2A Week 1 - Anaemia, Reb Blood Cell Metabolism And Transfusion Flashcards
What is Erythropoiesis
The process which produces red blood cells (erythrocytes)
How is a RBC pliable
- Biconcave shape
- The band 3 protein is embedded within the lipid bilayer, providing a vertical scaffold.
What is the main protein component of RBC membrane
Spectrin
Describe structure of Haemaglobin in adults
A tetramer. Made up of 4 protein subunits each containing a haem molecule and iron at its core.
2 alpha globin chains
2 beta globin chains
This makes up HbA - the majority of haemoglobin found in a normal healthy adult
What are the 3 phases of haemoglobin production
- Embryonic
- Foetal
- Adult
What globin chains make up:
HbA
HbF
HBA2
HbA - 2 alpha and 2 beta chains - adult
HbF - 2 alpha and 2 gamma chains - foetal
HbA2 - 2 alpha chains and 2 delta chains - v low levels from week 30
When is the switch from HbF to HbA
After birth there is a switch which is complete by 3-6 months of age
Why is sickle cell and beta thalassaemia only seen after 6 months of age
The disease does not manifest at birth and can only be seen when beta chains in HbA are made as in these genetic conditions, there is a mutation of the beta chain.
Why is there different haemoglobin in the foetus and adult
HbF has a higher affinity for oxygen allowing oxygen to flow from the maternal to foetal circulation readily across the placenta
What is the lifespan of a RBC
Approx. 120 days
What removes old RBC
Macrophages (phagocytosis)
Located in:
- spleen
- liver
- marrow - acts as quality control to prevent damaged cells from entering circulation
What is anaemia
Reduced grams of Hb/L blood
- below the age/sex adjusted normal range
Occurs as a result of
- low RBC count
- low haemoglobin
- low haematocrit
What is haematocrit
The % or ratio, of the blood made up of RBCs (AKA packed cell volume)
When may the haematocrit be low
Low number of RBC - anaemia, infection (increase in WBC), bleeding, leukaemia, malnutrition, haemolysis, chronic kidney disease
High amount of plasma - high altitude, dehydration, right sided heart failure, Polycythemia Vera, lung fibrosis
Signs and symptoms of anaemia
Symptoms
Fatigue and weakness
Breathlessness ‘dyspnoea’
Palpitations ‘tachycardia’
Muscle cramps
Angina or heart failure
Signs
Pallor - pale
Increased respiratory rate ‘tachypnoea’
Tachycardia
Low bp ‘hypotension’
Causes of low MCV anaemia (Microcytic anaemia)
T - thalassaemia
A - anaemia of chronic disease e.g. chronic infection, chronic immune activation and malignancy
I - iron deficient anaemia
L - lead poisoning (rare)
S - sideroblastic anaemia (rare)
Causes of Normal MCV anaemia (Normocytic anaemia)
Anaemia of chronic disease
Acute blood loss
Chronic renal failure
Mixed - B12/folate AND iron deficiency
Bone marrow disorders
Causes of High MCV anaemia (Macrocytic)
B12 or folate deficiency
Liver disease
Drugs inc. alcohol
Reticulocytosis (haemolysis)
Hypothyroidism
Myelodysplasia
Pregnancy
Name the 5 causes of reduced RBC production and give examples
- Defective stem cells
- inherited or acquired (drugs, infections, aplastic anaemia) - Defective maturation (lack of nutrients for DNA synthesis)
- B12 deficiency, myelodysplasia - Unhealthy microenvironment
- damage (radiation), lack of space ( fibrosis, primary or secondary cancer) - Absence of stimulation by growth factors
- low erythropoietin due to renal failure - Lack of components for RBC formation
- iron, B12, folate deficiency
What laboratory finding would you see for an anaemia with low RBC production
Normocytic and normochromic (unless iron, B12, folate deficient)
Reticulocytes not raised
What are some examples of anaemia of chronic disease
Chronic inflammation - RA, IBD
Chronic Infection - pneumonia, TB
Why does haemolysis occur in anaemia
Anaemia results when destruction > production
What is erythropoietic hyperplasia
when bone marrow increases production 6-8x normal rate
what do reticulocytes look like under a microscope?
they appear larger than RBC and purple as they retain RNA
the breakdown of RBC
Haemoglobin - bilirubin and then urobilinogen
signs and symptoms of haemolysis
Jaundice, Dark urine, Gallstones, (RBC pigment), +/- anaemia
blood test results in haemolysis
- Anaemia - normocytic or macrocytic (reticulocytosis)
-Raised reticulocyte count - Raised bilirubin
- Raised LDH – intracellular enzyme
- Low haptoglobin – haptoglobin binds to free haemoglobin, therefore levels are low in haemolysis as it is ‘mopped up’
give 2 examples of intrinsic membrane abnormalities leading to haemolysis
band 3 and spectrin
give 3 hereditary conditions resulting in RBC being unable to maintain their biconcave shape
Hereditary spherocytosis (HS)
Hereditary elliptocytosis (HE)
Hereditary stomatocytosis
what is the consequence of an abnormal RBC shape?
