Haematology - Erythropoiesis Flashcards
Development of RBCs - common myeloid progenitor
- Proerythroblast -> erythroblasts -> erythrocytes
- Proerythroblast: polychromatic (coloured stain bc high RNA content (blue), primitive RBCs (reticulocytes))
Development of RBCs - nucleated RBCs in blood
High demand for them because they are being released when immature
Development of RBCs -
requirements
- Iron, vitamin B12, folate (low = anemia (microcytic (Fe, central pallor, smaller) or macrocytic (B12/folate, larger because cells can grow but can’t divide)))
- Erythropoietin
Development of RBCs - erythropoietin
Glycoprotein, cortical interstitial kidney cells, synthesis=physiological response to kidney hypoxia, interacts with erythropoietin receptor on RBC progenitor membranes, stimulates bone marrow to produce more RBCs
Development of RBCs - iron
Synthesis of myoglobin + hemoglobin, cofactor for proteins and enzymes involved in energy metabolism (cytochromes a, b, c (ATP production), cytochrome P450 for hydroxylation reactions (all mitochondrial proteins)), respiration, DNA synthesis, apoptosis; healthy skin, mucous membranes, hair and nails (koilonychia, glossitis, angulus dermatitis)
Development of RBCs - iron (in normal western diet)
About 10-20 mg Fe/day, 1-2 mg absorbed by duodenum, haem iron (animal derived) -> ferrous (Fe2+), best absorbed; non-haem present mainly in ferric (Fe3+) form and required reducing substance action (ie ascorbic acid, vit. C) for absorption (sources often contain phrases, which further reduces absorption)
Development of RBCs - iron (sources)
Red meat 20% absorption, spinach 1.4%, soya beans 7%
Development of RBCs - iron (homeostasis)
No physiological mechanism for regulating iron excretion as iron can form free radicals that damage body tissues, iron loss is due to skin shedding
Development of RBCs - iron (absorption)
In gut carefully regulated according to body stores by hepcidin (absorption by stomach and release by liver blocked)
Development of RBCs - iron (hepcidin)
- Synthesis suppressed by erythropoietic activity,ensures iron supply by increasing ferroportin in duodenum enterocyte (increases Fe absorption); when storage Fe is high hepcidin synthesis is increased (binds and degrades ferroportin, prevents efflux of Fe from enterocyte, so lost when cell is shed into gut lumen, hepcidin production increased in inflammatory states (causes anemia because reduction in iron supply = anemia of chronic disease)
- Hepcidin = lower iron absorption, transport and availability, pro inflammatory cytokines (IL-1, TNFa, IL-6, IFNy (interferon)), lower erythropoiesis, turning into leukins and clotting factors + mediating effect of hepcidin directly reduce erythropoietin production
Development of RBCs - Vitamin B12 and Folate (general)
- Affect synthesis of thymidine (one of pyrimidine bases), effects of deficiency overlap (both inhibiting DNA synthesis and affecting all rapidly dividing cells (megaloplastic erythropoiesis), in bone marrow cells can grow but are unable to divide normally, epithelial surfaces of mouth and gut + gonads)
- Sources -> vit. B12 = meat, liver, kidney, fish, oysters, clams, eggs, milk, cheese, fortified cereals; folic acid = green leafy vegetables, cauliflower, Brussels sprouts, liver, kidney, whole grain cereals, yeast, fruit
Development of RBCs - Vitamin B12 absorption
Cleaved from food proteins by HCl in stomach, binds to proteins (haptocorrins) and intrinsic factor (IF) made in gastric parietal cells, duodenum -> cleared from haptocorrin and binds to glycoprotein intrinsic factor (transports vitamin B12 to ileum where B12-intrinsic fatty complex absorbed), in circulation bound to transport protein transcobalamin, disorders: inadequate intrinsic factor levels, celiac disease (ileum), lack of stomach acid (achlorydria), pernicious anemia (inadequate IF secretion), malabsorption
Development of RBCs - Folate absorption
Mainly duodenum and jujenum, RDA: 100 micrograms, total body stores ~ 10 mg, requirements increase in pregnancy and when there is high RBC production
Red Cell Function (General)
120 days then broken down in spleen, dependent on membrane integrity, haemoglobin structure and function, cellular metabolism (defect = haemolysis)
Red Cell Function (membrane integrity - general)
Biconcave (manoeuvrability through capillaries), membrane made up of lipid bilayer supported by cytoskeleton with transmembrane proteins = maintains integrity, shape, and elasticity/deformability
Red Cell Function (membrane integrity - Disruption of vertical linkages in membrane)
Usually ankyrin/spectrin, hereditary spherocytosis (autosomal dominant, spherocytes -> cells approximately spherical in shape, round regular outline without central pallor, results from loss of cell membrane without loss of equivalent cytoplasm amount, les flexible RBCs removed prematurely by spleen (haemolysis))
Red Cell Function (membrane integrity - Disruption of horizontal linkages in membrane)
Hereditary elliptocytosis (elliptocytes may also occur in Fe deficiency, will have central pallor (hypochromic), less numerous))
Red Cell Function (haemoglobin structure and function - general)
- Haem moiety of Hb carries O2, each erythrocyte ~300 million Hb molecules
Red Cell Function (haemoglobin structure and function - Oxygen dissociation curve Bohr effect, left and right shift)
- Higher CO2 and lower pH = lower affinity of Hb for O2 (right shift, also greater 2,3-diphosphoglycerate (DPG, competes with haemoglobin to bind O2)); increases O2 delivery proportionally to metabolic activity (metabolically active peripheral tissues (ie skeletal muscle) lead to higher pCO2 (ie because of lactic acid) which reduces local blood pH)
- HbS also has lower O2 affinity
- Left shift -> gives up O2 less readily, HbF, higher CO and low 2,3 DPG
Red Cell Function (cellular metabolism - general)
Highly adapted, meet energy requirements via ATP, maintenance of haemoglobin function, membrane integrity and deformability, RBC volume
Red Cell Function (cellular metabolism - 2,3 DPG)
- produced by Rapaport-Luebering shuttle, allosteric effector (modulates Hb O2 affinity)
- binds to beta-globin chain in central cavity of Hb molecule
- role in adaptive response to anemia, hypoxia and high altitude
Red Cell Function (cellular metabolism - G6PD and glutathione metabolism general)
Important enzyme in hexose mono phosphate (HMP) shunt (tightly coupled to glutathione metabolism which protects RBCs from oxidant damage (may be generated in bloodstream (ie during infection) or exogenous (ie drugs, broad beans)))
Red Cell Function (cellular metabolism - G6PD deficiency)
Most prevalent enzyme disorder (~ 400 million people worldwide), x-linked inheritance (usually hemizygous (an individual who has only one member of a chromosome pair or chromosome segment rather than the usual two, often used to describe X-linked genes in males who have only one X chromosome) males but sometimes homozygous females), intermittent, severe intravascular haemolysis as result of infection/exposure to exogenous oxidant, distribution parallels malaria, selective advantage (resistance to falciparum anaemia), appearance of irregularly contracted cells (smaller than normal, lose central pallor, irregular outline)m Hb is reduced and forms Heinz bodies (inclusions within red blood cells composed of denatured hemoglobin)
RBC Terminology - Size
- microcytic: smaller
- normocytic: normal
- macrocytic: larger, can be round/oval/polychromatic, caused by lack of vitamin B12/folic acid (megaloblastic anemia)+liver disease and ethanol toxicity+haemolysis (polychromasia, pregnancy)
