Last edited: 8/11/2021

1. ERYTHROPOIESIS: RED BLOOD CELL FORMATION

Erythropoiesis: Red Blood Cell Formation | Part 1 Medical Editor: Dr. Sofia Suhada M. Uzir

OUTLINE (C) CELLS PRODUCED

I) ERYTHROPOIESIS
II) REVIEW QUESTIONS
III) REFERENCES

I) ERYTHROPOIESIS
Formation of RBCs is called erythropoiesis

(A) LOCATION
(1) Sites – In order Figure 2. RBCs [European Pharmaceutical Review]
Yolk Sac
Liver
(D) GROWTH FACTORS/ MOLECULES REQUIRED
Spleen
Bone marrow (RED) (Spongy bone trabeculae) (1) Erythropoietin (EPO)
o Skull
Made by PCT cells in kidney due to hypoxia
o Sternum
Hypoxia stimulus:
o Pelvis
o Anemia
o Epiphyses of long bones
o Obstructive Lung disease
o Restrictive Lung Diseases
o Obstructive sleep apnea
o Heart Failure
o Circulatory Shock
o Atherosclerosis
o Thromboembolisms
o Cyanide or Carbon monoxide poisoning
(2) EPO production
Hypoxia
o ↓ Degradation of hypoxia inducible factor (HIF)
o ↑ HIF in kidney cells
HIF transcription factor
o Activates genes that become expressed and lead to
synthesis of a protein called EPO
o EPO then travels to red bone marrow where it acts on
Figure 1. Hematopoiesis - bone marrow [News Medical] myeloid stem cells
 This converts myeloid stem cells into RBC
precursor cells
(2) Mnemonic
Young Liver Synthesizes Blood cells

(B) DRIVING FACTOR

Blood loss
o Ulceration
o Stab wound
Hypoxia
o Inadequate oxygen delivery to tissue
o Production of more RBC to supply more oxygen
Anemia

Figure 3. Erythropoiesis induced by hypoxia [Learnhaem]

ERYTHROPOIESIS: RED BLOOD CELL FORMATION HEMATOLOGY: Note #1. 1 of 3

(3) Requirements (iii) In the ileum
B12 o Intrinsic factors bind with the transport protein
Folate  Receptor mediated endocytosis
Iron  Vitamin B12 is released into the circulation
Carbohydrates through the basolateral membrane
Fats • Binds with transcobalamin I & II
Amino acids
(4) Iron metabolism
(E) SEQUENCE OF DEVELOPMENT
Iron ingested from food/supplements in Fe3+ state
(1) RBC pathway
(i) In duodenum – enterocytes Hemocytoblast → myeloid stem cell → proerythroblast →
o A ferro-reductase enzyme known as duodenal basophilic erythroblast → polychromatic erythroblast →
cytochrome B converts Fe 3+ into Fe 2+ orthochromatic erythroblast → reticulocyte → erythrocyte
o Then Fe 2+ is brought into duodenal cell with H+ by (RBC) Figure 5
DMT-1
o Once in duodenal cell: (i) Basophilic erythroblasts
 Fe 2+ binds with apoferritin converting into ferritin o Stain blue
 Ferritin can bind with multiple ferritins forming  RNA stains blue
hemosiderin
 Ferritin can release Fe 2+ on basal surface of cell (ii) Polychromatic Erythroblasts
where a feroportin channel transports Fe2+ from o Stain blue & red
duodenal cell into blood  RNA is being translated into proteins which stain
 Before the Fe 2+ binds to transferrin red
• It is oxidized to Fe 3+ by hephaestin
• Transferrin carries the Fe 3+ in the blood to (iii) Orthochromatic Erythroblasts
various organs o Stain red
o Must bound to transferrin because it can  RNA has been translated to proteins which stains
undergo Fenton reaction producing free red
radicals
(iv) Reticulocytes
(ii) In the liver
o Have no nucleus or organelles after the
o There are hepatocytes that can detect the changes in orthochromatic erythroblast spit them out
iron levels o The reticulocytes mature into erythrocytes in 2-3 days
 It produces hepcidin
B12 and folate are needed for DNA synthesis and
• Hepcidin controls the activity of feroportin by
maturation in developing RBC’s
blocking it
• This is to control the amount of iron
• Too much iron is toxic
o HFE protein
 Controls hepcidin
 In hemochromatosis, there is no production of
functional HFE protein
 Hence, iron overload occurs

