Diagnosis and Management of Thalassemias in Pediatrics. This seminar was prepared by me during my internship at AJIMS.

1. Dr. Anup G

2. …continuing the session…
…with:
Diagnosis &
Management

3. Diagnosis
• Clinical examination
• Laboratory investigations
• Radiological findings
Source: IAP

4. Lab workup
• Peripheral Smear Examination
• Reticulocyte count
• Iron studies
• Hb Electrophoresis
– HbF, HbA2 and other abnormal hemoglobins
• Other tests
Source: IAP

5. Peripheral Smear
• Diagnostic test
• Shows:
– Microcytosis
– Macrocytosis
– Hypochromia
– Poikilocytosis
– Polychromasia
– Basophilic stippling
– Fragmented erythrocytes
– Target cells
– Large number of normoblasts Source: IAP

6. Peripheral smear
Peripheral smear in beta thalassemia minor showing
microcytes (M), target cells (T), and poikilocytes(P).
Source: eMedicine

7. Peripheral smear from a patient with beta thalassemia
major showing more marked microcytosis (M) and
anisopoikilocytosis (P) than in thalassemia minor.
Target cells (T) and hypochromia are prominent.
Source: eMedicine

8. Supra vital stain in hemoglobin H disease that reveals Heinz bodies
(golf ball appearance)
Source: eMedicine

9. Reticulocyte count
• Normal Reticulocyte count is <1%
• In Thalassemia, counts are 2% to 8%
Source: IAP

10. Iron studies
Osmotic fragility Reduced
Serum Iron levels Increased
TIBC Reduced
Transferritin saturation Increased
Ferritin level Increased
Bone marrow examination Normoblastic erythroid
hyperplasia
Iron staining of marrow Increased hemosiderin
Source: IAP

11. Excessive iron in a bone marrow preparation
Source: eMedicine
Bone marrow examination

12. Hb electrophoresis
• It is a DIAGNOSTIC test
• Fetal Hb is increased in the patient
• HbA2 is over 3.4% in both parents
Source: IAP

13. Other laboratory findings
• Abnormalities in
– SGOT
– SGPT
– GGT
– Serum Bilirubin
– Serum Calcium
– Glucose Tolerance Curve
– Endocrinological studies
• Periodic testing of these values is essential
Source: IAP

14. Radiological findings
• Widening of medulla due to bone marrow
hyperplasia
• Thinning of cortex and trabeculation in long
bones, metacarpals and metatarsals
• Skull X-ray: “Hair on end” or “Crew cut”
appearance
Source: IAP

15. Skull X-ray
Thalassemia: x-ray film of the skull showing new bone formation on
the outer table, producing perpendicular radiations characterized as a
"crew haircut“ or “hair-on-end” appearance
Source: Robbins 7/e

16. Hand x-ray
Mosaic pattern produced by trabeculation in the bones of the hand of a patient
with thalassemia major. Note the rectangular contour of the metacarpals.
Source: Wintrobe’s Clinical Hematology 11/e

17. Anteroposterior radiograph of the forearm
A fracture is noted in the distal radius. Evidence of medullary expansion
and cortical thinning is observed.
Source: eMedicine

18. Radiograph of the ribs
Erosions of the inferior cortical margins of the third, fourth, and fifth
ribs are noted.
Source: eMedicine

19. Dr. Anup G
Anteroposterior radiograph of the lumbar spine
Osteopenia is present; note striated appearance of the vertebral bodies
resulting from preservation and thickening of the vertical trabeculae.
Clips from a previous cholecystectomy are present. Source: eMedicine

20. Management
Source: IAP
Step byStep by
stepstep
approachapproach
essentialessential

21. Repeated PRBC Transfusions
• Goals:
– Prevent anemia
– Suppress endogenous erythropoeisis
• To prevent abnormal fragile RBCs being produced
• Who requires transfusion?
– Thalassemia Major
– Thalassemia intermedia with
• Hb < 7g%
• Evidence of skeletal changes & growth retardation
Source: IAP