RBC more easily damaged
macrophage removal in spleen + liver - shortened RBC life
what laboratory findings would you see for an inherited RBC membrane defect disorder
anaemia - usually mild
reticulocytosis
bilirubin raised
LDH raised
blood film shows abnormally shaped RBC
direct antibody test negative (Coombs test)
what investigations would be done
FH
blood film
haemolysis screen
special tests e.g., EMA binding (uses flow cytometry)
genetic testing
what is the treatment for RBC membrane defect disorders
folic acid
splenectomy (HS)
Give an example of an intrinsic enzyme defect which causes haemolysis
G6PD deficiency - oxidant stress
how does G6PD deficiency cause haemolysis
G6PD produces NADPH. Therefore, when G6PD deficient, RBC cannot regenerate glutathione via NADPH. Therefore, RBC breakdown
clinical signs of G6PD deficiency
-X-linked recessive – male>female suffers
-Common in Africa and the Mediterranean
-Acute episodes haemolysis following oxidant stress e.g. Drugs, Infections, Moth balls, Fava beans
what is autoimmune haemolytic anaemia
when antibodies attacking host RBC – resulting in premature removal of the red cells by the spleen
what test is done to diagnose autoimmune haemolytic anaemia?
Direct Antiglobulin Test (Coombs)
Autoimmune Haemolytic Anaemia (AIHA) can be triggered by hot or cold - which antibody is which?
Warm: antibody reacts with RBC at 37°C (IgG)
Cold: antibody reacts with RBC below 37°C (IgM)
causes of warm IgG haemolytic anaemia
Warm IgG - leads to extravascular haemolysis
- Idiopathic
- Secondary e.g. SLE, CLL, low grade lymphoma, drugs (penicillin)
What laboratory findings would you see for AIHA
Haemolysis
- Anaemia
- Reticulocytosis
- raised LDH
- raised unconjugated bilirubin
positive DAT (Coombs)
blood film - spherocytes IgG; agglutination IgM
Spherocytes - warm AIHA, the blood film reveals spherocytes (red cells with no central pallor).
Agglutination - cold AIHA, due to Ig, RBC clump on the blood film.
how do you manage AIHA
- remove or treat underlying cause e.g., drug/lymphoma.
- keep patient warm if IgM (cold reacting)
- folic acid - prevent depletion of folic acid leading to worsening of the anaemia
- transfusion
- immune suppression
- corticosteroids (warm), monoclonal anti CD20 antibody rituximab (cold and warm)
- splenectomy for resistant cases (less helpful if IgM) – most successful in cases of warm haemolysis
give 3 examples of microangiopathic haemolytic anaemia
TTP: thrombotic thrombocytopenic purpura
DIC: disseminated intravascular coagulation
HUS: haemolytic uremic syndrome
What will you see on a blood film with anaemia due to mechanical trauma?
Schistocytes - fragmented RBC
give an example of an infection which causes anaemia AND haemolysis
malaria
give 5 examples of chemical and physical agents which can cause haemolysis
- drugs dapsone (oxidative haemolysis)
- copper - Wilson’s disease
- lead
- burns
- snake and spider bites
what does PNH stand for
paroxysmal nocturnal haemoglobinuria
how does PNH cause haemolysis
acquired defect marrow stem cells. defect in anchorage of surface proteins because of absence of glycosylphosphatidylinositol (GPI). RBC rendered sensitive to lysis by complement
These cells are resistant to being broken down by complement
A normal (CD55+, CD59+) RC can withstand the hazard of complement activation
What is thalassaemia
reduced/no alpha or beta chains
classification of alpha and beta thalassaemia
α thalassaemia: too few α chains
β thalassaemia: too few β chains
what is the difference between thalassaemia major or trait
Thalassaemia major - no α/β chains
Thalassaemia trait - reduced α/β chains
what are the clinical features of β thalassaemia major?
usually due t gene mutation
-severe anaemia from 3-6 months – as HbF decreases
- enlargement liver and spleen
- expansion of bone marrow – causing deformity of long bones and facial bones
* In the UK, β thalassaemia major is detected by new-born screening programme
what are the clinical features of alpha thalassaemia major
usually a result of gene deletion
- fatal in utero (hydrops fetalis) – from heart failure (hydrops) - all haemoglobins from the foetal stage onwards contain α chains and cannot be produced in their absence.
- there is complete absence of all 4 α genes and consequently no α chain production.
- People born with only 1 out of 4 functioning α genes have HbH disease.
- HbH is a tetramer of four β chains - variable phenotype with some requiring lifelong regular transfusion and others being very mildly affected.
what are the clinical features of β thalassaemia trait
1 of the 2 genes affected, 1 is normal
- mild microcytic anaemia
- asymptomatic
2 people with β trait have a 1in4 chance of a child with β thalassaemia major.
- Patients have an increase in HbA2, which is made up of 2 α and 2 δ globin chains.
what are the clinical features of α thalassaemia trait
1-2 of the 4 genes affected
- mild microcytic anaemia
- asymptomatic
- ‘carrier’ – can pass gene to child
- α thalassaemia trait is very similar clinically to β thalassaemia trait
how many genes code for alpha chains
4
how many chromosomes have genes for alpha chains
2
what happens when 2 genes are deleted from the same chromosome and have a partner with alpha trait
a child with no alpha genes can be conceived
