RBC production and Survival Flashcards
What factors affect erythropoiesis?
Eryhtropoietin Iron Vit B12 Folate Eryhtroid precursors
What treatment options are available for deficiencies in B12 & folate?
*B12 - Hydroxycobalamin 1mg im
Folate - Folic acid 5mg a day orally
*Hydroxycobalamin = injectible form of B12 given when B12 absorption problems in gut
B12 absorption involves IF made by gastric parietal cells.
TCI is secreted to prevent damage by salivary glands, protecing B12 from degradation
Why does erythropoiesis occur?
Stimulated by hypoxia due to
- Decreased RBC count
- Decreased Hb
- Decreased O2 availability
What pathological factors is RBC production effected by?
- Renal disease causes ineffective erythropoiesis
- Reduced bone marrow erythroid cells causes aplastic
anaemia and marrow infiltration by leukemia or other
malignancies
How is Iron obtained in the body?
Obtained via diet in meat, eggs, vegetables & dairy foods
5-10% absorbed (1mg) in duodenum and jejunum
Gastric secretion of HCl and absorbic acid aid absorption
What are the different types of hereditary hemolytic anemia?
Hameoglobinopathies
- Sickle cell diseases
- Thalassemias
RBC enzymopathies
- G6PD deficiency
- PK deficiency
RBC Membrane disorders
- Hereditary spherocytosis
- Hereditary ellipocytosis
Describe the blood oxygen levels during homeostasis
Blood oxygen levels are normal
Describe Hereditary spherocytosis
Loss of membrane integrity - RBC becomes spherical
due to deficiency in proteins with vertical interactions between membrane skeleton and lipid bilayer
What are the causes of folate deficiency?
Inadequate intake
- Poor nutrition
Absorption defects
- coeliac disease
- Crohn’s dx
- Tropical Sprue
Increased demands/losses
- Pregnancy
- Haemolysis
- Cancer
Drugs
- anticonvulsants
What is the significance of the glycolytic pathway?
Glycolytic pathway generates ATP
- to maintain RBC shape and deformabilty
- Regulates intracellular [cation] via Na+/K+ pump
What are the consequences of Pk deficiency?
PK deficiency is autosomal recessive
=> causes build up of glycolytic intermediates
(2,3-biphosphoglycerate which shifts oxygen diss.
curve to right) -> low O2 affinity
=> low intracellular ATP generation
affects membrane structure causing RBCs to have
arrowheads (irregularly contracted cells)
Outline the process of erythropoiesis due to hypoxia
- O2 levels reduced in blood
- Kidney (and liver) release EPO hormone
- Erythropoietin stimulates red bone marrow
- Enhanced erythropoiesis increases RBC count
- Increases O2 carrying ability of blood
How does the body destroy its own RBCs in AIHA?
AIHA anemic Red cells are coated with IgG alone or with a compliment enabling them to be taken up by rectoendothelial macrophages for degradation
How is folate transported around the body?
Folate weakly binds to albumin transport protein
What is the evolutionary benefit of acute hemolysis?
G6PD deficiency is X linked
Pateints with G6PD deficiency have to avoid particular oxidative drugs
- (quinone based anti malaria drugs)
When G6PD deficiency is treated with primaquine leads to a mild/severe acute hemolytic anemia
stimulating H2O2 production
Providing protection against severe anemia
What are the causes of iron deficiency?
Decreased uptake
- inadequate uptake
- malabsorption
Increased demand
- pregnancy
- growth spurt
Increased loss
- GI bleed
- Excess loss in menses
What are the consequences of RBC integral proteins defetcs?
Defects in Ankyrin, Spectrin, Band 3 or protein 4.2 leads to destabilisation of the overlying lipid bilayer and release of lipids into microvesicles
Causes hereditary elipocytosis
How does a PK deficiency cause mishapen RBCs?
ATP is depleted so cells lose large amounts of K+ & water
Cells become dehydrated and rigid
cation pump fails to function
Causes chronic non-spherocytic hemolytic anemia
=> excess haemolysis leads to jaundice and gall stones
What are the precursor stages of erythrocytes?
Hemocytoblasts -> proerythroblast -> early, late erythroblasts -> normoblast -> reticulocyte -> eyrthrocyte
How does acute hemolysis occur?
Acute hemolysis caused by exposure to oxidant stress
Causes Hb to precipitate into heinz bodies
What is menses?
Blood and other matter discharged rom the uterus during menstruation
Where are globin genes found?
