BLOOD
• Enormous importance in the practice of
medicine
• Clinicians examine it more often than any
other tissue when trying to determine the
cause of disease in their patients
BLOOD
COMPOSITION AND FUNCTIONS
• Components:
– Although blood appears to be a thick, homogeneous
liquid, the microscope revels that it has both cellular
and liquid components
– Blood is a specialized connective tissue consisting
of living cells, called formed elements, suspended in a
nonliving fluid matrix, blood plasma
– The collagen and elastic fibers typical of other
connective tissues are absent from blood, but
dissolved fibrous proteins become visible as
fibrin strands during blood clotting
WHOLE BLOOD
•
Blood that has been centrifuged
separates into three layers:
– Erythrocytes: 42 to 47%
• Red blood cells that transport
oxygen
– Buffy coat: less than 1%
• Thin, whitish layer
• Leukocytes: WBC
• Platelets: cell fragments that help
stop bleeding
– Plasma: 55%
•
The blood hematocrit represents
the percentage of erythrocytes in
whole blood
– Male: 47% +/- 5%
– Female: 42% +/- 5%
PHYSICAL CHARACTERISTICS
BLOOD
• Sticky, opaque fluid with a characteristic metallic
taste (salty taste)
• Color:
– Oxygen-rich: scarlet
– Oxygen-poor: dark red
• Higher density and viscosity than water, due
to the presence of formed elements
• Blood is slightly basic (alkaline):
– pH= 7.35-7.45
• Temperature: 380C or 100.40F
– Always slightly higher than body temperature
BLOOD VOLUME/WEIGHT
• Accounts for about 8% of body weight
• Average volume in healthy adult:
– Male: 5-6 L (about 1.5 gallons)
– Female: 4-5 L (about 1.2 gallons)
• About 7% to 8% of the body weight
– Human of about 150 lbs: 11 pounds of blood
BLOOD FUNCTIONS
• Distribution: Distribution functions of
blood include:
– Medium for delivery of oxygen (from lungs)
and nutrients (from digestive system)
– Removal of metabolic wastes from cells to
elimination sites (to the lungs for elimination
of carbon dioxide, and to the kidneys for
disposal of nitrogenous wastes in urine)
– Transporting hormones from the endocrine
organs to their target organs
BLOOD FUNCTIONS
• Regulation: Regulatory functions of blood include:
– Maintaining appropriate body temperature by absorbing and
distributing heat throughout the body and to the skin surface to
encourage heat loss
• Water has a high specific heat
– Maintaining normal pH in body tissues
• Many blood proteins and other bloodborne solutes act as buffers to
prevent excessive or abrupt changes in blood pH that could
jeopardize normal cell activities
• Acts as the reservoir for the body’s “alkaline reserve” of bicarbonate
atoms
– Maintaining adequate fluid volume in the circulatory system
• Salts and blood proteins act to prevent excessive fluid loss from the
blood into tissues
– Fluid volume in the blood vessels remains ample to support efficient
blood circulation to all parts of the body
BLOOD FUNCTIONS
• Protection: Protective functions of
blood include:
– Preventing blood loss:
• When a blood vessel is damaged, platelets and
plasma proteins initiate clot formation, halting
blood loss (clotting mechanism)
– Preventing infection:
• Drifting along in blood are antibodies, complement
proteins, and white blood cells, all of which help
defend the body against foreign invaders such as
bacteria and viruses (immune system)
BLOOD PLASMA
•
•
•
•
•
Straw-colored, sticky fluid
Mostly water (90%)
Contains over 100 different dissolved solutes including nutrients, gases, hormones,
wastes, products of cell activity, ions, and proteins
Plasma proteins account for 8% of plasma solutes
– Except for hormones and gamma globulins, most plasma proteins are produced by the liver
– Serve a variety of functions
• 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 oxygen
– Albumin accounts for some 60% of plasma protein
• Acts as a carrier of certain molecules
• Contributes to the osmotic pressure (pressure that helps to keep water in the
bloodstream)
– Sodium ions are the other major solute contributing to blood osmotic pressure
Kept relatively constant by various homeostatic mechanisms
– Example:
• When blood protein drops, the liver makes more protein
• When blood becomes too acidic (acidosis), both the respiratory system and the kidneys
are called into action to restore plasma’s normal, slightly alkaline pH
FORMED ELEMENTS
• Erythrocytes, leukocytes, and platelets, have
some unusual features
– 1. Two are not even true cells
• Erythrocytes have no nuclei or organelles
• Platelets are cell fragments
• Only leukocytes are complete cells
– 2. Most survive in the bloodstream for only a few days
– 3. Most blood cells do not divide
• They are continuously renewed by division of cells in bone
marrow, where they originate
STAINED BLOOD
WRIGHT’S STAIN
STAINED BLOOD
WRIGHT’S STAIN
• A stained smear of
human blood under
the microscope:
– Disc-shaped red
blood cells
– Spherical white
blood cells
– Scattered platelets
that look like debris
ERYTHROCYTES
• Red blood cells (RBC):
– Small cells that are
biconcave discs—flattened
discs with depressed
centers
• Thin centers appear lighter in
color than their edges
– They lack nuclei (anucleate)
and most organelles, and
contain mostly hemoglobin
(Hb)
• Hemoglobin is an oxygenbinding protein pigment that is
responsible for the transport
of most of the oxygen in the
blood
• Hemoglobin is made up of the
protein globin bound to the
red heme pigment
ERYTHROCYTES
• Red Blood Cell:
– Other proteins act as
antioxidant enzymes that rid
the body of harmful oxygen
radicals
– Most of the other proteins
function mainly to maintain the
plasma membrane or promote
changes in RBC shape
• Spectrin:
– Flexible network of proteins
that maintains the shape of
RBC
– Gives flexibility to change
shape as needed (twisting
and turning as RBC passes
through capillaries with
diameters smaller than
RBC)
ERYTHROCYTES
• Pick up oxygen in the capillary beds of the lungs and releases
it to tissue cells across other capillaries throughout the body
• Transports some 20% of the carbon dioxide released by tissue
cells back to the lungs
• Structural characteristic contributes to its gas transport
functions:
– 1. Small size and biconcave shape provide a huge surface area relative
to volume (30% more surface area than comparable spherical cells
