S5 Haemiglobinopathies and Haemolytic Anaemias Flashcards
Why might anaemia develop?
- Linked to the bone marrow - reduced/dysfunctional erythropoiesis, abnormal haem synthesis, abnormal globin chain synthesis
- Linked to the peripheral RBCs - abnormal structure, mechanical damage, abnormal metabolism
- Excessive bleeding
- Linked to removal - increased removal by the RES
What are haemoglobinopathies?
Inherited, usually autosomal recessive, globin chain mutations that alter the structure/function/stability of the haemoglobin tetramer
What are two examples of haemoglobinopathies?
- Sickle cell anaemia (abnormal chain variants with altered stability and/or function)
- Thalassaemias (reduced/absent expression of normal globin chains)
What are the 3 major types of haemoglobin in adults (in order of amount present) and what are their globin chains?
- HbA (2 alpha, 2 beta)
- HbA2 (2 alpha, 2 delta)
- HbF (2 alpha, 2 gamma)
Why do humans have different Hb expressed at different times in development?
As an adaptive response to variations in oxygen requirements
What chromosome are the alpha and beta globin chains on? How many copies of each are on the chromosomes?
Alpha - chromosome 16 - 2 on maternal, 2 on paternal so 4 in total)
Beta - chromosome 11 - 1 on each chromosome so 2 in total
In which populations are thalassaemias more prevalent?
South Asian, Mediterranean, Middle Eastern (beta) Far East (alpha)
What are the 4 types of alpha-Thalassaemia? How many genes are deleted from each?
- Silent carrier state (1 gene)
- Alpha-Thalassaemia trait (2 genes)
- Haemoglobin H (HbH) disease (3 genes)
- Hydros fetalis (4 genes)
Describe silent carrier alpha-Thalassaemia.
It is asymtomatic.
The person is a carrier of the disease without symptoms
Describe alpha-Thalassaemia trait. What is it’s severity? What are the RBCs like?
Both genes on one chromosome 16, or one gene on each chromosome are deleted.
Minimal/no anaemia
Microcytic and hypochromic
Describe Haemoglobin H (HbH) disease. What is it’s severity? What are the RBCs like?
Moderately severe
RBCs are microcytic, hypochromic and there are target cells and Heinz bodies
Describe hydrops fetalis. What is it’s severity?
All 4 alpha genes are deleted, so excess gamma-globin forms tetramers in foetus (Hb Bart) - this is unable to deliver oxygen to tissues
Severe - usually results in intrauterine death
In beta-Thalassaemias, is the disease often caused by deletion or gene mutation?
Gene mutation
What are the 3 types of Beta-Thalassaemia?
- Beta-Thalassaemia minor/Beta-Thalassaemia trait
- Beta-Thalassaemia intermedia
- Beta-Thalassaemia major
What is the severity and genotype of Beta-Thalassaemia minor/Beta-Thalassaemia trait?
Severity - usually asymptomatic with mild anaemia (very microcytic and hypochromic RBCs)
Genotype - heterozygous with 1 normal, 1 abnormal gene
What do Beta0 and Beta+ mean?
Beta0 - total absence of product
Beta+ - reduction of globin production
What is the severity and genotype of Beta-Thalassaemia intermedia?
Severity - sever anaemia (not enough to need regular blood transfusions)
Genotype - heterozygous (can be mild variants of homozygous, severe variants of heterozygous or double heterozygous)
What is the severity and genotype of Beta-Thalassaemia major?
Severity - severe transfusion-dependent anaemia (manifests 6-9 months after birth as synthesis switches from HbF to HbA)
Genotype - homozygous
What will a blood smear show for a patient with Thalassaemia?
- hypocromic and microcytic RBCs - due to low Hb
- anisopoikilocytosis
- target cells
- nucleated RBCs
- Heinz bodies
How do unaffected globin chains contribute to the defective nature of the RBC?
If in excess, insoluble aggregates of alpha chains form in Beta-Thalassaemia.
These Hb aggregates are oxidised and lead to premature death of erythroid precursors in bone marrow (ineffective erythropoiesis) and excessive destruction of mature RBCs i the spleen (shorter RBC survival) - haemolytic anaemia as was all thalassaemia
What are the consequences of Thalassaemia?
- extramedullary haemopoiesis occurs to compensate which results in splenomegaly, hepatomegaly and expansion of haemopoiesis into the bone cortex (impairs growth and causes classical skeletal abnormalities)
- reduced oxygen delivery results in stimulation of EPO contributes to the drive to make more defective RBCs
- iron overload due to excessive absorption of dietary iron due to ineffective haemopoeisis and repeated blood transfusions being required to treat the disease
- reduced life expectancy
How can you treat Thalassaemia?
