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Physiology of the Blood
Dr. Mohamamd Alqudah, BDS, Ph.D
Department of physiology and biochemistry
Office location M2, fifth floor
Office hours
2-3 Monday- Thursday
Email: [email protected]
Outline
 General overview of the blood
Hematopoiesis Guyton 32
Physiology of Red Blood Cells (RBCs) Guyton 32
Physiology of White Blood Cells (WBCs) Guyton 33&34
Blood coagulation and homeostasis Guyton 35
Blood groups and transfusion Guyton 36
Lecture # 1
General overview of blood
Blood characteristics
Components of blood
General functions of blood
Characteristics of Blood
 Blood is the only fluid tissue in the body
Blood is a complex connective tissue in which living cells, the formed elements, are suspended in the nonliving fluid
called plasma.
 Cells of the body are served by two fluids
1) The blood
transports nutrients and wastes
1) The interstitial flood
bathes the cells of the body
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Characteristics of Blood
Volume: A person has 4 to 6 liters of blood, depending
on his or her size. Of the total blood volume in the
human body, 38% to 48% is composed of the various
blood cells, also called formed elements. The remaining
52% to 62% of the blood volume is plasma, the liquid
portion of blood.
Color: Arterial blood is bright red because it contains
high levels of oxygen. Venous blood has given up much
of its oxygen in tissues, and has a darker, dull red color.
pH: The normal pH range of blood is 7.35 to 7.45, which
is slightly alkaline. Venous blood normally has a lower pH
than does arterial blood because of the presence of more
carbon dioxide.
Viscosity: Blood is about three to five times thicker than
water so flows more slowly than water
Blood volume
Volume of the blood
 The average blood volume of an adult is about 7% of body weight, or about 5 litters
Adult male - 5-6 liters
Adult female - 4-5 liters
 55% of blood is plasma and 45% is red blood cells, these percentage vary with many factors such as gender, weight
and other factors.
 Determination of blood volume
Direct method: removal of all blood in experimental conditions with animals.
Indirect method: (dye dilution) injection of known amount of radio-labeled albumin or Evans blue dye to
measure plasma volume and you know the Hematocrit, the blood volume will be:
Total blood volume =
Plasma volume
1- Hematocrit
Blood viscosity
• It is the inherent resistance of blood to flow due to internal friction of
adjacent blood layers sliding past each other.
• Factors that contribute to blood plasma
1. Plasma proteins and electrolytes (specifically; albumin and fibrinogen),
Plasma is about 1.8 more viscous than water.
2. Blood cells( especially red blood cells)
3. Temperature, cold blood is thicker and flows slowly.
4. Blood velocity
5. Vessel radius
Blood viscosity
**Plasma is about 1.8 more viscous
than water this is due mainly to
presence of plasma protein. Whole
blood viscosity is 3-4 times of that of
water. This is due to presence of RBCs.
Viscosity is increased when
hematocrit value or no. of RBCs rise.
**Increased viscosity will decrease
blood flow through blood vessels.
Plasma osmotic pressure is 300 mmol/L or 770kPa
(1) Crystal osmotic pressure results from NaCl and modulates water distribution between
inside and outside of cells.
(2) Colloid osmotic pressure results from albumin and regulates water distribution between
inside and outside of capillary.
Components of the blood
Components of Blood
(Hematocrit)
Components of Blood
1.Formed elements 45% of whole blood
• Known as percent packed cell volume
granular leukocytes
neutrophils
eosinophils
basophils
agranular leukocytes
lymphocytes = T cells, B cells, and natural killer cells
monocytes
Platelets (special cell fragments)
In the buffy coat
Red blood cells ( erythrocytes ) Hematocrit
White blood cells ( leukocytes )
Blood smear
Formed elements of the blood
Components of Blood
2. Plasma ( blood without cells) 55% about 3 litters
water, amino acids, proteins, carbohydrates, lipids, vitamins, hormones, electrolytes, wastes
