Blood

• Blood is a highly differentiated, complex living
tissue that pulsates through the arteries to
every part of the body
• It interacts with individual cells via an
extensive capillary network
• Returns to the heart through the venous
system

• Many of functions undertaken in the
capillaries, where the blood flow slows
dramatically,
• This allows for diffusion and transport of
oxygen, glucose, and other molecules across
the monolayer of endothelial cells that form
the thin capillary walls

• In addn to transport, blood and the cells
within it mediate other essential aspects of
immunity and hemostasis
• human body is continually invaded by
pathogenic microorganisms that enter
through skin cuts, mucous membranes, and
other sites of infection and tissue disruption

• To oppose the microbes, the body has
developed a highly sophisticated immune
system.
• Cells of the immune system, the white blood
cells, are derived from bone marrow
precursors and are delivered to their sites of
action by blood

• These leukocytes, exert their effects in
conjunction with antibodies and protein cofactors
in blood
• The body is also threatened by consequences of
vascular leak or hemorrhage as a result of even
the most innocuous tissue injury.
• A highly organized clotting system, consisting of
blood platelets that work in conjunction with
blood plasma clotting factors, prevents excessive
fluid loss by rapidly forming a hemostatic plug.

• The platelets also release potent biological
cofactors during the development of the
hemostatic plug, which promote wound
healing, prevent further infection, and
promote the development and vascularization
of new tissue.

Functions of blood
• Transport of substances from one area of the
body to another
• Immunity, the body’s defense against disease
• • Hemostasis, the arrest of bleeding
• • Homeostasis, the maintenance of a stable
internal environment

Transport
• Blood carries products from one area of the
body to another, including CO₂, O₂, antibodies,
acids and bases, ions, vitamins, cofactors,
hormones, nutrients, lipids, gases, pigments,
minerals, and water.
• Transport is one of the primary and most
important functions of blood, and blood is the
primary

Immunity
• Blood leukocytes are involved in the body’s
battle against infection by microorganisms.
• Blood leukocytes, working in conjunction with
plasma proteins, continuously patrol for
microbial pathogens in the tissues and in the
blood.
• In most cases, penetrating microbes are
efficiently eliminated by the sophisticated and
elaborate antimicrobial systems of the blood

Hemostasis
• Bleeding is controlled by the process of
hemostasis.
• Complex and efficient hemostatic mechanisms
have evolved to stop hemorrhage after injury
• Their failure can quickly lead to fatal blood loss
• Both physical and cellular mechanisms participate
in hemostasis.
• These mechanisms, like those of the immune
system, are complex, interrelated, and essential
for survival

Homeostasis
• Homeostasis is a steady state that provides an
optimal internal environment for cell function
• By maintaining pH, ion concentrations,
osmolality, temperature, nutrient supply, and
vascular integrity, the blood system plays a
crucial role in preserving homeostasis.
• Homeostasis is the result of normal
functioning of the blood’s transport, immune,
and hemostatic systems.

• Plasma composed mostly of water (93%) with
various dissolved solutes, including proteins,
lipids (fats), carbohydrates, aa’s, vitamins
among others
• The solutes play crucial roles in homeostasis,
such as maintaining normal plasma pH and
osmolality

Blood cells
• 3 types
Erythrocytes (red blood cells),
Leukocytes (white blood cells), and
Platelets (thrombocytes).
• Each ml of blood contains
• 4 to 6 million RBC’s
• 4,500 to 10,000 WBC’s
• 50,000 to 400,000 platelets.
• There are several subtypes of leukocytes, defined
by morphological differences discussed later

Erythrocytes
• Erythrocytes are the most numerous cells in
blood.
• Are biconcave disks
• Lacking a nucleus with a diameter of about 7μm
and a maximum thickness of 2.5 μm.
• Shape optimizes the SA Increasing the efficiency
of gas exchange.
• They maintains the shape by virtue of complex
membrane skeleton, which consists of an
insoluble mesh of fibrous proteins attached to
the inside of the plasma membrane.