• Because no point within its cytoplasm is far from the surface, the biconcave
disc shape is ideally suited for gas exchange
– 2. Discounting water content, an erythrocyte is over 97% hemoglobin,
the molecule that binds to and transports respiratory gases
– 3. Because erythrocytes lack mitochondria and generate ATP by
anaerobic mechanisms, they do not consume any of the oxygen they
are transporting, making them very efficient oxygen transporters
ERYTHROCYTES
ELECTRON MICROGRAPH
of
ERYTHROCYTES
ERYTHROCYTES
• Major factor contributing to blood viscosity (state of
being sticky, gummy, gelatinous):
– Women typically have a lower RBC count than men
• Female:
– 4.3 to 5.2 million/cubic millimeter (million/mm3)
» 1 ml / cc / cm3 = 1,000 mm3
» 4.3 to 5.2 billion/ml
• Male:
– 5.1 to 5.8 million/cubic millimeter (million/mm3)
» 1 ml / cc / cm3 = 1,000 mm3
» 5.1 to 5.8 billion/ml
– When the number of RBC increases beyond the normal
range, blood viscosity rises and blood flows more slowly
– When the number of RBC drops below the lower end of the
range, the blood thins and flows more rapidly
HEMOGLOBIN
• Protein that makes RBC bind easily and
reversible with oxygen
• Most oxygen carried in the blood is
bound to hemoglobin
• Normal values are:
• 14-20 grams per 100 ml of blood (14-20g/100 ml)
in infants
• 13-18 g/100 ml in adult males
• 12-16 g/100 ml in adult females
HEMOGLOBIN
HEMOGLOBIN
•
•
•
•
•
Made up of the protein globin
bound to the red heme pigment
Globin consists of four
polypeptide chains—two alpha
and two beta—each bound to a
ringlike heme group
Each heme group bears an
atom of iron set like a jewel in
its center
Since each iron atom can
combine reversibly with one
molecule of oxygen, a
hemoglobin molecule can
transport 4 molecules of
oxygen
A single RBC contains about
250 million hemoglobin
molecules, so each of these tiny
cells can transport about 1
billion molecules of oxygen
HEMOGLOBIN
• The fact that hemoglobin is contained
in erythrocytes, rather than existing
free in plasma, prevents it:
– 1. From breaking into fragments that would
leak out of the bloodstream (through the
rather porous capillary membranes)
– 2. From contributing to blood viscosity and
osmotic pressure
HEMOGLOBIN
• In the lungs, oxygen binds to iron, the
hemoglobin, now called oxyhemoglobin,
assumes a new three-dimensional shape
and becomes ruby (bright) red
• In the tissues, oxygen detaches from
iron, hemoglobin resumes its former
shape, and the resulting
deoxyhemoglobin, or reduced
hemoglobin, becomes dark red
HEMOGLOBIN
• About 20% of the carbon dioxide
transported in the blood combines with
hemoglobin
• Binds to globin’s amino acids rather
than with the heme group forming
carbaminohemoglobin
– Occurs more readily when hemoglobin is in
the reduced state (dissociated from oxygen)
HEMOGLOBIN
PRODUCTION OF ERYTHROCYTES
•
Hematopoiesis, or blood cell
formation, occurs in the red
bone marrow:
– Bones of the axial skeleton and
girdles, and in the proximal
epiphyses of the humerus and
femur
•
Erthropoiesis, the formation of
erythrocytes, begins when a
myeloid stem cell is transformed
to a proerythroblast, which
develops into mature erythrocytes
– Process takes about 5-7 days
– On average, the marrow turns out
an ounce of new blood containing
some 100 billion new cells each
and every day
ERYTHROPOIESIS
Regulation and Requirements
for
Erythropoiesis
• Number of circulating erythrocytes is remarkably constant and
reflects a balance between red blood cell production and
destruction:
– Balance is important because:
• Too few erythrocytes leads to tissue hypoxia (oxygen deprivation)
• Too many makes the blood undesirably viscous
– To ensure that the number of erythrocytes in blood remains within the
homeostatic range, new cells are produced at the incredibly rapid
rate of more than 2 million per second in healthy people
• Erythrocyte production is controlled by the hormone
erythropoietin
• Dietary requirements for erythrocyte formation include iron, vitamin
B12 and folic acid, as well as proteins, lipids, and carbohydrates
• Blood cells have a short life span due to the lack of nuclei and
organelles; destruction of dead or dying blood cells is
accomplished by macrophages
Hormonal Controls
for
Erythropoiesis
•
Direct stimulus for erythrocyte formation
is provided by erythropoietin (EPO), a
glycoprotein hormone:
– Normally, a small amount of EPO
circulates in the blood at all times and
sustains red blood cell production at a
basal rate
– The liver produces some EPO
– The kidneys play the major role in EPO
production
• When kidney cells become
hypoxic (inadequate oxygen), they
accelerate their release of
erythropoietin
– The male sex hormone testosterone
also enhances EPO production by the
kidneys
• Because female sex hormones do
not have similar stimulatory
effects, testosterone may be at
least partially responsible for the
higher RBC counts and
hemoglobin levels seen in males
– A wide variety of chemicals released by
leukocytes, platelets, and even reticular
cells stimulates bursts of RBC
production
ERYTHROPOIETIN MECHANISM
Hormonal Controls
for
Erythropoiesis
• The drop in normal blood
oxygen levels that triggers
EPO formation can result
from:
• 1. Reduced numbers of RBC
due to hemorrhage or excess
RBC destruction
• 2.Reduced availability of
oxygen, as might occur at high
altitudes or during pneumonia
• 3.Increased tissue demands
for oxygen (common in those
who engage in aerobic
exercise)
Hormonal Controls
for
Erythropoiesis
•
•
Too many erythrocytes or
excessive oxygen in the
bloodstream depresses
erythropoietin production
It is NOT the number of
erythrocytes in blood that
controls the rate of
erythropoiesis
– Control is based on their ability
to transport enough oxygen to
meet tissue demands
•
Hypoxia (oxygen deficit) does
NOT activate the bone marrow
directly
– Instead it stimulates the kidneys,
which in turn provide the hormonal
stimulus that activates the bone
marrow
HOMEOSTATIC IMBALANCE
• Renal dialysis patients whose kidneys have failed
produce too little erythropoietin (EPO) to support normal
erythropoiesis
– They routinely have RBC counts less than half that of healthy
individuals
– Genetically engineered (recombinant) EPO has helped such
