9. Haemoglobinopathies And Haemolytic Anaemias Flashcards
What are haemoglobinopathies?
Inherited disorders that cause defects in globin chain synthesis
Usually autosomal recessive
What are the 2 types of haemoglobinopathies?
Abnormal globin chain variants with altered sability and/or function
Reduced or absent expression of normal globin chains
Give an example of each of the haemoglobinopathies
Sickle cell disease
Thalassaemias
What is haemoglobin?
Tetramer of 4 globin polypeptide chains
2 alpha and 2 non-alpha chains (beta, delta or gamma)
Each globin chain is complexed with an oxygen binding haem group
What are the types of haemoglobin?
A - 2 alpha 2 beta, ~95% in adult
A2 - 2 alpha 2 delta, ~ 3% in adult
F - 2 alpha 2 gamma <1% in adults (fetal haemoglobin)
Which chromosomes are the alpha and beta globin genes on?
Alpha - 16
Beta - 11
How many of each gene do humans have?
Have 4 alpha genes (2 on maternal and 2 on paternal)
Have 2 beta genes (1 on each chromosome)
What does normal expression of globin genes cause?
Under tight control to ensure a 1:1 ratio of alpha to non-alpha globin chain proteins
What can defects in the regulation of expression of globin genes result in?
Both relative and absolute amounts of globin chain proteins and can result in beta thalassaemia or alpha thalassaemia
Where are the thalassaemias more prevalent?
Beta thalassaemia - south Asian, Mediterranean, Middle East
Alpha thalassaemia - Far East
What are the different diseases of alpha thalassaemia caused by different number of alpha globin genes deleted?
1 gene deleted - silent carrier state
2 genes deleted - alpha-thalassaemia trait
3 genes deleted - haemoglobin H disease
4 genes deleted - hydrops fetalis
Increase in severity down the list
Describe alpha thalassaemia trait
Minimal or no anaemia
Either both genes on one chromosome 16 or one gene on each chromosome 16 deleted
Microcytosis and hypochromia in RBCs
Resembles beta thalassaemia minor
Describe haemoglobin H disease (HbH)
Moderately severe
Tetramer of beta-globin (HbH) form resulting in microcytic, hypochromic anaemia with target cels and Heinz bodies
Resembles beta thalassaemia intermedia
Describe hydrops fetalis
Sever, usually results in intrauterine death
All 4 alpha genes deleted
Excess gamma-globin forms tetramer in foetus (Hb Bart) that is unable to deliver oxygen to tissues
What are beta0 and beta+?
Beta0 denotes total absence of production
Beta+ denotes reduction of globin production
Describe beta thalassaemia minor or beta thalassaemia trait
Usually asymptomatic with mild anaemia (very microcytic and hypochromic RBCs)
Resembles alpha thalassaemia trait
Heterozygous with 1 normal and one abnormal gene (beta0/beta or beta+/beta)
Describe beta-thalassaemia intermedia
Sever anaemia but not enough to require regular blood transfusions
Resembles haemoglobin H disease
Genetically heterozygous (can be homozygous, heterozygous or double heterozygous)
Describe beta-thalassaemia major
Sever transfusion-dependent anaemia
Becomes manifest 6-9 months after birth as synthesis switches from HbF to HbA
Homozygous
What with a peripheral blood smear from patient with severe thalassaemia typically show?
Hypochromic and microcytic RBCs
Anisopoikilocytosis with frequent target cells and circulating nucleated RBCs and Heinz bodies
What does aggregation and oxidation of haemoglobin in thalassaemia cause?
Premature death or erthroid precursors within bone marrow leading to ineffective erythropoiesis
Excessive destruction of mature red cells in spleen leading to shortened RBC survival
Why does extramedullary haemopoiesis occur in thalassaemia and what does it result in?
Body’s attempt to compensate but results in splenomegaly, hepatomegaly and expansion of haemopoiesis in bone cortex
This impairs growth and causes classical skeletal abnormalities
What does reduced oxygen delivery in thalassaemia lead to?
