BLOOD  Transport Hemoglobin

 Can concentrate Hemoglobin

- It is a liquid connective tissue that consists of
 Contain a large quantity of carbonic
cells surrounded by a liquid extracellular
anhydrase, an enzyme that catalyzes the
matrix.
reversible reaction between carbon
- The extracellular matrix is called blood
dioxide (CO2) and water to form carbonic
plasma, and it suspends various cells and cell
acid (H2CO3), increasing the rate of this
fragments.
reaction several thousand-fold.
FUNCTIONS OF BLOOD
PRODUCTION OF THE RED BLOOD CELLS
 Transports oxygen, carbon
 Early Weeks of Embryonic Life: Nucleated
dioxide, nutrients, hormones,
RBC are produced in the yolk sac; Yolk Sac is
heat, and wastes.
also the 1st site of blood formation.
 Regulates pH, body temperature,
 Middle Trimester of Gestation: Liver is the
and water content of cells.
main organ to produce RBC but reasonable
 Protects against blood loss through clotting,
numbers are also produced by spleen and
and against disease through phagocytic white
lymph nodes.
blood cells and proteins such as antibodies,
 Last month of Gestation and After Birth:
interferons, and complement.
RBC are produced exclusively in the Red Bone
RED BLOOD CELLS / ERYTHROCYTES Marrow.
 At 5 years of Age: All bones of your body will
- Contain the oxygen-carrying protein produce RBC
hemoglobin, which is a pigment that gives  At 20 years of Age: The marrow of the long
whole blood its red color bones, except for the proximal portions of the
- Biconcave disk having a mean of diameter of humeri and tibiae, becomes quite fatty and
about 7.8μm and a thickness of 2.5μm at the produces no more RBCs
thickest point and 1μm or less in the center.  At 20 years of Age Beyond: most RBCs
- Average Volume: 90-95μm3 continue to be produced in the marrow of the
- Your RBC is a bag that can be deformed into membranous bones, such as the vertebrae,
any almost shape because the normal cells sternum, ribs, and ilia. Even in these bones,
has a great excess of a cell membrane for the the marrow becomes less productive as age
quantity of the material inside. (Hindi sila increases
marupture dahil strong ang plasma
membrane nila at saka flexible pa ito) GENESIS OF BLOOD CELLS
- Concentration of RBC in blood
1. PLURIPOTENTIAL HEMATOPOIETIC STEM
a. Male: 5,200,000 mm3
CELL
b. Female: 4,700,000 mm3
- AKA: Hemocytoblasts
- RBCs can concentrate hemoglobin in the cell
- It is where all the cells of the circulating blood
fluid up to about 34g in each 100mm of cells.
are eventually derived.
- ↓Hemoglobin: ↓Red Blood Cell
- Hematocrit(Hct): Volume of Percentage of
the Red Blood Cells
- When it is in Normal Level
a. The whole blood of men contains an average
of 15g of hemoglobin per 100 mL
b. The whole blood of men contains an average
of 14g of hemoglobin per 100mL

FUNCTIONS:
 Carries O2 from lungs to the tissues.

- As these cells reproduce, a small portion of
them remains exactly like the original
pluripotential cells and is retained in the bone
marrow to maintain a supply of these,
although their numbers diminish with age
- Most of these cells undergo differentiation to
form other cell type
2. COMMITED STEM CELLS
- They are intermediate stage cells are very
much like the pluripotential stem cells, even
though they have already become committed
to a particular line of cells
3. When cultured, it will produce colonies of
specific types of blood cells
4. COLONY FORMING UNITS-ERYTHROCYTES
- A committed stem cells that produced
erythrocytes.
5. GROWTH INDUCERS/ GROWTH AND
REPRODUCTION INDUCER
- Controlled growth and reproduction of the
different stem cells
6. INTERLEUKINS-3
- Promotes growth and reproduction of
virtually all the different types of committed
stem cells
STAGES OF DIFFERENTIATION OF RED BLOOD
CELLS
1. PROERYTHROBLASTS
- Under appropriate stimulation, large
numbers of these cells are formed from the
CFU-E stem cells
2. BASOPHIL ERYTHROBLASTS
- Formed when your proerythroblasts starts to
divide multiple times.