***Plasma is obtained when unclotted blood is centrifuged. The fluid above cellular elements is PLASMA.
Characteristics of Plasma
1. Straw-colored liquid
2. Mainly water 90%
3. Includes many dissolved substances
Nutrients, Salts (metal ions)
Respiratory gases
Hormones
Proteins, Waste products
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Plasma proteins: you can separate plasma protein by electrophoresis
1) Albumin: 60% synthesized in the liver, main function is to provide colloid
osmotic pressure in the plasma
2) Globulin: 36% of plasma proteins, made in the liver except gamma
globulins
1-globulins e.g. antitrypsin
2-globulins e.g. Angiotensinogen
-globulins e.g. Transferrin
-globulins immunoglobulins IgA, IgD, IgE, and IgM: made in plasma cells
3) Fibrinogen: fibrin, fibers (4% of plasma proteins), produced from the liver
Blood Coagulation
Plasma proteins
Most plasma proteins are produced by the liver,
except for hormones and gamma globulins. Gamma
globulins are formed by plasma cells.
8% by weight of plasma volume
Plasma proteins serve a variety of functions, but
they are not taken up by cells to be used as fuels or
metabolic nutrients as are most other plasma
solutes, such as glucose, fatty acids, and amino
acids.
 Note: hypoproteinemia is seen in
a. liver diseases….less formation
b. kidneys disease….loss of protein
PLASMA ELECTROLYTES
1. Electrolyte release ions when dissolved in water
2. include: sodium, potassium, calcium, magnesium,
chloride, bicarbonate, phosphate and
sulfate ions
3. Function:
maintain osmotic pressure and the pH
of the plasma.
NUTRIENTS AND GASES
1. Nutrients : simple sugars, amino acids,, nucleotides and lipids
2. Blood gases: oxygen and carbon dioxide
NONPROTEIN NITROGEN SUBSTANCES
1. contain nitrogen but are not proteins
2. include: urea, uric acid, creatine & creatinine
3. digestion  amino acids
4. nucleic acid catabolism  uric acid & urea
5. creatine metabolism  creatinine
Plasma VS Serum
Serum is plasma from which fibrinogen and other coagulation proteins have been removed as
a result of clotting. It contains high level of serotonin (released from platelets during clotting).
***It is obtained when clotted blood is centrifuged. The fluid above clotted blood is SERUM
General functions of the blood
1. Transportation
Gases: O2 & CO2
Nutrients: Amino acids, lipids, glucose, etc.
Hormones: pituitary, thyroid, pancreas, ovary, and
testes, synthesize hormones brought by blood to tissu
requiring them.
waste products: urea, lactic acid , creatinine
Electrolytes:
Na+ K+ Cl- Ca++
2. Regulation
Blood pH: H2CO3, lactic acid, citric acid, NH3, HCO3- tend to lower or raise blood pH. Buffer systems help
maintain pH within limits.
Fluid balance: plasma colloid osmotic pressure
Body temperature: coolant properties of water and vasodilatation of surface vessels dump heat
3. Protection
Infection
Blood loss
WBC , antibodies
platelets, clotting factors
Hematology lab tests
 The complete blood count (CBC) include a hemogram and differential
white blood cell (WBC) count.
 The hemogram includes the enumeration of WBCs, red blood cells (RBCs), and
platelets
 The WBC count with differential enumerates the different WBC types
 Tests designed to assist the accuracy of RBCs number, structure and function
RBC count
 Hgb concentration
hematocrit(Hct)
 RBC indices.
 RBC count: is the part of the CBC that determines the number of RBCs found in
a cubic centimeter of blood.
 Hemoglobin Hgb : 300 million molecules of Hgb in one RBC.
 Hematocrit:
Hct represents the percentage of the total volume
of RBCs relative to the total volume of
whole blood in a sample
Note: Hgb and Hct levels parallel, in that Hct levels are 3 times the Hgb level
This relationship is altered if RBCs are abnormal in size or shape or if the synthesis
of Hgb is defective.
RBC Indices
RBC indices are calculated mean values that are used to define the size, weight, and Hgb
content of the RBC. They are mainly used to classify anemias.
RBC indices consist:
 Mean Corpuscular volume (MCV)
Mean corpuscular volume. MCV describes the RBC by size or volume.
The MCV classifies RBCs as microcytic, normocytic, and macrocytic
MCV is a calculated value obtained by dividing the Hct by the RBC count.
