This document discusses hemoglobinopathies, which are hereditary disorders of hemoglobin. It focuses on sickle cell disease and thalassemias. Sickle cell disease is caused by a mutation that replaces valine for glutamic acid on the beta globin chain, causing hemoglobin S. This polymerizes and deforms red blood cells, leading to anemia, pain crises, infections, strokes, and other complications. Thalassemias involve reduced production of the alpha or beta globin chains, resulting in imbalanced globin synthesis and hemolysis. Common symptoms include anemia, spleen and liver enlargement, and iron overload from frequent transfusions in thalassemia major. Diagnosis involves blood tests

1. Dr.B.SOORYA NARAYANAN
PG – UNIT -2
HEMOGLOBINOPATHIES

2. INTRODUCTION
 HEREDITARY DISORDER OF HEMOGLOBINS
ARE BROADLY TWO GROUP
A) HEMOGLOBINOPATHY
B) THALASSAEMIAS

3. NORMAL HAEMOGLOBIN
 Normally different
hemoglobin are
synthesized in
embryo , fetus and
adult.

4.  Normal hemoglobins are tetramers of two
α-like and two β-like globin polypeptide
chains.
 α-like: 141 amino acids ( chromosome 16)
 β-like: 146 amino acids ( chromosome 11)

5. CLASSIFICATION
 Structural hemoglobinopathies : hemoglobins with
altered amino acid sequences eg HbS
 Thalassemias : defective biosynthesis of globin chains
 Thalassemic hemoglobin variants : structurally
abnormal Hb associated with co‐inherited thalassemic
phenotype
a) HbE,
b) Hb Constant Spring,
c) Hb Lepore
 Hereditary persistence of fetal hemoglobin
 Acquired hemoglobinopathies
A. Methemoglobin
B. Sulfhemoglobin
C. Carboxyhemoglobin
D. HbH in erythroleukemia

6. SICKLE CELL DISEASE
 SCD is an inherited chronic hemolytic anemia
whose clinical manifestations arises from
tendency of the hemoglobin to polymerize and
deform red cells into the circulation .
 GENETICS
In 6th position in beta globin chain of
hemoglobin VALINE replaces the GLUTAMIC
ACID .

7. PATHOLOGY

8. EFFECT OF SICKLE CELL
 ON ERYTHROCYTE
A) Membrane damage leading to cellular
dehydration
B) Cells become adherent to vascular
endothelium
C) There will be both intravascular and extra
vascular hemolysis
D) There will be reduced ability of the red cells to
deform .
F) Finally there will be loss of response of vessel
to NO leading to thrombosis ultimately

9. CLINICAL MANIFESTATIONS
 Clinical symptoms will vary among people with SCD.
 Usually the symptoms are more severe in people with
HbSS or sickle thalassemia.
 ANAEMIA
1) It mainly depends upon the underlying β – globulin
genotype.
2) the baseline hemoglobin will be comparatively low than
normal individuals .
3) patients with low HB are at high risk of developing stroke
and renal dysfunction.
4) patients with raised HB are at increased risk to develop
painful episode , AVN , Acute chest syndrome .

10.  ANAEMIA CONT ….
5) boys are more anemic than female in first
decade , but in adults HB value falls in womens.
6) Gradual fall in HB value will be due to varied
causes , like
1) iron def , 2) folic acid / b12 def 3) CRF
7) An acute fall in HB may be due to
1) APLASTIC CRISIS
2) SPLENIC SEQUESTRATION.

11.  ACUTE PAINFUL SYNDROME
1) It is the most frequent symptom which is
mainly due to vaso-occlusion.
2) more common in young adults than old age.
3) one third of SCD patients do not experience
acute painful syndrome.
4) cold , dehydration , infection , stress usually
precipitate the attack.
5) in children it presents as HAND-FOOT
SYNDOME ( dactylitis) due to bone infarction .
6) other areas are back , chest , extremity and
abdomen.

12. X ray sickle cell hand foot syndrome

13.  INFECTIONS
1) Early loss of splenic function leads to increased
risk of infection and sepsis.
2) pneumococcal infection is a serious problem in
SCD patients which may need prophylaxis and
vaccination.
3) Meningitis , pneumonia , osteomylitis , uti and
sepsis are common clinical spectrum.
NEUROLOGICAL COMPLICATIONS
1) TIA / STROKE / FOCAL SEIZURE are the
common clinical manifestation of SCD
2) precipitating factors are 1) low HB 2) high
TC 3) low HBF 4) high systolic BP.