patients immeasurably and has also become a substance of
abuse in athletes—particularly in professional bike racers
and marathon runners seeking increased stamina and
performance
• Consequence could be deadly:
– By injecting EPO, healthy athletes increase their normal RBC
volume from 45% to as much as 65%
– Then, with dehydration that occurs in a long race, the blood
concentrates even further, becoming a thick, sticky “sludge” that
can cause clotting, stroke, and even heart failure
Dietary Requirements
for
Erythropoiesis
•
•
Raw materials required for erythropoiesis include the usual nutrients
and structural material—proteins, lipids, and carbohydrates
Iron is essential for hemoglobin synthesis
– 65% of the body’s iron supply is in hemoglobin
– Remainder is stored in the liver, spleen, and bone marrow
– Because free iron ions (Fe2+, Fe3+) are toxic
• Iron is stored in cells as protein-iron complexes such as ferritin and hemosiderin
• In blood, iron is transported loosely bound to a transport protein called transferrin
•
Small amounts of iron are lost each day in feces, urine, and
perspiration
– Male: 0.9 mg/daily
– Female: 1.7mg/daily
• In woman, the menstrual flow accounts for the additional losses
•
Two B-complex vitamins—vitamin B12 and folic acid—are necessary
for normal DNA synthesis
– Even slight deficits jeopardize rapidly dividing cell populations, such as
developing erythrocytes
Fate and Destruction
of
Erythrocytes
•
•
The anucleate condition of
erythrocytes carries with it
some important limitations
RBCs:
– Are unable to synthesize new
proteins, to grow, to divide
– Become old as they lose their
flexibility and become increasingly
rigid and fragile, and their
contained hemoglobin begins to
degenerate
– Useful life span of 100 to 120
days, after which they become
trapped and fragment in smaller
circulatory channels,
particularly in those of the
spleen (RBC graveyard)
LIFE CYCLE
OF
RED BLOOD CELLS
Fate and Destruction
of
Erythrocytes
•
Dying RBC are engulfed and
destroyed by macrophages
– Heme of their hemoglobin is split
off from globin
– Iron is salvaged, bound to protein
(as ferritin or hemosiderin), and
stored for reuse
– Balance of the heme group is
degraded to bilirubin, a yellow
pigment that is released to the
blood and binds to albumin for
transport:
• Picked up by the liver cells, where
it is metabolized to urobilinogen
– Most of this degraded pigment
leaves the body in feces, as a
brown pigment called stercobilin
– The protein (globin) part of
hemoglobin is metabolized or
broken down to amino acids,
which are released to the
circulation
ERYTHROCYTES DISORDERS
ANEMIAS
• Condition in which the blood has
abnormally low oxygen-carrying
capacity
– Inadequate to support normal metabolism
• It is a symptom of some disorder rather
than a disease in and of itself
– Individuals are fatigued, often pale, short of
breath, and chilly
ERYTHROCYTES DISORDERS
ANEMIAS
• An insufficient number of red blood
cells due to:
– Blood loss
– Excessive RBC destruction
– Bone marrow failure
ERYTHROCYTES DISORDERS
ANEMIAS
•
Hemorrhagic anemias:
– Results from blood loss
– Acute:
• Blood loss is rapid (stab wound)
– Chronic:
• Blood loss is slight but persistent
– Ulcer, hemorrhoids
•
Hemolytic anemias:
– Erythrocytes rupture, or lyse, prematurely
• Hemoglobin abnormalities, transfusion of mismatched blood, certain bacterial and
parasitic infections
•
Aplastic anemia:
– Destruction or inhibition of the red marrow by certain bacterial toxins, drugs, and
ionizing radiation
• Because marrow destruction impairs formation of all formed elements, anemia is just
one of its signs
• Defects in blood clotting and immunity are also present
– Blood transfusions are a temporary solution until a marrow transplant or umbilical
stem cell tranfusion can be performed
ERYTHROCYTES DISORDERS
ANEMIAS
• Low hemoglobin content: when hemoglobin molecules are
normal, but erythrocytes contain fewer than the usual number,
a nutritional anemaia is always suspected
– Iron-deficiency anemia:
• Generally a secondary result of hemorrhabic anemias
• Could also result from inadequate intake of iron-containing foods and
impaired iron intake
– Resulting erythrocytes produced are called microcytes (small and pale)
• Athlete’s anemia: temporary due to vigorous exercise, blood volume can
increase diluting the blood
– Quickly reverse in a day or so
– Pernicious anemia:
• Deficiency of vitamin B12
• Because meats, poultry, and fish provide ample amounts of the vitamin, diet
is rarely the problem except for strict vegatarians
• Deficient Intrinsic factor: A substance called intrinsic factor, produced by
the stomach mucosa, must be present for vitamin B12 to be absorbed by
intestinal cells
– Treatment with vitamin B12
ERYTHROCYTES DISORDERS
ANEMIAS
• Abnormal hemoglobin: usually a
genetic basis
– Thalassemias:
• People of Mediterranean ancestry
– One of the globin chains is absent or faulty
– Erythrocytes are thin, delicate, and deficient in
hemoglobin
– RBC count low
– Monthy transfusions
ERYTHROCYTES DISORDERS
ANEMIAS: Abnormal Hemoglobin
•
Sickle-cell anemia: results from a change in just 1 of the 287 amino
acids in a beta chain of the globin molecule
– Shape of the hemoglobin changes resulting in the RBC becoming crescent
shaped
– Any form of exercise:
• Stiff, deformed erythrocytes rupture easily and tend to dam up in small vessels
• Low oxygen delivery, leaving victim gasping and in pain
– Standard treatment: transfusion
ERYTHROCYTES DISORDERS
ANEMIAS: Abnormal Hemoglobin
• Sickle-cell anemia occurs chiefly in black
races who live in the malaria belt of Africa
and among their descendents:
– Malarian parasite does not survive in a sickle cell
since these cells loss potassium an essential element
for parasite survival
– Genetic recessive trait
– Since RBCs do not sickle in fetus: Genetic
engineering trying to reverse the gene back to its
infancy (before it activates) and block it
SICKEL CELL ANEMIA
ERYTHROCYTES DISORDERS
• Polycythemia is characterized by an abnormal
excess of RBCs
– Increase viscosity
– Most often a result of bone marrow cancer
• Secondary Polycythemias: results when less
oxygen is available or erythropoietin production
increases
– Appears in individuals living at high altitudes