- 1st Generation of the cells.
- Accumulates very little hemoglobin
3. POLYCHROMATOPHIL ERYTHROBLAST
- Nadistengrate lang si Nucleus into fragment
4. ORTHOCHROMATIC ERYTHROBLAST
- Nadistengrate lang si Nucleus into fragment
5. RETICULOCYTES
- At this stage, the cells become filled with
hemoglobin to a concentration of about 34%,
the nucleus condenses to a small size, and its
final remnant is absorbed or extruded from
the cell
- At the same time, the endoplasmic reticulum
is also reabsorbed.
- It still contains a small amount of basophilic
material, consisting of remnants of the Golgi
apparatus, mitochondria, and a few other
cytoplasmic organelles
- During this reticulocyte stage, the cells pass
from the bone marrow into the blood
capillaries by diapedesis (squeezing through
the pores of the capillary membrane)
6. MATURE ERYTHROCYTES
- The remaining basophilic material in the
reticulocyte normally disappears within 1 to
2 days
- Because of the short life of the reticulocytes,
their concentration among all the RBCs is
normally slightly less than 1 percent
ERYTHROPOIETIN
- A circulating hormone that regulates Red
Blood Cell Production
- Transports oxygen to the tissue
- (-) Erythropoietin = Hypoxia (little or no
effect in RBC production)
- (+) Erythropoietin System is Functional =
Hypoxia causes a marked increase in
erythropoietin production and the
erythropoietin, in turn, enhances RBC
production until the hypoxia is relieved.
- Low Oxygen (primary stimulus) = RBC
Production
- Formed mainly by your kidneys (90%) and
liver (10%)
- Erythropoietin is secreted mainly by
fibroblast-like interstitial cells surrounding
the tubules in the cortex and outer medulla,
where much of the kidney’s oxygen
consumption occurs
- *Renal Tissue Hypoxia: ↑ Tissue Level HIF-
1; HIF-1 will binds to a hypoxia response
element will reside in the erythropoietin gene
and it will increase erythropoietin synthesis.
 - Removal of Kidney or destruction of kidney =
anemic; because the 10 percent of the normal
erythropoietin formed in other tissues
(mainly in the liver) is sufficient to cause only
one third to one half the RBC formation
needed by the body
NEUTRANSMITTER FOR NON-RENAL SENSOR
HYPOXIS
1. Epinephrine
2. Norepinephrine
3. Prostaglandin
MOST COMMON HEMOGLOBIN CHAIN
- Alpha and Beta
FACTORS THAT DECREASE OXYGENATION
- Low Blood Volume
- Anemia
- Low Hemoglobin
- Poor Blood Flow
- Pulmonary Disease
STORED IRON
- AKA: FERRITIN
SICKLE CELL ANEMIA
- Pinalitan si Amino Acid Valine into
Glutamic Acid
- Pwede niya marupture si blood vessels
ERYTHROPOIETIN STIMULATES PRODUCTION OF
PROERYTHROBLASTS FROM HEMATOPOIETIC
STEM CELLS.
- ↓ Low Oxygen Supply: Erythropoietin begins
to formed within minutes to hours until it
reaches to its maximum production in 24
hours.
- No new RBCs appear in the circulating blood
until about 5 days later
- It has been determined that the important
effect of erythropoietin is to stimulate the
production of proerythroblasts from
hematopoietic stem cells in the bone marrow
- once the proerythroblasts are formed, the
erythropoietin causes these cells to pass
more rapidly through the different
erythroblastic stages than they normally do,
further speeding up the production of new
RBCs
- Rapid Production of the RBC continues as
long as the person remains in low oxygen
state or until enough RBC have been
produced to carry adequate amounts of
oxygen to the tissues despite the low level of
oxygen
- When sufficient amount is oxygen is
established = erythropoietin production
decreases to a level that will maintain the
required number of RBCs but not an excess
- (-) Erythropoietin = RBC are formed by the
bone marrow
- (+) Large amount Erythropoietin together
with iron = RBC production can rise to
perhaps 10 or more times normal.