 Mean corpuscular hemoglobin (MCH) This
This value is the index that measures the average weight of Hgb in the RBC.
Mean corpuscular hemoglobin concentration
This index is a measure of the average concentration of Hgb in the RBC per unit volume.
(Normochromic, hypochromic and hyperchromic
Hematopoiesis
 Hematopoietic process
 Regulation of Hematopoiesis
 Chronological Sites for Hematopoiesis
 Nutritional requirement for hematopoiesis
Hematopoiesis
 Hematopoiesis is the process of blood cells
(erythrocyte (red blood cell, RBC), leukocyte (white
blood cell, WBC) and thrombocyte (platelet, P))
formation in the bone marrow from hematopoietic
stem cells.
All blood cells are derived from a common stem cell called Pluripotent
hematopoietic stem cell (PHSC)
Hemopoietic process
1: Hemopoietic stem cells- Pluripotent hematopoietic stem cell (PHSC)
Unlimited self renewal, steady numbers, active differentiation.
2: committed progenitors
directional differentiation (CFU-GEMM, CFU-E, CFUGM, CFU-MK, CFU-TB). [CFU: colony- forming unit
3: precursors
morphologic occurrence of various original blood cells.
PHSC differentiates to become:
either a) Myeloid progenitor cell
or b) Lymphoid progenitor
cell
Myeloid
Myeloid RBC’s and WBC’s and
platelets
Lymphoid B and T cells and
Lymphoid
Hematopoiesis
Proliferative potential
differentiation
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Pluripotent hematopoietic stem cell (PHSC) features




Self renewal in high degree, a small portion of them remains exactly
like the original pluripotential cells and is retained in the bone marrow to
maintain a supply of these, although their numbers diminish with age.
Multi- directional differentiation
High proliferative capacity, Hematopoietic stem cells
produce about 1×1011 blood cells releasing to blood for use.
Surface sign
According to CFU (colony forming unit), using fluorescenceactivated cell sorting (FACS), its main surface sign is
CD34+CD38-Lin-and CD34-CD38-Lin-.
Note
CD: cluster of differentiation of antigen on the white blood
cells;
Lin: systemic specific antigen on the hematopoietic cells.
Hematopoietic Microenvironment
1) stem cell(s)
1) stromal cells
2) growth factors
endothelial cells, fibroblasts, adipocytes, macrophages,
Hematopoietic Microenvironment
Stromal cells:
fibroblasts
endothelial cells
adipocytes
Growth Factors
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Regulation of hematopoiesis
 The process of hematopoiesis is under tight control by
multiple proteins called growth factors
 Growth factors control the growth and reproduction of
different stem cells
 Another group of growth factors ( differentiation
inducers) control the differentiation process.
 Each of the differentiation inducers cause the one type of
committed stem cells to differentiate one or more step
towards the final cell type
 responsible for basal hematopoiesis and maintaining
blood counts in normal ranges
Hematopoiesis
ERYTHROPOIESIS
GRANULOPOIESIS
GROWTH
FACTORS
MEGAKARYOPOIESIS
LYMPHOPOIESIS
generation of each specific lineage of mature blood cells is regulated
by a specific set of hematopoietic growth factors.
Hematopoietic growth factors
Growth Factors
Function: stimulate progenitor of
the followings:
GM-CSF (granulocytemacrophage CSF)
Granulocyte-monocyte
G-CSF (granulocyte CSF)
Granulocyte
M-CSF (macrophage CSF)
Monocyte
EPO (Erythropoietin)
Erythrocyte
IL-1,3,6 (Interleukin-3, 1, 6)
Myeloid lineage
TPO (Thrombopoietin)
Platelet
Sites of Hemopoietic Activity
Bone marrow
Yolk sac
Vertebra
Liver
Sternum
Rib
Spleen
Femur
Tibia
1
3
FETAL MONTHS
20
ADULT
Nutritional requirement of hematopoiesis
 Blood cell production (hematopoiesis) is a dynamic process that
requires the replenishment of more than 7 × 109 blood cells
(leukocytes, erythrocytes and platelets) per kg body weight per
day
 Therefore, as would be expected, their maturation and rate of production
are affected greatly by a person’s nutritional status.

