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PoM > Haematology - Erythropoiesis > Flashcards

Haematology - Erythropoiesis Flashcards

1
Q

Development of RBCs - common myeloid progenitor

A
  • Proerythroblast -> erythroblasts -> erythrocytes

- Proerythroblast: polychromatic (coloured stain bc high RNA content (blue), primitive RBCs (reticulocytes))

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2
Q

Development of RBCs - nucleated RBCs in blood

A

High demand for them because they are being released when immature

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3
Q

Development of RBCs -

requirements

A
  • 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
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4
Q

Development of RBCs - erythropoietin

A

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

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5
Q

Development of RBCs - iron

A

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)

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6
Q

Development of RBCs - iron (in normal western diet)

A

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)

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7
Q

Development of RBCs - iron (sources)

A

Red meat 20% absorption, spinach 1.4%, soya beans 7%

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8
Q

Development of RBCs - iron (homeostasis)

A

No physiological mechanism for regulating iron excretion as iron can form free radicals that damage body tissues, iron loss is due to skin shedding

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9
Q

Development of RBCs - iron (absorption)

A

In gut carefully regulated according to body stores by hepcidin (absorption by stomach and release by liver blocked)

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10
Q

Development of RBCs - iron (hepcidin)

A
  • 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
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11
Q

Development of RBCs - Vitamin B12 and Folate (general)

A
  • 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
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12
Q

Development of RBCs - Vitamin B12 absorption

A

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

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13
Q

Development of RBCs - Folate absorption

A

Mainly duodenum and jujenum, RDA: 100 micrograms, total body stores ~ 10 mg, requirements increase in pregnancy and when there is high RBC production

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14
Q

Red Cell Function (General)

A

120 days then broken down in spleen, dependent on membrane integrity, haemoglobin structure and function, cellular metabolism (defect = haemolysis)

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15
Q

Red Cell Function (membrane integrity - general)

A

Biconcave (manoeuvrability through capillaries), membrane made up of lipid bilayer supported by cytoskeleton with transmembrane proteins = maintains integrity, shape, and elasticity/deformability

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16
Q

Red Cell Function (membrane integrity - Disruption of vertical linkages in membrane)

A

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))

17
Q

Red Cell Function (membrane integrity - Disruption of horizontal linkages in membrane)

A

Hereditary elliptocytosis (elliptocytes may also occur in Fe deficiency, will have central pallor (hypochromic), less numerous))

18
Q

Red Cell Function (haemoglobin structure and function - general)

A
  • Haem moiety of Hb carries O2, each erythrocyte ~300 million Hb molecules
21
Q

Red Cell Function (haemoglobin structure and function - Oxygen dissociation curve Bohr effect, left and right shift)

A
  • 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
22
Q

Red Cell Function (cellular metabolism - general)

A

Highly adapted, meet energy requirements via ATP, maintenance of haemoglobin function, membrane integrity and deformability, RBC volume

23
Q

Red Cell Function (cellular metabolism - 2,3 DPG)

A
  • 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
24
Q

Red Cell Function (cellular metabolism - G6PD and glutathione metabolism general)

A

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)))

25
Q

Red Cell Function (cellular metabolism - G6PD deficiency)

A

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)

26
Q

RBC Terminology - Size

A
  • 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)
27
Q

RBC Terminology - Size (microcytic)

A

Defect in haem synthesis (iron deficiency/anemia of chronic disease), defect in globin synthesis (thalassemia, can be alpha or beta based on defect chain)

28
Q

RBC Terminology - color

A

1/3 diameter = pale (centre has less Hb), hypochromia = larger area of central pallor (lower Hb content and flatter cell, often alongside microcytosis), polychromasia = increased blue tinge to cytoplasm, indicates that cell is young, one cause of microcytosis

29
Q

RBC Terminology - reticulocytes

A

Detected with new methylene blue, young RBCs, higher RNA content (detected by stain), reticulocytosis = high reticulocyte number, may occur as response to bleeding/RBC destruction

30
Q

RBC Terminology - anisocytosis

A

More variation in size (usually in patients with 2 populations of RBCs ie patient with iron deficiency receiving replacement theory)

31
Q

RBC Terminology - poikilocytosis

A

More variation in shape, target cells (accumulation of Hb in central pallor, obstructive jaundice, liver disease, haemoglobinopathies, hyposplenism), sickle cells (polymerisation of HbS which in deoxy form is much less soluble than HbA, HbS when 1/2 copies of abnormal beta globin gene (beta^s) are inherited, beta^s -> charged glutamic acid residue in position 6 is replaced by uncharged valine molecule, sickle cell anemia = first condition described as being caused by protein defect (1948)), RBC fragments (schistocytes, may result from shearing process caused by platelet-rich blood clots in small blood vessels (ie disseminated intravascular coagulation, DIC)

32
Q

RBC Terminology - reference range

A

Derived from carefully defined reference population, samples collected from healthy volunteers with defined characteristics, analysed using instruments and techniques that will be used for patient samples, data analysed by appropriate statistical technique

33
Q

RBC Terminology - normal range

A

Not all results within it are normal and not all results outside reference range are abnormal

34
Q

RBC Terminology - blood film examination

A

Size, shape, age (polychromasia), poikilocytes

35
Q

Red Cell Function (haemoglobin structure and function - HbA vs HbF)

A

HbA = tetramer (4 subunits each with globin chain (2 alpha, 2 beta) bound to haem group), each haem group = ferrous iron ion (Fe2+) held in porphyrin ring (each Fe2+ can bind 1 O2 molecule)
- HbF = 2 alpha and 2 gamma globin chains

36
Q

Red Cell Function (haemoglobin structure and function - Oxygen dissociation curve general)

A
  • Describes relationship between pO2 and O2 saturation, sigmoid shape because of cooperativity
  • P50 = pO2 at which Hb is half saturated with oxygen (HbA = 26.6 mmHg) so easier O2 delivery

PoM (33 decks)

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