Maturation of Red Blood Cells Requires
Vitamin B12 (Cyanocobalamin) and
Folic Acid
- Important for final maturation of the RBCs
are two vitamins, vitamin B12 and folic acid
- Both of these vitamins are essential for the
synthesis of DNA because
each, in a different way, is required for the
formation of thymidine triphosphate, one of
the essential building blocks of DNA.
(-) Vitamin B12 and Folic Acid: Failure of nuclear
maturation and cell division ↣ production of
macrocytes (flimsy membrane often irregular,
large and oval shaped; they are capable of carry
oxygen kaso they are very fragile kaya short life
lang sila); Maturation failure of the RBC to be
mature.
TISSUE OXYGENATION
- ↓Oxygen Level to tissue = ↑ RBC production
- Anemia = Bone Marrow starts to produce
large quantities of RBC production.
- Destruction of Bone Marrow due to X-ray
Therapy = causes hyperplasia of the
remaining bone marrow, to supply the
demand for RBCs in the body.
- High Altitude, where quantity of Oxygen
decreases = Oxygen transported to the tissues
decreases = RBC decreases
Maturation Failure Caused by Poor Absorption
of Vitamin B12 from the Gastrointestinal Tract—
Pernicious Anemia.
 - Often occurs in the disease pernicious anemia, to release this oxygen readily in the
in which the basic abnormality is an atrophic peripheral tissue capillaries, where the
gastric mucosa that fails to produce normal gaseous tension of oxygen is much lower than
gastric secretions. in the lungs
- The parietal cells of the gastric glands secrete
HEMOGLOBIN FORMATION
a glycoprotein called intrinsic factor, which
combines with vitamin B12 in food and - Normal Value
makes the B12 available for absorption by the a. Male: 15g/dL
gut. b. Female: 14g/dL
- Synthesis of hemoglobin begins in the
MECHANISM
proerythroblasts↣ It will continue in the
 Intrinsic factor binds tightly with the vitamin reticulocytes stage↣Leaving of erythrocytes
B12. In this bound state, the B12 is protected in the bone marrow and will pass to the
from digestion by the gastrointestinal bloodstream↣ Formation of Hemoglobin
secretions. until they become mature erythrocytes.
 Still in the bound state, intrinsic factor binds
IRON METABOLISM
to specific receptor sites on the brush border
membranes of the mucosal cells in the ileum - Iron is important for the formation of
 Vitamin B12 is then transported into the hemoglobin
blood during the next few hours by the - Also important for other essential elements
process of pinocytosis, carrying intrinsic - Normal: 4-5g
factor and the vitamin together through the - 65%: Hemoglobin
membrane. - 4%: Myoglobin
- 1%: Various Heme Compounds that promote
(-) Intrinsic Factor = decreases availability of
intracellular oxidation
vitamin B12 because of faulty absorption of the
- 0.1%: Combined with the protein transferrin
vitamin.
in the blood plasma
Maturation Failure Caused by Folic Acid - 15-30%: Stored for later use, mainly in the
(Pteroylglutamic Acid) Defciency reticuloendothelial system and liver
parenchymal cells, principally in the form of
 Folic acid is a normal constituent of green
ferritin.
vegetables, some fruits, and meats
(especially liver). However, it is easily TRANSPORTATION OF IRON
destroyed during
cooking.
 Also, people with gastrointestinal
absorption abnormalities, such as the
frequently occurring small intestinal
disease called sprue, often have serious
difficulty absorbing both folic acid and
vitamin B12.
 Therefore, in many instances of
maturation failure, the cause is deficiency
of intestinal absorption of both folic acid
and vitamin B12
HEMOGLOBIN
- It can combine loosely and reversibly with
oxygen
- Primary function of hemoglobin in the body is
to combine with oxygen in the lungs and then - When iron is absorbed from the small
intestine it immediately combines with a b-
 globulin called apotransferrin, to form
transferrin, which is transported in the
plasma.
- This iron is loosely bound. Excess iron in the
blood is deposited in liver hepatocytes and in
reticuloendothelial cells of the bone marrow.
- Once inside the cell's cytoplasm, iron
combines with the protein apoferritin to form
ferritin.
- Varying quantities of iron can combine in
clusters of iron radicals in the ferritin.
- When the quantity of iron in the plasma
decreases to less than normal, iron is
removed from ferritin quite easily and
transported by transferrin in the plasma to
the portions of the body where it is needed.
