Red Blood Cell Production and Survival Flashcards
Describe red blood cell production.
HAEMOCYTOBLAST (Stem Cell)
PROERYTHROBLAST (Committed Cell) - first recognisable precursor within bone marrow
EARLY ERYTHROBLAST
LATE ERYTHROBLAST
NORMOBLAST
RETICULOCYTE
ERYTHROCYTE
Maturation and production occurs within marrow
Describe the hormonal control of erythropoiesis.
- Stimulus: hypoxia due to decreased RBC count, decreased amount of haemoglobin or decreased availability of O2.
- There are reduced levels of O2 in the blood
- The paratubular cells in the kidney (and liver, to a smaller extent) release erythropoietin.
- Erythropoietin stimulates redbone marrow.
- Enhanced erythropoietin increases RBC count.
- This increases the O2-carrying ability of the blood.
What is required for erythropoiesis (red blood cell production)?
- Fe2+
- Vitamin B12
- Amino acids (to make globin)
- Folic Acid/Folate
- Erythroid precursors
VITAMIN B12 and FOLIC ACID
- Both are essential for red blood cell maturation and DNA synthesis.
- both needed for the formation of thymidine triphosphate.
- B12 is the coenzyme for methionine synthase in methylation of homocysteine to methionine
A deficiency in either of them causes abnormal and diminished DNA, leading to failure of nuclear maturation. Megaloblastic anaemia can also occur, with macroovalocytes and hypersegmented neutrophil.
DEFICIENCIES ALSO CAUSE THE FOLLOWING
Oval macrocytes
Reduced WBC and platelet count
Megoblast change in bone marrow
Hypersegmented neutrophils
B12 only- demyelination of CNS
VITAMIN B12
- Main foods : Liver, meat, fish
- Daily requirement: 1-2µg
- Body stores: 2-3mg (sufficient for 2-4yrs)
- Absorption site: Ileum
- Transport in plasma : Bound to TCI; TCII for uptake
FOLATE
Main foods : Liver, greens & yeast
Daily requirement: 100-150µg
Body stores: 10-12mg (for 4 months)
Absorption site: Duodenum, Jejunum in form of MTHF
Transport in plasma: Weakly bound to albumin
VITAMIN B12 DEFICIENCY CAUSES
INADEQUATE INTAKE:
- vegans
ABSORPTION DEFECT:
- tropical sprue (malabsorption disease, flat villi, affects the small intestine)
- coeliac disease
- blind loop syndromes (small intestine bacterial overgrowth, compete for B12)
- TC1 is secreted by salivary glands and protects B12 from degradation. So deficiencies of TC1 can also cause B12 deficiency
IF DEFICIENCY (INTRINSIC FACTOR DEFICIENCY, IF needed for B12 absorption):
- pernicious anaemia - autoimmune gastric atrophy, which leads to the loss of an intrinsic factor production needed for absorption of B12 - very common cause of deficiency
- Crohn’s disease (GI tract affected)
- gastrectomy and other causes (where parietal stomach cells are affected, so can’t make IF)
FOLATE DEFICIENCY CAUSES
INADEQUATE UPTAKE:
- poor nutrition
ABSORPTION DEFECT:
- coeliac disease
- Crohn’s disease
- tropical sprue
INCREASED DEMAND/LOSSES:
- pregnancy
- haemolysis
- cancer
DRUGS;
- anticonvulsants (inhibit folate absorption)
Treatment:
B12 - Hydroxycobalamin - an injectable form of vitamin B12 that is given when there are problems with absorption of this vitamin from the gut
Folate: -Folic acid: 5mg/day oral
Describe iron.
SOURCES: meat, eggs, vegetables, dairy foods
Gastric secretion (HCl) and ascorbic acid help absorption.
5-10% absorbed (1mg) principally in duodenum and jejunum.
HIF enhances expression of iron absorbing gene
List some causes of an iron deficiency.
DECREASED UPTAKE OF IRON:
- inadequate intake
- malnutrition
INCREASED DEMAND:
- pregnancy
- growth spurt
INCREASED LOSS:
- GI bleed
- excess less in menses
MALABSORPTION
List some other causes of the failure of RBC production.
- RENAL DISEASE: ineffective erythropoiesis
- REDUCED BONE MARROW ERYTHROID CELLS due to the following:
- APLASTIC ANAEMIA
- MARROW INFILTRATION BY LEUKAEMIA/OTHER MALIGNANCIES: it infiltrates the bone marrow and inhibits RBC production
Ability of RBC to survive depends on
- Cytoplasmic enzymes involve in metabolic pathways because mature RBCs have no nucleus, mitochondria or ribosomes therefore unable to carry out oxidative phosphorylation and protein synthesis
What are three ways in which haemolytic anaemia can be classified?
