Disorders of

Haemoglobin
Dr Nilukshi Perera

Consultant Haematologist
 Hereditary disorders of
Haemoglobin
 Haemoglobinopathies:
Production of structurally defective haemoglobin due to abnormalities in the formation
of the globin moiety of the molecule

 Thalassaemias:
Due to reduced rate of production of normal haemoglobin due to absent or decreased
synthesis of one or more types of globin polypeptide chains
Geographical distribution of clinically important
haemoglobinopathies and thalassaemias
.

 Thalassaemia has near worldwide

distribution .
 Hb S is concentrated in Africa
 Hb E is most prevalent in South
East Asia.
Hb-A is the major adult
hemoglobin.
 Normal Human haemoglobins
Haemoglobin Structure

Hb A 22
Adult Hb A2 22

Hb F 22
Fetal Hb Barts 4

Hb Gower 1 22
Embryonic Hb Gower 2 22
Hb-Portland 22
.

 The  like globin genes form a

linked cluster on chromosome 16.
  globin gene cluster is positioned
on chromosome 11.
Inheritance
The Thalassaemias

 Normally production of  and  chains are balanced.

 There are two main groups.
 thalassaemias
 thalassaemias
 In beta thalassaemia Hb A is reduced & increased Hb F or Hb
A2 is seen.
 The lack of  chains lead to accumulation of  chains within
developing red cells resulting in premature destruction of cells
in the marrow causing ineffective erythropoiesis.
 Thalassaemia
 Two different types of disorders
ºThalassaemia: complete absence of  chains.
+ Thalassaemia: Incomplete suppression of  chain
production.
 Clinically three forms:
 Thalassaemia major
 Thalassaemia minor ( thalassaemia trait)
 Thalassaemia intermedia
 Thalassaemia trait

 Heterozygous state/carrier state

 Clinically little or no anaemia, no
symptoms and has normal life
expectancy.
 Hb is normal or mildly reduced.
 Hypochromic and microcytic anaemia
 Hb Electrophoresis /HPLC shows
increased Hb A2 (3.5-7%)
β thalassaemia trait

 Low MCV and MCH

 BP- Hypochromic microcytic red cells,
target cells, irregularly contracted cells
and basophilic stippling.
 RCC is increased
 Family screening is important.
Basophilic stippling
There is interference of breakdown of RNA by inhibiting the enzyme pyrimidine 5’
nucleotidase, causing accumulation of denatured RNA in red cells.
Beta thalassaemia trait
  Homozygous state
 Thalassaemia major  Can be either + or  º
 Clinically:
1. Newborn infant normal
2. Insidious onset anaemia
in first year of life
3. Transfusion dependent
4. Obvious splenomegaly
5. Hepatomegaly +
6. Changes in the
skeletal system
 Develop iron overload and organ
dysfunction in early adolescence
 Death after the first decade
Partial or lack of HbA synthesis ↓MCHC & MCH
Hypochromia & microcytosis

Normal

Thalassaemia
Reticulocytes undergo intramedullary death

Inadequate production + ineffective

erythropoiesis + haemolysis Anaemia
↑Haemolysis ↑demands of phagocytic function 
hyperplasia of phagocytes Hepatosplenomegaly

To compensate anaemia extramedullary

haemopoiesis in liver, spleen & brain
Organomegaly
↑Erythropoiesis marrow expansion & thinning
of cortex of skull bone Thalassaemia facies
Thalassemia face
Expansion of BM
Hepatosplenomegaly
β thalassemia major
Male 18 years
Cooley’s Anemia

 This is another name for β

Thalassemia Major, because
Cooley was the first one to
describe these cases.
Laboratory investigations

 Hb Low
 Blood picture: Target cells, NRBC,
irregularly contracted cells,
poikylocytosis
 Haemoglobin electrophoresis:/HPLC
Increased Hb F
 Both parents are carriers
β Thalassemia Major
β Thalassemia Major

Target cells, NRBC, microcytosis, poikilocytosis

 Beta thalassaemia

 thalassaemia intermedia  thalassaemia major

 Dependent on blood transfusions.
 Anaemia, splenomegaly,  Expanded bone marrow.
leg ulcers, bony
deformability, occasional  Bony deformities.
transfusion needed.  Hb 3-7 g/dL
 Chelation therapy
• chelatior
Treatment

 Blood transfusion
 Iron chelation therapy
 Splenectomy
 Management of cardiac and endocrine
complications.
 Psychological support
 General health care and lifestyle
 BM transplantation
 Gene therapy
Thalassemics:
Blood
Transfusion
 .

 Iron chelation
 Deferoxamine,
subcutaneous infusion,
urinary excretion
 Deferiprone, oral, urinary excretion
 Deferasirox, oral, faecal excretion
Good iron chelation using desferoxamine (iron chelator) prolongs the life expectancy
of Cooley’s anemic patients, otherwise cardiac failure, liver cirrhosis, and endocrine
deficiencies could occur and causing death.
 Thalassaemias

 There is defective  chain synthesis with depression of Hb A, Hb A2, and Hb F.

 Leads to excess of  chains with 4( Hb Barts) & unstable  chain precipitate to form
4 (Hb H)
 Classification depends on genetic lesion
 There are 4  genes.
 Normal person genotype is  /  
 Thalassaemias Trait

 Less common then β Thalassaemias.