• This structural arrangement allows it great
flexibility as it twists and turns through small,
curved vessels.
• In addition to structural proteins of the
membrane, several functional proteins are
found in the cytoplasm of erythrocytes.
• These include hemoglobin (the major oxygen-
carrying protein), antioxidant enzymes, and
glycolytic systems to provide cellular energy

• In normal men, average number RBC’s per
cubic millimeter is 5,200,000 (±300,000);
• In women, about 4,700,000 (±300,000).
• Persons living at high altitudes have greater
numbers RBC’s
• RBC’s can concentrate hemoglobin in the cell
fluid up to about 34 grams in each 100
milliliters of cells

Red Blood Cells
• Erythrocytes
• Function is transportation of Oxygen
• Has other functions
• Carriage of carbon dioxide
• Acid base balance
• Biconcave discs
• Shape can change as they squeeze through
the capillaries

• Mean of 5.2 million +/- 300,000 in normal men
and about 4.7 +/- 300,000 in women
• People at higher attitudes have more RBC’s
• Contain haemoglobin
• About 34g in 100ml of RBC’s
• When Hb defficient, the % of Hb in RBC’s may fall
below this value
• Volume of red cells may also decrease in case of
diminished Hb

• when Hb formation is deficient, the % of Hb in
the cells may fall considerably below this value,
and the volume of the red cell may also decrease
due diminished Hb to fill the cell.
• When the hematocrit (the % of blood that is
cells—normally, 40 to 45% ) and the quantity of
Hb in each respective cell are normal, the whole
blood of men contains an average of 15 grams Hb
per 100 ml of cells; and 14g per 100ml in women

• Hemoglobin, consists of a globin (or protein)
portion and four heme groups, the iron-
carrying portion.
• Has Mwgt of 64,500.
• This complex protein possesses 4 polypeptide
chains: two α globin molecules of 141 amino
acids each and two β globin chains each
containing 146 amino acid

• Some chemicals block the O₂ transporting
function of Hb.
• Carbon monoxide (CO) rapidly replaces oxygen
in HbO2, resulting in the formation of the
stable compound carboxyhemoglobin (HbCO).
• The formation of HbCO accounts for the
asphyxiating properties of CO.

Erythrocyte destruction
• RBC’s circulate for about 120 days after
release from bone marrow.
• Some of the old cells break up (hemolyze) in
bloodstream, but majority are engulfed by
macrophages in the monocyte-macrophage
system.
• The Hb once released on destruction of RBC’s
is metabolically catabolized and eventually
reused in the synthesis of new Hb

Copyright 2009, John Wiley & Sons, Inc.
Shapes of RBC and Hemoglobin

Production of RBC’s
• In the early weeks of embryonic life, primitive,
nucleated RBC’s produced in the yolk sac.
• In mid trimester of gestation, mainly from liver
with some from spleen and lymph nodes.
• In last month of gestation and after birth,
produced exclusively in the bone marrow
• Produced in bone marrow of all bones till 5
years of age

Pluripotential Hematopoietic Stem Cells,
Growth Inducers, and Differentiation Inducers
• All blood cells begin their lives in the bone
marrow from a single type of cell called the
pluripotential hematopoietic stem cell (PPSC)
• As these cells reproduce, a small portion of
them remains exactly like the original PPSC
and is retained in the bone marrow to
maintain a supply of these, though their
numbers diminish with age

• most of the reproduced cells, then
differentiate to form the other cell types
• The intermediate stage cells are very much
like the PPSC, even though they have already
become committed to a particular line of cells
and are called committed stem cells.

• Growth inducers promote growth but not
differentiation of the cells.
• This is the function of another set of proteins
called differentiation inducers.
• Each of these causes one type of committed
stem cell to differentiate one or more steps
toward a final adult blood cell

• Formation of the growth and differentiation
inducers is itself controlled by factors outside the
bone marrow.
• For RBC’s, exposure of the blood to low O₂ for a
long time results in growth induction,
differentiation, and production of greatly
increased numbers of RBC’s
• In case of some WBC’s, infectious diseases cause
growth, differentiation, and eventual formation
of specific types of WBC’s needed to combat each
infection

HEMATOLOGY
Hematopoiesis
• In humans, occurs in bone marrow
exclusively
• All cellular elements derived from
pluripotent stem cell (PPSC)
• PPSC retains ability to both replicate itself
and differentiate
• Types of differentiation determined by the
influence of various cytokines

Formation of Blood Cells
• Stem cells in bone marrow
– Reproduce themselves
– Proliferate and differentiate
• Cells enter blood stream through sinusoids
• Formed elements do not divide once they
leave red bone marrow

Formation of Blood Cells
• Pluripotent stem cells produce
– Myeloid stem cells
• Give rise to red blood cells, platelets, monocytes, neutrophils,
eosinophils and basophils
– Lymphoid stem cells give rise to
• Lymphocytes
• Hemopoietic growth factors regulate differentiation and
proliferation
– Erythropoietin – RBCs
– Thrombopoietin – platelets
– Colony-stimulating factors (CSFs) and interleukins – WBCs

