Thalassemia Etiology, Pathogenesis, Clinical features, Diagnosis, Management

1. THALASSEMIA
DR SHAHNAWAZ F SHAH
MD, FPM, FIAPM,FCPM (MUHS)
Interventional Spine & Pain Physician
Surat

6. HEMOGLOBIN A
 Hemoglobin A2 (2 alpha, 2 delta)
Small amounts in body
α
α
β
 Fetal Hemoglobin (2 alpha, 2 gamma)
β

7. Copyright ©1997 BMJ Publishing Group Ltd.

8. NORMAL HUMAN HAEMOGLOBINS

9. 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.

10. CHROMOSOMES
 Thalassemia is inherited as an autosmal recessive
disease.

11. 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.

12. EPIDEMIOLOGY IN INDIA
 In India prevalence of this gene varies 1-17 %
 There are around 65,000 - 67,000 thalassemia patients
in our country
 Common in certain Communities like sindhis, punjabis,
khatris, khukrajas, bhanushalies, baniyas, lohanas, kuchies,
mahars, kolies, agries, goudas, lingayats

13. Classification
β thalassemia α thalassemia Misc thalassemia
syndrome
T. Major Hydropes fetais HbS- thal
T. Intermedia Hbh disase HbE- thal
T. Trait A-thalassemia trait HbD-thal
T. Minima A-b-thal
HPHF
Y-Thal,
d-thal

14. 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)

15. 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

16. 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

17. CLINICAL OUTCOMES OF ALPHA THALASSEMIA
 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 microscopy
 Bart’s Hydrops fetalis
• Hb Bart‟s
• fatal hydrops fetalis
- fluid build-up in fetal compartments, leads to death
occurs in utero

18. 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

19. 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

20. 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

21.  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

22. 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

23. PATHOPHYSIOLOGY..CONT..

24. 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 .

25. 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

26. COMPLICTIONS ..CONT..
 Cardiac complications
 Liver complications
 Endocrine complications
 Bone complications
 Other complications
Infections: yersinia,parvovirus B19
Dental Complications
Growth retardation
Leg ulcers

27. 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 weight is
associated with high risk of cardiac death in
thalassemia

28. 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

29. 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.

30. 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%)

31. 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

32. 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
hypersplenism
 Splenectomy should be delayed till the patient is 5
years of age as there is risk of overwhleming sepsis
below this age

33.  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

34. IMMUNIZATION PRIOR TO SPLENECTOMY
 Pneumcoccal vaccine. 0.5 ml SC
 Meningococcal vaccine:
 Quadravalent meningococcal (Menactra) 0.5
mL IM upper deltoid.
 Haemophilus b conjugate : One dose

35. CAUSES OF DEATH
 Congestive heart failure
 Arrhythmia
 Sepsis secondary to increased susceptability to
infection post spleenectomy
 Multiorgan failure due to hemochromatosis

36. THALASSEMIA FACIAL BONE
ABNORMALITIES.
These changes include:
Bossing of the skull
Hypertrophy of the maxilla,
exposing the upper teeth
Depression of nasal bridge
Periorbital puffiness
THALASSEMIA MAJOR
LEG ULCER
Leg ulcers can occur in all
types of hereditary hemolytic
anemias, including sickle cell
disease and hereditary
spherocytosis.

37. THALASSEMIA
MAJOR
Note the pallor, short
stature,massive
hepatosplenomegaly,
and wasted

38. THALASSEMIA
BONE
ABNORMALITIES
Note the “hair on end”
appearance of the
cortical bone caused
by expansion of the
bone marrow.
The subperiosteal
bone grows in
radiating striations,
which appears as
“hairs.”

40. LABORATORY
DIAGNOSIS OF
THALASSEMIA
44

41.  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

42.  The baseline serum ferritin and liver enzymes
including ALT,AST, bilirubin, lactate dehydrogenase
(LDH) should be measured.
 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.

43. HB ELECTROPHORESIS

44. LAB DIAGNOSIS
 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

45. 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.

46. 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

47. 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?

48. TYPE OF TRANSFUSION
 Leuko-reduced 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

49. 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.

50. 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)

51. 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

52. 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).

53. INITIATION OF CHELATION THERAPY
 Serum ferritin >1000ng/dl
 Patient has received 15-20 transfusions
 Hepatic iron concentration exceeds 3.2mg/ g dry
weight

54. 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

55. 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 .

56.  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

57. 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.

58.  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

59. MANIPULATION OF HBF SWITCHING
 Hydroxyurea
 Histone Deacetylase Inhibitors
Butyric AcidAnalogs
 5-azacytidine,( risk of cancer –not used now)
 Erythropoietin has been tried to induce HbF
production with varying success

60. 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)

61. 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.

62. 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.
 Toconduct 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.

63. 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

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