o
o
o
Especially important to our discussion are :
Vitamin B12
Folic acid
Iron
Role of vitamin B12 and folic acid in synthesis
of cellular DNA**
**Bone marrow cellular elements are among the most rapidly
dividing cells in the body (because of continuous needed for RBCs
and WBCs).
Dividing cells needs continuous formation of DNA.
Both vit B12 and folic acid are needed for formation of thymidine
triphosphate (one of four nitrogen bases that form the DNA).
thymine
Role of vitamin B12 and folic acid in synthesis
of cellular DNA (cont.)**
**Because both Vitamin B12 and folic acid are needed for normal
formation of DNA, therefore nuclear maturation and cell division
of bone morrow cells (hematopoiesis) is not rapid and this leads to
larger cells (macrocytes).
The macrocytes have irregular ,oversized (large than normal) and
oval shape with fragile cell membrane.
Macrocytes are
red cells with an
increased size, 912µm in diameter
Abnormal cell membrane of RBCs leads to short life of RBCs.
Facts regarding Vitamin B12 (Cyanocobalamin )**
• Water soluble vitamin
• Vit B12 in diet can be destroyed by digestive enzymes. It is protected
by intrinsic factor
• Prolonged deficiency leads to irreversible neurological damage
• Its absorption from gatrointestinal tract (terminal ileum) needs
presence of intrinsic factor
• It is absorbed from terminal ileum with intrinsic factor by pinocytosis.
Sources of Vitamin B12
1.
2.
3.
4.
Fish
Eggs
Meat and liver
Dairy Products
** Dietary deficiency is
rare except in
vegetarians
Absorption of vitamin B12 (Cbl)
Dietary Cbl in the presence of acid and pepsin in the stomach is
liberated from binding to protein and then quickly binds to R factors
(Cbl -binding proteins) in saliva and gastric juice
R factor- Cbl complex is freed in the alkaline milieu of the duodenum by
the action of pancreatic proteases and then binds specifically and rapidly to
gastric-derived intrinsic factor (IF). IF is a 45 kDa glycoprotein with very high
affinity for Cbl.
The IF-Cbl complex binds to a specific ileal receptor, cubilin, from which it will be
absorbed into ileal enterocytes. Then it will exit into blood and bind to
transcobalamins II
This complex enters cells by receptor-mediated endocytosis.
Reference
Stanley L Schrier, MD
 The minimum amount of vitamin Cbl required each day to
maintain normal red cell maturation is only 1 to 3 micrograms
 Total body stores of Cbl are 2 to 5 milligrams, approximately
one-half of which is in the liver
 Therefore, 3 to 4 years of defective B12 absorption are
usually required to cause maturation failure anemia.
 Folic acid
 The daily folate requirement for unstressed adults is
estimated to be approximately 50mg/day
 Folate occurs in animal products and in leafy
vegetables in the polyglutamate form
 Dietary folate in the form of the polyglutamates is
cleaved to the monoglutamate in the jejunum where it
is absorbed
 Body stores are 5-10 mg (liver)
 Folate deficiency take place in a disease called sprue
Reference
Stanley L Schrier, MD
Megaloblastic anemia**
Both vitamin B12 and folate deficiency cause an identical
megaloblastic anemia
Pernicious anemia is due to primary deficiency of vitamin B12 secondary to failure of
vitamin B12 absorption from gastrointestinal tract. This absorption failure is due to
absence of intrinsic factor (atrophic gastric mucosa).
Megaloblastic anemia due to Deficiency of
vitamin B12
Causes of vitamin B12 deficiency:
1. Impaired absorption
a. Gastric atrophy: Auto immune disease can
destroys the parietal cells that secrete the I.F.
required for absorption of vit. B12.
b. Gastrectomy
c. Intestinal disease like ileal resection
in these cases treatment is
life long injections of
vitamin B12 (oral
administration wouldn't
be effecient!)