Erythropoiesis
– Starts in red bone marrow with
proerythroblast
– Cell near the end of development ejects
nucleus and becomes a reticulocyte
– Develop into mature RBC within 1-2 days
– Negative feedback balances production with
destruction
– Controlled condition is amount of oxygen
delivery to tissues
– Hypoxia stimulates release of erythropoietin

• in the bone marrow from a single type of cell
called the pluripotential hematopoietic stem
cell, from which all the cells of the circulating
blood are eventually derived.
• For RBC’s, differentiate to stem cell called
colony-forming unit–erythrocyte (CFU-E)
• Differentiates through several types of cells till
RBC’s formed

• High reticulocyte count in
• Acute bleeding
• Chronic blood loss
• Hemolytic anemia
• Erythroblastocis fetalis
• Kidney disease

• Low reticulocyte count
• Iron deficiency anemia
• Aplastic anemia
• Folic acid deficiency anemia
• Pernicious anemia
• Bone marrow failure due to drug toxicity
• Side effects due to radiation therapy

RBC Disorders
• 3 reasons
• 1) Increased RBC Destruction (Hemolytic anemia).
• 2) Decreased RBC Production
• 3) Blood Loss .

Increased RBC Destruction
• 1-Anemias secondary to membrane disorders
(herditary spherocytosis, hereditary
elliptocytosis)
• 2- Enzyme deficiencies (Glucose-6-phosphate
dehydrogenase, pyruvate kinase).
• 3- Hemoglobin Abnormalities
(hemoglobinopathies).
• 3- Antibody mediated destruction
• 4- Mechanical trauma

• Increased destruction of red blood cells in the
peripheral blood without evidence of ineffective
erythropoiesis is known as hemolytic anemia.
• Normally when the RBCs become senescent (after
120 days) they are removed from the peripheral
blood by macrophages in the spleen and liver.
• Hemolysis is the premature destruction of RBCs
due to intrinsic inherited defects in the RBCs or
because of acquired intravascular abnormalities.

• The principal stimulus RBC production in low
oxygen states is a circulating hormone called
erythropoietin,
• It is a glycoprotein wght of about 34,000.
• In its absence hypoxia has little or no effect in
stimulating RBC pd’n
• When erythropoietin system is functional,
hypoxia causes a marked increase in
erythropoietin production, and the
erythropoietin in turn enhances RBC production
until the hypoxia is relieved

• About 90% all erythropoietin is formed in the
kidneys with remainder formed mainly in the
liver.
• Not known exactly where in the kidneys the
erythropoietin is formed.
• Likely that the renal tubular epithelial cells
secrete the erythropoietin, because anemic blood
is unable to deliver enough oxygen from the
peritubular capillaries to the highly oxygen-
consuming tubular cells, thus stimulating
erythropoietin production.

• Hypoxia in other parts of the body, but not in the
kidneys, stimulates kidney erythropoietin secretion,
suggesting presence of other nonrenal sensor that
sends additional signal to kidneys to produce the
hormone.
• Both norepinephrine and epinephrine and
prostaglandins stimulate erythropoietin production.
• When both kidneys removed or when the kidneys are
destroyed by renal disease, person invariably becomes
very anemic since the because the 10% formed in
other tissues sufficient for only 1/3 to ½ RBC
Formation needed by the body.

• Due to continuous need to replenish RBC’s,
the erythropoietic cells of the bone marrow
are among the most rapidly growing and
reproducing cells in entire body
• As such, their maturation and rate of
production are affected greatly by a person’s
nutritional status.

• Esp important for final maturation of RBC’s are 2
vitamins, B12 and folic acid.
• Both essential for the DNA synthesis since in a
different way is required for the formation of
thymidine triphosphate, one of the essential
building blocks of DNA.
• As such, lack of either 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, in addition
to failing to proliferate rapidly, produce mainly larger
than normal RBC’s called macrocytes,
• The cell has a flimsy membrane, often irregular, large,
and oval instead of the usual biconcave disc.
• After entering the circulation, they are capable of
carrying oxygen normally, but their fragility causes
them to have a short life, ½ to 1/3 normal.
• As such, deficiency of either B12 or folic acid causes
maturation failure in the process of erythropoiesis.

• Common cause of maturation failure is lack of
absorption of Vit B12 (Pernicious Anemia)
• Parietal cells in stomach mucosa secrete
Intrinsic factor (IF) which binds to Vit B12
protecting it from digestion in stomach for
later absorption in ileum
• Lack of IF as in atrophic gastric mucosa will
lead to pernicious anemia

• Folic acid is a normal constituent of green
vegetables, some fruits, and meats (especially
liver).
• It is easily destroyed during cooking.
• Also, people with gastrointestinal absorption
abnormalities, such as the sprue, often have
difficulty absorbing both folic acid and vit B12.
• Therefore, in many instances of maturation
failure, the cause is deficiency of intestinal
absorption of both folic acid and vitamin B12.

