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Physiology of the RBCs

Presented by A/P Dr. Magdi El Sersi

At the end of the lecture student should be able to:


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Describe the morphological features of RBCs, their normal counts and their
function
Describe the structure of HB molecule, its function and normal concentration
Describe the life cycle of RBCs
Describe the production of new RBCs
Describe the fate of RBCs
Define anemia and outline the different classifications of anemia
List the different blood indices
Describe the physiological effect of anemia
Define polycythemia and outline its classification

References
1.

Textbook of Medical Physiology 12th edition By Guyton and Hall 2011

2.

Ganong's Review of Medical Physiology .


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Formed elements comprise 45% of blood and are:

Erythrocytes, leukocytes, and platelets


Only WBCs are complete cells
RBCs have no nuclei or organelles, and platelets are just cell fragments
Most formed elements survive in the bloodstream for only a few days
Most blood cells do not divide but are renewed by cells in bone marrow

ERYTHROCYTES (RBCS)
Non nucleated Biconcave discs
Mean diameter ~7.8
Thickness of 2.5 at the thickest point and 1 or
less in the center.
The average volume of the red blood cell is 90 to
95 3.
It has no mitochondria, or other organelles.
Filled with hemoglobin (Hb), a protein that functions
in gas transport

Importance of biconcave shape

Allows for flexibility and shape change while squeezing


through capillaries.
Increases the surface area for diffusion of gases while
decreasing the distance through which gases have to
diffuse.
Variations in the shape and dimensions of the red cell
are useful in the differential diagnosis of anemias

Cell Membrane
The membrane skeleton is made up of spectrin and is anchored to
the transmembrane protein band 3 by the protein ankyrin
Band 3 is also an important anion exchanger

Red Cell Fragility


In solutions with a lower osmotic pressure RBC swell, becoming spherical
and eventually lose their hemoglobin (hemolysis).
The hemoglobin of hemolyzed red cells dissolves in the plasma, coloring
it red.
When osmotic fragility is normal, red cells begin to hemolyze when
suspended in 0.5% saline
In hereditary spherocytosis the cells are spherocytic in normal plasma
and hemolyze more readily than normal cells in hypotonic NaCl solution.
Hereditary spherocytosis is one of the most common causes of hereditary
hemolytic anemia.
The spherocytosis is caused by abnormalities of the protein network that
maintains the shape and flexibility of the red cell membrane.

Number of Red Blood Cells in the Blood


Men: 5,200,000 (300,000) cells / mm3.
Women: 4,700,000 (300,000) cells / mm3.
This difference is mainly due to difference in hormonal
profile between the 2 sexes (male sex hormones,
androgens, stimulate hemopoiesis)

The number of circulating RBCs remains


constant and reflects a balance between RBC
production and destruction
Too few RBCs leads to tissue hypoxia
Too many RBCs causes undesirable blood viscosity

Erythrocyte Function
1.
2.

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The major function of RBCs is to transport hemoglobin, which in turn


carries respiratory gases.
They contain a large quantity of carbonic anhydrase, an enzyme that
catalyzes the reversible reaction between CO2 and water to form
carbonic acid (H2CO3).
The hemoglobin in the RBCs is an excellent acid-base buffer and
responsible for most of the acid-base buffering power of whole blood.

Structural characteristic of RBC which make them a


good gas transporter :
1.

Its small size and biconcave shape provide a huge surface area
relative to volume

2.

over 97% hemoglobin.

3.

Erythrocytes lack mitochondria and generate ATP by anaerobic


mechanisms, so do not consume any of the oxygen.

Hemoglobin molecule
Hemoglobin is composed of the protein globin each of which is
bound to a heme group
Globin is made up of 2 and chains,
Each heme group bears an atom of iron,
Each iron can bind to one O2molecule
So each hemoglobin molecule can transport 4 molecules of O2

If you know that there are 250 million molecules of Hb / cell you can imagine how
much oxygen is carried by each RBC

Function of Haemoglobin

Hemoglobin combines reversibly with oxygen


This is facilitative reaction

Each gram of hemoglobin combines with about 1.39 ml O2 / g Hb under

optimal conditions
But under normal conditions some hemoglobin exists in forms such as
Methemoglobin (metHb) an oxidized form of hemoglobin that has
an increased affinity for oxygen, resulting in a reduced ability to
release oxygen to tissues
Carboxyhemoglobin (COHb) Combined with CO
The oxygen carrying capacity of hemoglobin when fully saturated with
oxygen binds with 1.34 ml O2/ g Hb.

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Each molecule of hemoglobin can bind 4 molecules of oxygen to


give HbO2 (Oxyhemoglobin or oxygenated hemoglobin).