• Normal physiological response to the reduced atmospheric
pressure and lower oxygen content of the air
BLOOD DOPING
• Practiced by some athletes
• Artificially induced polycythemia:
– Athelete’s red blood cells are drawn off and then reinjected
a few days before event:
• Because the erythropoietin mechanism is triggered shortly
after blood removal, the erythrocytes are quickly replaced
• Then, when the stored blood is reinfused, a temporary
polycythemia results
– Since red blood cells carry oxygen, the additional infusion
should translate into increased oxygen-carrying capacity
due to a higher hematocrit, and hence greater endurance
and speed
– Other than problems that might derive from increased blood
viscosity, such as, temporary high blood pressure or
reduced blood delivery to body tissues, blood doping
seems to work
– Banned in OLYMPICS
LEUKOCYTES
General Structural and Functional Characteristics
– White blood cells, are the only formed
elements that are complete cells, with
nuclei and the usual organelles and make
up less than 1% of total blood volume
– Less numerous than red blood cells
• 4800-10,800 WBCs/mm3
• 4.8-10.8 million/ml (cc)(cm3)
– Leukocytes are critical to our defense
against disease:
• Protect the body from damage by bacteria, viruses,
parasites, toxins, and tumor cells
LEUKOCYTES
General Structural and Functional Characteristics
• WBCs have the ability to slip out of the
capillary blood vessels—process called
diapedesis—and the circulatory system is
simply their means of transport to areas of
the body where they are needed to mount
inflammatory or immune responses
– Once out of the bloodstream, leukocytes move
through the tissue spaces by amoeboid motion
• Whenever WBC are mobilized for action, the
body speeds up their production and twice
the normal number may appear in the blood
within a few hours
LEUKOCYTES
General Structural and Functional Characteristics
• Group into two major
categories on the basis of
structural and chemical
characteristics:
– Granulocytes contain
obvious membrane-bound
cytoplasmic granules
– Agranulocytes lack
obvious granules
• Most abundant to the least
abundant:
– Never let monkeys eat
bananas
– Neutrophils,
lymphocytes, monocytes,
eosinophils, basophils
LEUKOCYTES
General Structural and Functional Characteristics
– Granulocytes are a main group of leukocytes
characterized as large cells with lobed nuclei
(rounded nuclear masses connected by
thinner strands of nuclear material) and visibly
staining granules, all are phagocytic
• Larger and much shorter lived than erythrocytes
• Their membrane-bound cytoplasmic granules stain
specifically with Wright’s stain
TYPES OF LEUKOCYTES
GRANULOCYTES
NEUTROPHILS(a)
•
•
•
•
Most numerous type of leukocyte (50%70%)
Twice as large as erythrocytes
Called neutrophils because their granules
take up both basic (blue) and acidic (red)
dyes
They are chemically attracted to sites of
inflammation and are active phagocytes:
– Especially partial to bacteria and some
fungi
– Killing bacteria is promoted by a
process called respiratory burst
• Oxygen is actively metabolized
to produce potent germ-killer
oxidizing substances such as
bleach (calcium hypochlorite)
and hydrogen peroxide, and
defensin-mediated lysis occurs
– Defensins form protein
spears that pierce holes in
the membrane of the
ingested foe
GRANULOCYTES
EOSINOPHILS(b)
•
•
•
•
•
•
Account for 2% to 4% of all leukocytes and
are approximately the size of neutrophils
Deep red nucleus usually resembles an oldfashioned telephone receiver (two lobes
connected by a broad band of nuclear
material)
Cytoplasmic Granules affinity for acid dye
(eosin)
Most important role is to attack parasitic
worms, such as flatworms (tapeworms
and flukes) and roundworms (pinworms:
rectal area eggs/bedding and
hookworms: lungs/ intestines) that are
too large to be phagocytized
– These worms are ingested in food
(especially raw fish) or invade the body
via the skin and then typically burrow
into the intestinal or respiratory
mucosae
Release enzymes from their cytoplasmic
granules onto the parasite’s surface,
digesting it away
Lessen the severity of allergies by
phagocytizing immune (antigen-antibody)
complexes involved in allergy attacks
and inactivating certain inflammatory
chemicals released during allergic
reactions
GRANULOCYTES
BASOPHILS(c)
•
•
•
Rarest WBC: 0.5% to 1%
Slightly smaller than neutrophil
Histamine-containing granules
have affinity for basic dyes
(basophil)
– Inflammatory chemical that acts
as a vasodilator (makes blood
vessels dilate) and attracts
other WBC to the inflamed site
• Drugs called antihistamines
counter this effect
•
Granulated cells (mast cells)
similar to basophils are found
in connective tissue
– Both bind to a particular
antibody (immunoglobin E) that
causes the cells to release
histamine
TYPES OF LEUKOCYTES
•
•
•
•
a: Neutrophil
b: Eosinophil
c: Basophil
d: Small
Lymphocyte
• e: Monocyte
AGRANULOCYTES
• Main group of lymphocytes that lack
visibly cytoplasmic staining granules
• Although they are similar structurally, they
are functionally distinct and unrelated
cell types:
• T lymphocytes directly attack viral-infected and
tumor cells; B lymphocytes produce antibody
cells
• Monocytes become macrophages and activate
T lymphocytes
AGRANULOCYTES
LYMPHOCYTES (d)
•
•
Account for 25% of WBC
Second most numerous
leukocytes in the blood
– Only a small proportion of them
(mostly the small lymphocytes)
are found in the bloodstream
– Most are in lymphoid tissue
(lymph nodes, spleen, etc.), where
they play a crucial role in immunity
•
•
•
Large, dark-purple nucleus that
occupies most of the cell volume
T lymphocytes (T cells) function
in the immune response by acting
directly against virus-infected
cells and tumor cells
B lymphocytes (B cells) give rise
to plasma cells, which produce
antibodies (immunoglobulins)
that are released to the blood
AGRANULOCYTES
MONOCYTES (e)
•
•
•
•
Account for about 3% to 8% of
WBCs
Largest leukocytes
Nucleus distinctively U or kidney
shaped
When circulating monocytes
leave the bloodstream and enter
the tissues, they differentiate
into highly mobile macrophages
with prodigious appetites:
– Actively phagocytic
– Crucial in the body’s defense
against viruses, certain
intracellular bacterial parasites,
