Haemolytic Anaemia Flashcards
What is haemolytic anaemia?
Anaemia due to shortened RBC survival
MAIN BROAD FEATURES
- Reticulocytosis
- Unconjugated hyperbilirubinaemia
- Raised LDH (lactate dehydrogenase)
Describe the normal RBC lifecycle
-
RBC production (in bone marrow)
- Kidneys will produce EPO which signals for RBC production
- Requires B12, folate, globin chains, protoporphyrins
-
Circulating RBCs
- 120 days
-
Senescent RBCs
- As they age they will accumulate changes on their RBC membrane, recognised by liver + spleen (removal of these cells)
What are the metabolic pathways which occur in a mature RBC?
-
Glycolytic pathway
- ATP produced in RBCs through anaerobic glycolysis
-
Hexose-monosphosphate pathway
- Required to produce NADPH for reduced glutathione (GSH) production (protects from oxidative damage)
-
Rapoport Luebering shunt/ pathway
- Involved in producing 2,3 BPG (biphosphoglycerate)
What metabolic pathway produces 2,3 BPG (biphosphoglycerate) and what is its role?
- Produced by the Rapoport Luebering shunt
- Binds to haemoglobin reducing its affinity for oxygen
How does the body compesate for haemolysis?
- The bone marrow will compensate through increased RBC production
- Increased young cells in circulation
- Reticulocytosis
- Nucleated RBCs
What is the difference between compensated haemolysis and incompletely compensated haemolysis?
Compensated haemolysis = RBC production able to compensate for decreased RBC lifespain
Incompletely compensated haemolysis = RBC production unable to keep up with decreased RBC life span (decreased Hb)
What are the clinical findings of haemolytic anaemia?
- Jaundice
- Breakdown of RBC (unconjugated bilirubin)
- Pallor/fatigue
- Splenomegaly
- Dark urine
- Haemolytic crisis (increased anaemia and jaundice with infections and precipitants)
- Aplastic crisis (anaemia, reticulocytopenia, parvovirus infection)
What is an Aplastic crisis?
- When the body does not make enough new red blood cells to replace the ones already in the blood.
- You get anaemia and reticulocytopenia
- Can occur in parvovirus infection where it can trigger acute cessation of RBC production
What are chronic clinical findings of haemolytic anaemia?
- Gallstones (pigment) (NOT CHOLSTEROL)
- Splenomegaly
- Leg ulcers (due to nitric oxide scavenging from free Hb)
- Folate deficiency (increased use to make more RBC)
What are the laboratory findings of haemolytic anaemia?
- Normal/ low Hb
- Increased reticulocyte count
- Increased unconjugated bilirubin
- Increased LDH (lactate dehydrogenase)
- → released from haemolysed RBCs
- Low serum haptoglobin
- → protein binding free Hb
- Increased urobilinogen
- Increased urinary haemosiderin
- Abnormal blood film
What does a blood film look like in haemolytic anaemia?
- Reticulocytes
- Polychromasia (many immature RBCs)
- Nucleated RBCs
How can haemolytic anaemia be classified?
- Inheritance
- Congenital
- Acquired
- Site of RBC destruction
- Intravascular
- Extravascular
- Origin of RBC damage
- Intrinsic
- Extrinsic
Give examples of inherited congenital anaemia
-
Congenital/ Inherited
- Membrane disorders (Spherocytosis, Elliptocytosis)
- Enzyme disorders (G6PD def, PK deficiency)
- Hb Disorders (Sickle Cell Anaemia, Thalassaemia)
-
Acquired
- Immune (auto-immune haemolysis)
- Drugs
- Mechanical (leaking heart valves)
- Infections
- Burns
- Microangiopathic (high BP causes red cell fragmentation)
How is a RBC broken down in extravascular haemolysis?
Extravascular haemolysis
- Macrophage of reticuloendothelial system will break down RBC
- RBC will be broken down into (globin, iron and protoporphyrin)
- Globin is broken down to amino acids, iron binds to transferrin and transported to liver, protoporphyrin broken down to bilirubin and released to blood (unconjugated) where it is further broken down in liver and excreted in the urine
How is a RBC broken down in intravascular haemolysis?