22. What to transfuse?
• Coombs’ cross matched triple saline washed
packed cells
• Frozen cell transfusion
• Leucocyte filtered transfusion
• Nothing of the above available?
– Simple packed cell transfusion will do
Source: IAP
Expensive

23. How much to transfuse?
• Three types of transfusions:
• Most popular: Hypertransfusion
– Hb level is aimed at
• Maintaining mean Hb levels at 12.5 g%
• Pre transfusion level NOT LESS than 10 g%
Source: IAP
Type Hb to be maintained at
Low transfusion 6 to 10 g%
Hypertransfusion 10 to 12 g%
Supertransfusion > 12 to 14 g%

24. Advantages of hypertransfusion
• Permits normal growth and physical activities
• Suppresses erythropoiesis
• Prevents skeletal changes
• Prevents gastrointestinal iron absorption
• Also prevents extramedullary erythropoiesis
– Thus prevents splenomegaly ad hypersplenism
• Requirement of blood is high only at start of
therapy
• Iron overload is no more than low transfusion
Source: IAP

25. Amount of transfusion
• NOT more than 10 ml PRBCs/kg/day
– This raises Hb level by ~3.5 g%
• In most patients
– 10 ml PRBCs/kg every third week
– adequate to maintain pre-transfusion Hb level at
10 to 11 g%
Source: IAP

26. Rate of transfusion
• 5 to 7 ml/kg body weight/hour
– Avoids sudden increase in blood volume
• Patients with Cardiac insufficiency
– Transfusions every second week
– OR every week
– Prolong the duration of transfusion
• Decrease rate to 1 to 3 ml/kg body weight/ hour [NOT
more than 5 ml/kg/hr]
Source: IAP

27. How often to transfuse?
• Preferably at intervals of 2 to 4 weeks
– On an outpatient basis
Source: IAP
Precautions
• Donor blood must be
• From voluntary donor
• Cross-match using Coomb’s sera
• Screened for
• HIV, HepB, malaria, syphilis, HCV

28. Neocyte transfusion
• Neocytes are young RBCs
• Mean life span of normally transfused RBCs is 60
days
• Neocytes survive upto 90 days
– Reduces number of transfusions
• Drawbacks:
– Very expensive
– Highly skilled personnel & costly equipments required
– Processing is time-consuming
Source: IAP

29. Complications of transfusion
• Infections
– HepB, HepC and HepG viruses
– HIV
– Malaria
• Hemosiderosis
Source: Wintrobe’s Clinical Hematology 11/e

30. Hemosiderosis
• The abnormal accumulation of iron in the
tissues is Hemosiderosis
• If untreated, causes considerable morbidity
and, ultimately, leads to death
• Source of iron excess:
– Extensive hemolysis
– Repeated blood transfusions
– Increased gastrointestinal absorption
Source: Wintrobe’s Clinical Hematology 11/e

31. Hemosiderosis
• Organs affected:
– Heart (Myocardial iron toxicity)
• Cardiomegaly
• Left ventricular deterioration progress to congestive
heart failure
• Arrhythmias  Sudden death
– Liver
• Parenchymal siderosisFibrosisCirrhosis
– Lungs
• Ventilatory restrictive impairment  Pulmonary
insufficiency
Source: Wintrobe’s Clinical Hematology 11/e

32. Hemosiderosis
– Endocrine glands
• Directly or through the hypothalamic-pituitary axis
• Pubertal delay, growth retardation, thyroid
dysfunction, adrenal dysfunction & Diabetes mellitus
– Exocrine glands
• Sicca syndrome, xerostomia, and xerophthalmia
• ↓ pancreatic enzymes
– Eye
• retinal pigmentary changes
– Skin
• pigmentation
Source: Wintrobe’s Clinical Hematology 11/e

33. Assesment of Iron overload
• Serum ferritin concentration
– Above 1000 μg/dl  Overload
– Above 7500 μg/dl  Lethal
How to overcome Iron overload?
Answer : Chelation therapy
Source: IAP