The genes for globin chains occur in clusters on chromosomes
- 11 ( Ɣ β δ and 𝜺 )
- 16 (α and ζ)
Expression of β and α globin chains is closely regulated
What is the significance of Vit B12 and folate in erythropoiesis?
Both essential for RBC maturation and DNA synthesis
required for thymidine triphosphate formation
- (TTP nucleoside triphosphate used in vivo DNA
synthesis)
B12 is coenzyme for methionine synthase
- methylates homocysteine to methionine
What is AIHA anemia?
Autoimmune hemolytic anemia is a group of rare but serious blood disorders caused by antibody
production by the body against own red cells
Divided into cold/warm depending on the antibody’s strength of reaction with red cell at 37℃ or 40℃
What is sickle cell disease?
Group of Hb disorders with inherited sickle β globin gene
HbSS homozygous sickle cell is most common form
What is eyrhropoietin?
Erythropoietin EPO is a glycoprotein cytokine secreted by kidneys in response to cellular hypoxia
=> stimulates erythropoiesis
What is the effect of mutations in globin genes?
Abnormal synthesis of globin chains -> sickle cell disease
Reduced rate of normal globin synthesis -> Thalassemia
What are the consequences of G6PD deficiency?
Hb and RBC usually protected by GSH from:
- oxidant stress from H2O2 exposure
- Certain medications
- Infections
- Foods
G6PD deficiency causes NADPH and GSH generation impairment
What are the different forms of β thalassemia?
Mild microcytic anaemia - loss of 1 β globin gene
Thalassemia major - loss of both β globin genes
Ineffective erythrpoiesis caused by excess α chains precipitating in erythroblasts => haemolysis
What is the consequnce of deficiencies in folate/B12?
Deficiencies in either can cause abnormal and diminished RBC production
- leading to failure of nuclear maturation
- cause megaloblastic anemia with macroovalocytes and
hypersegmentation
Where in the gut is folate absorbed?
Absorbed at duodenum and jejunum
What are the results of extra and intravascular hemolysis?
Extravascular haemolysis is normal in spleen and liver
Intravascular haemolysis releases Hb into plasma = abnormal
How is Vitamin B12 obtained?
From animal origin foods, meat, fish, liver
Body stores 2-3mg daily sufficient for < 4 yrs
Describe what acquired haemolytic anaemia is?
Can be immune
- autoimmune
- alloimmune
- drug induced
or can be non immune
- red cell fragmentation
- infection
- secondary
How is eryhtropoiesis regulated?
Erythropoiesis is regulated by hormone EPO (eryhtropoietin)
What is the significance of G6PD in the pentose phosphate pathway?
- G6PD catalyses the first step in the pathway necessary
for NADPH production - NADPH required for GSH (glutathionine) maintenance
to protect RBC from oxidative damage
G6P converted to G6PD producing NADPH
Where in the body is Vitamin B12 absorbed?
In the ileum
How is α thalassemia caused?
Can be loss of 1,2,3 or 4 α globin chains
What is hemolytic anemia?
A form of anemia due to homolysis can be described as: - Hereditary/Congenital - Intrinsic/Extrinsic - Intravascular/Extravascular
How is Vitamin B12 transported around the body?
Binds to TCI for transport
Binds to TCII for uptake
What is the significance of the Pentose Phosphate pathway in RBCs?
10% of Red cell glucose is metabolised via Pentose phosphate pathway
What is eryhtropoiesis?
The process of red blood cell production
Where do we get folate into our body from?
Obtained from liver, greens and yeast
100-150g required daily
Body stores 10-12mg enough for 4 months
What ar ethe 2 main enzymes involved in mature RBC metabolic pathways?
Glucose-6-phosphate dehydrogenase (G6PD) : Glycolytic pathway Pyruvate Kinase (PK) : Pentose phosphate pathway
What are the causes of Vitamin B12 deficiency?
Inadequate intake
- veganism
Absorption defect
- Tropical sprue
- Coeliac dx
- Blind loop syndrome
Intrinsic Factor (IF) Deficiency
- Pernicious anemia
- Crohn’s
- Gastrectomy etc.
How are RBCs adapted to survive under stress?
Their life spans 120 days and can travel up to 300 miles through microcirculation in capillaries as small as 3.5um despite having a diameter of 7.8um
> red cells deformability enables them to squeeze
through spleenic sinus
RBC survival also dependent on cytoplasmic enzymes
involved in metabolic pathways
What is hereditary elipocytosis?
Clinically milder than spherocytosis
Due to mutation sin horizontal protein, spectrin leading to defective spectrin-ankyrin association
