibiotic
regime of Penicillin 250 mg BD life- long.

98. Disease Monitoring

100. Iron Overload Assessment (in DHA)
ϟ Serum Ferritin
ϟ T2 Cardiac MRI
ϟ Liver Iron Concentration

106. Monitoring Cardiac Status
ϟ History and physical examination
ϟ ECG
ϟ Echocardiography

107. Monitoring Endocrine Status
ϟ Diabetes
ϟ Hypothyroidism
ϟ Hypoparathyroidism
ϟ Hypogonadism
ϟ Menarche
ϟ Menstrual cycle regularity
ϟ Fertility status

108. Monitoring Hepatic and Coagulation Status
ϟ SGLT and ALT
ϟ PT
ϟ PTT
ϟ Assessment of liver and spleen spans

109. More investigations
ϟ Hearing assessment
ϟ Visual assessment
ϟ Viral screening: Hepatitis B and C; HIV
ϟ Vaccination assessment: Influenza and Hepatitis B vaccines
ϟ Assessment for splenectomy
ϟ Assessment for PICC line insertion

110. References

111. References
ϟ Slide Share: Thalassemia, The Medical Post.
ϟ Thalassemia, austincc.edu
ϟ Medscape

112. Thank You 