(iii) In red bone marrow

o The red bone marrow is the organ we need it in for
erythropoiesis
 Once Fe 3+ is taken to red bone marrow
• It is taken up into developing RBCs
• Binds with heme pigment called protoporphyrin
with the help of ferro-chelatase
• Eventually the heme will bind with the globin
chains and make hemoglobin
(5) Vitamin B12 and folic acid metabolism
Vitamin B12 and folic acid are ingested from food such as
leafy vegetables and red meat

(i) In duodenum
o Folic acid is absorbed across the gut, into the blood
stream

(ii) In stomach
o Parietal cells make proteins called intrinsic factors
 Intrinsic factors bind to vitamin B12

Figure 4. Causes of ineffective erythropoiesis

[Keep Maturation on Track]

2 of 3 HEMATOLOGY: Note #1. ERYTHROPOIESIS: RED BLOOD CELL FORMATION

 The precursor of all lines of blood cells is the
a. Myeloblast
b. Hemocytoblast
c. Proerythroblast
d. Progranulocyte

Megakaryocyte give rise to

a. Erythrocyte
b. Agranulocyte
c. Granulocytes
d. Thrombocytes

The production of red blood cells in the bone

marrow is regulated by
a. Renin
b. Angiotensin
c. Erythropoietin
d. Calcium

Which of the following is true regarding

thrombopoiesis?
a. In the red bone marrow
b. Produce RBCs
c. Uses EPO
d. Doesn’t give rise to platelet

Process of formation of blood corpuscles is called

a. Hemolysis
b. Hemozoin
c. Hemopoiesis
d. Haemoter

The blood corpuscles are of _________ kinds.

a. 5
b. 4
c. 2
d. 3

CHECK YOUR ANSWERS

III) REFERENCES
● Alila Medical Media. Shutterstock Hematopoiesis Bone Marrow
[digital image] https://www.news-medical.net/life-
Figure 5. Stages of erythropoiesis [Keep Maturation on Track] sciences/Hematopoiesis-Process.aspx
● European Pharmaceutical Review. Red blood cells with ability to
deliver drugs. 2020. [digital image]
https://www.europeanpharmaceuticalreview.com/news/121018/rese
II) REVIEW QUESTIONS
archers-synthesise-red-blood-cells-with-ability-to-deliver-drugs/
The hormone erythropoietin stimulates red blood ● Erythropoietin and the control of erythropoiesis. Learn Haem.
2019. [digital image]
cell production in the red bone marrow. Where in https://www.learnhaem.com/courses/anaemia/lessons/normal-
the body is erythropoietin produced? haematopoiesis/topic/normal-erythropoiesis/
a. Spleen ● Keep Maturation on Track. [digital image]
https://keepmaturationtrack.eu/ineffective-erythropoiesis/
b. Kidney ● Oxford University Press. Gaskell & Rostron: Therapeutics and
c. Liver Human Physiology. [Quiz]
d. Thyroid https://global.oup.com/uk/orc/pharmacy/ifp_therapeutics/student/mc
qs/ch09/
● Blood circulation. MCQ Biology. [Quiz]
Which of the following statements about https://www.mcqbiology.com/2014/02/mcq-on-haematopoietic-
erythrocytes is correct? system.html
a. They fight infection ● Le T, Bhushan V, Sochat M, Chavda Y, Zureick A. First Aid for
the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017
b. They clot blood ● Marieb EN, Hoehn K. Anatomy & Physiology. Hoboken, NJ:
c. They lack a nucleus Pearson; 2020.
d. They are produced in the spleen ● Boron WF, Boulpaep EL. Medical Physiology.; 2017.
● Urry LA, Cain ML, Wasserman SA, Minorsky PV, Orr RB,
Campbell NA. Campbell Biology. New York, NY: Pearson; 2020.
Where does hematopoiesis take place? ● Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL,
a. Lungs Loscalzo J. Harrison's Principles of Internal Medicine. New York
etc.: McGraw-Hill Education; 2018.
b. Pancreas ● Sabatine MS. Pocket Medicine: the Massachusetts General
c. Liver Hospital Handbook of Internal Medicine. Philadelphia: Wolters
d. Bone marrow Kluwer; 2020.