- A unique characteristic of the transferrin
molecule is its ability to bind strongly with
receptors in the cell membranes of the
erythroblasts and bone marrow.
- Transferrin is ingested via endocytosis into
the erythroblasts along with the bound iron.
- Transferrin delivers the iron directly to the
mitochondria, where heme is synthesized.
- When red blood cells have reached the end of
their life span and are destroyed, the
hemoglobin released is ingested by cells of
the monocyte-macrophage system.
- The free iron that is liberated can be stored in
the ferritin pool or reused for formation of
hemoglobin.
- A man excretes about 0.6 mg of iron
each day, mainly into the feces. Additional
quantities of iron are lost when bleeding
occurs. For a woman, additional menstrual
loss of blood brings long term iron loss to an
average of about 1.3 mg/day
ABSORPTION OF IRON FROM INTESTINAL TRACT
Secretion of moderate amount of apotransferrin in
the bile from the liver↣Apotransferrin binds with the
free iron and certain iron compounds such as
hemoglobin and myglobin↣Transferrin↣Transferrin
will bind with receptors in the membranes of the
intestinal epithelial cell↣Release in to the blood
capillaries in the form of plasma transferrin.
- Iron Absorption from the intestine is
extremely slow
- Even when tremendous quantities of iron are
present in the food, only small proportions
can be absorbed
LIFE SPAN OF RED BLOOD CELLS IN 120 DAYS
- RBCs do not have a nucleus, mitochondria, or
endoplasmic reticulum, they do have
cytoplasmic enzymes that are capable of
metabolizing glucose and forming small
amounts of adenosine triphosphate
DESTRUCTION OF HEMOGLOBIN BY
MACROPHAGES.
 When RBCs burst and release their
hemoglobin, the hemoglobin is phagocytized
almost immediately by macrophages in
many parts of the body, but especially by the
Kupffer cells of the liver and macrophages of
the spleen and bone marrow.
 During the next few hours to days, the
macrophages release iron from the
hemoglobin and pass it back into the blood, to
be carried by transferrin either to the bone
marrow for the production of new RBCs or to
the liver and other tissues for storage in the
form of ferritin.
 The porphyrin portion of the hemoglobin
molecule is converted by the macrophages,
through a series of stages, into the bile
pigment bilirubin, which is released into the
blood and later removed from the body by
secretion through the liver into the bile; this
process
CLINICAL NOTES
ANEMIA
- Means a deficiency of red blood cells and can
be caused by rapid loss of red blood cells or
slow production of red blood cells.
- Blood loss anemia occurs after significant
hemorrhage. The body is able to replace the
plasma within 1 to 3 days; however, the
concentration of red blood
cells remains low.
 - After significant hemorrhage, a period of 3 to
4 weeks is required to return the number of
red blood cells to normal levels.
1. APLASTIC ANEMIA
- It is the result of nonfunctioning bone
marrow, which may be due to exposure to
gamma radiation for cancer treatment or
toxic chemicals such as insecticides or
benzene in gasoline.
- Autoimmune disorders such as lupus
erythematosus result in an immune system
attack on the healthy cells of the bone
marrow, which destroys stem cells and may
lead to aplastic anemia.
- Individuals with severe aplastic anemia
usually die unless they are treated with blood
transfusions or bone marrow transplants.
2. MEGALOBLASTIC ANEMIA
- It is the result of a lack of vitamin B12, folic
acid, or intrinsic factor. Lack of these
substances leads to slow reproduction of the
erythrocytes in the bone marrow. As a result,
these erythrocytes grow into large, odd-
shaped cells called megaloblasts.
3. HEMOLYTIC ANEMIA
- It is the result of fragile red blood cells that
rupture as they pass through the capillaries.
- With hemolytic anemia, the number of red
blood cells that form is normal or in excess of
normal; however, because these cells are
extremely fragile, their life span is very short.
- Sickle cell anemia is a type of hemolytic
anemia caused by an abnormal composition
of the globin chains of hemoglobin.
- When this abnormal hemoglobin is exposed
to low concentrations of oxygen, it
precipitates into long crystals inside the red
blood cell. This causes the cell to have an
abnormal sickle shape and to be extremely
fragile.