and chronic infections such as
tuberculosis
– Important in activating
lymphocytes to mount the
immune response
Production and Life Span of
Leukocytes
• Leukopoiesis, the formation of white blood cells
– Is hormonally stimulated
– These hormones, released mainly by macrophages and T
lymphocytes, are glycoproteins that fall into two families of
hematopoietic factors, interleukins and colony-stimulating
factors (CSFs)
• Interleukins are numbered ( e.g., IL-3, IL-5)
• Most CSFs are named for the leukocyte population they stimulate
– Example: Granulocyte-CSF (G-CSF) stimulates production of
granulocytes
• Many of these hematopoietic hormones (erythropoietin (EPO) and
several of the CSFs) are used clinically to stimulate the bone
marrow in:
– Cancer patients who are receiving chemotherapy (which suppresses
the marrow)
– Marrow transplants
– AIDS patients
Production and Life Span of
Leukocytes
•
Leukopoiesis involves
differentiation of hemocytoblasts
along two pathways:
– Lymphoid stem cells which
produce lymphocytes
– Myeloid stem cells which give
rise to all other formed
elements
– Bone marrow stores mature
granulocytes and usually contains
10 to 20 times more granulocytes
than are found in the blood
• The normal ratio of
granulocytes to erythrocytes
produced is about 3:1
– Reflects the much
shorter life span (0.5 to
9.0 days) of the
granulocytes, most of
which die combating
invading microorganisms
LEUKOCYTE FORMATION
Production and Life Span of
Leukocytes
• Despite their similar
appearances, the two
types of agranulocytes
have very different
lineages
• Like granulocytes,
monocytes diverge
from common myeloid
stem cells
• Lymphocytes derive
from the lymphoid stem
cell
Leukocyte Disorders
• Leukopenia is an abnormally low white
blood cell count
– Commonly induced by drugs, particularly
glucocorticoids and anticancer agents
Leukocyte Disorders
•
•
•
•
•
Leukemia: refers to a group of cancerous conditions involving white blood
cells
Leukemias are clones of a single white blood cell that remain unspecialized
and divide out of control, impairing normal bone marrow function
The leukemias are named according to the abnormal cell type
primarily involved:
– Example:
• Myelocytic leukemia involves myeloblast descendants
• Lymphocytic leukemia involves the lymphocytes
Leukemia is:
– Acute (quickly advancing) if it derives from blast-type cells like
lymphoblast
• Primarily affect children
– Chronic (slowly advancing) if it involves proliferation of later cell stages
like myelocytes
• Seen more often in elderly people
Without therapy, all leukemias are fatal; only the time course differs
Leukocyte Disorders
• In all leukemias, the bone marrow becomes almost totally
occupied by cancerous leukocytes and immature WBCs flood
into the bloodstream
– Because the other blood cell lines are crowded out, severe anemia and
bleeding problems also result
• Other symptoms include fever, weight loss, and bone pain
• Although tremendous numbers of leukocytes are produced,
they are nonfunctional and cannot defend the body in the usual
way
– The most common causes of death are internal hemorrhage and
overwhelming infections
• Irradiation and administration of antileukemic drugs to destroy
the rapidly dividing cells have successfully induced remissions
(symptom-free periods) lasting from months to years
• Bone marrow or umbilical cord blood transplants are used in
selected patients when compatible donors are available
Leukocyte Disorders
• Infectious mononucleosis:
– Once called the “kissing disease”
– Highly contagious viral disease most often seen in
children and young adults
– Caused by the Epstein-Barr virus
– Excessive numbers of agranulocytes, many of which
are atypical
– Tired and achy, and has a chronic sore throat and a
low-grade fever
– No cure, but with rest the condition typically runs
its course to recovery in a few weeks
PLATELETS
• Platelets are not
complete cells, but
fragments of large cells
called megakaryocytes
• Platelets are critical to the
clotting process, forming
the temporary seal when
a blood vessel breaks
• Formation of platelets
involves repeated mitosis
of megakaryocytes
without cytokinesis
STAINED BLOOD
WRIGHT’S STAIN
PLATELETS
• The granules contain an impressive array of
chemicals that act in the clotting process,
including serotonin, Ca2+, a variety of
enzymes, ADP, and platelet-derived growth
factor (PDGF)
• Anucleate, they age quickly and degenerate
in about 10 days if they are not involved in
clotting
• Circulate freely, kept mobile but inactive by
molecules (nitric oxide, prostaglandin I2)
secreted by endothelial cells lining the blood
vessels
PLATELET FORMATION
•
•
•
Regulated by a hormone called
thrombopoietin
Progeny of the hemocytoblast and the
myeloid stem cell
Repeated mitoses (pl) of the
megakaryoblast occur, but
cytokinesis does not:
–
Final result is the megakaryocyte, a
bizarre cell with a huge, multilobed
nucleus and a large cytoplasmic mass
•
•
•
•
•
Presses up against capillaries in the
marrow and sends cytoplasmic
extensions into the bloodstream
Extensions rupture, releasing the
platelet fragments seeding the blood
with platelets
Plasma membrane associated with
each fragment quickly seal around the
cytoplasm to form the grainy, roughly
disc-shaped platelets
150,000-400,000 platelets/mm3
150,000,000-400,000,000 platelets/cc
(cm3) (ml)
PLATELET FORMATION
HEMOSTASIS
ARREST OF BLEEDING
• A break in a blood vessel stimulates
hemostasis, a fast, localized response to
reduce blood loss through clotting:
– Involves many blood coagulation factors normally
present in plasma as well as some substances that
are released by platelets and injured tissue cells
• During hemostasis, three phases occur in
rapid sequence:
– 1.Vascular spasms are the immediate
vasoconstriction response to blood vessel injury
– 2.Platelet Plug Formation
– 3.Coagulation (blood clotting)
Hemostasis
Vascular Spasms
• The immediate response to blood vessel injury is
constriction of the damaged blood vessel
(vasoconstriction)
• Factors that trigger this vascular spasm include:
– Direct injury to vascular smooth muscle
– Chemicals released by endothelial cells and platelets
– Reflexes initiated by local pain receptors
• The value of the spasm response is obvious: A
