122 Erythropoiesis

Question 1

Erythron

Answer 1

• •The progenitor and mature red blood cells are the erythron
• •Oxygen required for aerobic metabolism is supplied by circulating mature red blood cells (RBCs)
• •The bone marrow continuously renews the supply of red blood cells
• •Erythropoiesis is a highly regulated process

Question 2

Hematocrit

Answer 2

• –Packed red cell volume
• –The volume of blood composed of erythrocytes in 1 ml of blood
• –Total body hematocrit is volume of RBC in the body divided by the total blood volume
• –Simplest and most widely used estimate for size of red cell mass
• –Measure of concentration of RBC, and not of total body red cell mass
• –Influenced by changes in plasma volume
  
  • •Therefore not accurate measure of RBC mass in situations of dehydration or polycythemia

Question 3

Measurement of Blood Compartments

Answer 3

Question 4

Blood measurement after hemorrhage

Answer 4

Question 5

Erythropoiesis

Answer 5

• •Rate of new red blood cell (RBC) production varies based on
  
  • –Rate of red blood cell destruction/loss
  • –Tissue oxygen requirements
    
    • •Oxygen content of hemoglobin
    • •Hemoglobin affinity for oxygen (oxygen dissociation curve)

Erythropoietin (EPO)

• •Measured in the serum
• •Produced by the renal interstitial cells
• •Levels are primarily a function of
  
  • –Severity of anemia OR
  • –Hypoxia
• •Other factors affect the erythropoietin level
  
  • –Erythroid marrow mass
• •Erythropoietin binds to erythroid progenitors in marrow
• •Ex. If less progenitors in the marrow then higher circulating erythropoietin levels
  
  • –Inflammatory cytokines: IL-1, IL-6, tumor necrosis factor (TNF-α), transforming growth factor (TGF-β)
• •Responsible for lower than normal erythroid marrow response in patients with inflammatory disease states

Erythroid Production

• •Ability to increase RBC production significantly when anemia develops
  
  • –Red blood cell production can increase 2-5 times normal
• •Full marrow response takes days
• •A rise in reticulocytes is noted in about 4-5 days
• •Increase in hemoglobin may take a week or more

Mature Erythroid Response

• •Dependent on: –Severity of anemia, Hypoxia, Presence of normal pool of stem cells, Supply of essential nutrients (Iron, Vitamin B12, folate, copper, amino acids), Anatomical structure of the bone marrow (Abnormal with radiation damage to marrow or myelofibrosis)

Question 6

Erythropoietin production and anemia

Answer 6

Question 7

Erythropoietin–erythropoietin receptor (EPO–EPOR)

Answer 7

• •EPO travels to the marrow where it binds to EPOR
• •Results in
  
  • –Stimulation of erythroid cell division
  • –Erythroid differentiation
  • –Prevention of erythroid progenitor apoptosis
• •Angiotensin II and Insulin-like growth factor-1 (IGF-1)
  
  • –May have an erythropoietin-like role in some situations

Question 8

REd Cell Survival

Answer 8

•Reticulocytes

• –0-3 days in the marrow
• –0.5-1.5 days in the peripheral circulation
• –If released early from the marrow in response to anemia then may exist in peripheral circulation for 2-4 days

•Mature red blood cell

• –120 days in peripheral circulation

Question 9

Reticulocytes

Answer 9

• •Immature RBCs
• •No longer contain a nucleus, but have residual RNA
• •Retains mitochondria, ribosomes, centriole and Golgi apparatus
• •Staining of cells with methylene blue stains these structures
• •Indicator of increased production of RBCs
  
  • –If marrow production is adequate expect the percentage to increase as the hemoglobin decreases

Question 10

Measurement of Erythroid marrow production

Answer 10

• •Marrow erythroid/granulocyte ratio (E/G ratio)
  
  • –Evaluating a bone marrow aspirate sample
  • –Normal ratio is 1:3-4 E/G
  • –In the stimulated stated ratio can be 1:1 or higher
• •Reticulocytes
  