14. 3) Angiography shows stenosis or complete
occlusion of vessels or even aneurysm formation
( MOYAMOYA DISEASE)
4) clinical features are weakness , coma , speech
disturbances , visual disturbances , headache
and even death.
5) SCD patients with neurological complaints has
to be evaluated with CT or MRI as needed .
6) Transcranial doppler ultrasound ( TCD) was
used as an effective tool in screening to detect
stenosis in asymptomatic patients.

15.  PULMONARY COMPLICATIONS
1) ACUTE CHEST SYNDROME : presents with
dyspnea , hypoxia , fever , chest pain and
pulmonary infiltrates.
PATHOLOGY
vaso-occlusion , infection , embolization of bone
marrow .
TREATMENT includes – oxygen supplementation ,
incentive spirometry , antibiotics , brochodilators
persistant hypoxia may need exchange
transfusion and mechanical ventilation.
OTHER PULMONARY COMPLICATIONS
1) obstructive airway disease
2) pulmonary hypertension.

16.  RENAL COMPLICATIONS.
1) papillary necrosis
2) Occlusion of vasa recta -
3) glomerulonephritis.
4) Hyposthenuria,
• PRIAPISM
• AVN
• LEG ULCERS
• BONE INFARCT .

17. SICKLE CELL TRAIT
 HbS <50%, HbA >50%
 Normal life span with very rare
complications.
 Complications include sudden death during
exercise, splenic infarcts at high altitude,
hematuria, hyposthenuria, bacteriuria, renal
medullary carcinoma.
 No restriction on activities.

18. DIAGNOSIS
 PERIPHERAL SMEAR.
Sickle shaped or cigar shaped deformed rbc
average reticulocyte count is 10 %
platelet count and white blood count may also
be increased.
howell-jolly bodies may be present.
• HB ELECTROPHORESIS – diagnostic
shows HBS band ( cellulose acetate
electrophoresis)

19.  SICKLING TEST : sickling of RBC can be
induced by adding a drop of blood with sodium
metabisulfite.
 HPLC
 PRENATAL DIAGNOSIS – Detection of GAC----
GTC MUTATION.
 OTHERS –
1) ESR - reduced
2) Raised LDH
3) Reduced haptoglobin

21. TREATMENT
 PAIN MANAGEMENT - Specific therapy for
pain varies greatly but generally
includes the use of acetaminophen or a
non-steroidal agent early in the course
of pain, followed by escalation to
acetaminophen with codeine or a
short- or long-acting oral opioid.Some
patients require IV morphine

22.  HYDROXYCARBAMIDE - Used in SCD patients
with severe clinical manifestations .
1)It increases the concentration of HBF.
2)Its use had effectively reduced the painful
episodes and acute chest syndrome.
3)Dose = 20 mg/kg / day to a max of
2000mg/day
 INFECTIONS – Usually third generation
cephalosporins or high dose penicillins are used .

23.  EXCHANGE TRANSFUSION - Severe acute
vaso-occlusive crisis , intractable pain , stroke ,
priapism and acute chest syndrome .
 ALLOGENEIG HEMATOPOIETIC STEM CELL
TRANSPLANTATION is performed as a curative
procedure
 Decitabine is used to improve HBF levels in
patients not responding to hydroxycarbamide .

25.  THALASSAEMIA are group of disorder with a
genetically determined reduction in the rate of
synthesis of one or more types of normal
hemoglobin polypeptide chain .
 Thalassemia is an inherited autosomal recessive blood
disorder.

26. BETA THALASSAEMIAS
 A genetic mutation in beta thalassaemia leads to
reduced production of beta chain with raised
alpha chain and decreased amount of HB A .
 Beta globin synthesis is controlled by one
gene on each chromosome 11

27. • Alpha thalassemia is the result of deficient or absent
synthesis of alpha globin chains, leading to excess beta
globin chains.
•Alpha globin chain production is controlled by
two genes on each chromosome 16
Alpha Thalassemia

28. CLASSIFICATION OF THALASSAEMIAS
type Hb
g/dl
Hb‐Electrophoresis Clinical Syndrome
α‐ thalassaemias
Hydrops foetalis 3‐10 Hb Barts(γ4)100% Fatal in utero/early pregnency
Hb‐H disease 2‐12 HbF(10%) Hemolytic anaemia
α‐ thalassaemias 10‐14 N No anemia(RBC‐MH)
β‐ thalassaemias
β‐ thalassaemias major <5 HbA(0‐50%)
HbF(50‐98%)
Severe congenital HA/require BT
β‐ thalassaemias
intermedia
5‐10 Variable Severe anaemia
β‐ thalassaemias minor 10‐12 HbA2(4‐9%)
HbF(1‐5%)
Mostly asymtomatic

29. BETA THALASSAEMIA –
PATHOLOGY
 In β-thalassemia, there is an excess of α-globin
chains relative to β and α- globin tetramers (α4)
are formed. These inclusions interact with the
red cell membrane and shorten red cell survival,
leading to anemia and increased erythroid
production.
 The γ-globin chains are produced in increased
amounts, leading to an elevated Hb F (α2γ2).

