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Prepared by

RED BLOOD CELL Darien Liew Daojuin


ERYTHROPOIESIS, METABOLISM AND SENESCENCE 1 June 2017
ERYTHROPOIESIS
Process of RBC production In renal failure, EPO is fail to be
produced, resulting in anemia.
Occurs in the bone marrow
Regulated by erythropoietin (EPO) Treatment: exogenous recombinant
Produced by kidneys (90%) when oxygen EPO.
tension in the parenchyma is low.
10% of EPO is produced in the liver.

Essentials
Iron oxygen carrying pigment
Folic acid (B9) - required for nucleoprotein
synthesis and maintenance in erythropoiesis
Vitamin B6, B12
ERYTHROPOIETIN
CELLULAR CHANGES
Cellular changes that occur during erythroid differentiation include
1. a decrease in cell size
2. condensation of nuclear chromatin
3. a decrease in nuclear diameter
4. an accumulation of hemoglobin in the cytoplasm (increased
acidophilia)
5. a decline in ribosome numbers in the cytoplasm (decreased
basophilia)
6. ejection of the nucleus.
STAGES OF ERYTHROPOIESIS
1. Proerythroblast unipotential stem cells
2. Basophillic erythroblast synthesise hemoglobin
3. Prochromatophillic erythroblasts synthesise hemoglobin
4. Normoblasts extrusion of pyknotic (degenerated/dead) nucleus
5. Reticulocytes
maturation to RBC in 24-48 hours
digestion of their remaining organelles and assumption of the biconcave shape.
RETICULOCYTES
Reticulocytes are the first non-nucleated red cell, which contains
ribosomal material in the cytoplasm.
It has a faint blue tinge polychromasia
They lose their ribosomal material and mature over 3 days,
subsequently release into the circulation.

Increase number of reticulocytes reflects increased erythropoeisis.


ERYTHROCYTES
Erythrocytes leave the bone marrow as reticulocytes in to
the circulation
Undergo final maturation within 24-48 hours.
Mature erythrocytes circulate for approximately 120 days
before they get phagocytosed by macrophages in the
spleen (and also bone marrow and liver).
RED CELL STRUCTURE
Red cell membrane is deformable to pass through the smallest
capillary
Filamentous proteins are attached to the lipid bilayer via special linkage
proteins.
Inherited abnormalities of any of these proteins will result in
Loss of membrane as cells pass through the spleen
Formation of abnormally shaped red cells spherocytes or elliptocytes
METABOLISM
Without mitochondria, RBC undergoes anaerobic glycolysis (Embden-
Meyerhof Pathway) and the pentose phosphate pathway in the
cytosol.
This pathway maintains the glutathione (GSH) in a reduced state. Glutathione is
necessary to combat oxidative stress to the red cell.

Failure of this mechanism will result in reduced membrane flexibility of the RBC
and causes leakiness; and oxidation of Hb molecule producing methaemoglobin
and precipitation of globin chains as Heinz bodies localised on the inside of the
membrane.
Heinz bodies are found in G6PD deficiency,
NADPH deficiency, alpha thalassaemia,
chronic liver disease, hypersplenism.

Heinz bodies can result in bite cells


(degmacyte). These "bites" result from the
removal of denatured hemoglobin by
macrophages in the spleen. Commonly found
in G6PD deficiency.
90% of glucose is metabolised through
the Embden-Meyerhof pathway and
10% through the latter.

The Embden-Meyerhof pathway


produces ATP, pyruvate and lactic acid
while the hexose monophosphate
pathway provides the reducing power
for the red cell in the form of NADPH.
HEMOGLOBIN
Hemoglobin is composed of 4 globin chains, each surrounding an iron-
containing porphyrin pigment molecule heme.
Globin chains are a combination of two alpha and two non-alpha
chains.
Hemoglobin A (/) 90% of adult hemoglobin.
Haemoglobin F (/ ) predominant in fetus.

chains are produced by two genes on chromosome 16.


chains are produced by a single gene on chromosome 11.
OXYGENATION OF HEMOGLOBIN
Bohr effect Hydrogen ions and carbon
dioxide added to blood cause a reduction
in the oxygen-binding affinity of
haemoglobin.

