Lecture 9 Flashcards
What are haemoglobinopathies? (Inherited disorders?
Defect in the Hb chain synthesis
-sickle cell (abnormalities of chains- variance, so difference in stability/function)
-thalassaemia (reduced/absent expression of NORMAL globin chains)
(Inherited disorders)
What are the types of Hb as you age?
- embryonic Hb’s
- Hb F (2 alpha + 2 gamma) (Foetal)
- Hb A (2 alpha + 2 beta) (adult)
How many alpha globin genes does a person have?
4
2 on each chromosome
What is thalassaemia?
Defect in regulation of expression of globin genes
Beta/alpha gene expression affected (often in excess)
-genetic
What are the 4 types of alpha thalassaemia?
- HYDROPS FETALIS: No alpha genes remaining-results in early uterine death
- SILENT CARRIER STATE: 3 functional alpha globin genes (asymptomatic)
- ALPHA THALASSAEMIA TRAIT: 2 globin genes (both on 1 chromosome, or 1 on each chromosome 16 deleted)- microcytic and hypochromic RBC’s.
- HAEMOGLOBIN H DISEASE: 3 alpha globin genes deleted- moderately severe
Different types of B thalassaemia?
B0= total absence of production from the gene B+= reduction of globin chain production
- B thalassaemia minor/trait: asymptomatic, mild anaemia with microcytic/hypochromic RBC’s (carrier of abnormal gene)
- B thalassaemia intermedia: severe anaemia, not enough to require blood transfusion
- B thalassamia major:transfusion dependent anaemia (homozygous)
What does relative excess of unaffected globin chain cause?
In B thalassaemia you get insoluble aggregates of the alpha chains, which can be oxidised, causing premature death of erythropoietin precursors- ineffective erythropoiesis
- more RBC’s are being destroyed than being released into blood = reduced oxygen capacity
- spleen destroys RBC’s leading to shortened survival (haemolytic anaemia)
What does a blood smear for someone with thalassaemia look like?
-hypochromic
-microcytic
(Due to low Hb)
-target cells, Heinz bodies, uncleared red blood cells due to bone marrow working really hard
What are the consequences of thalassaemia?
- extramedullary haemopoiesis (results in splenomegaly, hepatomegaly,expansion of haemopoises to cortex of bone= as occurring in other sites than the marrow)
- reduced oxygen delivery= stimulation of erythropoietin making more defective RBC’s
- causes iron overload
What are some treatments for thalassaemia?
- red cell transfusion
- iron chelation (binding of iron to reduce iron loading into tissues)
- folic acid (to support ertyhropoiesis)
- holistic care (cardio, endocrine, psychological, ophthalmology-these are affected by iron overload)
- immunisation
- stem cell transplantation (to replace defective RBC production)
- pre-conception counselling for at risk couples + antenatal screening
- pre-conception counselling
What is sickle cell disease?
-autosomal recessive (HbSS: homozygous causes severe sickling)
-mutation in B globin gene
-have valine where glutamic acid should’ve been
Mutant Hb molecule containing the mutated B globin gene protein is HbS
-irreversible sickle cells cause occlusion in small blood vessels
Why is anaemia usually mild in sickle cell?
-HbS more readily gives up oxygen compared to HbA
-problems occur in low oxygen state: deoxygenated HbS forms polymers causing a sickle shape
(These sickle cells can bounce back to normal)
-eventually the sickle cells wil become irreversibly sickled which are less deformable so cause vasocclusion
When is the sickle shape permanent?
Repeated sickling of cells
How does sickle cell clinically present?
-end organ damage due to acute thromboses of oxygen depriveation
-retinopathy
-splenic atrophy
-avascular necrosis
-stroke (blood circulation affected in brain)
-acute chest syndrome
-osteomyelitis
-skin ulcers (as skin becomes oxygen deprived)
-kidney infarcts
-priapism (unwanted erection for long time)
All reduced life expectancy
Where can haemolysis occur?
- blood vessels (intravascular haemolysis)
- spleen/wider RES (extravascular haemolysis)
Can bone marrow compensate for haemolysis?
- it can compensate by increasing production of EPO: but only up to a point
- if haemolysis exceeds capacity of marrow to compensate (6 fold increase), rate of destruction exceeds rate of production leading to anaemia
What are some symptoms of haemolytic anaemia?
- overworking of red pulp leading to splenomegaly
- accumulation of bilirubin > jaundice
- pigment gallstones made of bilirubin and calcium salts
- massive sudden haemolysis can cause cardiac arrest due to lack of oxygen delivery
- cause hyperkalaemia due to release of intracellular contents
Lab findings in haemolytic anaemia?
- raised reticulocytes (as marrow tries to compensate)
- raised bilirubin (breakdown of haem)
- raised LDG (red cells rich in this enzyme)
What are some causes of haemolytic anaemia?