• Blood loss anemia
• After rapid hemorrhage, body replaces the fluid
portion of the plasma in 1 to 3 days,
• This leaves a low conc’n of RBC’s
• If a 2nd hemorrhage does not occur, the RBC conc’n
returns to normal within 3 to 6 weeks.
• In chronic blood loss, a person frequently cannot
absorb enough iron from GIT to form Hb as rapidly as it
is lost.
• RBC’s that are much smaller than normal with too little
Hb inside them are formed giving rise to microcytic,
hypochromic anemia,

• Aplastic Anemia.
• Bone marrow aplasia means lack of functioning
bone marrow.
• Eg, A person exposed to γ radiation from a
nuclear bomb blast can sustain complete
destruction of bone marrow, followed in a few
weeks by lethal anemia.
• Excessive x-ray treatment, certain industrial
chemicals, and even drugs to which the person
might be sensitive can cause the same effect.

Megaloblastic Anemia.
• Lack of any of Vit B12, folic acid, and IF from the stomach mucosa, leads
to slow reproduction of erythroblasts in the bone marrow.
• As a result, the RBC’s grow too large, with odd shapes, and are called
megaloblasts.
• Thus, atrophy of the stomach mucosa, as occurs in pernicious anemia, or
loss of the entire stomach after surgical total gastrectomy can lead to
megaloblastic anemia.
• Also, patients who have intestinal sprue, in which folic acid, vitamin B12,
and other vitamin B compounds are poorly absorbed, often develop
megaloblastic anemia.
• In these states the erythroblasts cannot proliferate rapidly enough to form
normal numbers of RBC’s,
• The RBC’s formed are mostly oversized, have bizarre shapes, and have
fragile membranes.
• They rupture easily, leaving the person in dire need of an adequate
number of red cells.

Hemolytic Anemia
• Different abnormalities of the RBC’s, many of
which are hereditarily acquired, make the cells
fragile, so that they rupture easily as they go
through the capillaries, especially through the
spleen.
• Though the no. RBC’s formed may be normal,
the life span of the fragile red cell is so short
that the cells are destroyed faster than they
can be formed, and serious anemia results.

• Some of these types of anemia are
Hereditary spherocytosis:
• RBC’s are very small and spherical rather than
being biconcave discs.
• Cells cannot withstand compression forces since
they don’t have the normal loose, baglike cell
membrane structure of the biconcave discs.
• On passing through the splenic pulp and some
other tight vascular beds, they are easily ruptured
by even slight compression.

• In sickle cell anemia, cells have an abnormal type
of Hb, HbS , containing faulty beta chains in the
Hb molecule
• When this Hb is exposed to low conc’n of oxygen,
it precipitates into long crystals inside the RBC’s
• These crystals elongate the cell and give it the
appearance of a sickle other the biconcave
• The precipitated Hb also damages the cell
membrane with the cells becoming highly fragile,
leading to serious anemia.

• The patients frequently experience a vicious circle
of events called a sickle cell disease “crisis,” in
which low oxygen tension in the tissues causes
sickling, which leads to ruptured RBC’s, which
causes a further decrease in oxygen tension and
still more sickling and red cell destruction.
• Once the process starts, it progresses rapidly,
eventuating in a serious decrease in red blood
cells within a few hours and, often, death.

• Hereditary spherocytosis is characterized by
numerous spherocytes
• Caused by a molecular defect in one or more
of the proteins of the red blood cell
cytoskeleton
• Spherocytes have reduced surface membrane
area relative to the RBC volume.
• Results in hemolysis

• Glucose-6-phosphate dehydrogenase (G-6-PD)
deficiency is the most common enzyme
deficiency known to cause hemolysis.
• G-6-PD reduces NADP (nicotinamide-adenine
dinucleotide phosphate) to NADPH. • NADPH
reduces oxidized glutathione (GSSH) to its
reduced form GSH.
• GSH prevents oxidation of RBC membranes and
hemoglobin.
• Leads to hemolysis

Decreased RBC Production
1. Microcytic anemias which is anemia secondary to
decreased hemoglobin synthesis due to iron
deficiency. RBC’s are small and often hypochromic
2. Thalessemia, an inherited inherited genetic disorder
where abnormal Hb produced. This leads to hemolysis
of the RBC’s
3. Megaloblastic anemia where there is abnormalities of
DNA synthesis bue to lack of Vitamin B12 and/ or Folic
acid. Characterized by many large immature and
dysfunctional red blood cells- megaloblasts, in the
bone marrow.