  • –Clinical measure of effectiveness of RBC production
• •Erythron iron turnover
  
  • –Measurement of radioactive-iron incorporation into RBC

Question 11

Disorders with Impaired Erythropoiesis

Answer 11

Decreased erythroid progenitors

• –Primary bone marrow failure
  
  • •Ex. Aplastic anemia
• –Suppression of erythroid marrow production
  
  • •Medications
    
    • –Chemotherapy or others
  • •Infections
    
    • –Ex. HIV

Abnormalities in RBC maturation

• –Congenital
  
  • •Ex. Thalassemia
• –Acquired
  
  • •Ex. Iron deficiency, Vitamin B12 deficiency

Question 12

Red Blood Cell Structure

Answer 12

• •Biconcave disc
• •No nucleus or mitochondria
• •Hemoglobin makes up about 33% of the cell
• •RBC membrane allows is to be pliable in order to navigate microvasculature
• •RBC energy is supplied by glycolysis
  
  • –Anaerobic glycolysis: Embden-Meyerhof pathway – ATP, NADH
  • –Oxidative glycolysis: Hexose monophosphate shunt - NADPH

Question 13

Hemoglobin Structure

Answer 13

• –A tetramer
  
  • •Each monomer has a heme and a globin
  • •4 heme groups for each hemoglobin molecule
• –Heme
  
  • •Iron chelated to protoporphyrin ring
  • •Each heme group is covalently bound to a globin monomer
  • •Each heme group can reversibly bind one oxygen molecule
• –Globin chains
  
  • •Protein subunit that binds heme
  • •Different hemoglobins are defined by various globin chains
  • 4 globin chains per hemoglobin (2a2”non-a”)
• Biosynthesis of Heme
  
  • •90% of heme biosynthesis occurs in erythroid precursors
  • Liver is the predominant site of non-erythroid heme synthesis

Question 14

Timeline of human hemoglobin genes expressed

Answer 14

Question 15

Methods to ID hemoglobin types

About Hemoglobin Variants

Answer 15

• •More than 1000 variants have been described
• •Many arise as single nucleotide mutations
• •Variants initially designated by letters of the alphabet
  
  • –Hemoglobin S (Sickle hemoglobin)
  • –Hemoglobin C, D, E
• •Many variants designated by the geographic region where they were first described
  
  • –Hemoglobin Koln, Zurich, Punjab
• •Variants alter hemoglobin structure and biochemical properties with physiological effects ranging from insignificant to severe

Question 16

Hemoglobin synthesis

Answer 16

• •Maximal hemoglobin synthesis occurs in mature marrow erythroblasts, but persists to a lesser degree in reticulocytes
• •Heme
  
  • –Protoporphyrin synthesis and iron incorporation occurs in mitochondria
• •Globin chains
  
  • –Assembled by cytoplasmic ribosomes
• •Final assembly of the hemoglobin molecule occurs in the cell cytoplasm

Question 17

Disorders of the RBC

Answer 17

Question 18

RBC degradation

Answer 18

Question 19

Hemoglobin Oxygen Dissociation

Answer 19

• •Affinity of hemoglobin for oxygen is influenced by
  
  • –Temperature
  • –pH (Bohr Effect)
  • –CO2 concentration
  • –Level of RBC 2,3-BPG (biphosphoglycerate) also known as 2,3-DPG (diphosphoglycerate)
• •Deoxyhemoglobin stimulates production of 2,3-BPG

Of note: Fetal hemoglobin is leftward shifted compared to maternal so that O2 is transferred

Question 20

Bohr Effect

Answer 20

• •When the concentration of CO2 in the blood increases, this causes the pH in the blood to decrease become more acidotic.
• •As a consequence, oxygen is released from the hemoglobin in the red blood cells, therefore causing a reduction in the saturation of hemoglobin.
• •Effect is immediate
• •Ex. Blood perfusing an exercising muscle will be able to deliver more of its oxygen to the tissue because of the low tissue P02 (oxygen consumption) and Bohr effect causing right shift in the oxygen dissociation curve