Polycythemia
- It is a condition in which the number of red
blood cells in the circulation increases owing
to hypoxia or genetic aberration. Individuals
who live at high altitudes have physiologic
polycythemia as a result of the thin
atmosphere.
- Polycythemia can also occur in individuals
with cardiac failure because of decreased
delivery of oxygen to the tissues.
a. Polycythemia vera
- It is a genetic aberration in the
hemocytoblastic cell line.
- The blast cells continue to produce red blood
cells even though too many blood cells are
present in the circulation. The hematocrit can
rise to 60% to 70%.
- Polycythemia greatly increases the viscosity
of the blood; as a result, blood flow through
the vessels is often sluggish.
HEMOSTASIS AND BLOOD COAGULATION
HEMOSTASIS
- Means prevention of blood loss.
- Whenever a vessel is severed or ruptured,
hemostasis is achieved by several
mechanisms:
 Vascular constriction,
 Formation of a platelet plug,
 Formation of a blood clot as a result of blood
coagulation,
 Eventual growth of fibrous tissue into the
blood clot to close the hole in the vessel
permanently
1. VASCULAR CONSTRICTION
- Blood vessel has been cut or ruptured or
trauma will result smooth wall muscle
contraction; reduction of blood flow
- Contraction results from
 Local Myogenic Spasm (aid in the loss of
blood by briefly constricting the muscle
where the broken blood vessel is located)
 Local Autacoid Factors from the
traumatized tissues and blood
platelets
 Nervous Reflexes (initiated by pain
nerve impulses or other sensory impulses
that originate from the traumatized vessel
or nearby tissues)
- The more severely a vessel is traumatized,
the greater the degree of vascular spasm.
 - The spasm can last for many minutes or even
hours, during which time the processes of
platelet plugging and blood coagulation can
take place.
PHYSICAL AND CHEMICAL CHARACTERISTIC
OF PLATELETS
- AKA: Thrombocytes
- They are minute discs 1 to 4 μm in diameter
- Formed in the bone marrow from
megakaryocytes
a. MEGAKARYOCYTES
- Extremely large hematopoietic cells in the
marrow
- The megakaryocytes fragment into the
minute platelets either in the bone marrow or
soon after entering the blood, especially as
they squeeze through capillaries.
- Normal Value: 150-450x103 per μL
STRUCTURES INSIDE THE CYTOPLASM OF
PLATELETS
1. Actin and Myosin and thrombosthenin
(cause platelets to contract)
2. Residuals of both the endoplasmic
reticulum and the Golgi apparatus
- Synthesize various enzymes and especially
store large quantities of Ca2+
3. Mitochondria and Enzyme Systems
- Capable of forming ATP and ADP
4. Enzyme Systems that synthesize
prostaglandins
- Which are local hormones that cause many
vascular and other local tissue reactions
5. FIBRIN-STABILIZING FACTOR
6. GROWTH FACTOR
- Causes vascular endothelial cells, vascular
smooth muscle cells, and fibroblasts to
multiply and grow, thus causing cellular
growth that eventually helps repair damaged
vascular walls
- On your platelet cell membrane surface is a
coat of glycoproteins that repulses adherence
to normal endothelium and yet causes
adherence to injured areas of the vessel wall,
especially to injured endothelial cells and
even more so to any exposed collagen from
deep within the vessel wall
- Life Cycle: 8-12 days only
- Can be eliminated from the circulation mainly
by tissue macrophage system.
- ½ of platelets are removed by the
macrophages from the spleen.
MECHANISM OF PLATELET PLUG FORMATION
- It only happens when there is a very small
vascular hole from the body
1. Platelets come in contact with a damaged
vascular surface
- Platelets rapidly change their own
characteristics drastically
2. SWELLING
- Assume irregular forms with numerous
irradiating pseudopods protruding from their
surfaces
3. CONTRACTION OF CONTRACTILE
PROTEINS
- It will release a granules that contains
multiple active factors
- They will become sticky so that they adhere
to collagen and to a protein called Willeband
Factor (that leaks into the traumatized tissue
from the plasma; they secrete large quantities
of ADP; and their enzymes form thromboxane
A)
4. ADP and THROMBOXANE ACT ON NEARBY
PLATELETS
- Stickiness of these additional platelets causes
them to adhere to the original activated
platelets
5. AT THE SITE OF A PUNCTURE IN A BLOOD
VESSEL WALL, THE DAMAGED VASCULAR
WALL ACTIVATES SUCCESSIVELY
 - Increasing numbers of platelets that attract
more and more additional platelets, thus
forming a platelet plug
- This plug is loose at first, but it is usually
successful in blocking blood loss if the
vascular opening is small.