strongly constricted artery can significantly reduce
blood loss for 20-30 minutes, allowing time for
platelet plug formation and blood clotting to occur
Hemostasis
Platelet Plug Formation
• Platelets play a key role in hemostasis by forming a
plug that temporarily seals the break in the vessel
wall
• They also help to orchestrate subsequent events that
lead to blood clot formation
• As a rule, platelets do not stick to each other or to
the smooth endothelial linings of blood vessels:
– When endothelium is damaged and underlying collagen fibers
are exposed, platelets, with the help of a large plasma protein
called von Willebrand factor (VWF) synthesized by endothelial
cells, adhere tenaciously to the collagen fibers and undergo
some remarkable changes
• They swell, form spiked processes, and become sticky
Hemostasis
Platelet Plug Formation
•
Once attached, the platelets are
activated by the enzyme thrombin
and their granules begin to break
down and release several
chemicals:
–
–
–
•
Serotonin: enhances the vascular
spasm (vessel constriction)
Adenosine diphosphate (ADP):
potent aggregating agents that attract
more platelets to the area and cause
them to release their contents
Thromboxane A2: short-lived
prostaglandin derivative that is
generated and released, stimulates
both previous events
Thus, a positive feedback cycle that
activates and attracts greater and
greater numbers of platelets to the
area begins and, within one minute, a
platelet plug is built up, which further
reduces blood loss
BLOOD CLOTTING
Hemostasis
Coagulation (Blood Clotting)
• Blood is transformed from a
liquid to a gel
• Final three phases:
– 1. A complex substance called
prothrombin activator is
formed
– 2. Prothrombin activator
converts a plasma protein
called prothrombin into
thrombin, an enzyme
– 3. Thrombin catalyzes the
joining of fibrinogen
molecules present in
plasma to a fibrin mesh,
which traps blood cells and
effectively seals the hole until
the blood vessel can be
permanently repaired
Hemostasis
Coagulation (Blood Clotting)
• Coagulation, or blood clotting, is a multi-step
process in which blood is transformed from a liquid
to a gel
• Over 30 different substances are involved
• Factors that promote clotting are called clotting factors,
or procoagulants
– Although vitamin K is not directly involved in coagulation,
this fat-soluble vitamin is required for the synthesis of four
of the procoagulants made by the liver
• Factors that inhibit clot formation are called
anticoagulants
• Whether or not blood clots depends on a delicate
balance between these two groups of factors
Hemostasis
Coagulation (Blood Clotting)
• The procoagulants are
numbered I to XIII according to
the order of discovery; hence
the numerical order does not
reflect the reaction sequence
• Tissue factor (III) and Ca2+ (IV)
are usually indicated by their
names, rather than by
numerals
• Most of these factors are
plasma proteins made by the
liver that circulates in an
inactive form in blood until
mobilized
BLOOD CLOTTING
Coagulation (Blood Clotting)
Phase 1
Two Pathways to Prothrombin Activator
•
•
•
•
•
Clotting in the body may be initiated by
either the intrinsic or extrinsic pathway
Clotting in a test tube (outside the
body) is initiated only by the intrinsic
mechanism
Each pathway requires ionic calcium
and involves the activation of a series
of procoagulants, each functioning as
an enzyme to activate the next
procoagulant in the sequence
Each pathway cascades toward a
common intermediate, factor X
Once factor X has been activated, it
complexes with calcium ions, PF3, and
factor V to form prothrombin
activator
–
This step is usually the slowest step of
the blood clotting process, but once
prothrombin activator is present, the
clot forms in 10 to 15 seconds
Coagulation (Blood Clotting)
Phase 2
Common Pathway to Thrombin
• Prothrombin activator
catalyzes the
transformation of the
plasma protein
prothrombin to the
active enzyme
thrombin
Coagulation (Blood Clotting)
Phase 3
Common Pathway to the Fibrin Mesh
• Thrombin catalyzes the
polymerization of fibrinogen
(another plasma protein made
by the liver)
• Fibrinogen molecules align into
long, hair-like, insoluble fibrin
strands
– They glue the platelets
together and make a web that
forms the structural basis of
the clot
• In the presence of fibrin,
plasma becomes gel-like and
traps formed elements that
try to pass through it
Coagulation (Blood Clotting)
Phase 3
Common Pathway to the Fibrin Mesh
• In the presence of calcium
ions, thrombin also activates
factor XIII (fibrin stabilizing
factor), a cross-linking enzyme
that binds the fibrin strands
tightly together and
strengthens and stabilizes the
clot
• Clot formation is normally
complete within 3 to 6 minutes
after blood vessel damage
– Extrinsic pathway is more
rapid:
• In cases of severe trauma it
can promote clot formation
within 15 seconds
Clot Retraction and Repair
• Clot retraction is a process in which the
contractile proteins (actin and myosin) within
platelets contract and pull on neighboring fibrin
strands, squeezing serum (plasma minus the
clotting proteins) from the clot and pulling
damaged tissue edges together
• Even as clot retraction is occurring, vessel
healing is taking place
– Repair is stimulated by platelet-derived growth factors
(PDGF)
• Released by platelets: stimulates smooth muscle and
fibroblasts to divide and rebuild the wall restoring the
endothelial lining
Fibrinolysis
• A clot is not a permanent solution to blood vessel
injury
• Process called fibrinolysis removes unneeded clots
through the action of the fibrin-digesting enzyme plasmin
(clot buster)
– Because small clots are formed continually in vessels
throughout the body, this cleanup detail is crucial
– Without fibrinolysis, blood vessels would gradually become
completely blocked
• Most plasmin activity is confined to the clot, and any
plasmin that strays into the plasma is quickly destroyed
by circulating enzymes
– Begins within two days and continues slowly over several days
until the clot is finally dissolved
Factors Limiting Clot Growth or
Formation
• Normally, two homeostatic mechanisms prevent
clots from becoming unnecessarily large:
– 1. Swift removal of clotting
– 2. Inhibition of activated clotting factors