Platelets are formed from what type of cell?

a. Melanocytes
b. Macrophages
c. Astrocytes
d. Megakaryocytes

ERYTHROPOIESIS: RED BLOOD CELL FORMATION HEMATOLOGY: Note #1. 3 of 3

 Last edited: 8/11/2021

1. LIFESPAN AND DESTRUCTION

Erythropoiesis: Lifespan & Destruction | Part 2 Medical Editor: Dr. Sofia Suhada M. Uzir

OUTLINE II) SITES OF DESTRUCTION

I) THE BASICS (1) Sinusoidal capillaries

II) SITES OF DESTRUCTION
Found in:
III) SEQUENCES OF EVENTS
IV) REVIEW QUESTIONS Spleen
V) REFERENCES Liver
Red Bone marrow

I) THE BASICS
Lifespan of RBCs 100-120 days
o As RBCs reach this time the cytoskeleton and
hemoglobin function start declining
 → So, it’s out with the old and in with the new
Cytoskeleton
Proteins in the cytoskeleton help with flexibility and
pliability to squeeze through small capillaries
o Spectrin protein Figure 1. Cut section of sinusoidal capillary
 Webbed-like protein [Pearson Education]
o Ankyrin
 Bind spectrin to cell membrane
o Glycophorin
o Band 3 protein 4.1 & 4.2
As RBCs getting older, it becomes less flexible and more
rigid.

III) SEQUENCES OF EVENTS

(1) Old RBCs (B) GLOBIN CHAINS

Move through the sinusoids in these organs Is one of the products of hemoglobin break down by
o RBCs gets stucked in the intercellular clefts macrophages
o They get phagocytosed by macrophages The other is heme
o The hemoglobin in the RBC is broken down in the It will further break down into amino acids
macrophage into: o The amino acids can be recycled to help in the
 Globin chains erythropoietic cycle again
 Heme
Globin chains include
o Alpha
o Beta
o Delta
o Gamma

(i) Hemoglobin types

o Adults
 2 alpha + 2 beta
o Fetal hemoglobin
 2 alpha + 2 gamma
o Hemoglobin A2
 Very rare type
 2 alpha + 2 delta

Figure 2. Recycling of RBCs [Bio Ninja]

LIFESPAN AND DESTRUCTION HEMATOLOGY: Note #1. 1 of 3

 (C) HEME
Is one of the products of hemoglobin broken down by
macrophages
The other is globin chains
It will further break down into iron and biliverdin which
gets broken down into bilirubin Figure 3.
(1) Iron
The iron that is released from heme can bind with
apoferritin
o Forming ferritin
Ferritin molecules polymerize
o Form hemosiderin that is stored in tissues like the
liver and macrophages
(2) Bilirubin
Biliverdin get broken down into bilirubin
Bilirubin is very toxic if it gets into the blood stream
causing neurotoxicity
Spit out of macrophage in the unconjugated form and
binds to albumin where it is transported to the liver

(i) In the liver

o Unconjugated bilirubin binds with glucuronic acid Figure 3. Bilirubin metabolism simplified
 Forms conjugated bilirubin [Lab Technologist Farukh]
• Soluble
 Will be secreted into bile
• Bile helps with fat digestion
• Will be released in the duodenum through the
hepatopancreatic ampulla

(ii) In the duodenum

o The bile is released into the duodenum
 Helps to emulsify fat
o Bilirubin in the bile gets broken down to
urobilinogen by the bacteria enzymes (such as
proteases)
 Small amounts of urobilinogen is absorbed across
GIT and into blood where it is taken to kidneys
and added into urine
• This is called urobilin
• Causes yellow coloration of the urine
 Some of it can be recycled and reconjugated with
glucuronic acid through the enterohepatic
circulation Figure 4.
 The remaining urobilinogen in the GIT gets
converted into → stercobilin by bacteria in colon
• This pigment gives feces its brown hue

NOTE: Figure 4. Detailed destruction of erythrocyte [Oncohema Key]

o Another name for urobilinogen in the GIT is fecal
stercobilinogen
o The colour of stool and urine is a good clinical indicator
if there is an obstruction in the biliary pathway where
bilirubin cannot be secreted
o Gallstone obstructed in the common bile duct can push
bilirubin into the blood stream → deposits into different
tissues
 Yellowish coloration = jaundice