d. Infestation with Fish tapeworm (Diphyllobothrium latum)
2. Decreased vitamin B12 intake- seen in vegetarian
Iron metabolism
Iron is very important to our body:
Hemoglobin synthesis
It is an essential element of myoglobin, cytochromes,
cytochrome oxidase, peroxidase, catalase
Iron distribution in our body, total body Iron is 4-5 g:
65% of which is in the form of hemoglobin
4% myoglobin
1% various heme compounds
.1% plasma transferrin
15-30% is stored in reticuloendothelial cells and liver
parenchymal cells mainly in the form of ferritin
Daily iron loss average 1-2 mg
Man .6mg female about 1.3
Copyright © Cornell University
Iron absorption, transport and storage
Copyright © Cornell University
Iron uptake by erythroid progenitors
Copyright © Cornell University
Regulation of total body iron
Copyright © Cornell University
Physiology of Red Blood Cells (RBCs) Erythrocytes
 Structural characteristics
 Hemoglobin
 Erythropoiesis
 Erythrocytes destruction
 Anemia
 Polycythemia
Shape and Size of Red Blood Cells. 1 µm

No nucleus (anucleate) or organelles (no mitochondria,
no endoplasmic reticulum)
 biconcave discs having a mean diameter of about 7.8
micrometers and a thickness of 2.5 micrometers at the
thickest point and 1 micrometer or less in the center.
The average volume (MCV) of the red blood cell is 90
to 95 cubic micrometers (fL).
 The red blood cell is a “bag” that can be deformed into
almost any shape
 Filled with hemoglobin
 Concentration of Red Blood Cells in the Blood
Men 5,200,000 (±300,000); women, it is 4,700,000 (±300,000)
7.8
Quantity of Hemoglobin Hb in the Cells.
 RBCs concentrate Hb in their cytoplasm
 Each 100 ml of RBCs , the concentration of Hb is about 34g
(MCHC)
- This is the maximum metabolic limit and normal people always
Hb near the maximum value
- If hematocrit (Hct) is normal, then Hb is one third of Hct value
Hct =45% then Hb = 15
Each gram of Hb can bind 1,34 ml of O2
So 100 ml of blood carry 20 ml of O2 in man
Women the amount is less.
Production of Red Blood Cells
Erythropoiesis
•
•
•
In early weeks of pregnancy, a primitive nucleated
RBC are formed in yolk sac
Middle trimester of fetal life- Liver (mainly), spleen,
lymph nodes.
Last month of pregnancy and after birthexclusively from Bone marrow
Sites of RBC formation in different ages
0-5 Y …..all bones of the body
5-20 Y…. The shaft of long bones become
fatty and its contribution to form RBC
reduced gradually and stops completely
after 20 y. Heads of long bones continue to
form RBC
After 20 Y….. Almost in membranous
bones
Relative rates of RBC production in bone
marrow of different bones at different ages
Production of Red Blood Cells
Erythropoiesis
Stages of Differentiation of Red Blood Cells
The first cell that can be identified as
belonging to the red blood cell series is
the proerythroblast
The first-generation cells are called basophil
erythroblasts, very little hemoglobin
At the satge of reticulocytes, the nucleus
condenses to a small size, and its final
remnant is absorbed or extruded from the
cell. At the same time, the endoplasmic
reticulum is also reabsorbed
Reticulocytes pass from bone marrow into
blood capillaries by diapedesis
In the blood stream the remaining basophilic
material will disappear in 1-2 days and
mature erythrocytes will developed
Regulation of Red Blood Cell
 The total mass of red blood cells in the circulatory system
is regulated within narrow limits, so
(1) adequate red cells are always available to provide
sufficient transport of oxygen from the lungs to the tissues,
yet
(2) the cells do not become so numerous that they
impede blood flow.
 Any condition that causes the quantity of oxygen
transported to the tissues to decrease ordinarily
increases the rate of red blood cell production
- Anemia
These conditions produce tissues hypoxia leading to increase
- Bone marrow destruction
in RBCs production, Hct & total blood volume will increase
- Very high altitude
- Cardiac failure
- Lung disease
Regulation of Red Blood Cell Production—Role of
Erythropoietin
 How does hypoxia induce erythropoiesis?
Erythropoietin
 Erythropoietin is a glycoprotein with a molecular
weight of about 34,000.
 Produced mainly by the kidneys (90%) but the liver
produces some (10%).