Hb4 + 4O2

Hb4O8

Maximal capacity of Hb to bind O2 is also known as the Oxygen carrying capacity of


Hb. The most important factor determining Hb-oxygen saturation is the PO2 of
blood

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Oxygen is transported in two forms


Bound to hemoglobin 98.5%
Dissolved in plasma 1.5%

Oxygen is relatively insoluble in water, only

3 ml can be dissolved in 1 L of blood at the


normal arterial PO2 of 100 mmHg.
The other 197 ml of oxygen in a liter of

arterial blood, is transported in the


erythrocytes reversibly combined with
hemoglobin.

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The amount of oxygen physically dissolved in the blood depends on its solubility
and is proportional to partial pressure (Henrys law)

Gas content = solubility * partial pressure

At 37oC the solubility of O2 in blood is 0.03 ml/L for every mm Hg increase in


partial pressure.

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CO2 is transported in 3 forms:


Physically dissolved (7%)

In combination with hemoglobin

(23 %, in the form of carbamino


hemoglobin).
As bicarbonate (70%)

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The first reaction is rate-limiting and is very slow unless catalyzed by the

enzyme carbonic anhydrase


Carbonic acid dissociates rapidly into a bicarbonate ion and a hydrogen ion
Once formed, most of the bicarbonate moves out of the erythrocytes into the

plasma via a transporter that exchanges one bicarbonate for one chloride ion

(chloride shift or Hamburger phenomenon).

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Quantity of Hemoglobin in the Red Cells


In normal people, the percentage of hemoglobin is almost

always near the maximum in each cell.

When Hb formation is deficient, the % of Hb in the cells may

fall and the volume of the RBC also decrease because of


diminished hemoglobin to fill the cell.

Men : average of 15 gm/100 ml.


Women: average of 14 gm/100ml.

Erythropoiesis
Production of Red Blood Cells

Erythropoiesis

During this reticulocyte stage, the cells pass from the bone marrow into the blood
capillaries by diapedesis
within 1 to 2 days the cell become a mature erythrocyte.
Because of the short life of the reticulocytes, their concentration is normally slightly
less than1%

CONTROL OF ERYTHROPOEISIS

I. Hormonal control

1. Erythropoietin

Glycoprotein (65 amino acids)

90% from kidneys 10% live

Stimulated mainly by Hypoxia

Anaemia

Hemorrhage

High altitude

Lung disease

Heart failure
Norepinephrine and epinephrine and
several of the prostaglandins stimulate
erythropoietin production.
also stimulates the release of reticulocytes
to the circulation.

Hormonal Controlcont
2. Other hormones
Androgens, Thyroid, cortisol & growth hormones are essential
for normal red cell formation
Androgens e.g. testosterone: increase erythropoiesis through
directly stimulating bone marrow and indirect stimulation of
erythropoietin release .
Thyroid hormones (T3 and T4): stimulate the metabolism
of all body cells including the bone marrow
Glucocorticoids: stimulates the general metabolism of all
cells including the bone marrow.

II. Nutritional requirements for RBC formation


1. Amino acid
For synthesis of Hemoglobin

2. Iron
Essential for the synthesis of Hemoglobin.
Deficiency causes Microcytic, Hypochromic Anemia.
3. B12 (Cyanocobalamine) & Folic Acid:
Deficiency causes Megaloblastic Anemia Or Pernicious

4. Other elements:
Vit C -Iron absorption, Copper, Cobalt, zinc, manganese

Maturation of RBCs Requires


Vitamin B12 and Folic Acid
Both of vitamin B12 and folic

acid are essential for the


synthesis of DNA

Intrinsic factor (a glycoprotein

secreted by the parietal cells of


the gastric glands) combines
with vitamin B12 in food and
makes the B12 available for
absorption by the gut.

Effect of Deficiency of Vitamin B12 and Folic Acid


lack of either vitamin B12 or folic acid
causes abnormal and diminished
DNA and, consequently, failure of
nuclear maturation and cell division.
The erythroblastic cells of the bone
marrow:
Fail to proliferate rapidly.
Produce mainly macrocytes.
The cell has a flimsy membrane and
is often irregular, large, and oval
instead of the usual biconcave disc.

FATE OF RED BLOOD CELLS


Life span in blood stream is 60-120 days
Old RBCs are phagocytosed and/or lysed mainly extravascular in the
reticulo-endothelial system (Liver, Spleen and Bone marrow).

