Red Blood Cells Production + Survival Flashcards
Define erythropoiesis
🔴production
How many 🔴 per day?
10¹²
Features of a proerythroblast?
1st recognizable cell in erythroid series
large cell w loose, lacy chromatin, visible nucleus + nucleolus, basophilic cytoplasm
What’s the basophilia caused by?
large number of polyribosomes involved in synthesis of Hb
Features of basophilic erythroblast?
strongly basophilic cytoplasm (blue) made of polyribosomes, condensed nucleus, no visible nucleolus
Features of polychromatic erythroblast?
polyribosomes decrease, cytoplasm filled w Hb (pink red)
Features of orthochromatic erythroblast?
nucleus condenses, no basophilia (pink) –>uniformly acidophilic cytoplasm
Features of normoblast?
cell has cytoplasmic protrusions, expels nucleus (encased in thin cytoplasm) –>engulfed by macrophages
Features of reticulocyte?
small number of polyribosomes, when dyed w brilliant cresyl blue, aggregate forming stained network, synthesises 35% Hb
What is Hb synthesised by + %?
65% erythroblast
35% reticulocyte
Features of mature erythrocyte?
no polyribosomes
How’s 🔴 synthesised from stem cell in red bone marrow?
- hemocytoblast
- proerythroblast
- basophilic (early)erythroblast
- polychromatic (late)erythroblast
- orthochromatic erythroblast
- normoblast
- reticulocyte
- mature erythrocyte
What stimulates erythropoiesis + causes?
low tissue oxygenation eg hypoxia, decrease in Hb, decrease in O2
Describe the process of hypoxia
- stimulus
- low O2 levels in blood
- kidney + liver releases erythropoietin
- stimulates red bone marrow
- enhanced erythropoietin increases 🔴 count
- increase O2 carrying ability in blood
- normal blood O2 levels
Where’s 90% of erythropoietin produced?
properitubular cells of kidneys
What’s erythropoietin?
heavily glycosylated polypeptide hormone, of 165 AA molecular weight daltons 30,400
What’s iron controlled by?
total body iron status
intracellular iron levels
Erythropoiesis
DMT-1 at brush border of enterocyte transporting iron into cells + ferroportin at basal membrane transporting iron from enterocytes into circulation
How + where’s iron absorbed?
5-10% absorbed (1mg)in duodenum+jejunum
HCl + ascorbic acid
How’s iron absorption regulated?
DMT-1 at brush border of enterocyte transporting iron into cells + ferroportin at basal membrane transporting iron from enterocytes into circulation
Why’s iron needed for 🔴 production?
For synthesis of Hb
How much iron in normal western diet?
15mg daily
Describe process of Hb synthesis
- 2 irons bind to transferrin
- transferrin binds to transferrin receptor on cell
- endocytosis:
- ferritin or iron in mitochondria
- transferrin reused
- ferritin accumulate excess iron
- lysosomes engulf ferritin + degrade into insoluble storage=hemosiderin
- iron in mitochondria + simultaneously glycine + succinyl coA condenses under action of rate limiting δ-aminolevulinic synthase in presence of pyridoxal phosphate (vit B6) coenzyme
- forms δ-ALA
- in cytoplasm biochemical reactions:
- 2 δ-ALA condense forming pyrrole =porphobilinogen (PBG)
- forms protoporphyrin
- in mitochondria combines w Fe2+ -> haem
- cytoplasm globin synthesis
- globin binds w haem -> Hb
What are the diff causes of Iron deficiency?
- reduced intake: red meat + veg
- malabsorption: coeliac, gastrectomy, gastric bypass, atrophic gastritis
- chronic blood loss: GI bleed (ulcer, NSAID, carcinoma, colitis), menorrhagia, PNH (paroxysmal nocturnal haemoglobinuria)
- increased demand: preg, growth spurt
Why does iron demand increased in preg?
for increase maternal red cell mass of about 35%, transfer of 300mg of iron to foetus
What’s the treatment of iron deficiency?
ferrous sulphate supplement 200 mg 3x daily
What are the metabolic functions of B12?
acts as coenzyme for:
-methionine synthase in methylation of homocysteine to methionine in cytosol
-conversion of L-methylmalonyl coA to succinyl coA in mitochondria
(for 🔴 maturation + DNA synthesis)
What does B12 deficiency cause?
abnormal + diminished DNA —> no nuclear maturation
What conditions arise from B12 deficiency?
Megaloblastict anaemia : active folate forms unformed so DNA synthesis fails
Neuropsychiatric manifestations:peripheral + autonomic neuropathy, subacute combined
degeneration of the spinal cord, optic atrophy, mood-behaviour changes, psychosis, cognitive prob
What are the diff causes of B12 deficiency?