- During the subsequent process of blood
coagulation, fibrin threads form.
- These threads attach tightly to the platelets,
thus constructing an unyielding plug.
IMPORTANCE OF THE PLATELET MECHANISM
FOR CLOSING VASCULAR HOLES
 Extremely important for closing minute
ruptures in very small blood vessels that
occur many thousands of times daily.
BLOOD COAGULATION
- 3rd Mechanism for blood clotting
a. Severe Trauma: 15-20 seconds clotting
b. Minor Trauma: 1-2 minutes clotting
- Within 3 to 6 minutes after rupture of a
vessel, the entire opening or broken end of
the vessel is filled with clot if the vessel
opening is not too large.
- After 20 minutes to an hour, the clot retracts,
which closes the vessel still further.
FIBROUS ORGANIZATION OR DISSOLUTION OF
THE BLOOD CLOT
- Once a blood clot has formed, it can follow
one of two courses:
 It can become invaded by fibroblasts,
which subsequently form connective tissue
all through the clot
 It can dissolve
- Most Common in small hole in the blood
vessel: Invasion by Fibroblasts
MECHANISM OF BLOOD COAGULATION
GENERAL MECHANISM
- Procoagulants: Promote Coagulation
- Anticoagulants: Inhibit Coagulation
Clotting takes place in three essential steps:
1. In response to rupture of the vessel or
damage to the blood itself, a complex cascade
of chemical reactions occurs in the blood
involving more than dozen blood coagulation
factors. The net result is formation of a
complex of activated substances collectively
called prothrombin activator
2. The prothrombin activator catalyzes
conversion of prothrombin into thrombin.
3. The thrombin acts as an enzyme to convert
fibrinogen into fibrin fibers that enmesh
platelets, blood cells, and plasma to form the
clot.
CONVERSION OF PROTHROMBIN TO THROMBIN
1. PROTHROMBIN ACTIVATOR
- It is formed as a result of rupture of a blood
vessel or as a result of damage to special
substances in the blood
2. THE PROTHROMBIN ACTIVATOR, IN THE
PRESENCE OF SUFFICIENT AMOUNTS OF
IONIC CALCIUM
- Causes conversion of prothrombin to
thrombin
3. THE THROMBIN CAUSES
POLYMERIZATION OF FIBRINOGEN
MOLECULES INTO FIBRIN FIBERS WITHIN
ANOTHER 10 TO 15 SECONDS
- The rate limiting factor in causing blood
coagulation is usually the formation of
prothrombin activator and not the
subsequent reactions beyond that point
- Platelets also play an important role in the
conversion of prothrombin to thrombin
because much of the prothrombin first
attaches to prothrombin receptors on the
platelets already bound to the damaged tissue
PROTHROMBIN AND THROMBIN
1. Prothrombin
- It is present in normal plasma in a
concentration of about 15 mg/dl.
- It can be split into thrombin
 - Formed continually by the liver, and it
is continually being used throughout the body
for blood clotting
- Vitamin K: required by the liver for normal
activation of prothrombin, as well as a few
other clotting factors
- (-) Vitamin K or Liver Disease: Decrease
prothrombin level.
CONVERSION OF FIBRINOGEN TO FIBRIN—
FORMATION OF THE CLOT
FIBRONOGEN
- Formed in the liver, and liver disease can
decrease the concentration of circulating
fibrinogen
- Due to its molecular size, it normally leaks
from the blood vessels into the interstitial
fluids,
- When the permeability of the capillaries
becomes pathologically increased, fibrinogen
does leak into the tissue fluids in sufficient
quantities to allow clotting of these fluids in
much the same way that plasma and whole
blood can clot.
