3. Red Cells 1 Flashcards
what is anaemia?
Reduction in red cells or their haemoglobin content
Overall a reduction in haemoglobin
Not a diagnosis- it’s the result of something
Job is to find out why they are anaemic, not that they are anaemic.
There are multiple aetiologies, what are they?
Blood loss
Increased destruction (haemolysis)
Lack of production
Defective production
where are RBCs made?
bone marrow
Eventually lose the nucleus
Reticulocyte is immature RBC and you do get some in the peripheral blood, and if you have to compensate for loss of RBC then you get more reticulocytes in the peripheral blood
where does red cell breakdown occur and what is their life span?
Occurs in the reticuloendothelial system - Macrophages in Spleen, liver, lymph nodes, lungs etc
Normal red cell lifespan 120 days
what is the process of red cells breaking down?
Globin = Amino acids –reutilised
Haem = Iron-recycled into haemoglobin, Haem – biliverdin -> bilirubin
Bilirubin - bound to albumin in plasma
From red cell breakdown - unconjugated
Mature red blood cell- “erythrocyte”
what 3 things make up a red blood cell?
Membrane
Enzymes
Haemoglobin
Congenital Anaemias:
Genetic defects described - what areas can they affect?
In red cell membrane
In metabolic pathways (Enzymes)
In haemoglobin
Congenital Anaemias:
Most reduce red cell survival - Result in _________
Carrier states often “______”
Prevalence _______ geographically
haemolysis
silent (Often autosomal recessive conditions, not always though)
varies
what is Hereditary Spherocytosis?
Most common forms autosomal dominant
Defects in 5 different structural proteins described - Ankyrin, Alpha Spectrin, Beta Spectrin, Band 3, Protein 4.2
Red cells are spherical - Cells lose biconcave disc structure
Removed from circulation by the RE system (extravascular) - Lifespam is reduced as recognised as being abnormal
Phenotype we describe but the genetic abnormality varies between family
what is the clinical presentation of Hereditary Spherocytosis?
Clinical presentation-variable (Variable as depending on what structural protein is affected):
- Anaemia
- Jaundice (neonatal – more sevre)
- Splenomegaly
- Pigment gallstones
what is the treatment of hereditary spherocytosis?
- Folic acid (increased requirements)
- (blood) Transfusion
- Splenectomy (main site of destruction of these cells) if anaemia very severe
Red Cell Metabolism Disorders:
Glucose 6 Phosphate Dehydrogenase (G6PD) (G6PD protects cells form free radicles and oxidative damage)
Protects red cell proteins (Haemoglobin) from oxidative damage:
- Produces NADPH - Vital for reduction of glutathione
- Reduced glutathione scavenges and detoxifies reactive oxygen species
what is G6PD Deficiency?
G6PD deficiency is a genetic disorder that most often affects males. It happens when the body doesn’t have enough of an enzyme called glucose-6-phosphate dehydrogenase (G6PD). G6PD helps red blood cells work. It also protects them from substances in the blood that could harm them
Commonest disease causing enzymopathy (a disorder that results in missing or defective enzymes) in the world - Many genetic variants
Cells vulnerable to oxidative damage
Confers protection against malaria - Most common in malarial areas
X Linked - Affects males, Female carriers
what is the clinical presentastion of G6PD deficiency?
Clinical Presentation - Variable:
- Variable degrees of anaemia
- Neonatal Jaundice
- Splenomegaly
- Pigment Gallstones
what are Triggers to haemolysis in G6PD deficiency?
Infection
Acute illness eg.DKA
Broad (Fava) Beans “Favism”
Drugs
what is the structure of haemaglobin?
2 beta and 2 alpha chain
4 haem molecules
Main function is gas transfer, Carries oxygen
what is the function of haemaglobin?
Gas exchange:
- O2 to tissues
- CO2 to lungs
Normal adult haemoglobin:
Adult haemoglobin (HbA) composed of haem molecule and what else?
- 2 alpha (a) chains
- 4 alpha genes (Chr16)
- 2 beta (b) chains
- 2 beta genes (Chr 11)
Normal Adult Hb:
- Hb A (aabb) – 97%
- Hb A2 (aaδδ) – 2%
- Hb F (aaγγ) – 1%
Haemoglobinopathies - wht are they?