2 of 3 HEMATOLOGY: Note #1. LIFESPAN AND DESTRUCTION

 IV) REVIEW QUESTIONS
All of the following are the site of RBCs
What is the approximate formation of bilirubin in destruction, except
adults? a. Liver
a. 150-220 mg b. Lung
b. 50-70mg c. Spleen
c. 250-350 mg d. Bone Marrow
d. 500-700 mg
CHECK YOUR ANSWERS
Which of the following statement is NOT true?
a. Bilirubin is lipophilic in nature V) REFERENCES
b. Biliverdin reductase is an ATP dependent soluble ● Cut section of sinusoidal capillary. Pearson Education [digital
enzyme image] https://slideplayer.com/slide/17455779/
● Bio Ninja. Human Physiology. Recycling of erythrocyte [digital
c. Albumin has 2 binding sites for bilirubin image] https://ib.bioninja.com.au/options/option-d-human-
d. Heme oxygenase enzyme produces biliverdin, physiology/d3-functions-of-the-liver/erythrocyte-recycling.html
ferrous ion and CO ● Lab Technologist Farukh. Bilirubin Metabolism in The Body
Simplified [digital image]
https://m.facebook.com/1681813371896372/posts/bilirubin-
Which form of energy is required for the working of metabolismin-in-bodythe-heme-present-in-the-hemoglobin-and-
complex enzyme system? other-prote/3133705743373787/
a. ATP ● Oncohema Key. Introduction to Increased Destruction of
Erythrocytes [digital image] https://oncohemakey.com/introduction-
b. ADP to-increased-destruction-of-erythrocytes/
c. NAD ● Oxford University Press. Gaskell & Rostron: Therapeutics and
d. None of the above Human Physiology. [Quiz]
https://global.oup.com/uk/orc/pharmacy/ifp_therapeutics/student/mc
qs/ch09/
What happens to the globin part of hemoglobin after ● GPATINDIA. Pharamcophore Edulabs India. Catabolism of
its dissociation? Hemoglobin and MCQs For Pharmacist, GPAT, NEET, GATE and
CSIR NET Exams. 2021. [Quiz] https://gpatindia.com/catabolism-of-
a. Excreted through urine hemoglobin-and-mcqs-for-pharmacist-gpat-neet-gate-and-csir-net-
b. Stored in liver exams/APA citation guide. (2016). http://www.bibme.org/citation-
c. Degraded to its amino acid guide/apa/
● Le T, Bhushan V, Sochat M, Chavda Y, Zureick A. First Aid for
d. None of the above the USMLE Step 1 2018. New York, NY: McGraw-Hill Medical; 2017
● Marieb EN, Hoehn K. Anatomy & Physiology. Hoboken, NJ:
What would happen to red blood cells if the heme Pearson; 2020.
group were removed from hemoglobin? ● Boron WF, Boulpaep EL. Medical Physiology.; 2017.
● Urry LA, Cain ML, Wasserman SA, Minorsky PV, Orr RB,
a. Red blood cells would not be able to bind oxygen Campbell NA. Campbell Biology. New York, NY: Pearson; 2020.
b. Red blood cells would not be able to reproduce ● Jameson JL, Fauci AS, Kasper DL, Hauser SL, Longo DL,
c. White blood cells would not be able to reproduce Loscalzo J. Harrison's Principles of Internal Medicine. New York
etc.: McGraw-Hill Education; 2018.
d. Blood clot formation would be inhibited ● Sabatine MS. Pocket Medicine: the Massachusetts General
Hospital Handbook of Internal Medicine. Philadelphia: Wolters
The secretion of bilirubin from hepatocytes to Kluwer; 2020.
canaliculi are an energy-dependent process. The
transporter protein involved in this protein is
a. MRP2 protein
b. Active transport coupled with Na K ATPase
c. Bilirubin transporting protein
d. Chylomicron

In the intestine, bacterial degradation of bilirubin

forms urobilinogen. Urobilinogen is a colorless
bilirubin derived product that is further oxidized to
form the following pigments except
a. Urobilin
b. Mesobilin
c. Stercobilin
d. Exobilin

When red blood cells are worn out, part of their

components are recycled while others are
disposed. Select the incorrect statement about
destruction of red blood cells.
a. The greenish pigment, biliverdin, is recycled to the
bone marrow
b. Iron is carried to the bone marrow by a protein called
transferrin
c. Biliverdin and bilirubin impart color to bile
d. Macrophages in the liver and spleen destroy worn
out red blood cells

Life span of RBC is

a. Around 90 days
b. Around 50 days
c. Around 125 days
d. Around 115 days

LIFESPAN AND DESTRUCTION HEMATOLOGY: Note #1. 3 of 3