ROLE OF THE SPLEEN


The spleen is an important blood filter that removes aged

or abnormal red cells


It also produces RBCs when required as well as
lymphocytes, plasma cells and antibodies (site for
extramedullary haemopoiesis)

Erythrocyte Disorders
Anemia deficiency of hemoglobin in the blood( low
oxygen-carrying capacity)
This can be caused by
i. Decrease number of RBCs
ii. Decrease hemoglobin in the cells
Anemia is a symptom rather than a disease
Blood oxygen levels cannot support normal metabolism
Signs/symptoms include fatigue, paleness, shortness of
breath, and chills

Laboratory evaluation of anemia:


Red blood cells indices:
7 values related to RBCs are reported in the CBC including

1. Hemaoglobin (directly measured )


2. Red blood cell count (directly measured )
3. Haematocrit (Hct) (directly measured )

4. Mean corpuscular volume (MCV)


5. Mean corpuscular haemoglobin (MCH).
6.

Mean corpuscular Haemoglobin.concentration (MCHC).

7.

Red blood cell distribution width(RDW).

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Hematocrit (PCV)
It is the percentage ratio of RBCs volume
to the total blood volume.

number of RBC
ECF ; Dehydration

Mean Corpuscular Volume (MCV)


This is the average volume of one red cell.

MCV =

PCV X 10
RBCs count in millions/ L

The average value is 90 fL ( 3).


The normal range is 75 to 100 fL (normocytes).
RBCs with MCV above 100 fL are macrocytes,
and those with MCV less than 75fL are microcytes.

Mean Corpuscular Hemoglobin (MCH):


This is the average amount of Hb in one RBC in picograms
(pg).

Hb content (mg/dL) X 10
MCH =
RBCs count in millions/ L

The average value is 30pg.


The normal range is 26 to 34 pg (normochromic cells).
Below 26 pg. the cells are hypochromic
Above 34 pg. the cells are hyperchromic.

Mean corpuscular Hb concentration (MCHC):


This is the average amount of Hb per 100 mL of RBCs.

MCHC =

Hb content (mg/dL)
X 100
PCV

The average value is 34 %.


The normal range is 33-35 g/100 mL RBCs

Red blood cell distribution width (RDW):


The coefficient of variation of RBC volume (indicates the
degree of anisopoikilocytosis)
Normal RDW value is 10-14%

Morphological classification of anemia


1. Normocytic normochromic anemia:

Normal MCV (size of RBCs) and normal MCH and


MCHC (amount of Hb in each RBC), but total RBCs
count is decreased.
Causes of normocytic normochromic anemia:

Acute blood loss (hemorrhage).

Bone marrow depression by drugs, x-ray or


malignant disease (Aplastic anemia).

Excessive hemolysis (destruction) of RBCs

2- Microcytic hypochromic anemia:


It is a type of anemia with small size of RBCs (MCV <75fL) and less
amount of Hb than normal (MCH <26pg and MCHC <32%)
Causes: Iron deficiency due to:

Decreased iron intake or normal intake but increase the demand

Decreased iron absorption

Chronic blood loss

3- Macrocytic Normochromic anemia:

It is a type of anemia in which RBCs is large in size .

Causes: Deficiency of vitamin B12 and folic acid.

Etiological classification of Anemia:


I- Anemia Due To decreased Hemoglobin Content
Iron-deficiency anemia results from:
A secondary result of hemorrhagic anemia
Inadequate intake of iron-containing foods
Impaired iron absorption
Pernicious anemia results from:
Deficiency of vitamin B12
Lack of intrinsic factor needed for
absorption of B12

II- Insufficient Erythrocytes


Hemorrhagic anemia result of acute or chronic loss of
blood
Hemolytic anemia prematurely ruptured erythrocytes
Aplastic anemia destruction or inhibition of red bone
marrow.

III- Abnormal Hemoglobin


Thalassemias absent or faulty globin chain in hemoglobin
Erythrocytes are thin, delicate, and deficient in hemoglobin
Sickle-cell anemia results from a defective gene coding for
an abnormal hemoglobin called hemoglobin S (HbS)
HbS has a single amino acid substitution in the beta chain
This defect causes RBCs to become sickle-shaped in low
oxygen situations

Effect of anemia
The effects of anemia are
mostly on the circulatory
system:
It increases the work load
on the heart.
It is accompanied by
hyperdynamic circulation
and functional murmurs.
It leads to tissue hypoxia
and acute heart failure

Polycythemia
Polycythemia is an abnormal excess of erythrocytes
It increases blood viscosity, causing it to sludge, or flow
sluggishly.
It is classified to:
A. Primary polycythemia
i. Acquired ; Polycythemia vera
ii. Hereditary
B. Secondary polycythemia
High altitude , Smoking , Hypoxemia, Chronic lung
disease ,Sleep apnea.