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Year One: Pesky Things > Red Blood Cell Production and Survival > Flashcards

Red Blood Cell Production and Survival Flashcards

1
Q

How many RBC produced in a day?

A

 1012 RBC/day

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2
Q

Summarise the stages of RBC production

A 
→HEMOCYTOBLAST (Stem Cell)
→PROERYTHROBLAST (Committed Cell)
→ EARLY ERYTHROBLAST
→ LATE ERYTHROBLAST
→ NORMOBLAST
→RETICULOCYTE
→ ERYTHROCYTE
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3
Q

What is the relationship between RBC production and ambient O2?

A

inversely related

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4
Q

What is EPO?(3)

A
  • Epo is a glycosylated polypeptide hormone.
  • 90% produced by the kidneys as a result of low oxygen tension in the kidneys
  • It stimulates marrow production of rbc
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5
Q

What is HIF?(3)

A
  • HIFs are heterodimers formed by 1 of 3 oxygen-regulated α subunits and a constitutive β subunit.
  • The oxygen-dependency of prolyl-hydroxylase domain enzymes (PHDs), which target HIFα for proteasomal degradation, provides the basis of a widespread oxygen-sensing mechanism.

 HIF enhances expression of iron-absorbing gene.

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6
Q

What is ferroportin?

A

Iron absorbing proteins

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7
Q

What is hepcidin?(2)

A

Hepcidin, which is predominately produced by the liver, serves as a master regulator of iron homeostasis.

Hepcidin inhibits intestinal iron reabsorption and iron release from macrophages, thereby reducing iron availability by binding to ferroportin and induces it internalisation and degradation

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8
Q

How does HIF-a regulate RBC production?(4)

A

In the presence of sufficient oxygen, HIF-α is hydroxylated by PHD (prolyl hydroxylase domain).

  1. Hydroxylated HIF-α is recognized by vHL, which results in proteasomal degradation.
  2. In hypoxic conditions or PHD inhibition, HIF-α accumulates in the cytosol and forms a heterodimer with HIF-β, the hypoxia-insensitive unit.
  3. The heterodimer translocates to the nucleus and acts as a transcriptional factor that binds to HREs
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9
Q

Describe absorption of iron(3)

A

 Normal Western diet provides 15mg daily.
 5-10% absorbed (1mg) principally in duodenum and jejunum.
 gastric secretion (HCl) and ascorbic acid help absorption.

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10
Q

Which two molecules regulate iron absorption?

A

Iron absorption is regulated by DMT-1 and ferroportin

DMT-1 is a channel regulated by ferroportin

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11
Q

Where are DMT-1 and ferroportin found?

A

DMT-1 at the brush border of the enterocyte transporting iron into cells and ferroportin at the basal membrane then transport iron from enterocytes into circulation

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12
Q

What are the causes of Iron deficiency?(3)

A

Decreased uptake
• Malabsorption - (atrophic gastritis, coeliac disease)

Increased demand
• In pregnancy, increased iron demand is needed for increase maternal red cell mass of about 35%, transfer of 300mg of iron to foetus

Increased loss:
• GI tract bleed (ulcer, NSAID, carcinoma, colitis)

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13
Q

Why are folic acids and B12 important?

A

 Both essential for RBC maturation & DNA synthesis

 Both needed for formation of thymidine triphosphate.

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14
Q

What is the role of B12?

A
  1. • Essential for formation of thymidine triphosphate; essential building block of
  2. • B12 is a cofactor for methionine synthase in the methylation of homocysteine from methyl tetrahydrofolate, essential for DNA synthesis
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15
Q

What can folic acid deficiency do?

A

• Folate def causes megaloblastic anaemia by inhibiting thymidylate synthesis, a rate limiting step for DNA synthesis

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16
Q

How is B12 absorbed?

A

• B12 is absorbed in distal SI by the help of IF

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17
Q

What are the causes of B12 deficiency?

A

inadeqate intake: vegans

absorption defect: tropical sprue, coeliac disease

IF deficiency: Pernicious anaemia, Chron’s

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18
Q

What are the causes of folate deficiency?

A

Poor nutrition
Coeliac, tropical sprue

Pregnancy, Haemolysis, cancer

Drugs: anticonvulsants

19
Q

What is pernicious anaemia?

A

Commonest cause of B12 def, it’s due to autoimmune gastric atrophy resulting in loss of intrinsic factor production required for absorption of B12.

20
Q

What is Crohn’s disease?(2)

A

a type of inflammatory bowel disease (IBD) that may affect any part of the gastrointestinal tract from mouth to anus.

Signs and symptoms often include abdominal pain, diarrhoea (which may be bloody if inflammation is severe), fever, and weight loss.

21
Q

What is tropical sprue?

A

an acquired malabsorptive condition of in the intestines caused by inflammation or flattened villi

22
Q

How can folate and B12 deficiency be treated?

A

nB12 - Hydroxycobalamin: 1mg im , Folate: -Folic acid 5mg/day oral

23
Q

What are some stresses that are placed on RBCs?

A
  1. RBC circulate for approx. 120 days without nuclei or cytoplasmic organelles
  2. 300 miles travelled through microcirculation
  3. 7.8 m diameter to fit into capillaries as small as 3.5 m
24
Q

Two mechanisms that destroy RBCs

A

increasing RBC age (senescence)

  1. the other to a random process that destroys intact RBCs, or portions of an intact RBC (eg, vesicles) independent of their age (random haemolysis).
25
Q

What are the metabolic processes of RBCs?

