BLOOD Enormous importance in the practice of medicine Clinicians examine it more often than any...
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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 Enormous importance in the practice of medicine Clinicians examine it more often than any other tissue when trying to determine the cause of disease
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
Slide 2
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
Slide 3
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%
Slide 4
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: 38 0 C or 100.4 0 F
Always slightly higher than body temperature
Slide 5
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
Slide 6
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
Slide 7
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 bodys 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
Slide 8
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)
Slide 9
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 plasmas normal, slightly
alkaline pH
Slide 10
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
Slide 11
STAINED BLOOD WRIGHTS STAIN
Slide 12
A stained smear of human blood under the microscope:
Disc-shaped red blood cells Spherical white blood cells Scattered
platelets that look like debris
Slide 13
ERYTHROCYTES Red blood cells (RBC): Small cells that are
biconcave discsflattened 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 oxygen- binding 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
Slide 14
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)
Slide 15
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
Slide 16
ERYTHROCYTES
Slide 17
ELECTRON MICROGRAPH of ERYTHROCYTES
Slide 18
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/mm 3 ) 1 ml / cc / cm 3 = 1,000 mm 3 4.3 to 5.2
billion/ml Male: 5.1 to 5.8 million/cubic millimeter (million/mm 3
) 1 ml / cc / cm 3 = 1,000 mm 3 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
Slide 19
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
Slide 20
HEMOGLOBIN
Slide 21
Made up of the protein globin bound to the red heme pigment
Globin consists of four polypeptide chainstwo alpha and two
betaeach 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
Slide 22
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
Slide 23
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
Slide 24
HEMOGLOBIN About 20% of the carbon dioxide transported in the
blood combines with hemoglobin Binds to globins amino acids rather
than with the heme group forming carbaminohemoglobin Occurs more
readily when hemoglobin is in the reduced state (dissociated from
oxygen)
Slide 25
HEMOGLOBIN
Slide 26
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
Slide 27
ERYTHROPOIESIS
Slide 28
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 B 12 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
Slide 29
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
Slide 30
ERYTHROPOIETIN MECHANISM
Slide 31
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)
Slide 32
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
Slide 33
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 athletesparticularly 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
Slide 34
Dietary Requirements for Erythropoiesis Raw materials required
for erythropoiesis include the usual nutrients and structural
materialproteins, lipids, and carbohydrates Iron is essential for
hemoglobin synthesis 65% of the bodys iron supply is in hemoglobin
Remainder is stored in the liver, spleen, and bone marrow Because
free iron ions (Fe 2+, Fe 3+ ) 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 vitaminsvitamin B 12 and folic acidare necessary for
normal DNA synthesis Even slight deficits jeopardize rapidly
dividing cell populations, such as developing erythrocytes
Slide 35
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)
Slide 36
LIFE CYCLE OF RED BLOOD CELLS
Slide 37
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
Slide 38
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
Slide 39
ERYTHROCYTES DISORDERS ANEMIAS An insufficient number of red
blood cells due to: Blood loss Excessive RBC destruction Bone
marrow failure
Slide 40
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
Slide 41
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) Athletes 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 B 12 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 B 12 to be absorbed by intestinal cells Treatment with
vitamin B 12
Slide 42
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
Slide 43
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
Slide 44
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
Slide 45
SICKEL CELL ANEMIA
Slide 46
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
Slide 47
BLOOD DOPING Practiced by some athletes Artificially induced
polycythemia: Atheletes 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
Slide 48
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/mm 3 4.8-10.8 million/ml (cc)(cm 3 ) Leukocytes
are critical to our defense against disease: Protect the body from
damage by bacteria, viruses, parasites, toxins, and tumor
cells
Slide 49
LEUKOCYTES General Structural and Functional Characteristics
WBCs have the ability to slip out of the capillary blood
vesselsprocess called diapedesisand 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
Slide 50
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
Slide 51
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
Wrights stain
Slide 52
TYPES OF LEUKOCYTES
Slide 53
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
Slide 54
GRANULOCYTES EOSINOPHILS(b) Account for 2% to 4% of all
leukocytes and are approximately the size of neutrophils Deep red
nucleus usually resembles an old- fashioned 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 parasites 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
Slide 55
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
Slide 56
TYPES OF LEUKOCYTES a: Neutrophil b: Eosinophil c: Basophil d:
Small Lymphocyte e: Monocyte
Slide 57
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
Slide 58
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
Slide 59
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 bodys defense against
viruses, certain intracellular bacterial parasites, and chronic
infections such as tuberculosis Important in activating lymphocytes
to mount the immune response
Slide 60
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
Slide 61
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
Slide 62
LEUKOCYTE FORMATION
Slide 63
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
Slide 64
Leukocyte Disorders Leukopenia is an abnormally low white blood
cell count Commonly induced by drugs, particularly glucocorticoids
and anticancer agents
Slide 65
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
Slide 66
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
Slide 67
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
Slide 68
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
Slide 69
STAINED BLOOD WRIGHTS STAIN
Slide 70
PLATELETS The granules contain an impressive array of chemicals
that act in the clotting process, including serotonin, Ca 2+, 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 I 2 ) secreted
by endothelial cells lining the blood vessels
Slide 71
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/mm 3
150,000,000-400,000,000 platelets/cc (cm 3 ) (ml)
Slide 72
PLATELET FORMATION
Slide 73
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)
Slide 74
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
Slide 75
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
Slide 76
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 A 2 :
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
Slide 77
BLOOD CLOTTING
Slide 78
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
Slide 79
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
Slide 80
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 Ca 2+ (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
Slide 81
BLOOD CLOTTING
Slide 82
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, PF 3, 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
Slide 83
Coagulation (Blood Clotting) Phase 2 Common Pathway to Thrombin
Prothrombin activator catalyzes the transformation of the plasma
protein prothrombin to the active enzyme thrombin
Slide 84
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
Slide 85
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
Slide 86
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
Slide 87
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
Slide 88
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
Slide 89
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
Slide 90
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 A 2 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
Slide 91
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
Slide 92
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
Slide 93
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)
Slide 94
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
Slide 95
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
Slide 96
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 individuals 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 recipients 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
Slide 97
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 4 o C is about 35 days When freshly collected
blood is transfused, heparin is the anticoagulant used
Slide 98
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 persons blood cells to be
classified into several different blood groups (ABO, Rh, M, N,
Duffy, Kell, Lewis, etc.)
Slide 99
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 GenotypePhenotype AOA AAA BOB BBB ABAB OOO
Slide 100
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
persons 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
Slide 101
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 recipients
antibodies attack and rupture the donor RBCs
Slide 102
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 babys 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 mothers immune response
and prevents her sensitization
Slide 103
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 babys 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 babys Rh + blood is removed, and Rh -
blood infused Within 6 weeks, the transfused Rh - erythrocytes have
been broken down and replaced with the babys own Rh + cells
Slide 104
Transfusion Reactions: Agglutination and Hemolysis When
mismatched blood is infused, a transfusion reaction occurs in which
the donors red blood cells are attacked by the recipients plasma
agglutinins (Note: the donors plasma antibodies may also be
agglutinating the hosts RBCs, but they are so diluted in the
recipients 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
Slide 105
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
Slide 106
Transfusion Reactions: Agglutination and Hemolysis Donors 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
Slide 107
BLOOD TYPING
Slide 108
Slide 109
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 recipients
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)
Slide 110
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
ones general health status in relation to normal blood values
Slide 111
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