ACTION OF THROMBIN ON FIBRONOGEN TO
FORM FIBRIN
 The fibrin monomer molecule polymerizes
with other fibrin monomer molecules to form
the long fibrin threads that produce the
reticulum of the clot.
 The newly formed fibrin reticulum is
strengthened by a substance called fibrin-
stabilizing factor, which normally is present
in small amounts in plasma.
 This substance is also released from
platelets entrapped in the clot.
 Fibrin-stabilizing factor, an enzyme, causes
covalent bonding between the fibrin
monomer molecules and adjacent fibrin
threads, thereby strengthening the fibrin
meshwork.
BLOOD CLOT
- Composed of a meshwork of fibrin fibers
running in all directions and entrapping
blood cells, platelets and plasma.
- The fibrin fibers also adhere to damaged
surfaces of blood vessels; therefore, the blood
clot becomes adherent to any vascular
opening and thereby prevents further blood
loss.
CLOT RETRACTION AND EXPRESSION OF SERUM
 Within a few minutes after a clot is formed, it
begins to contract and usually expresses most
of the fluid from the clot within 20 to 60
minutes
 Serum cannot clot because it fibrinogen and
most other blood clotting factors
 Platelets are necessary for clot retraction to
occur.
 Platelets entrapped in the clot continue to
release procoagulant substances, one of the
most important of which is fibrin-stabilizing
factor, which causes more and more cross-
linking bonds between adjacent fibrin fibers.
 Platelets contribute directly to clot
contraction by activating platelet
thrombosthenin, actin, and myosin molecules,
which are all contractile proteins in the
platelets and cause strong contraction of the
platelet spicules attached to the fibrin (This
action also helps compress the fibrin
meshwork into a smaller mass)
 The contraction is activated and accelerated
by thrombin, as well as by calcium ions
released from calcium stores in the
mitochondria, endoplasmic reticulum, and
Golgi apparatus of the platelets.
 As the clot retracts, the edges of the broken
blood vessel are pulled together, thus
contributing still further to hemostasis
POSITIVE FEEDBACK OF CLOT FORMATION
 Once a blood clot has started to develop, it
normally extends within minutes into the
surrounding blood—that is, the clot initiates
a positive feedback to promote more clotting
 Most important causes of this clot promotion
is that the proteolytic action of thrombin
allows it to act on many of the other blood
clotting factors in addition to fibrinogen.
 Once a critical amount of thrombin is formed,
a positive feedback develops that causes still
more blood clotting and more and more
thrombin to be formed; thus, the blood clot
 continues to grow until blood leakage
ceases
DURING THE INITIATION OF COAGULATION,
PROTHROMBIN ACTIVATOR IS FORMED IN TWO
BASIC WAYS.
- Via the extrinsic pathway, which begins with
trauma to the vascular wall and surrounding
tissue,
- Via the intrinsic pathway, which begins in the
blood itself.
- Both pathways involve a series of b-globulin
plasma proteins.
- These blood clotting factors are proteolytic
enzymes that induce the successive cascading
reactions of the clotting process.
THE EXTRINSIC MECHANISM FOR INITIATING
THE FORMATION OF PROTHROMBIN ACTIVATOR
- Begins with trauma to the vascular wall or
extravascular tissues and occurs according to
the following three steps:
1. RELEASE OF TISSUE THROMBOPLASTIN
- Traumatized tissue releases a complex of
several factors called tissue thromboplastin;
these factors include phospholipids from the
membranes of the traumatized tissue and a
lipoprotein complex that functions as a
proteolytic enzyme.
2. ACTIVATION OF FACTOR X TO FORM
ACTIVATED FACTOR X
- The lipoprotein complex of tissue
thromboplastin complexes with blood
coagulation factor VII and in the presence of
tissue phospholipids and calcium ions acts
enzymatically on factor X to form activated
factor X
3. EFFECT OF ACTIVATED FACTOR X TO
FORM PROTHROMBIN ACTIVATOR
- The activated factor X immediately forms
a complex with the tissue phospholipid
released as part of the tissue thromboplastin
and with factor V to form a complex called
prothrombin activator.
- Within a few seconds this splits prothrombin
to form thrombin, and the clotting process
proceeds as previously described.
