S2: Red Blood Cells - Production and Survival Flashcards
What is proerythroblast and normoblast?
- Proerythroblast is the first recognisable RBC precursor in marrow
- Maturation to late normoblast occurs in marrow
Explain how red blood cell production is controlled by tissue oxygenation
- Decreased O2 a tissues (e.g. hypoxia due to low RBC count, decreased Hb, decreased availability of O2)
- Kidney senses this and secretes erythropoietin
- Erythropoietin stimulates red bone marrow which produces more RBC
- This increases O2 carrying capability of blood which increases O2 levels at tissues
List what is needed for RBC production
- EPO (erythropoietin)
- Iron
- Vitamin B12
- Folate
- Erythroid precursors
Sources of iron
Meat
Eggs
Vegetables
Dairy foods
Absorption of Iron
Mostly occurs in duodenum and jejunum
- Gastric secretion (HCl) and ascorbic acid help absorption
- DMT-1 and ferroportin transports iron from cell to circulation
- Iron then binds to a RBC protein transferrin
Explain haemoglobin synthesis
- Transferrin transports iron to cell
- Iron-transferrin complex binds transferrin receptor
- Through endocytosis, iron is released into cell
- Iron is shunted into mitochondria and used for synthesis of haemoglobin
Causes of iron deficiency
Decreased uptake:
- Inadequate intake
- Malabsorption - problems in small intestine e.g. coeliac disease
Increased demand:
- Pregnancy - increase in 30% RBC volume which uses iron
- Growth spurt- Increase Hb needed to transport O2 to growing deficiency
Increased loss:
- GI bleed
- Excess loss in menses
Describe microcytic, hypochromic anaemia
- Commonest cause of anaemia (iron deficiency)
- Low Hb level
- RBC are paler, smaller and may be pencil shaped
- RBC distribution is bigger (more variation)
Describe function of vitamin B12 and folic acid
- Both essential for RBC maturation and DNA synthesis
- Both needed for formation of thymidine triphosphate
- B12 is coenzyme for methionine synthase in methylation of homocysteine to methionine
- Deficiency in either of them causes abnormal and diminished DNA leading to failure of nuclear maturation
Causes of vitamin B12 deficinecy
Inadequate intake:
- Vegans
Absorption defect:
- Tropical sprue
- Coeliac disease
- Blind loop syndrome - inflammatory bowel changes allowing bacterial overgrowth which competes for available B12
IF deficiency:
- Permicious anaemia
- Crohn’s
- Gastrectomy and others
What is intrinsic factor (IF)?
Why does IF deficiency cause Vitamin B12 deficiency?
IF is secreted by parietal cells in the stomach
- It binds to B12 and transports it to the ileum before binding to a receptor releasing B12
- Is needed for absorption of B12
Causes of Folate deficiency
Inadequate intake:
- Poor nutrition
Absorption defect:
- Coeliac disease
- Crohns disease
- Tropical sprue
Increase demand/loss:
- Pregnancy
- Haemolysis
- Cancer
Drugs:
- Anticonvulsants
Describe macrocytic anaemia
- Occurs in folate and B12 deficiencies
- MCV > 95 fl (cells are much bigger)
- Oval macrocytes of blood film
- May have reduced WBC and platelets
- Megaloblastic change in bone marrow
- Hypersegmented neutrophils
- Symptoms include diarrhoea and neurological problems e.g. confusuin, memory loss
- In B12 deficiency only there is demyelination in the CNS
For vitamin B12 describe:
- Foods found in
- Absorption site
- Transport in plasma
- Therapeutic form
Found in animal origin only - meat, liver, fish
Absorbed in the ileum
Transported in plasma bound to TCI, TCII for uptake
Hydroxocobalamin
For folate describe:
- Foods found in
- Absorption site
- Transport in plasma
- Therapeutic form
Found in greens, yeast and especially liver
Absorbed from duodenum and jejunum
Transported in plasma weakly bound to albumin
Folic acid
Described stress placed on RBC and what happens to faulty RBC?