Stimulation of EPO which further contributes to the drive to make more defective red cells
Why does iron overload occur in thalassaemia?
Excessive absorption of dietary iron due to ineffective haematopoiesis
Repeated blood transfusions required to treat anaemia
Causes premature death
What are the treatments for thalassaemia?
Red cell transfusion
Iron chelation (delays iron overload)
Folic acid (help support erythropoiesis)
Immunisation
Holistic care (cardiology, endocrine, physiological, ophthalmology)
Stem cell transplantation
Pre-conception counselling for at risk couples and antenatal screening
What is sickle cell disease?
Autosomal recessive disease resulting from mutation of beta-globin gene
GAG codon changed to GTG resulting in glutamic acid being substituted by valine
Mutant haemoglobin molecule called Haemoglobin S
Where is the HbS gene most commonly found?
Found in ~30% of W African population as it confer protection against malaria
When do problems occur with sickle cell anaemia?
In low oxygen state (due to chest infection, when cold, vasoconstriction in peripheries etc) as deoxygenated HbS forms polymers that case red cells to form a sickle shape
What is the problem with irreversible sickle red cells?
They are less deformable and can cause occlusion in small blood vessels (sticky)
What are the 3 types of sickle cell crises?
Vaso-occlusive - painful bone crises, organ (chest, spleen)
Aplastic (often triggered by parvovirus)
Haemolytic
End organ damage occurs as result of acute thromboses or O2 deprivation
What can occlusion in small blood vessels cause?
Retinopathy Splenic atrophy Avascular necrosis Acute chest syndrome Stroke Kidney infarcts
What inherited defects can cause haemolytic anaemia?
Glycolysis defect
Pentose-P pathway
Membrane protein
Haemoglobin defect
What acquired factors can cause haemolytic anaemia?
Mechanical damage Antibody damage Oxidant damage Heat damage Enzymatic damage
Where can haemolysis occur?
Blood vessels (intravascular haemolysis) Spleen and wider RES (extravascular haemolysis)
What are the key laboratory findings in haemolytic anaemia?
Raised reticulocytes
Raised bilirubin
Raised LDH
What are the consequences of haemolytic anaemia?
Accumulation of bilirubin leading to jaundice and possible pigment gallstones
Overworking red pulp leads to splenomegaly
Massive sudden haemolysis can cause cardiac arrest due to lack of oxygen delivery to tissues and hyperkalaemia due to release of intracellular contents
What are the inherited effects in red cell membrane structure?
Hereditary spherocytosis
Hereditary eliptocytosis
Hereditary pyropoikilocytois
Describe hereditary spherocytosis
Many cells take on spherical shape
Ankyrin, spectrin, protein 4.2 or band 3 defects disrupt membrane-cytoskeletal interactions
Cells less flexible and more easily damaged
Describe hereditary eliptocytosis
Many cells elliptical rather than biconcave disc shape
Spectrin defect most common
Also defects in band 4.1, band 3 and glycophorin C proteins
Describe hereditary pyropoikilocytosis
Spectrin defect
Severe form of hereditary elliptocytosis
Abnormal sensitivity of red cells to heat
Similar morphology to that seen in thermal burns
What acquired damage can cause haemolytic anaemias?
Microangiopathic haemolytic anaemias result from mechanical damage e.g.
- sheer tress as cells pass through a defective heart valve
- cells snagging on fibrin strands in small vessles where increased activation of clotting cascade has occurred
Heat damage
Osmotic damage
Forms schistocytes
What are autoimmune haemolytic anaemias?
Cause by antibodies brining to red cell membrane proteins
Can result from infections or cancers of lymphoid system
Classified as either warm (IgG) or cold (IgM) based on temperature antibodies react best at
Spleen recognises antibody bound cells as abnormal and removes them
Red cell lifespan reduced
