W10 RBC production + survival Flashcards
Hormonal Control of Erythropoiesis
Imbalance so stimulus = Hypoxia due to decreased RBC count, decreased amount of hg or decreased availability of O2
Reduced O2 levels in blood
Kidney + liver (smaller extent) release erythropoetin
Erythropoetin stimulates red bone marrow
Enhanced eryhtropoiesis increases RBC count
Increases O2 carrying ability of blood
What else besides EPO?
Iron
Vitamin B12
Folate
Erythroid precursors
Iron sources
Meat, eggs, vegetables, dairy foods
Iron absorption
Normal Western diet provides 15mg daily.
5-10% absorbed (1mg) principally in duodenum and jejunum.
Gastric secretion (HCl) and ascorbic acid help absorption
Causes of Iron deficiency
Decreased uptake:
Inadequate intake
Malabsorption
Increased demand:
Pregnancy
Growth spurt
Increased loss:
GI bleed
Excess loss in menses
Vitamin B12 and Folic Acid
Both essential for RBC maturation & 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 & diminished DNA, leading to failure of nuclear maturation
Causes of Vitamin B12 deficiency
Inadequate intake:
Vegans
Absorption defect:
Tropical sprue
Coeliac dx
Blind loop syndromes
IF deficiency:
Pernicious anaemia
Crohn’s
Gastrectomy & others
Causes of folate deficiency
Inadequate intake:
Poor nutrition
Absorption defect:
Coeliac disease
Crohn’s dx
Tropical sprue
Demand/ losses:
Pregnancy
Haemolysis
Cancer
Drugs:
Anticonvulsants
What happens in folate & B12 deficiencies?
Megaloblastic anemia, with macroovalocytes
and hypersegmented neutrophil
Treatment:
B12 - Hydroxycobalamin: 1mg im
Folate: -Folic acid: 5mg/day oral
Hydroxocobalamin
an injectable form of vitamin B12 that is given when there are problems with absorption of this vitamin from the gut
Absorption of B12
Involves IF made by gastric parietal cells.
TC1 is secreted by
TC1 is secreted by salivary glands and protects B12 from degradation
Vitamin B12 main foods
Animal origin only:
Liver, meat, fish
Vitamin B12 daily requirement
1-2µg
Vitamin B12 body stores
2-3mg
(sufficient for
2-4yrs)
Vitamin B12 absorption site
Ileum
Vitamin B12 transport in plasma
Bound to TCI; TCII for uptake
Folate main foods
Especially liver, greens & yeast
Folate daily requirement
100-150µg
Folate body stores
10-12mg
for 4mths
Folate absorption site
Duodenum, Jejunum
Folate transport in plasma
Weakly bound to albumin
What else can affect of RBC prod?
Renal dx - ineffective erythropoiesis
Reduced BM erythroid cells
Aplastic anaemia
Marrow infiltration by leukaemia or other malignancies
Red cell deformability
squeezing through a splenic sinus
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
Stress placed on RBC
life span 120 days
300 miles travelled through microcirculation
7.8 m diameter
capillaries as small as 3.5 m
AIHA
Autoimmune hemolytic anemia
Caused by antibody production by the body against its own red cells: divided into cold and warm depending on whether the antibody reacts more strongly with red cell at 37oC or 4oC
Red cells are usually coated with
Red cells are usually coated with IgG alone or with compliment, therefore taken up by the RE macrophages. Destruction occurs generally in the RE
Immune
Autoimmune
Alloimmune
Drug induced
Non-immune
Red Cell fragmentation
Infection:
Secondary
Haemoglobinopathies
Hereditary
Sickle cell diseases
Thalassaemias
Red Cell enzymopathies
Hereditary
G6PD deficiency
PK deficiency
Red Cell membrane disorders
Hereditary spherocytosis
Hereditary elliptocytosis
Hereditary spherocytosis
Loss of membrane integrity, the RBCs become spherical
Common hereditary haemolytic anaemia in N. Europ.