RBC have a lifespan of 120 days and travel 300 miles through microcirculation. They are 7.8 microns in diameter while capillaries are as small as 3.5 microns.
Faulty RBC are haemolysed
Types of acquired haemolytic anaemia
Immune
- Autoimmune
- Alloimmune
- Drug induced
Non Immune
- Red Cell Fragmentation e.g. caused by valve replacement
- Infection: secondary
Types of Hereditary haemolytic anaemia
Red cell membrane disorder
- Hereditary sphreocytosis
- Hereditary elliptocytosis
Red Cell Enzymopathies
- G6PD deficiency
- PK deficiency
Haemoglobinopathies
- Sickle cell diseases
- Thalassaeias
Describe hereditary spherocytosis (hereditary haemolytic anaemia)
- Loss of membrane integrity, the RBC becomes spherical
- Deficiency in proteins with vertical interactions between membrane skeleton and the lipid bilayer
Describe hereditary elliptocytosis (hereditary haemolytic anaemia)
- Clinically milder than hereditary spherocytosis
- Mutations in horizontal interactions e.g. spectrin, ankyrin, protein 4.1
What are the two main red cell enzymes and what two metabolic pathways do they support?
- Glucose 6-phosphate dehydrogenase (G6PD)
This supports the Pentose Phosphate Pathway. - Pyruvate Kinase (PK). They act on the glycolytic pathway
What happens in G6PD deficiency AKA enzymopathy?
NADPH and GSH generation is impaired so acute haemolysis occurs on exposure to oxidant stress (e.g. oxidative drugs, fava beans or infections). It also causes Hb precipitation - Heinz bodies.
- It is X linked
- Seen in ethnic groups with haemoglobinpathies
- G6PD deficiency leads to HA upon treatment with primaguine which stimulates H2O2 formation
Function of glycolytic pathway to RBC
- Generates ATP: To maintain red blood cell shape and deformability and regulates intracellular cation concentration via cation pumps (Na+/K+ pump –> 3 Na+ out and 2K+ in)
Describe Pyruvate Kinase (PK) deficiency
- Autosomal recessive disorder
- Results in low intracellular ATP generation affecting red cell membrane structure
- ATP-depleted cells lose large amount of potassium and water, becoming dehydrated and rigid because cation pumps fail to function.
- This causes chronic non-spherical haemolytic anaemia and excess haemolysis leads to jaundice, gallstones.
Describe non-spherical haemolytic anaemia seen in G6PD deficiency and PK deficiency
G6PD –> contracted cells (Hb precipitation)
PK–> Prickle cells with spikes
What do mutations or deletions of genes for globin chains lead to?
- Abnormal synthesis of globin chain as in Sickle Cell Diseases
- Reduced rate of synthesis of normal globin chains as in thalassaemia
What is sickle cell disease?
Group of Hb disorders with inherited sick B-globin gene.
A in GAG is replaced with T giving GTG (val0
What is sickle cell disease?
Group of Hb disorders with inherited sick B-globin gene.
A in GAG (Glu) is replaced with T giving GTG (val)
Sickle cell anaemia is homozygous and most common (HbSS)
Describe B-thalassaemia
- Loss of 1 B-chain causes thalassaemia trait (minor mild microcytic anaemia)
- Loss of both B chain causes thalassaemia major
- Excess a-chains precipitate in erythroblasts causing haemolysis and ineffective erythropoiesis
Describe alpha-thalassaemia
- There can be loss of 1, 2, 3, or 4 alpha chains
- Loss of 1 or 2 causes mild microcytic anaemia
- Loss of 3 causes moderate anaemia - Hb H disease
- Loss of 4 causes death in utero (hydrops fetalis)
Why type of anaemia does thalassemia cause?
Microcytic anaemia
Compare the shape of RBC in sickle cell and thalassemia
Sickle cell –> RBC are sickle shaped
Thalassaemia –> Target cells, tear drop shaped
