RBC disorders (4) Flashcards
Haematolytic anaemia:
Anaemia due to increased red blood cell destruction (or increased erythropoiesis) – broken down
Microskeletal defects (membrane defects):
Hereditary spherocytosis – defect in the cytoskeleton (gene defect for the protein that makes up the membrane)
Membrane permeability defects (membrane defects):
Hereditary stomatocytosis – ion channel defects
Deficiencies in Hexose Monophosphate Shunt (Enzymopathies):
Glucose 6-Phosphate Dehydrogenase (6PD) Deficiency – defects the way the blood cell gets energy via glycolysis
Deficiencies in the Emben-Myerhof Pathway (Enzymopathies):
Pyruvate Kinases deficiency
Membrane disorders:
- Hereditary spherocytosis (HS) – this lecture and most common
- Hereditary Elliptocytosis (HE) – this lecture
- Hereditary Stomatocytosis
- Hereditary Xerocytosis
- Autoimmune haemolytic anaemia
- Paroxysmal nocturnal haemoglobinuria
Hereditary spherocytosis (HS):
- Most common hereditary HA in Northern Europeans
- Usually autosomal dominant, variable expression – 1 parent
- Defects in proteins involved in vertical interactions between membrane cytoskeleton and lipid bilayer
- Red cells normal biconcave shape but become increasingly spherical as progress through spleen/RE system – not flexible
- RBC Die prematurely - Every time it goes through the spleen, it gets more narrow and therefore more spherical, showing defects
What happens in HS?
Majority of genetic defects that occur in hereditary spherocytosis are Ankyrin and spectrin and band 3 in the plasma membrane
You either end up with reduced synthesis of the protein, an unstable protein or dysfunction
The problems of HS:
- need to be able to say which protein influences what
- band 3 will have genes that have reduced function which is incooperated onto the membrane
- the membrane is destabilised which loses its flexible links to the lipid bilayer – increased production of red blood cells when there is loss
- you have a loss of surface area to volume ratio
- often the cells are small and lose biconcave shape, becomes trapped in splenic chords and splenic conditioning occurs when RBC try to squeeze through the spleen
- leading to further loss (more spherical cell) and then is broken down, has a limited number of time it can move through but is eventually destroyed as it cannot handle the pressure
Clinical features of HS:
- Anaemia
- Jaundice typically fluctuating – bile products used to break down red blood cells, leading to the person becoming yellow as the break down doesn’t occur efficiently
- Splenomegaly – usually the answer to write in exams
Haematological findings (in the lab, blood count, on a blood film):
- Reticulocytes 5-20% - pre red blood cell (normal retic value is 1-1.5% in anaemia)
- Blood film: microcytes
Investigation & Treatment:
- Osmotic fragility test increased
- Splenectomy principle form of treatment (can remove which increases the lifespan) – need spleen to protect against routine infections
Laboratory test: Osmotic fragility
- Results representative of both typical and severe spherocytosis are shown.
- A “tail,” representing very fragile erythrocytes that have been conditioned by the spleen, is common in many HS patients prior to splenectomy.
Not done very often, but place red blood cells in a hypotonic solution, more solutes in the solution than inside the cell so water moves into the cell, membrane is looked at
Hereditary Elliptocytosis (HE):
- Various membrane protein abnormalities including spectrin, protein 4.1 and glycophorin C
- EL2 and EL3: Most common genetic defects are in genes for α-spectrin or β-spectrin
Red cell metabolism:
- Red cell maturation - Loss of organelles
- However mature red blood cells still need energy to maintain a healthy cell
There are 3 main processes to mature RBCs:
- Initiation and maintenance of glycolysis
- Maintenance of cation concentrations
- Maintenance of the red cell in biconcave form
The glycolytic pathway serves three functions in the RBC:
- NADPH production - Hexose monophosphate shunt (Pentose phosphate)
- ATP production - Embden-Meyerhof pathway
- 2,3 diphosphoglycerate (2,3 DPG) production - Rapaport-Luebering Shunt – moves the dissociation curve to the right as affinity increases
Hexose monophosphate (pentose phosphate) pathway:
- Approx 5-10% of glycolysis occurs by this pathway
- NADPH generated (prolongs life of red cell)
- pool of reducing energy - iron (how it is used) and hence haemoglobin in correct functional state (otherwise cannot carry oxygen around the body)
- if the cell comes under oxidative stress the amount of glucose passing through the shunt can be increased to provide more reducing power
What does G6PD do?
- Regenerates NADPH, allowing regeneration of glutathione
- Protects against oxidative stress
- Lack of G6PD leads to haemolysis during oxidative stress - infection, medication, fava beans
- Oxidative stress leads to Heinz body formation, extravascular hemolysis
Features of G6PD:
- Enzyme activity reduced /deficient
- Most common enzymopathy (nearly 1% of the world population)
- X-linked inheritance – really rare in women
- At least 400 variants - point mutations and deletions
- Resistance to malaria - Affected areas (large overlap with malarial areas)
- West Africa, Mediterranean, Middle East, South East Asia
Clinical features of G6PD:
- Precipitated by infection, illness, drugs or Fava (broad) beans
- Rapid intravascular haemolysis in the blood vessels and extravascular means in the spleen
- Haemoglobinuria (blood in urine) – increased amount of broken down blood cells and blood loss found in urine
Haematological Findings of G6PD:
- Heinz bodies (oxidized, denatured haemoglobin)
- Bite cells and Blister cells.
- Heinz bodies bind to the red cell membrane, alter its rigidity, resulting in premature destruction in the spleen.
Treatment for G6PD:
- stop drug
2. treat infection
X linked recessive G6PD:
- Synthesis of G6PD determined by X chromosome
- Usually only males affected
- Heterozygous females (intermediate enzyme activity) usually not symptomatic
Embden-Meyerhof pathway:
- Embden-Meyerhof pathway uses about 90-95% of glucose in red blood cell
- Glucose metabolised to lactic acid
- 1 molecule of glucose generates 2 molecules of ATP
- provides energy for maintenance of red cell volume, shape and flexibility
Pyruvate kinase deficiency Defects:
- Autosomal recessive
- Over 100 different mutations
- Anaemia - severity varies
- Jaundice usual, gallstones frequent
Haematological Findings of PK:
- Cells rigid and lose flexibility – due to reduced ATP levels
- Reduced haemoglobin levels – less able to hold oxygen
- Macrocytosis – harder to move through blood vessels
Treatment for PK:
- Splenectomy
2. Blood transfusions