- inadequate intake : vegans
- malabsorption : FBCM, pernicious anaemia, gastrectomy, ileal resection, coeliac, chronic pancreatitis, crohn’s
- inherited : hereditary intrinsic factor def, TC def
What’s Food-bound cobalamin malabsorption (FBCM) + causes?
in older people impaired ability to release B12 from food
Instrinsic factor intact + clinical manifestations rare
Caused by gastric dysfunction, reduced gastric
acid secretion by:
gastric resection
treatment w proton pump inhibitors
persistent infection w Helicobacter pylori
What’s Pernicious anaemia ?
Commonest
autoimmune gastric atrophy so loss of intrinsic factor production
What’s instrinsic factor?
made by gastric parietal cells to absorb B12
What’s Crohn’s disease + symptoms?
inflammatory boweldisease(IBD) affecting any part of GI
abdominal pain, diarrhoea (bloody if severe inflammation), fever, weight loss
How do you investigate B12 def + what would you see?
-Haematological test:
FBC - macrocytic anaemia, leucopenia, thrombocytopenia
Blood film - hypersegmented neutrophils, oval macrocytes
Bone marrow examination- megaloblasts
-Serum B12- plasma homocysteine
What would you see in the investigation results of macrocytic anaemia?
Mean Corpuscular Volume >95 fl Oval macrocytes on blood film reduced 🔴+platelets Megaloblastic change in bone marrow Hypersegmented neutrophils B12 only - Demyelination in CNS
Role of folate?
for 🔴 maturation + DNA synthesis:
- as coenzyme for thymidine triphosphate synthesis
- as coenzyme for remethylation of homocysteine to methionine
Why can folate def occur quickly?
Daily adult requirement is 100-150µg
, body stores 10-12mg for 4 months
What’s dietary folate + response to heat?
In liver, leafy veg, yeast
Folate is heat-label so destroyed at high heat
What are the diff causes of folate deficiency?
- inadequate intake : 🙁nutrition
- malabsorption : coeliac, Crohn’s, tropical spruce, 🍺
- demand/losses : preg, haemolytic, cancer
- antifolate drugs : anticonvulsants, methotrexate, metformin, (Anti Epileptic Drug treatment reduces folate + B12 serum levels)
How does Sulphonamide work as a antimicrobial agent?
inhibit folate synthesis + vital for bacteria survival in the case of antibiotics
What’s Tropical sprue(TS) + symptoms?
acquired malabsorptive condition of probable infectious aetiology
altered small bowel mucosa, chronic diarrhoea, multiple vitamin + nutrient def
How do you investigate folate def?
-Haematological test:
FBC - macrocytic anaemia, leucopenia, thrombocytopenia
Blood film - hypersegmented neutrophils, oval macrocytes
Bone marrow examination- megaloblasts
-Serum folate; plasma homocysteine elevated
What’s the treatment for folate def?
Folic acid tablets 5mg daily for 3-4months
Where’s B12 absorbed?
Ileum
Where’s folate absorbed?
Duodenum + jujunum
How’s B12 transported in plasma?
Bound to TCI
TCII for uptake
How’s folate transported in plasma?
Weakly bound to albumin
What’s the usual therapeutic form of B12?
Hydroxocobalamin 1mg, im
What’s the usual therapeutic form of folate?
Folic acid tablets 5mg/d, 3-4mths
What’s Hydroxocobalamin?
injectable B12 given when prob w absorption from gut
What’s TCI?
secreted by salivary glands, protects B12 from degradation
What are bone marrow failure syndromes?
Group of disorders, inherited or acquired that:
affect HSC which involves cell lines
replace marrow w malignant cells
–> failure of erythropoiesis
What can affect HSC by involving cell lines?
Aplastic anaemia
What are the diff types of Aplastic anaemia?
Congenital: Fanconi anaemia, Dyskeratosis congenital
Acquired: Drugs, Radiation, Malignancy
What causes the bone marrow to become malignant cells?
Leukaemia, lymphoma
What are the diff stresses put on 🔴?
lifespan 120 days
300 miles travelled via microcirculation
8μm diameter
capillaries 3.5µm
What does 🔴longevity depend on?
deformability
E supply for cation pump
NADPH supply against oxi-stress
cytoplasmic E involved in metabolic pathways
Define 🔴 deformabilty
squeezing via splenic sinus
Diff ways haemolytic anaemia can be aquired?
- Immune: autoimmune, alloimmune, drug induced
- Non immune:🔴fragmentation, infection, secondary
Diff ways haemolytic anaemia can be hereditary?