 Produced in response to tissue hypoxia
 Renal tissue hypoxia leads to hypoxia inducible factor-1
(HIF-1
 HIF-1 stimulates erythropoietin production
Another factors increases erythropoietin production:
1. Androgen
2. alkalosis
3. Catecholamine
Effect of Erythropoietin in Erythrogenesis.
 Binding of erythropoietin on its
receptors activates the
transcription of antiapoptotic
molecules and inactivates the
proapoptotic proteins
 Erythropoietin receptors are
expressed on CFU-E and the
subsequent cells but are not
expressed on reticulocytes and
RBCs
S. Elliott et al./ Experimental Hematology 2008;36:1573–
1584
Effect of Erythropoietin in Erythrogenesis.
Erythropoietin will stimulate the production of
proerythroblasts
Will facilitate the passage of the RBC precursors from one
stage to another
There will be a negative feed back mechanism for
erythropoietin production when the O2 carrying capacity of
the blood is back to normal
Normal erythropoiesis requires amino acids, Vit. B12, Iron and folate in proper amounts
Formation of Hemoglobin
 Hb formation begins at the stage of proerythroblasts and continues to the stage of
reticulocytes
 Hemoglobin molecule
compose of 4
hemoglobin chains
 There are four different
chains of hemoglobin
(alpha, beta, gamma
and delta chain)
 Hemoglobin A (64,458)
is a combination of two
alpha and two beta
chain
About 300 million molecules of
HB in every red cell.
Each molecule of HB carries 4
oxygen O2 molecules.
Normal values:
Females: 14 g/100ml blood
Males: 15 g/100 ml blood
Oxygenated Hemoglobin
Bright Red (systemic)
*Deoxygenated Hemoglobin
dull (venous circulation)
Life Span of Red Blood Cells is About 120 Days
 Even erythrocytes are anucleated they have many cytoplasmic enzymes:
(1)maintain flexibility of the cell membrane
(2) maintain membrane transport of ions
(3) keep the iron of the cells’ hemoglobin in
the ferrous form rather than ferric form
(4) prevent oxidation of the proteins in the
red cells
 In old RBCs the enzymatic activity of these cells will drop dramatically, they
lose their flexibility and become increasingly rigid and fragile, and their
contained hemoglobin begins to degenerate.
Erythrocyte Destruction
• Macrophages in spleen, liver and red bone marrow
phagocytize dying RBC.
• Globin – breaks into amino acids, which can be reused to
produce other proteins
• Heme – iron and porphyrin
• Fe – removed and recycled in spleen
• Porphyrin – converted to bilirubin (bile pigment)
• Yellow pigment secreted by liver into bile, which is excreted in urine and
feces
Anemias
Anemia means deficiency of hemoglobin in the blood, which can be
caused by either
too few red blood cells
too little hemoglobin in the cells
decrease in blood’s oxygen-carrying capacity
Examples of Anemia :
1. Blood loss anemia: acute and chronic blood loss
2. Aplastic anemia lack of functioning bone marrow (aplasia) radiation,
chemotherapy, toxin material such as insecticides, autoimmune and
idiopathic
3. Megaloplastic anemia vit. B12, folic acid, pernicious anemia, sprue
4. Hemolytic anemia: hereditary spherocytosis, sickle cell anemia and
erythroblastosis fetalis
Effect of anemia on cardiovascular system**
Decreased
viscosity
anemia
Decreased
resistance to
blood flow
hypoxia
Dilatation of
blood vessels
What will happen during exercise?
More blood
returns to
the heart
More cardiac output
Polycythemia**
Primary polycythemia (polycythemia vera)
polycythemia
(Means increased RBCs no.)
Due to increased activity of hemocytoblastic cell of
bone marrow
Secondary polycythemia
Due to hypoxia, high altitudes and heart
failure
Effects of polycythemia on CVS*
Increased cardiac
output
Blood volume
Polycythemia Leads to
Increased venous
return
Hematocrit
viscosity
decreased blood flow
Decreased venous return
to the heart
Decreased cardiac output
Increased blood pressure
More O2 is extracted from Hb and thus
deoxygenated blood is increased leading
to bluish discoloration of the skin
(cyanosis)