- RBC will not be systematically broken down but Hb will be released as free Hb into blood + urine
Describe the normal RBC membrane structure
- Lipid bilayer is anchored to the cytoskeleton by a number of different proteins
- Mutations in proteins affecting the anchoring of lipid bilayer to cytoskeleton will affect membrane stabillity
What are the two inherited membrane disorders which cause haemolytic anaemia?
- Hereditary spherocytosis
- Hereditary elliptocytosis
What is hereditary spherocytosis?
Defects in vertical interaction between lipid bilayer and cytoskeleton
- Spectrin
- Band 3
- Protein 4.2
- Ankyrin
What is the effect of hereditary spherocytosis?
In what form is this inherited?
- Decreased membrane deformabillity (deformation required to fit through capillaries)
- Inherited in autosomal dominant fashion
What does the blood film look like on an individual with hereditary spherocytosis?
- Rounder more spherical RBCs
- Absence of ring of central pallor
What is hereditary elliptocytosis?
Defects in proteins involved in HORIZONTAL interactions between lipid bilayer and cytoskeleton
- Protein 4.1
- Glycophorin C
- Spectrin (HPP)
What can be the effect of oxidative stress on RBCs?
- Oxidant radicals oxidise Hb
- This will denature and aggregate and cause formation of Heinz bodies (common in G6PD)
- Heinz bodies (inclusions within RBCs composed of denatured Hb)
- Oxidised membrane protein = reduced RBC deformabillity
Describe the inheritance pattern of glucose-6-phosphate dehdyrogenase deficiency (G6PD)
- Hereditary X-linked disorder
- Females can display symptoms due to X-inactivation
- Affects the hexose monophosphate shunt
What are features of G6PD deficiency?
- Oxidative haemolysis
- Film
- Bite cells
- Blister and ghost cells
- Heinz bodies
- Reduced G6PD activity on enzyme assay
- May be falsely normal if reticulocytosis
What is the feature on a blood film of pyruvate kinase deficiency?
Prickle cells
What is the role of pyruvate kinase in RBC metabolism?
Required to generate ATP, essential for membrane cation pumps (deformabillity)
What is the structure of normal adult haemoglobin?
Two alpha (chromosome 16) and two beta (chromosome 11)
What is the structure of adult (A2) haemoglobin?
Two alpha (16) and two delta (11) chains
What is the clinical significance behind globin expression during the neonatal period?
Alpha chains are needed on in embryonic life, but beta chains are more vital after birth at about 4-5 weeks old
Therefore it is important when diagnosing haemoglobinopathies because almost all the clinically significant ones affect the beta chains, meanining the foetus is unharmed in the neonatal period (less than 4 weeks old)
→ Alpha thalassaemias are usually fatal in utero
What is the most common thalassaemia? Describe the different types.
Most common thalassaemia = beta thalassaemia
This is autosomal recessive (two parents will need to have the beta thalassaemia trait)
- Beta thalassaemia trait = one mutated gene and one normal gene on chromosome 16
- Beta thalassaemia major = two mutated genes on chromosome 16
- However not absolute as there can be variability
What is beta thalassaemia major treatment?
Transfusion dependant in 1st year of life
If not transfused
- Failure to thrive
- Progressive hepatosplenomegaly
- Bone marrow expansion causing skeletal abnormalities
- Death in 1st five years of life from anaemia
Describe sickle cell disease
- Autosomal recessive
- Point mutation in the beta globin gene (GTA - GTG)
- Glutamic acid to Valine
- Forms an insoluble Hb tetramer when deoxygenated causing polymerisation
- Resulting in sickle shaped cells
- Point mutation in the beta globin gene (GTA - GTG)
What are the clinical and laboratory findinds of Sickle Cell Disease?
How can you confirm diagnosis of sickle cell anaemia?
Sickle Solubillity Test
- Expose blood to reducing agent, HbS precipitated, positive in trait and disease
Electrophoresis
- Analyse structure of Hb
HPLC Test
- Not definitive, need sickle solubillity test
REMINDER LOOKING FOR CHANGE IN BETA GENE