- RBC transfusion from childhood
- iron chelation to delay the iron overload
- folic acid to support erythropoiesis
- immunisation
- holistic care to manage complications
- stem cell transplantation for some to replace defective RBC production
- preconception counselling for at risk couples and antenatal screening
How does sickle cell disease arise?
Autosomal recessive disease resulting from a mutation of the beta-globin gene - GAG codon changed to GTG - so glutamate is substituted by valine - mutated Hb molecule is called HbS
What is the anaemia like if you are heterozygous for HbS?
Mild asymptomatic anaemia
Why do about 30% of the West African population have the HbS gene?
It protects against malaria (example of natural selection)
What is HbSS?
Homozygous sickle cell anaemia, it is the most common cause of severe sickling syndrome
Describe how HbS can be co-inherited?
Can be co-inherited with another abnormal Hb e.g. with beta-Thalassaemia (HbS Beta-Thal) which causes a sickling disorder
Why is the anaemia usually mild in someone with sickle cell disease?
As HbS readily gives up oxygen in comparison to HbA
When do problems arise if someone has sickle cell disease?
In low oxygen states - deoxygenated HbS forms polymers that cause RBCs to form a sickle shape (usually reversible but if many sickling cycles can become irreversible)
What do irreversible sickle cells cause?
They are less deformable and so can cause occlusion in small blood vessels
What are the 3 types of crises with sickle cell anaemia?
- vaso-occlusive (most common)
- aplastic (often triggered by parvovirus)
- haemolytic
What 9 things can vaso-occlusion cause?
- retinopathy
- splenic atrophy
- avascular necrosis
- acute chest syndrome
- stroke
- osteomyelitis
- skin ulcers
- kidney infarcts
- priapism (constant penile erection)
How is sickle cell disease treated?
- folic acid
- penicillin and vaccinations (due to being hyposplenic)
- hydroxycarbamide - increased HbF levels and other effects
- red cell exchange
What two ways can haemolytic anaemias arise?
- inherited due to a defective gene
* acquired due to damage to cells
Where can haemolysis occur?
- in blood vessels - intravascular haemolysis
* in the spleen and wider RES - extravascualr haemolysis
Can bone marrow compensate against haemolysis?
It can by increasing production, but only up to a point (6 fold before reaches this point) and then anaemia develops
What are 4 ways a defective gene can cause haemolytic anaemia?
- glycolysis defect (pyruvate kinase deficiency limiting ATP production)
- pentose phosphate pathway (G6PDH deficiency leads to oxidative damage)
- membrane protein (hereditary spherocytosis)
- haemoglobin defect (sickle cell disease)
What are 5 ways a damage to cells can cause haemolytic anaemia?
- mechanical damage (microangiopathic anaemia)
- antibody damage (autoimmune haemolytic anaemia)
- oxidant damage (exposure to chemicals/oxidants)
- heat damage (severe burns)
- enzymatic damage (snake venom)
What laboratory findings are found with haemolytic anaemias?
- raised reticulocytes as the bone marrow is trying to compensate
- raised bilirubin due to break down of Haem
- raised LDH as RBCs are rich in this enzyme
What issues arise from bilirubin accumulation?
Jaundice and associated risk of complications like pigment gallstones (made up of bilirubin and calcium salts)
How does haemolysis cause cardiac arrest?
If the haemolysis is sudden and massive
What are 3 inherited defects in RBC membrane structure?
- hereditary spherocytosis
- hereditary eliptocytosis
- hereditary pyropoikilocytosis
What is hereditary spherocytosis?
Cells take on a spherical shape due to ankyrin, spectrin, protein 4.2 or band 3 defects which disrupt the membrane-cytoskeletal interactions.
The cells are less flexible and so are more easily damaged
What is hereditary eliptocytosis? What is the most common defect?
Cells are elliptical rather than biconcave disc shape
Spectrin defect (but can also have defects in band 4.1, band 3 and glycophorin C proteins
What is hereditary pyropoikilocytosis? What do the cells have an abnormal sensitivity to?
A spectrin defect - severe form of hereditary eliptocytosis
Cells have an abnormal sensitivity to heat
How do microangiopathic haemolytic anaemias result from mechanical damage?
Due to shear stress as the cell passes through a defective heart valve (e.g. aortic valve stenosis)
Or cells snag on fibrin strands in small vessels where increased activation of the clotting cascade has occurred (e.g. disseminated intravascular coagulation (DIT))
What are schistocytes?
Fragments resulting from mechanical damage
It is an indicator that some sort of pathology is present
How do autoimmune haemolytic anaemias arise?
Autoantibodies bind to RBC membrane proteins (result from infections or cancers of the lymphatic system). The spleen recognises the antibody bound cells as abnormal and removes them so the RBC lifespan is reduced so anaemia develops
How are autoantibodies IgG and IgM classed in haemolysis?
IgG - warm
IgM - cold
Based off temps antibodies react best at