34. Chelation therapy
• “chelate” = combine a metal with a
compound and convert it into a complex
form, unutilisable and easily excretable by
the body
• Iron chelation helps by eliminating the iron
introduced by transfusion
• Main sources of chelatable iron:
– the intracellular labile pool (derived from lysosomal catabolism of
ferritin and from transferrin)
– iron derived from red cell catabolism in
macrophages
Source: Wintrobe’s Clinical Hematology 11/e

35. Chelators
• Two are presently in use:
– Deferoxamine B (DFO)
• hexadentate, forms stable iron-chelate complexes
using a single molecule
– Deferiprone
• bidentate, requires three molecules to coordinate all
six sites and tends to dissociate from iron at low
concentrations.
Source: Wintrobe’s Clinical Hematology 11/e

36. Desferroxamine(DFO)
• 1 gram DFO binds with 85 gram of Iron
• Should be started before the age of 3 years
• Dose
– 30 to 70 mg/kg/day
– Daily(min 5 to 6 times per week)
• Route
– Subcutaneously over 6 to 8 hours by an infusion
pump
• Goal: keep serum ferritin levels below 1000 ng/ml
Source: IAP

37. DFO toxicity
• Parenteral
– Bradycardia
– hypo/hypertension
– Rigors
– Headache
– Photophobia
– excess heat/cold
• Subcutaneous
– Local pain & Induration
– Irritability & Redness
• Visual abnormalities (reversible)
Due to histamine liberation
Source: IAP

38. DFO toxicity (continued)
• High frequency sensorineural hearing loss (reversible)
– In 4 to 38% of patients
• Delayed linear growth
– When treatment started in children < 3 years
Source: IAP

39. Antero-posterior (A) and
lateral (B) views of the lumbar
spine of a 15-year-old with
thalassemia major,
demonstrating flat vertebral
bodies due to desferrioxamine
C: Desferrioxamine toxicity. The
growth plate of the distal ulna is
wide, and the metaphysis exhibits a
cuplike deformity with sclerotic and
irregular borders.
D: A similar picture is present in the
metaphyses of the femur and fibula
A
D
C
B
Source: Wintrobe’s Clinical Hematology 11/e

40. Role of Vitamin C
• Vit.C helps in conversion of hemosiderin to ferritin
• This helps in chelation
• 100 mg Vit.C daily before DFO administration helps in better
chelation
• Very high doses of Vit.C can cause tissue damage and cardiac
decompensation even DEATH!
Source: IAP

41. Deferiprone
• Oral chelating agent
• Mobilises Iron from hemosiderin, transferrin
and ferritin
• Dose: 75 mg/kg/day (achieves iron excretion
equivalent to that achieved with 40 mg/kg/day of DFO)◊
• Lesser toxic effects than DFO
• Lesser cost than DFO
• To improve compliance and efficacy, combined
therapy of DFO and Deferiprone is also followed
– Deriprone 75 mg/kg/day on weekdays (4-5 days)
– DFO 40 to 50 mg/kg subcutaneous infusion for 6 to 8 hours in the weekend
(2 days) Source: IAP
◊Source: Wintrobe’s Clinical Hematology 11/e

42. Rx of complications
• Anemia
– taken care by transfusions & Folate
supplementation
• Iron overload
– Chelation therapy
• Splenomegaly / hypersplenism
– Splenectomy
– Post splenectomy vaccination is a must
– Rare nowadays due to use of hypertransfusion
Source: IAP

43. Other modalities
• Bone marrow transplantation
• Pharmacological methods to increase
gamma chain synthesis
• Gene replacement therapy
• Newer drugs
Source: IAP

44. Prevention
• Screening: HbA2 level in (would be) parents
• Population education
• Genetic counselling
• Therapeutic abortion
Source: IAP

45. Recent advances
• 5 – Azacytidine
• Hydroxyurea
• Butyrates
• ICL – 670
• Genetic engineering  Stem cell therapy
Source: IAP

46. Bibliography
• Nelson Textbook of Pediatrics, 18/e
• IAP Textbook of Pediatrics
• Essential Pediatrics, OP Ghai et al, 7/e
• Pathological Basis of Disease, Robbins &
Cotran, 6/e
• Wintrobe’s Clinical Hematology 11/e
• eMedicine.com