Inherited (defective gene making cells more fragile)
- glycolysis defect
- membrane protein (hereditary spherocytosis)
- defect in Hb (sickle cell)
- pentose P pathway (G6PDH deficiency leads to oxidative damage)
Acquired (damage to cells)
- mechanical damage
- antibody damage (autoimmune)
- oxidant damage
- heat damage
- enzymatic damage (snake venom)
How do symptoms present on sudden haemolytic anaemia ?
Badly
-if chronic body manages to adapt slightly so oxygen dissociation curve shifts
What is jaundice and how does it present?
Build up of bilirubin
- yellow discolouration of skin and sclera of eye
- urine dark due to conjugated bilirubin
What are some causes of acquired damage of haemolytic anaemia?
- microangiopathic haemolytic anaemia (from mechanical stress: defective heart valve-stenosis, snagging on fibrin strands where there is activation of clotting cascade)
- heat damage from burns
- osmotic damage (drowning)
What is autoimmune haemolytic anaemia?
- self antibodies binding to red cell membrane proteins
- differentially bind at different temperatures depending on the antibody
- spleen recognises antibody bound cells as abnormal and removes them
How are haemoglobinopathies usually inherited?
Autosomal recessive
What chromosome is the alpha globin gene on?
Chromosome 16 (2 on paternal chromosome, 2 on maternal chromosome- so 4 in total)
Where is the beta globin chain found?
On chromosome 11
Along with alpha, gamma and delta
Why are there so many globin gene types?
To form different Hb tetramers from different combinations of globin chains.
How many beta globin genes does a person have?
2 (1 on each chromosome)
What is normal expression of globin genes?
Under tight control
1:1 ratio of alpha: non-alpha globin chains
In what populations is thalassaemia more prevalent?
South Asian, Mediterranean, Middle East (beta), Far East (alpha)
What occurs in Hydrops fetalis?
All 4 alpha globin genes deleted.
Excess of gamma globin genes, which form teramers in foetus (Hb Bart) which is unable to deliver oxygen to the tissues.
In alpha-thalassaemia trait do you get anaemia?
Minimal/none
What occurs in Haemoglobin H disease?
Tetramers of B globin chains form (HbH)
RBC’s are microcytic and hypochromic, with target cells & Heinz bodies
What is Beta thalassaemia usually due to?
Caused often by gene mutation rather than deletion
What is Beta thalassaemia trait/minor usually mistaken for?
Iron deficiency (But in thalassaemia the degree of microcytic/hypochromic RBC’s is much higher for the degree of anaemia)
What is Beta thalassaemia intermedia?
Severe anaemia but not enough to require blood transfusion.
-physiology of individual will adapt, so oxygen is given up to tissues
-adulthood: iron loading problems
(Heterozygous)
What is B thalassaemia major?
Severe transfusion dependent anaemia.
Homozygous (B0/B0 or B+/B+)
(Manifests 6-9 months after birth as synthesis switches from HbF to HbA)
Often seen in places without screening
What is haemolytic anaemia?
When the RBC’s are prematurely destroyed.
Why do children with thalassaemia have impaired growth?
Short stature
Skeletal abnormalities (bones swell)
-haemopoiesis in bone marrow moves to cortex
What is the major premature cause of death in thalassaemia?
Iron overload
Occurs due to excessive absorption of iron, blood transfusions
What does ineffective erythropoiesis lead to?
Increased dietary iron absorption
Is the heterozygous HbS state symptomatic?
Only mildly causes asymptomatic anaemia
-carrier state
Where in the world is the HbS gene common?
West Africa (protects against malaria)
Other than HbSS, what Hb causes sickling disorder?
HbS being coinherited with another abnormal Hb
HbSC
How is the sickle shape permanently adopted in a RBC?
-tetramers of HbS form under normal oxygen tension
-HbS forms polymers under low oxygen tension forming sickle shape
REPEATED SICKLING CYCLES
-irreversibly sickled RBC causing occlusion of small vessels
What are the 3 crises of sickle cell disease?
Crises- medical manifestations of sickle cell
- Vaso-occlusive (cause bone crises, organ damage)
- Aplastic (bone marrow stops working-triggered by parvovirus)
- Haemolytic
What are pigment gallstones due to?
Composed of bilirubin and calcium salts
What are some inherited defects in red cell membrane structure?
- hereditary spherocytosis (cells take sphere shape, so less flexible and easily damaged)
- hereditary eliptocytosis (elliptical shape)
- hereditary pyropikilocytosis (severe form of eliptocytosis, abnormal sensitivity of RBC’s to heat)
What proteins are effected in hereditary spherocytosis/eliptocytosis/pyropikilocytosis?
Spherocytosis: ankyrin, spectrin, protein 4.2, Band 3 defects disrupt the membrane/cytoskeleton interactions
Eliptocytosis: spectrin defect most common (defects in band 3, band 4.1, glycophorin C proteins)
Pyropikilocytosis: spectrin defect
What are damaged fragments resulting from mechanical damage called?
Schistocytes
Why could self antibodies be present on RBC’s?
- infection
- cancer of immune system which can produce these antibodies
What immunoglobulins bind at cold/warm temperatures to the RBC?
Warm: IgG
Cold: IgM