deficiency in proteins with vertical interactions between the membrane skeleton and the lipid bilayer
Hereditary elliptocytosis
Clinically milder
- mutations in horizontal protein, spectrin, leading to defective spectrin-Ankyrin association
Two main enzymes
Two main enzymes
Glucose-6-Phosphate Dehydrogenase (G-6-PD)
Pyruvate Kinase (PK)
Support 2 main Metabolic Pathways
Pentose Phosphate pathway
Glycolytic pathway
GSH protection of Hb + RBC membranes
Hb and rbc membranes are usually protected by reduced glutathione (GSH) from oxidant stress from the exposure to H2O2, certain medications, foods, or even infections. Heinz bodies are oxidised, denatured Hb
NADPH
a role in protecting the red blood cell from oxidative damage
NADPH in turn is required for the maintenance of reduced
glutathione (GSH)
GSH
acts as an anti-oxidant
G6PD catalyses the first step in the hexose monophosphate shunt which is necessary for producing NADPH
a tripeptide that protects the RBC from oxidative damage
What happens in G6PD deficiency?
NADPH and GSH generation impaired
Acute haemolysis on exposure to oxidant stress: oxidative drugs, fava beans (broad beans) or infections
Hb precipitation – Heinz bodies
G6PD deficiency most common known enzymopathy, estimated to affect 400 million people worldwide.
…….but have evolutionary benefit
G6PD def. X-linked
G6PD deficiency is X-linked, and seen in the same ethnic groups as haemoglobinopathies
Patients w/G6PD def. have to avoid
have to avoid particular oxidative drugs, e.g. sulphonamides, dapsone, and notably quinone based anti-malarial drugs
G6PD def. leads to
leads to HA upon treatment with primaquine which stimulates H2O2 formation
G6PD def. patients protected from
patient have protection against severe malaria
Glycolytic pathway
Generates ATP
to maintain red cell shape and deformability
regulates intracellular cation conc. via cation pumps (Na/K pump), 3Na+ out 2K+ in
PK def. results in
PK is an autosomal recessive disorder, with more than 100 mutations documented, resulting in low intracellular ATP generation affecting membrane structure.
“block” in glycolysis =
causes a build up of glycolytic intermediates, including 2,3 biphosphoglycerate, which binds to and shifts the oxygen dissociation curve to the right
2,3 diphosphoglycerate
What happens in PK deficiency
ATP is depleted:
cells lose large amount of potassium & water, becoming dehydrated & rigid.
because cation pumps fail to function.
causes chronic non-spherocytic haemolytic anaemia
excess haemolysis leads to jaundice, gallstones
What do we see when we have G6PD def.
film shows blistered cells (arrow), arrowheads show irregularly contracted cells
What do we see w/PK def.
autosomal recessive, 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
Defects of band 3, spectrin, ankyrin, or protein 4.2 lead to
destabilisation of the overlying lipid bilayer and release of lipid in microvesicles
Mutations or deletions may lead to;
Abnormal synthesis of globin chain as in Sickle Cell Diseases.
Reduced rate of synthesis of normal globin chains as in Thalassaemia.
The genes for globin chains occur in…
clusters on chromosomes.
11 (ε, γ, δ and β)
16 (ζ and α 1+2)
Normal adult blood has 3 types of Hb
HbA (α2β2), HbF (α2γ2), HbA2 (α2δ2)
Group of Hb disorders with inherited sickle beta-globin gene
Sickle Cell Anaemia (HbSS), homozygous, most common;
heterozygote conditions: HbS/ßthal, HbSC, HbSD
SCA definition
point mutation leading to single amino acid change in beta-globin (sub of valine for glutamic acid; A to T)
It’s the clinically most impt abnormality
SCA details of mutation
HbS/βthal, MCV & MCH are lower than HbSS, clinical picture is of SCA, splenomegaly
Hb C – lysine replaces GA at position 6
Hb D glutamine replaces GA
Hb E lysine replaces GA at position 26
Beta-thalassaemia
Loss of 1 beta-chain causes mild microcytic anaemia (thalassaemia trait)
Loss of both (beta^0) causes thalassaemia major
Excess α-chains precipitate in erythroblasts causing haemolysis and ineffective erythropoiesis
Alpha-thalassaemia
There can be loss of 1, 2, 3 or 4 alpha chanis