- 🔴 membrane disorder: spherocytosis, elliptocytosis
- Haemoglobinopathies: sickle cell diseases, thalassaemias
- 🔴 enzymopathies: G6PD def, PK def
Features of hereditary spherocytosis?
Loss of membrane integrity --> spherical 🔴 Common in N. Europe. def in proteins w vertical interactions between membrane skeleton+lipid bilayer - spectrin, ankyrin
Features of hereditary elliptocytosis?
mutations in horizontal interactions eg spectrin-ankyrin, protein 4.1
What do mutations or deletions of globin chains lead to?
Abnormal synthesis - Sickle Cell Diseases.
Reduced rate of synthesis - Thalassaemia
What are the genes on chromosomes 16 + 11?
16 - zeta ζ, α1, α2
11 – epsilon, γglutamic, γalanine, δ, β
What are the 3 types of Hb in normal adult blood?
HbA (α2β2), HbF (α2γ2), HbA2 (α2δ2).
What’s Sickle Cell Disease + diff types?
Group of Hb disorders w/inherited sickle β-globin gene
-Homozygous Sickle Cell Anaemia (Hb SS) COMMON
GAG -> GTG so Val
-heterozygote conditions (HbS/ βthal, HbSC, HbSD)
HbS/βthal, MCV & MCH 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.
Features of β-thalassaemia?
Loss of 1 βchain causes mild microcytic anaemia
Loss of both β⁰ = thalassaemia major
Excess α-chains ppt in erythroblasts = haemolysis + ineffective erythropoiesis
Features of α-thalassaemia?
Loss of 1/2/3/4 α-chains:
1/2 = mild microcytic anaemia
3 = moderate anaemia - Hb H disease
4 = death in utero (hydrops fetalis)
What do HbS C look like?
rhomboidal + spherocytic cells
Why does 🔴 survival depend on cytoplasmic E in metabolic pathways?
unable to do oxidative phosphorylation + protein synthesis
Role of cytoplasmic E?
maintain pliability of membrane,
maintain membrane transport of ions
keep the Hb iron in ferrous form not ferric form
prevent oxidation of proteins in 🔴
Describe the process of pentose phosphate pathway
- Glucose -> G6P
- G6P -> 6PG by G6PD
- produces NADPH
- reduces glutathione (GSSH) -> GSH
- (NADPH -> NADP)
- GSH is anti-oxidant by conversion to GSSG + removes oxidants
- Cycle restart (anti-oxidants reduced by excess alcohol consumption)
- Pentose phosphate shunt provides NADPH maintaining GSH levels when GSSG formed
How’s 10% of 🔴 glucose is metabolized?
Pentose Phosphate Pathway (Hexose Monophosphate Shunt HMS)
Role of G6PD?
glucose-6phosphatedehydrogenase
catalyses G6P-> 6PG 1st step of pentose phosphate shunt producing NADPH
Role of NADPH?
reduced nicotinamide adenine dinuclotide phosphate
- protects 🔴 from oxidative damage
- maintains GSH by reducing GSSH -> GSH
Role of GSH?
reduced glutathione
- anti-oxidant by removing oxidants to convert to GSSG
- tripeptide protects Hb +🔴 membranes from oxidant stress from exposure to H2O2, medications, foods, infections
Role of G6P?
glucose-6-phosphate
-converted to 6PG by G6PD producing NADPH
Role of 6PG?
6-phosphogluconate
converted from G6P by G6PD producing NADPH
What are heinz bodies?
when Hb ppt out due to oxidants
What happens in G6PD def (enzymopathy)?
-No NADPH + GSH production:
Acute haemolysis when oxidant stress: oxidative drugs, fava beans, infections
Heinz bodies
What’s G6PD def + benefit?
enzymopathy X-linked occurs in same ethnic groups as haemoglobinopathies affects 400M people resistant to malaria
Why’s the pyruvate kinase vital?
for glycolytic pathway which generates ATP to:
- maintain 🔴shape + deformability
- regulate intracellular cation conc via Na+/K+pump 3Na+out and 2K+in
What happens in PK def?
No ATP:
- cation pump failure - cells lose K+ + H2O
- chronic non-spherocytic haemolytic anaemia
- excess haemolysis = jaundice, gallstones
How does normal haemolysis occur?
extravascularly in macrophages in spleen:
iron (recycled + binds to transferrin)
globin -> AA(recycled)
protoporphyrin-> unconjugated bilirubin (travels to liver,gets conjugated, excreted)
How does abnormal haemolysis occur?
intravascularly (blood in urine)
