Haemoglobinopathies
Haemoglobinopathies
Haemoglobinopathies
Globin Synthesis
Genes for globin chains occur in 2 clusters:
chrom 11: ε, γ, δ, β
chrom 16: ζ, α1, α2
In the embryo and fetus, Gower 1, Portland, Gower 2and fetal Hb dominate at different
stages
Hb Gower 1: ζ2 ε2
Hb Portland: ζ2γ2
Hb Gower 2: α2ε2
Haemoglobinopathies
2 disorders:
1. Thalassaemia
2. Sickle cell Disease
Thalassaemia
A condition in which there is reduced rate of synthesis of one or more of the globin chains
This leads to:
o imbalanced globin‐chain synthesis
o defective Hb production
o damage to red cells or precursors from effects of globin subunits that are
produced in relative excess
ALPHA (α) THALASSAEMIA
Pathophysiology
Abnormal production of α chains excess production of γ-globin chains in foetus and newborn
or β-globin chains in children and adults
β-globin chains can form soluble, unstable tetramers which precipitate within the
cell, forming insoluble inclusions called Heinz bodies
These Heinz bodies damage the red blood cells damage to erythrocyte precursors
and ineffective erythropoiesis in the bone marrow, hypochromia and microcytosis of
circulating red blood cells
α‐thalassaemia Trait
Lab findings
• FBC:
RCC (red cell count) ↑ > 5.5 X 1012/L
MCV & MCH low
Iron deficiency anaemia should be ruled out
MCV/RCC ≤ 12 (Crude way)
Hb H Disease (β4)
3 gene deletion
Moderately severe anaemia (Hb 7‐11g/dL)
Microcytic, hypochromic anaemia
Splenomegaly
β‐chains form a tetramer, Hb H (β4)
β-thal intermedia
Moderate anaemia
No regular blood transfusions
β-thalassaemia major
Either no βchain (β0) or small amounts (β+) are synthesised
Severe anaemia 3-6 mons after birth, when switch from γ‐to β‐chain production should
take place
Excess α‐chains precipitate in erythroblasts and mature red cells → severe ineffective
erythropoiesis and haemolysis
Transfusion dependent
Clinical Features
Severe anaemia
Pallor, jaundice
Skull and other bones may be deformed secondary to erythroid hyperplasia with
intramedullary expansion and cortical bone thinning
Cardiac failure and arrhythmia, related to either severe anaemia or iron overload
Splenomegaly, due extramedullary haematopoiesis or extravascular haemolysis
Laboratory Diagnosis
FBC
o Hypochromic, microcytic anaemia.
o ↑ reticulocyte % with normoblasts & target cells in blood film
Hb Electrophoresis
o Completely absent Hb A (α2β2)
o All circulating Hb being HbF (α2γ2)
o Hb A2 %: normal, low or slightly raised
Treatment
Transfusions
Surgical Treatment e.g. splenectomy
Iron chelation in case of Iron overload
CURATIVE- Bone Marrow Transplant
Types
Sickle Hb (Hb S)
A mutant β‐globin chain in which adenine is replaced by thymine in the 6th position in
the β chain
In the DNA (gene) that codes for β‐globin chain, there is a single base change: adenine is
replaced by thymine
Epidemiology
Greatest prevalence in tropical Africa
Pts resistant to malaria
Morphology
Pathophysiology
Microvascular Occlusions
Depends on red cell membrane damage, inflammation
- slow or arrest RBC movement in microvascular beds
Sickle red cells express higher than normal levels of adhesion molecules and are sticky
Granulocytes release mediators during inflammation enhance the expression of
adhesion molecules on endothelial cells enhance the tendency of sickle red cells to
get arrested during transit through the microvasculature
Stagnation of red cells in vascular beds results in low O2 tension, sickling & vascular
obstruction
Depletion of NO also occurs
- sickle red cells release free HB
- Free Hb can bind & inactivate NO
o a potent vasodilator
o inhibitor of platelet aggregation
- So, low NO:
o increases narrowing of vessels (vascular tone)
o enhances platelet aggregation
- Causing cell stasis, sickling and thrombosis
Consequences:
- auto splenectomy: spleen enlarged by red pulp congestion caused by trapping of
sickle red cells in cords & sinuses. This chronic erythrostasis leads to splenic
infarction, fibrosis & progressive shrinkage by adolescence or early childhood
- Other infarctions can take place in subcutaneous tissue, bones, brain, liver,
kidney, retina, pulmonary bv’s ex: ulcers of lower legs
Vaso-occlusive crises
- or pain crises, are episodes of hypoxic injury and infarction that cause severe
pain in the affected region
- can be spontaneous or triggered by infection, dehydration & acidosis
- occurs mostly in bones, lungs, brain, liver, spleen, penis (priapism)
- cause hand-foot syndrome or dactylitis
- cause acute chest syndrome stroke
o a vaso-occlusive crisis in lungs
o causes pulmonary inflammation sluggish, spleen-like blood flow
sickling and vaso-occlusion
o compromises pulmonary function
o causes stroke due to adhesion of sickle red cells to arterial vascular
endothelium and vasoconstriction caused by the depletion of NO by free
Hb
o presents with fever, cough, chest pain, pulmonary infiltrates
Sequestration crisis
o occurs in children with intact spleen
o entrapment of sickle red cells enlarged spleen, hypovolemia, shock
Aplastic crisis
o result of infection of red cell progenitors by parvovirus B19
o PV B19 ceases erythropoiesis and worsens anaemia
Chronic hypoxia
o impairs generalized growth, development & organ damage (spleen, lungs,
kidneys, heart, lungs)
o hypertonicity in renal medulla provokes sickling hyposthenuria
dehydration
Diagnosis
by various tests & clinical findings
presence of irreversibly sickled cells
Laboratory Investigations
Solubility test
Sickling test
Electrophoresis
High-performance liquid chromatography (HPLC)
Molecular diagnosis
Treatment