• Aplastic anemia where there are
abnormalities of hematopoietic stem cell as in
aplastic anemia.
• May be caused by exposure to certain
chemicals, drugs, radiation, infection, immune
disease but cause is mostly unknown
• Will also affect production of other blood cells
• .

• Abnormalities of RBC precursors proliferation,
and failure of differentiation as in anemia of
chronic renal failure

• Decreased RBC production may result from a
• • Defective stem cell (aplastic anemia).
• lack of a necessary structural component (eg,
iron deficiency anemia).
• lack of an vitamin (Vitamin B12)
• unknown causes (anemia of chronic disease)

Anaemia
• Anemia is not a specific disease.
• Anemia can be defined as a reduction in the
haemoglobin concentration of the blood.
• Symptoms include fatigue, weakness, Fainting
, decreased appetite and occasionally chest
pain, shock or congestive heart failure.
• Physical signs of anemia are manifest by pallor
of the skin, nail beds, and mucous membranes
(conjunctiva). •

• It is critical to determine the cause of the
anemia.
• The most useful parameters of the Complete
Blood Count (CBC) to diagnose anemia are:
1-The Hematocrit (Hct)
2-Hemoglobin (Hgb)
3-Mean Corpuscular Volume (MCV).

Blood Groups and Blood Types
• Agglutinogens – surface of RBCs contain
genetically determined assortment of antigens
• Blood group – based on presence or absence
of various antigens
• At least 24 blood groups and more than 100
antigens
– ABO and Rh

ABO Blood Group
– Based on A and B antigens
– Type A blood has only antigen A
– Type B blood has only antigen B
– Type AB blood has antigens A and B
• Universal recipients – neither anti-A or anti-B
antibodies
– Type O blood has neither antigen
• Universal donor
– Reason for antibodies presence not clear

Antigens and Antibodies of ABO Blood Types

Red Blood Cell Antigens and
Blood Typing

ABO System
• There are several groups of red blood cell
antigens, but the major group is known as
ABO system
• In terms of the antigens present on the red
blood cell surface , a person may be :
Type A – with only A antigens
Type B – with only B antigens
Type AB – with both A and B antigens
Type O – with neither A nor B antigens

Type A – with only B antibodies
Type B – with only A antibodies
Type AB – with neither A nor B antibodies
Type O – with both A and B antibodies
Plasma Antibodies

Rh ( Rhesus ) factor
• Another group of antigens found on the red
blood cells
• People who have these antigens are said to be
Rh positive, whereas those who do not are Rh
negative

Hemolytic Disease
• Rh blood group
– People whose RBCs have the
Rh antigen are Rh+
– People who lack the Rh
antigen are Rh-
– Normally, blood plasma does
not contain anti-RH
antibodies
– Hemolytic disease of the
newborn (HDN) – if blood
from Rh+ fetus contacts Rh-
mother during birth, anti-Rh
antibodies made
• Affect is on second Rh+ baby

Erythrocyte Sedimentation Rate
• Almost any acute stress to the body (trauma,
infection, disease) induces a reaction called the
acute-phase response.
• In course of several hours, in response to infl
ammatory cytokines, liver rapidly synthesizes and
secretes into blood a no. of proteins that aid in
the host response to the threat.
• Among the proteins is fibrinogen, which causes
RBCs to cluster and increases their effective
density.

• When anticoagulated blood from a patient with
hyperfi brinogenemia is placed in a glass tube,
the RBCs fall more quickly under the influence of
gravity than when the blood is from a healthy
subject.
• After an hour, this sedimentation leaves a layer of
clear plasma on the top of the tube (≤15 mm
thick for normal blood and often >40 mm thick in
certain infl ammatory disorders).
• This rate of fall is called the erythrocyte
sedimentation rate (ESR)

• Although it is nonspecifi c because so many different
conditions can cause it to increase, the ESR is still widely
used by clinicians to assess the presence and severity of
inflammation.
• Is a simple technique, easily performed in a physician’s
office.
• As an example of its utility, a patient with an inflammatory
process that naturally waxes and wanes, such as lupus
erythematosus, may present with nonspecific complaints
such as fatigue, weakness, and achiness.
• An elevated ESR would suggest that these complaints are
due to the reactivation of the disease and not just to a poor
night’s sleep or depression

References
• Guyton, Textbook of Medical Physiology
• John Wiley & Sons Publications
• Ganong Review of Medical Physiology

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