- HEREDITARY/ CONGENITAL or ACQUIRED
ACQUIRED HAEMOLYTIC ANAEMIA
IMMUNE:
- Autoimmune (when the body itself fights red cells) - divided into cold and warm based on temperature at which autoimmune response occurs
- Alloimmune (when given blood fights the body)
- Drug-induced (when drugs induce the fighting)
NON-IMMUNE:
- Red cell fragmentation (when, for example, a heart valve is replaced, and when red blood cells flow through it, they get fragmented)
- Infection (eg. malaria)
- Secondary (eg. liver/ kidney diseases)
HEREDITARY CAUSES OF HAEMOLYTIC ANAEMIA
HAEMOGLOBINOPATHIES:
- sickle cell diseases
- thalassaemias
RED CELL ENZYMOPATHIES:
- G6PD deficiency
- PK deficiency
RED CELL MEMBRANE DISORDERS:
- hereditary spherocytosis (RBCs are spherical due to loss of membrane integrity -
deficiency in proteins with vertical interactions between the membrane skeleton and the lipid bilayer)
- hereditary elliptocytosis (RBCs are elliptical, oval-shaped - mutations in horizontal protein, spectrin causing defective spectrin-ankyrin associations)
- INTRINSIC FACTORS or EXTRINSIC FACTORS
- INTRAVASCULAR or EXTRAVASCULAR
Describe Sickle Cell Disease.
- Group of haemoglobin disorders with an inherited sickle β-globin gene.
- Sickle Cell Anaemia is homozygous (HbSS)
- The normal β-globin gene has the nucleotides GAG, which codes for glutamic acid. In the sickle β-globin gene, the A is replaced with a T, changing the amino acid made to Valine.
- Abnormal synthesis of globin chain
- Substitution causes formation of insoluble Hb tetramer when deoxygenated → polymerisation
There are other types of Sickle Cell Diseases, which are heterozygous:
- HbS/βthal
- HbSC
- HbSD
- HbSE
In sickle cell anaemia, see red blood cells shaped as a sickle and some target cells.
Describe thalassaemia.
- Two types of thalassaemia, β thalassaemia and α thalassaemia.
- Reduced rate of synthesis of normal globin chains
β THALASSAEMIA:
- The loss of one β-chain causes mild microcytic anaemia (a thalassaemia trait). The loss of both β-chains causes thalassaemia major.
- Means that an excess of α-chains precipitate into the erythroblasts, causing haemolysis and ineffective erythropoiesis.
α THALASSAEMIA:
- Can be a loss of one, two, three or four α-chains.
In thalassaemia, can see target cells and also cells that look like teardrops.
List (and briefly describe) the two main red cell enzymes.
The two main red cell enzymes are:
- Glucose-6-Phosphate Dehydrogenase (G6PD)
G6PD catalyses the first step in the hexose monophosphate shunt which is necessary for producing NADPH
- Pyruvate Kinase (PK)
They support two main metabolic pathways:
- Pentose Phosphate Pathway
- Glycolytic Pathway
Suggest what happens with the following deficiencies
- G6PD deficiency
- PK deficiency
GP6D deficiency
-Metabolic abnormality which is X-linked. In it, NADPH (required for maintenance of reduced glutathione) and GSH generation is impaired.
- Acute haemolysis occurs on exposure to oxidant stress, such as oxidative drugs or infections.
- Haemoglobin precipitates, causing red blood cells with denatured haemoglobin to be seen. Can also see blister/basket cells, which are red blood cells with the haemoglobin on one side.
- Commonly known as enzymopathy.
- Highly prevalent in places with high malaria rates, as the patients who become infected with malaria aren’t affected as severely, and are able to survive. Thus, it is evolutionarily beneficial in these regions
- Avoid sulphonamides and other oxidative drugs
PK deficiency
- ATP-depleted cells lose a large amount of potassium and water, and become dehydrated and rigid.
- This happens because cation pumps fail to function. This causes chronic, non-spherocytic haemolytic anaemia.
- Excess haemolysis leads to jaundice and gallstones.
- Dense red cells with spicules (prickle cells) may be seen on the peripheral blood film
Red Blood Cell Defects
Block in glycolysis in a RBC?
- build up of 2,3 biphosphate, which shifts the oxygen dissociation curve to the right
Defects in band 3, spectrin, ankyrin or protein 4.2 lead to:
- Destabilisation of the overlying lipid bilayer and release of lipid into microvesicles
HS - Deficiency in ankyrin spectrin
HE
- Mutated spectrin, defective spectrin-ankyrin association. Caused by Protein 4.1 deficiency
What happens in the luebering rapaport shunt?
- 2,3 DPG binds to deoxyhaemoglobin to stabilise at lower o2 affinity state
NADH reduces cytochrome b5 which reduces oxidised ferric ion of haemoglobin
If NADH wasn’t present in RBC, without the reaction haem iron would be oxidised to methemoglobin which cannot transport oxygen.
How do the following affect Haemoglobin Count, WBC Count, MCV, Platelet count, Mean Cell Hb, Red cell count?
- Thalassaemias
- Vitamin B12, Folate and Iron Deficiencies
- Sickle Cell Anaemia
ALPHA AND BETA THALASSAEMIA
- Reduced Haemoglobin Count
- Decreased Red Cell Count
- Reduced MCV and MCH
With examples compare and contrast microcytic and macrocytic anaemia.