Inherited abnormalities of haemoglobin synthesis
Reduced or absent globin chain production - Thalassaemia (alpha α, Beta β, delta δ, gamma γ)
Mutations leading to structurally abnormal globin chain - HbS (Sickle cell ), HbC, HbD, HbE, HbO Arab……
What are areas with high prevalence of haemoglobinopathies?
Countries where malaria was or is
Nearly all haemoglobinopathies are autosomal ________
_______ gives resistance against serve malaria disease
Recessive
Carrier
1 in 4 chance of having affected child
1 in 2 chance of being a carrier or “trait”
Sickle cell disease:
Sickle haemoglobin (HbS) composed of haem molecule and what?
- 2 α chains
- 2 β (sickle) chains - Point mutation
Mutations on both beta chains (carrier if only on one)
what are the Consequences of HbS Polymerisation?
Narrowed vessels and plugs causing vasal occlusion which causes the damage
what is the presentation of sickle cell?
Painful Vaso-occlusive crises - Bone
Chest Crisis
Stroke (sickling in the brain)
Increased infection risk - Hyposplenism
Chronic haemolytic anaemia - Gallstones, Aplastic crisis
Sequestration crises - Spleen, Liver
Sickle cell – painful crisis
what should be done?
•Severe pain - often requires opiates:
- Analgesia should be given within 30 mins of presentation
- Effective analgesia by 1 hour
- Avoid pethidine
- Hydration
- Oxygen - Given oxygen to prevent further sickling
- Consider antibiotics
what is the management of sickle cell disease?
Life long prophylaxis
- Vaccination (against things that cause infection)
- Penicillin (and malarial) prophylaxis
- Folic acid (due to increased haemolysis)
Acute events:
- Hydration
- Oxygenation
- Prompt treatment of infection
- Analgaesia - Opiates, NSAIDs
- Blood transfusion
Blood transfusion - Episodic or chronic
- Alloimmunisation
- Iron overload (if given to many transfusions)
Disease modifying drugs - Hydroxycarbamide (increases foetal haemoglobin levels, used in children and adults)
Bone marrow transplantation
Gene therapy
what is Thalassaemias?
The thalassaemias are a group of recessively autosomal inherited conditions characterised by decreased or absence of synthesis of one of the two polypeptide chains (α or β) that form the normal adult human haemoglobin molecule (HbA, α2/β2), which results in reduced haemoglobin in red cells, and anaemia
Reduced or absent globin chain production
Mutations or deletions:
In alpha genes (alpha thalassaemia)
- αα/αα
- α/αα “α+”
- –/αα “α0”
In beta genes (beta thalassaemia)
If lose one beta much less severe than both lost
If lose of beta chains then free alpha chains floating about this results in haemolysis
Thalassaemias – spectrum of clinical severity
what are the different severities?
Homozygous alpha zero thalassaemia (α0/α0 ) - No alpha chains, Hydrops Fetalis –incompatible with life
Beta thalassaemia major (Homozygous beta thalassaemia) - No beta chains, Transfusion dependent anaemia, Alpha not compatible with life but beta is
Non-transfusion dependent thalassaemia – “Intermedia” (transmissions at certain points in life) - Range of genotypes eg.HbE/beta thal, HbH disease
Thalassaemia minor (common) - “Trait” or carrier state, Hypochromic microcytic red cell indices, carrier state, mild anaemia and also gives small red cells, can be confused with iron deficiency
what is the presentation of Beta thalassaemia major?
•Severe anaemia - As gamma chains switched off and beta chains meant to be switched on you start to get anaemia
- Present at 3-6 months of age
- Expansion of ineffective bone marrow
- Bony deformities
- Splenomegaly
- Growth retardation
•Life expectancy untreated or with irregular transfusions <10 years
what is the treatment of Beta thalassaemia major?
•Chronic transfusion support - 4-6 weekly
- Normal growth and development
- BUT - Iron overloading (if you leave someone to have iron build up in organs they can die)
- Death in 2nd or 3rd decades due to heart/liver/endocrine failure if iron loading untreated
- Iron chelation therapy (removes the iron) - s/c desferrioxamine infusions (desferal), Oral deferasirox (exjade)
- Good adherence to chelation – life expectancy near normal - Requires regular monitoring, Ferritin and MRI scans
- Bone marrow transplantation-curative
•Inherited anaemias can result from defects in:
_________________
_________________
_________________
•Knowledge of normal red cell physiology important in understanding the mechanisms of disease
- Red cell membrane
- Red cell metabolism (enzymes) (G6PD deficiency)
- Haemoglobin production