 HPLC normal ,but low MCV and MCH with high RBC counts.
 /  chain synthesis studies or DNA analyses are needed to
diagnose
Alpha thlassaemiaa - HbH disease
Hb 81 g/L, MCV 59 fL
HbH inclusions = alpha thal
 Classification of  thalassaemia

clinical Genetic Genotype Numer of

genes
 Thal 2 (trait) Hetero +  /-  3
 Thal 1(trait) Homo + -/ - 2
Hetero  º  /-- 2
Hb H disease Double hetero -/-- 1
+/ º
Hb Bart’s Homozygous --/-- 0
Hydrops fetalis ºthalassemia
Alpha thalassaemia

 Reduced synthesis of alpha

chains

 One gene deletion

 (silent carrier)
 Two gene deletion
 alpha trait
 Three gene deletion
 (HbH disease)
 Four gene deletion
 (Barts hydrops fetalis)
 Alpha thalassaemia - Hb Barts
4 gene deletion
 Hb Barts =  tetramers.

 Fetal or early post natal death.

 Early detection important to

avoid maternal complications
(toxaemia, post-partum
haemorrhage).
 Hydrops Fetalis

The blood film of neonate with hemoglobin Bart’s

hydrops fetalis showing anisocytosis, poikilocytosis
and numerous nucleated red blood cells (NRBC).
 Haemoglobinopathies

 Production of structurally defective haemoglobin

due to abnormalities in the formation of the globin
moiety of the molecule.

 Sickle cell haemoglobin

 Haemoglobin C
 Haemoglobin D
 Haemoglobin E
 Hb S disoders
 Sickel cell anaemia (SS)
 Sickel cell trait (SA)
 Sickel beta thalassaemia
Sickle Cells
 Pathophysiology

Valine replaces glutamic acid at position 6 of

the  globin chain
Hb S is insoluble and forms crystals when
exposed to low oxygen tension
 Sickle Cell Anemia
 Autosomal recessive—HbA replaced by mutant HbS
 Under reduced O2 conditions, Hb molecules polymerize and RBCs sickle—
causes vaso-occlusive crises in microcirculation
 Acidosis, hypoxia, temp changes, dehydration, infection
 Sickle trait—
 Heterozygous
 1 in 12 people of African descent—also in Italians, Greeks, Saudi Arabians
 Not anemic, live normal life
 Sickle cell disease—
 Homozygous
 Survival correlates with frequency of vaso-occlusive crises
 >3 crises/year—median age of death is 35
 Fewer crises a year—may live into their 50s
 In general, reduces life expectancy by 25-30 years
Red Blood Cells from Sickle Cell
Anemia
Deoxygenation of SS erythrocytes leads to
intracellular hemoglobin polymerization, loss of
deformability and changes in cell morphology.

OXY-STATE DEOXY-STATE
 Sickle Cell Anemia
Clinical features:
 Severe, lifelong hemolytic anemia—jaundice, pallor, gallstone disease, high-output heart failure,
aplastic crises (provoked by parvovirus B19 infection)
 Painful bone crises—most common manifestation—multiple sites
 Hand-foot syndrome (dactylitis)—vascular necrosis of metacarpals/tarsals
 Acute chest syndrome—pulmonary infarcts
 Repeated splenic infarctions  autosplenectomy
 Avascular necrosis of joints—most common is hip
 Priapism
 CVAs--children
 Ophthalmologic complications
 Renal papillary necrosis with hematuria—common complication
 Chronic leg ulcers—typically over lateral malleoli
 Abdominal crisis—mimics acute abdomen
 Infections—encapsulated bacteria — H. influenzae, S. pneumoniae
 Osteomyelitis— Salmonella
 Delayed growth and maturation
Dactylitis

 Mainly children
 Affects metacarpals and metatarsals
 Backs of hands and feet swollen and tender
 Can be recurrent leading to permanent radiological abnormalities
Acute Chest Syndrome

 Common cause of death

 Chest wall pain with pleurisy, fever and SOB
 Resembles infection, infarction, PE
 Requires prompt and vigorous treatment
 10% mortality
 Bacteraemia in 3.5%
However,

 Symptoms of anaemia are milder than expected because Hb S

gives up O2 to tissues more readily than Hb A
 SS Sickle
cell
anaemia

Howell Jolly
Body

Erythroblast
 Sickle Cell Anemia
Diagnosis:
 Peripheral smear, sickle solubility test,hemoglobin electrophoresis/HPLC,
newborn screening tests
 HbS solubility test:
 Decreased solubility of HbS forms the basis of this test
 Blood is added to a buffered solution of a reducing agent eg. sodium dithionate
 HbS is precipitated by the solution
 Test does not discriminate between sickle cell trait and disease
Treatment:
 Avoid high altitudes, stay hydrated, treat infections promptly
 Early vaccinations
 Prophylactic penicillin
 Folic acid supplements (due to hemolysis)
 Manage pain—fluids, morphine, keep warm, supplemental O2
 Hydroxyurea—Elevate HbF
 Blood transfusion—not used unless necessary (acute chest syndrome, stroke,
priaprism that doesn’t respond, cardiac decompensation)
 Bone marrow transplant—not routinely performed, but may be more cost-
effective in long run
 Gene therapy
Sickle cell trait
 Sickle carriers are
asymptomatic but at a risk of
| |
sickling crisis in hypoxic
conditions.
| | |
 Hb electrophoresis/HPLC is
S A useful in confirming the
diagnosis.
Haemoglobin E disease and trait

 In Hb E disease and trait

the blood picture will
show hypo/micro blood
picture with target cell
 Hb electrophoresis/HPLC
will confirm the diagnosis