A

o Embden-Meyerhof pathway/ glycolytic pathway
o Hexose monophosphate shunt (or PPP)
o Luebering Rapaport Shunt
o Methaemoglobin reductase pathway

26
Q

What is the role of the RBC glycolytic pathway?

A

 Generates energy in ATP;
o to maintain red cell shape and deformability
o regulates intracellular cation conc. via cation pumps (Na/K pump),

27
Q

What can a ‘block’ in glycolysis lead to?

A

causes a build up of glycolytic intermediates, including 2,3 biphosphoglycerate, which binds to and shifts the oxygen dissociation curve to the right.

28
Q

Disorders of the Embden-Meyerhof Pathway

A

 ATP is depleted:
 cells lose large amount of potassium & water, becoming dehydrated & rigid, causes chronic non-spherocytic haemolytic anaemia

29
Q

What is PK?

A

an autosomal recessive disorder, with more than 100 mutations documented, resulting in low intracellular ATP generation affecting membrane structure.

30
Q

What are the variants of PK deficiency?(2)

A

HS – deficiency in ankyrin spectrin. HS is the commonest of the red cell membrane disorders. It is an autosomal dominant condition
HE – mutant in spectrin leading to defective spectrin-ankyrin association, protein 4.1 deficiency

31
Q

Luebering Rapoport Shunt’s role

A

 2,3 DPG binds to deoxyHb to stabilise at lower O2 affinity state
 this makes it harder for O2 to bind to Hb; favours O2 release

Pathway helps regulate oxygen release from Hb and delivery to tissue

32
Q

Describe the pentose phosphate pathway of RBCs

A

• 10% of red cell glucose is metabolized via the Hexose Monophosphate Shunt (HMS), otherwise known as the Pentose Phosphate Pathway (PPP).

  1. • G6PD (glucose6 phosphate dehydrogenase) is involved in the pentose phosphate pathway; one of the products of this pathway is NADPH which has a role in protecting the red blood cell from oxidative damage
33
Q

What is the role of G6PD in the PPP?

A

• G6PD catalyses the first step in the hexose monophosphate shunt which is necessary for producing NADPH.

  1. NADPH in turn is required for the maintenance of reduced glutathione (GSH), a tripeptide that protects the RBC from oxidative damage.
  2. G6P is converted to 6-phosphogluconate, by G6PD, generating NADPH .
34
Q

What is the role of GSH?

A

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

35
Q

What are the disorders of HMS?(4)

A
  • G6PD deficiency is X-linked, and seen in the same ethnic groups as haemoglobinopathies
  • Patients with G6PD deficiency have to avoid particular oxidative drugs, e.g. sulphonamides, dapsone, and notably quinone based anti-malarial drugs
  • G6PD def leads to HA (haemolytic anaemia) upon treatment with primaquine which stimulates H2O2 formation.
  • G6PD deficiency patient have protection against severe malaria.
36
Q

Describe the methaemoglobin reductase pathway(5)

A
  1. Methemoglobin (Hgb-Fe3+) is hemoglobin that contains non-functional oxidized ferric iron (Fe3+) rather than the functional form of ferrous iron (Fe2+).
  2. NADH produced in the glycolytic pathway is a cofactor for the enzyme methemoglobin reductase, which reverses the oxidation of iron and returns it to the normal reduced (Fe2+) state
  3. Methemoglobin is consist of two enzymes, cytochrome B5 and cytochrome B5 reductase.
  4. The enzyme cytochrome b5 reductase diaphorase I) is normally active and uses electrons from NADH and an electron carrier intermediate,
  5. cytochrome b5, to reduce ferric methaemoglobin back to normal ferrous haemoglobin.
37
Q

What is Methemoglobinemia?

A

occurs when we produce methaemoglobin faster than cytochrome b5 reductase can reduce it.

38
Q

What are the two ways haemolytic anaemia are classified?

A

Hereditary (congenital) or Acquired)

  1. Intrinsic or extrinsic
  2. Intravascular or extravascular
39
Q

How are acquired HAs further classified?

A

Immune:
Autoimmune
Alloimmune
Drug induced

Non-immune:
Red Cell fragmentation
Infection: Secondary

40
Q

How are hereditary HAs further classified?

A
  1. Red Cell memb disorders:
    Hereditary spherocytosis
    Hereditary elliptocytosis
  2. Red Cell enzymopathies
    G6PD deficiency
    PK deficiency
  3. Haemoglobinopathies
    Sickle cell diseases
    Thalassaemias
41
Q

Describe Hereditary spherocytosis(3)

A

 Loss of membrane integrity, the RBCs become spherical
 Common hereditary haemolytic anaemia in N. Europ.
o deficiency in proteins with vertical interactions between the membrane skeleton and the lipid bilayer: e.g. ankyrin def

42
Q

What is Hereditary elliptocytosis?

A

o mutations in horizontal interactions e.g. spectrin, ankyrin; actin, protein 4.1 deficiency.

43
Q

What is the difference between intravascular and extravascular haemolysis?

A

Intravascular hemolysis describes hemolysis that happens mainly inside the vasculature.
2. As a result, the contents of the red blood cell are released into the general circulation, leading to hemoglobinemia

Extravascular hemolysis occurs when RBCs are phagocytized by macrophages in the spleen, liver and bone marrow.
extravascular hemolysis is always occurring to some degree in our body when RBCs have finished living. This is mediated by phosphatidylserine expression on red blood cells

44
Q

What does a right shift in oxygen dissociation curve mean?

A 
acidosis 
1. increased hydrogen ions(low pH)
2. increased pCO2
3. increased temp
4. increase 2,3 BPG
hypercapnia

Year One: Pesky Things (20 decks)

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