• Rapidly moving blood disseminates clotting factors
before they can initiate a clotting cascade
• Thrombin that is not bound to fibrin is inactivated by
antithrombin III and protein C, as well as heparin
– Heparin, the natural anticoagulant contained in basophil and
mast cell granules and also produced by endothelial cells, is
ordinarily secreted in small amounts into the plasma
• It inhibits thrombin by enhancing the activity of antithrombin III
• Like most other clotting inhibitors, heparin also inhibits the intrinsic
pathway
Disorders of Hemostasis
Thromboembolytic
•
•
•
•
Results from conditions that cause undesirable clotting, such as roughening of
vessel endothelium, slow-flowing blood, or blood stasis (stoppage of normal
flow)
A clot that develops and persist in an unbroken blood vessel is called a thrombus
– If large enough, it may block circulation
– If it breaks away from the vessel wall and floats freely in the bloodstream, it
becomes an embolus
• Usually no problem until it encounters a blood vessel too narrow for it
to pass through (then it becomes an embolism, obstructing the vessel)
– Pulmonary embolisms
– Cerebral embolisms (stroke)
– Coronary arteries (heart attack)
Conditions that roughen the vessel endothelium, such as arteriosclerosis, severe
burns, or inflammation, cause thromboembolytic disease by allowing platelets to gain
a foothold
Slowly flowing blood or blood stasis (stoppage) is another risk factor,
particularly in bedridden patients and those taking a long flight in economy-class
seats
– Clotting factors are NOT washed away as usual and accumulate so that clot
formation finally becomes possible
Disorders of Hemostasis
Poor Clotting
• Arise from abnormalities that prevent normal clot formation, such as
a deficiency in circulating platelets, lack of synthesis of
procoagulants, or hemophilia
• Aspirin is an antiprostaglandin drug that inhibits thromoboxane A2
formation
– Hence, it blocks platelet aggregation and platelet plug formation
• Anticoagulant drugs:
– Dicumarol: Warfarin sodium
– Heparin: used for preoperative and postoperative cardiac patients and
those receiving blood transfusions
– Warfarin (Coumadin): interferes with the action of vitamin K in the
production of some procoagulants
• Rat poison
• Treatment of patients prone to atrial fibrillation (blood pools in the heart)
• Reduce stroke
Disorders of Hemostasis
Homeostatic Imbalance
• Disseminated intravascular coagulation:
widespread clotting occurs in intact blood
vessels and the residual blood becomes
unable to clot
– Blockage of blood flow accompanied by
severe bleeding follows:
• Common in:
– Complicated pregnancy
– Result of septicemia (presence of pathogenic
microorganisms in the blood)
– Incompatible blood transfusions
Disorders of Hemostasis
Bleeding Disorders
• Thrombocytopenia:
– Condition in which the number of circulating platelets
is deficient
– Spontaneous bleeding from small blood vessels all
over the body
• Even normal movement leads to widespread hemorrhage,
evidenced by many small purplish blotches, called petechiae,
on the skin
– Etiology:
• Condition that suppresses or destroys bone marrow
– Bone marrow malignancy, exposure to ionization radiation, or
certain drugs
Disorders of Hemostasis
Bleeding Disorders
• Impaired Liver Function:
– When the liver is unable to synthesize its usual supply
of procoagulants, abnormal, and often severe,
bleeding occurs
• Cause may range:
– From an easily resolved vitamin K deficiency
» Common in newborns
» After taking systemic antibiotics
» Fat absorption impairment (vitamin K is fat-soluble)
» Bacterial problem in colon (bacteria synthesize vitamin K)
– To nearly total impairment of liver function
» Hepatitis
» Cirrhosis
» Lack of bile production (required for fat and vitamin K
absorption)
Disorders of Hemostasis
Bleeding Disorders
• Hemophilias:
– Several different hereditary bleeding disorders
– Hemophilia A (classical hemophilia):
• Deficiency of factor VIII (antihemophilic factor)
• Sex-linked (primarily males)
– Hemophilia B:
• Deficiency of factor IX
• Sex-linked (primarily males)
– Hemophilia C:
• Deficiency of factor XI
• Less severe form seen in both sexes
Blood Loss
• The body can compensate for only so
much blood loss:
– 15-30% cause pallor and weakness
– Loss of more than 30% of blood volume
results in severe shock, which can be fatal
TRANSFUSION
AND
BLOOD REPLACEMENT
• Transfusion of whole blood is routine when blood loss is
substantial, or when treating thrombocytopenia
– Humans have different blood types based on specific antigens on RBC
membranes
– ABO blood groups are based on the presence or absence of two
types of agglutinogens
– Preformed antibodies (agglutinins) are present in blood plasma
and do not match the individual’s blood
– The Rh factor is a group of RBC antigens that are either present in
Rh+ blood, or absent in Rh- blood
– A transfusion reaction occurs if the infused donor blood type is
attacked by the recipient’s blood plasma agglutinins, resulting in
agglutination and hemolysis of the donor cells
• Plasma and blood volume expanders are given in cases of
extremely low blood volume
Transfusion of Whole Blood
• Routine when blood loss is substantial and when treating
thrombocytopenia
• Infusions of packed red cells (whole blood from which
most of the plasma has been removed) are preferred to
treat anemia
• Usual blood bank procedure involves collecting blood
from a donor and then mixing it with an anticoagulant,
such as certain citrate or oxalate salts, which
prevents clotting by binding with calcium ions
• Shelf life of the collected blood at 4oC is about 35
days
• When freshly collected blood is transfused, heparin is
the anticoagulant used
Human Blood Groups
• RBC plasma membranes, like those of all
body cells, bear highly specific glycoproteins
(antigens) at their external surfaces, which
identify each of us as unique from all others
– Since RBC antigens promote agglutination, they are
more specifically called agglutinogens
– At least 30 varieties of naturally occurring RBC
antigens are common in humans
– The presence or absence of each antigen allows
each person’s blood cells to be classified into several
different blood groups (ABO, Rh, M, N, Duffy, Kell,
Lewis, etc.)
