Haemolytic anaemias Flashcards
What is anaemia and what is haemolytic anaemia?
ANAEMIA = reduced haemoglobin level for the age and gender of the individual
HAEMOLYTIC ANAEMIA = anaemia due to shortened RBC survival
What constitutes the normal red blood cell cycle?
→ Red blood cells circulate for approximately 120 days without nuclei or cytoplasmic organelles.
→ Components needed for function and survival already are present when erythrocytes reach maturity.
→ 2x1011 RBC/day in the bone marrow
→ 300 miles travelled through microcirculation
→ 7.8 microns diameter; able to go through capillaries as small as 3.5 microns
→ RBC circulate for approx. 120 days without nuclei or cytoplasmic organelles
→ Removal senescent RBC by RES
What happens in haemolysis?
→ Shortened red cell survival 30 - 80 days
→ Bone marrow compensates with increased red blood cell production
→ Increased young cells in circulation = Reticulocytosis +/- nucleated RBC
→ Compensated haemolysis: RBC production able to compensate for decreased RBC life span = normal Hb
→ Incompletely compensated haemolysis: RBC production unable to keep up with decreased RBC life span = decreased Hb
What do you find clinically and chronic clinically in regards of symptoms in haemolytic anaemia?
→ Jaundice (billirubin)
→ Pallor/fatigue
→ Splenomegaly
→ Dark urine
→ Haemolytic crises-increased anaemia and jaundice → with infections/ precipitants
→ Aplastic crises-anaemia, reticulocytopenia with parvovirus infection
→ Chronic clinical findings
→ Gallstones - pigment
→ Leg ulcers (NO scavenging)
→ Folate deficiency - (increased use)
→ Urine may turn dark on standing due to excess urobilinogen.
→ Aplastic crises, usually precipitated by parvovirus infection which switches of erythropoiesis
What are laboratory findings for haemolytic anaemia?
→ Increased reticulocyte count
→ Increased unconjugated bilirubin
→ Increased LDH (lactate dehydrogenase)
→ Low serum haptoglobin protein that binds free haemoglobin
→ Increased urobilinogen
→ Increased urinary haemosiderin
→ Abnormal blood film
→ Haemosiderinis a brown iron-containing pigment usually derived from the disintegration of extravasated red blood cells.
→ Haptoglobin is a glycoprotein that binds free Hb.
How can you classify haemolytic anaemia?
-Inheritance
Hereditary
Acquired
-site of RBC destruction
Intravascular
Extravascular
-Origin of RBC damage
Intrinsic
Extrinsic
What is hereditary Spherocytosis?
What does management of HS include?
→ Common hereditary haemolytic anaemia
→ Inherited in autosomal dominant fashion (75%)
→ Defects in proteins involved in vertical interactions between the membrane skeleton and the lipid bilayer
→ Decreased membrane deformability
→ Bone marrow makes biconcave RBC, but as membrane is lost, the RBC become spherical
Management includes:
→ Monitor
→ Folic acid
→ Transfusion
→ Splenectomy
What are clinical features of Hereditary Spherocytosis?
→ Asymptomatic to severe haemolysis
→ Neonatal jaundice
→ Jaundice, splenomegaly, pigment gallstones
→ Reduced eosin-5-maleimide (EMA) binding – binds to band 3
→ Positive family history
→ Negative direct antibody test
How do red cells produce ATP since they do not contain mitochondria and cannot readily metabolise glucose aerobically?
→ Red cells do not contain mitochondria and can therefore not readily metabolize glucose aerobically and produce the ATP that way.
→ The metabolism of the human red blood cell consists of the Glycolytic pathway (Embden-Meyerhof pathway) and the Hexose Monophosphate shunt
→ For the red blood cells the pathways protect the haemoglobin molecule, the membrane lipids and structural proteins from oxidative stress.
→ They also assist in the structural integrity of the red cell and regulate the volume of the cell
→ These metabolic networks are also different to others in the respect that the red cell does not generate biomass:
its main task is to produce the necessary cofactors (ATP, NADPH, and NADH) for maintaining its osmotic balance and electro-neutrality and fighting oxidative stresses
more detail in recording but tbh I’m just lazy and can’t be bothered to try understand such details lol (in recording around 24 mins)
What is the role of the Hexose Monophosphate shunt?
What can oxidative stress cause? (from glucose-6-phosphate deficiency?)
→ Generates NADPH & reduced glutathione
→ Protects the cell from oxidative stress
→ Oxidative Stress can cause:
→ Oxidation of Hb by oxidant radicals (eg hydrogen peroxide) resulting denatured Hb aggregates & forms
Heinz bodies – bind to membrane.
Oxidised membrane proteins
reduced RBC deformability
What is glucose-6-phosphate deficiency?
→ G6PD is involved in the pentose phosphate pathway; one of the products of this pathway is NADPH which has a role in protecting the red blood cell from oxidative damage
→ NADPH - nicotinamide adenine dinucleotide phosphate reduced; GSH acts as an anti-oxidant
→ G6PD catalyses the first step in the hexose monophosphate shunt which is necessary for producing NADPH.
→ NADPH in turn is required for the maintenance of reduced
→ Glutathione (GSH), a tripeptide that protects the RBC from oxidative damage.
→ G6P is converted to 6-phosphogluconate, by G6PD, generating NADPH.
G6PD deficiency:
→ Common in African, Asian, Mediterranean and Middle Eastern populations
→ Mild in African (type A), more severe in Mediterranean’s (type B)
Clinical features range from asymptomatic to acute episodes to chronic haemolysis:
→ Oxidative precipitants
→ Infections
→ Fava/broad beans
→ Drugs (e.g. Ciprofloxacin, Dapsone, Nitrofurantoin Primaquine)
Features:
→ Haemolysis;
→ Film (bite cells, blister cells & Ghost cells; Heinz bodies (with mb)
→ Reduced G6PD activity on enzyme assay may be falsely normal if reticulocytotic
What is pyruvate kinase deficiency?
→ PK is an autosomal recessive disorder, with more than 100 mutations documented, resulting in low intracellular ATP generation affecting membrane structure.
→ The ATP generated is required for the red cell membrane pump in order to maintain red cell volume and high intracellular K+ levels. 3Na+ out 2K+ in
[regulate intracellular cation conc. via cation pumps (Na/K pump)],
→ The anaemia may worsen at times of infection or other stress; dense red cells with spicules (prickle cells) may be seen on the peripheral blood film.
→ PK required to generate ATP, essential for membrane cation pumps (deformability)
With a deficiency in Pyruvate kinase:
→ Cells lose large amount of potassium & water, becoming dehydrated & rigid.
→ Autosomal recessive
→ PK deficiency can cause Chronic anaemia
→ Mild to transfusion dependent
→ Improves with splenectomy
What comes together to form Haemoglobin?
Ferrous iron (Fe++) and Protoporphyrin IX both come together to form ‘haem’ which combines with ‘globin’ (2 alpha 2 beta chains) to form haemoglobin
What subunits make up the different forms of haemoglobin?
HbA- 2 alpha, 2 beta
HbA2- 2 alpha, 2 delta
HbF- 2 alpha, 2 gamma
Give an example of a quantitative and qualitative globin disorders
→ Quantitative - eg thalassaemia’s:
→ Production of increased/ decreased amount of a globin chain (structurally normal)
→ Qualitative – eg variant haemoglobins:
→ Production of a structurally abnormal globin chain