Haldane effect Oxygenation of


haemoglobin reduces its affinity for carbon
dioxide.

These effects help the exchange of carbon


dioxide and oxygen in the tissues.

Red cell metabolism produces 2,3-BPG


from glycolysis. 2,3-BPG accumulates
because it is sequestered by binding to
deoxyhaemoglobin. The binding of 2,3-
BPG stabilizes the T conformation and
reduces its affinity for oxygen.
When it is shifted to
the right, oxygen is
released more
readily. E.g when red
cells reach hypoxic
tissue.

Hemoglobin F is
unable to bind 2,3
DPG and has a left-
shifted curve this
ensures oxygenation
of the fetus blood.
HEMOGLOBIN SYNTHESIS

Haem is produced in the mitochondria.


It requires a coenzyme vitamin B6.
This process is inhibited by haem and
stimulated by EPO.
SENESCENCE
After a lifespan of 120 days, RBC gets destroye.

Intravascular vs. Extravascular Destruction

Hemolysis occurs within macrophages.


INTRAVASCULAR DESTRUCTION
RBC destroyed inside the vascular compartment.
Hb is bound to haptoglobin (glycoprotein).
Prevents toxicity
Triggers macrophages, initiating receptor mediated enocytosis (CD163)

Trauma to the RBC membrane that causes the cell contents, chiefly
hemoglobin, to spill directly into plasma.
Approximately 10% to 20% of normal RBC destruction is
intravascular, secondary to turbulence and anatomic restrictions in the
vasculature.
IRON SALVAGE
1. By binding to haptoglobin, hemoglobin avoids filtration at the
glomerulus and is saved from urinary loss. The complex is carried
to the liver, where the haptoglobin-hemoglobin complex is bound
to macrophage receptors and internalized into the macrophage.
2. A secondary mechanism of iron salvage involves hemopexin. In
hemoglobin that is not bound by haptoglobin, the iron becomes
oxidized, forming methemoglobin. The heme molecule (actually
metheme) dissociates from the globin and binds to another liver-
produced plasma protein, hemopexin. This binding also saves the
iron from urinary loss and prevents oxidation of cell membranes.
Hemopexin-metheme binds to hepatocyte receptors and is
internalized.
EXTRAVASCULAR DESTRUCTION
Macrophages in the spleen, liver and
bone marrow (reticuloendothelial
system) remove the senescent RBC from
circulation.
Any reduction in cell deformability
makes their entrance difficult to the
spleen, resulting in splenic sequestration
and phagocytosis.
HEMOLYTIC ANEMIA
INTRODUCTION
Anemia can result from increased
red cell destruction, impaired red
cell production or blood loss.
In hemolytic anemia, the primary
focus would be in the context of red
cell destruction.
Hemolytic anemia is defined as
anemia due to a shortened survival
of circulating red blood cells (RBCs)
due to their premature destruction.
RBC undergoing hemolysis can occur
either intravascularly or
extravascularly (e.g. spleen).
INTRAVASCULAR VS EXTRAVASCULAR
CLINICAL FINDINGS

Intravascular Extravascular
Hemoglobinemia Jaundice
Hemoglobinuria Reduced levels of haptoglobin
Hemosiderinuria Elevated levels f LDH
Unconjugated hyperbilirubinemia Splenomegaly
Jaundice
Massive Acute tubular necrosis
Reduced haptoglobin levels
High levels of LDH
REFERENCE
http://accessmedicine.mhmedical.com.ezproxy.lib.monash.edu.au/cont
ent.aspx?sectionid=42045308&bookid=563&jumpsectionID=420464
59&Resultclick=2
https://clinicalgate.com/introduction-to-increased-destruction-of-
erythrocytes/
Kumar and Clark, 8th Edition
Davidsons Principles and Practice of Medicine, 22nd Edition