ABO Blood Groups
• Based on the presence or absence of two
agglutinogens, type A and type B
• A,B dominants O
• A + B are codominant
– Genotype
•
•
•
•
•
•
AO
AA
BO
BB
AB
OO
Phenotype
A
A
B
B
AB
O
ABO Blood Groups
• Unique to the ABO blood group is the presence in
the plasma of preformed antibodies (agglutinins)
• The agglutinins act against RBCs carrying ABO
antigens that are NOT present on a person’s own red
blood cell
– Newborn lacks these antibodies but they form within 2 months
– Reach peck levels between 8 and 10
– Slowly decline throughout life
• Blood Groups
–
–
–
–
A anti-B
B anti-A
AB no anti
O anti-A and anti-B
Rh Blood Groups
• There are at least eight different types of Rh agglutinogens,
each of which is called an Rh factor
– Only three of these, the C, D, and E antigens, are fairly common
• Rh antigen first discovered in the rhesus monkey than in
humans
• 85% Rh+
• Unlike the ABO system, anti-Rh antibodies are not
spontaneously formed in the blood of Rh- individuals
– However, if an Rh- person receives Rh+ blood, the immune system
becomes sensitized and begins producing anti-Rh antibodies against
the foreign antigen soon after the transfusion
• Hemolysis does not occur after the first such transfusion because it takes
time for the body to react and start making antibodies
• The second time, and every time thereafter, a typical transfusion reaction
occurs in which the recipient’s antibodies attack and rupture the donor RBCs
HOMEOSTATIC IMBALANCE
• Important problem related to the Rh factor occurs in pregnant
Rh- women who are carrying Rh+ babies
– First such pregnancy usually results in the delivery of a healthy
baby
– But, when bleeding occurs as the placenta detaches from
the uterus, the mother may be sensitized by her baby’s Rh+
antigens that pass into her bloodsream
• She will form anti-Rh antibodies unless treated with RhoGAM
before or shortly after she has given birth
– RhoGAM is a serum containing anti-Rh agglutinins
» Because it agglutinates the Rh factor, it blocks
the mother’s immune response and prevents her
sensitization
HOMEOSTATIC IMBALANCE
Rh Problem
• If the mother is not treated and becomes pregnant
again with an Rh+ baby, her antibodies will cross
through the placenta and destroy the baby’s RBCs,
producing a condition known as hemolytic disease
of the newborn, or erythroblastosis fetalis
• The baby becomes anemic and hypoxic (oxygen
deficiency)
• Brain damage and even death may result unless
transfusions are done before birth to provide the fetus
with more erythrocytes for oxygen transport
– One or two exchange transfusions are done after birth
– The baby’s Rh+ blood is removed, and Rh- blood infused
– Within 6 weeks, the transfused Rh- erythrocytes have been
broken down and replaced with the baby’s own Rh+ cells
Transfusion Reactions:
Agglutination and Hemolysis
•
When mismatched blood is infused, a transfusion reaction occurs in
which the donor’s red blood cells are attacked by the recipient’s
plasma agglutinins (Note: the donor’s plasma antibodies may also be
agglutinating the host’s RBCs, but they are so diluted in the recipient’s
circulation that this does not usually present a serious problem)
– Results in:
• The oxygen-carrying capability of the transfused blood cells is
disrupted
• The clumping of RBCs in small vessels hinders blood flow to tissues
• But more devastating, is the consequence of hemoglobin escaping
into the bloodstream
– Circulating hemoglobin passes freely into the kidney tubules,
and in high concentration it precipitates, blocking the kidney
tubules and causing renal shutdown
– If shutdown is complete (acute renal failure), the person may
die
Transfusion Reactions:
Agglutination and Hemolysis
• Treatment of transfusion reactions is
directed toward preventing damage by
infusing alkaline fluids to dilute and
dissolve the hemoglobin and wash it
out of the body
– Diuretics, which increase urine output, are
also given
Transfusion Reactions:
Agglutination and Hemolysis
• Donor’s blood is the most important
• Pooled blood transfusions carry the risk of
transfusion reactions and transmission of
life-threatening infections
• Selection of Autologous Transfusions
has risen
– Elective surgery
BLOOD TYPING
Plasma and Blood Volume Expanders
• Plasma can be administered to anyone
without concern about a transfusion reaction
because the antibodies it contains become
harmlessly diluted in the recipient’s blood
– Except for red blood cells, plasma provides a
complete and natural blood replacement
• Plasma expanders: osmotic properties
increases the fluid volume of the blood
– Purified human serum albumin
– Dextran
– Isotonic salt solutions (normal saline, multiple
electrolytes)
DIAGNOSTIC BLOOD TESTS
• Changes in some of the visual properties of blood can signal
diseases such as anemia, heart disease, and diabetes
• Differential white blood cell counts are used to detect
differences in relative amounts of specific blood cell types
– Example: high eosinophil: parasitic infection or an allergic
response somewhere in the body
• Prothrombin time, which measures the amount of prothrombin in
the blood, and platelet counts evaluate the status of the hemostasis
system
• SMAC (chemistry profile), SMA12-60, and complete blood count
(CBC) give comprehensive values of the condition of the blood
– Provide a comprehensive picture of one’s general health status
in relation to normal blood values
DEVELOPMENTAL ASPECTS OF
BLOOD
• Prior to birth, blood cell formation occurs
within the fetal yolk sac, liver, and spleen,
but by the seventh month, red bone
marrow is the primary site of
hematopoiesis
• Fetal blood cells form hemoglobin-F, which
has a higher affinity for oxygen than adult
hemoglobin, hemoglobin-A