30. • THALASSEMIA MINOR - heterozygous disorder
resulting in mild hypochromic, microcytic hemolytic
anemia.
• THALASSEMIA INTERMEDIA - Severity lies
between the minor and major.
• THALASSEMIA MAJOR - homozygous disorder
resulting in severe life long transfusion- dependent
hemolytic anemia.

32. ALPHA THALASSAEMIA
 Normal production of alpha chains is absent which
results in excess production of gamma- globin chains
in the fetus and newborn or beta- globin chains in
children and adults.
 The β-globin chains are capable of forming
soluble tetramers (beta-4, or HbH)
 This form of hemoglobin is still unstable and
precipitates within the cell, forming insoluble
inclusions called Heinz bodies

34. CLINICAL FEATURES
• Anemia
• Marked hepatosplenomegaly
• Marrow hyperplasia frontal bossing & prominent
malar eminence
• Chipmunk facies, thalassemic facies
• Iron overload
• Growth retardation
• Delayed puberty, DM
• Cardiomegaly
• High output failure
• Gall stones

35. Chipmunk facies, thalassemic
facies
maxillary marrow hyperplasia and frontal bossing

36. DIAGNOSIS
 Most persons with thalassemia trait are found
incidentally when their complete blood count
shows a mild microcytic anemia

37. Hair on end appearance

38. Use of RDW Values in the
Diagnosis of Thalassemia
Microcytic Anemia
Children 6 months ‐6 years of age:
MCV <70fl Children 7 to 12 years of
age: MCV <76fl
↓
RDW
↓ ↓
Normal Elevated (>15)
↓ ↓
Favors Thalassemia Ferritin level
↓ ↓
Normal(>100ng/mL) Low(<10ng/mL)
↓ ↓
Favors Thalassemia Favors Iron
Deficiency
anemia

39. The hemoglobin
electrophoresis
3
4

40. TREATMENT
• Blood transfusion to maintain hematocrit
• Folate supplementation
• Avoid iron therapy
• Desferrioxamine for iron chelation
• Splenectomy
• Allogenic bone marrow transplantation
• Gene therapy
• Antenatal diagnosis of thalassemia syndromes is now
widely available.
• DNA diagnosis is based on PCR amplification of
fetal DNA, obtained by amniocentesis or chorionic
villus biopsy .

41. HAEMOGLOBIN E
 It is mainly found in south east part of asia , india,
burma , srilanka .
 GENETICS : 26th position in beta chain lysine or
glutamic acid .
 TYPES
HbE trait , HbE disease
Patient are mostly asymptomatic , may have mild
jaundice with PS showing marked hypochromia ,
target cells and reduced MCV , MCH .
Patients usually have mild anaemia .

42. HAEMOGLOBIN D
 Mostly found in north west india , pakistan and
iran.
 It was originaly called as HbD LOS ANGLES
 GENETICS : 121th position in beta chain
glutamine for glutamic acid .
 HbD mobility in electrophoresis cellulose acetate
is identical as HbS .
 HbD do not sickle .

43. ACQUIRED
HEMOGLOBINOPATHIES
 METHAEMOGLOBINAEMIA
1) Excess accumulation of methaemoglobin in
red cell.
2) Methaemoglogin lacks capacity to carry
oxygen.
CAUSES :
1) Drugs ( sulphonamides , primaquine , nitrates ,
kcl.)
2) toxin exposure : nitrobenzene and aniline
CLINICAL FEATURES :
Cyanosis , headache , tachycardia , muscular
cramps , weakness ,

44.  DIAGNOSIS
chocolate brown colour of blood .
spectroscopic identification of methaemoglobin .
usually clinical : cyanosis with no or little
dyspnea.
Treatment : to remove the cause .
methylene blue 2mg/kg in 1 % aqueous solution.

45.  SULPHAEMOGLOBINAEMIA
Abnormal sulphur containing haemoglobin .
does not act as an oxygen carrier .
caused by ingestion of sulphur containing
drugs.
it is irreversible .
clinical feature : cyanosis.
diagnosis : spectroscopy