- Activated factor X is the protease that causes
splitting of prothrombin to thrombin.
THE INTRINSIC MECHANISM FOR INITIATING THE
FORMATION
OF PROTHROMBIN ACTIVATOR
- Begins with trauma to the blood or exposure
of the blood to collagen in the traumatized
vascular wall.
- This occurs via the following cascade of
reactions:
1. Activation of factor XII and release of
platelet phospholipids
- Through trauma, factor XII is activated to
form a proteolytic enzyme called activated
factor XII.
- Simultaneously, the blood trauma damages
blood platelets, which causes the release of
platelet phospholipids containing a
lipoprotein called platelet factor III, which
plays a role in subsequent clotting reactions.
2. ACTIVATION OF FACTOR XI
- The activated factor XII acts enzymatically on
factor XI to activate factor XI.
- This second step in the intrinsic pathway
requires high-molecular-weight kininogen.
3. ACTIVATION OF FACTOR IX BY ACTIVATED
FACTOR XI
- The activated factor XI then acts
enzymatically on factor IX to activate it.
4. ACTIVATION OF FACTOR X
- The activated factor IX, acting in concert with
factor VIII and with platelet phospholipids
and factor III from the traumatized platelets,
activates factor X. When either factor VIII or
platelets are in short supply, this step is
deficient.
- Factor VIII is the factor that is missing in the
person who has classic hemophilia. Platelets
are the clotting factor lacking in the bleeding
disease called thrombocytopenia
5. ACTIVATION OF ACTIVATED FACTOR X TO
FORM PROTHROMBIN ACTIVATOR.
 - the same as the last step in the extrinsic
pathway (i.e., activated factor X combines
with factor V and platelets or tissue
phospholipids to form the complex called
prothrombin activator).
- The prothrombin activator in turn initiates
cleavage of prothrombin to form thrombin,
thereby setting into motion the final clotting
process.
CALCIUM IONS ARE REQUIRED FOR BLOOD
CLOTTING
 Except for the first two steps in the intrinsic
pathway, calcium ions are required for
promotion of all the reactions; in the absence
of calcium ions, blood clotting does not occur.
 Fortunately, the calcium ion concentration
rarely falls sufficiently low to affect the
kinetics of blood clotting significantly.
 When blood is removed, it can be
prevented from clotting by reducing the
calcium ion concentration below the
threshold level for clotting.
 This can be accomplished through either
deionization of the calcium via reaction with
substances such as a citrate ion or
precipitation of the calcium with substances
such as an oxalate ion.
PREVENTION OF BLOOD CLOTTING IN THE
NORMAL VASCULAR SYSTEM—INTRAVASCULAR
ANTICOAGULANTS
 The most important factors for the
prevention of clotting in the normal vascular
system are
1. The smoothness of the endothelium
- Which prevents contact activation of the
intrinsic clotting system;
2. A layer of glycocalyx in the endothelium
- Which repels the clotting factors and platelets
3. a protein bound with the endothelial
membrane (called thrombomodulin)
- Which binds thrombin.
- The thrombomodulin-thrombin complex also
activates a plasma protein called protein C,
which inactivates activated factors V and VIII
- When the endothelial wall is damaged, its
smoothness and its glycocalyx-
thrombomodulin layer are lost, which
activates factor XII and platelets and initiates
the intrinsic pathway of clotting.
- Agents that remove thrombin from blood,
such as the fibrin threads that form during
the process of clotting and an a-globulin
called antithrombin III, are the most
important anticoagulants in the blood.
- Thrombin becomes absorbed to the fibrin
threads as they develop; this prevents the
spread of thrombin into the remaining blood
and prevents excessive spread of the clot.
- The
thrombin that does not adsorb to the fibrin
threads combines with antithrombin III,
which inactivates the thrombin.
HEPARIN
- In the presence of excess heparin, removal
of thrombin from the circulation is almost
instantaneous.
- Mast cells located in the pericapillary
connective tissue throughout the body and
the basophils of the blood produce heparin.
- These cells continually secrete small amounts
of heparin that diffuse into the circulatory
system.
LYSIS OF BLOOD CLOT
 Plasminogen is a plasma protein that when
activated becomes a substance called
plasmin, a proteolytic enzyme that resembles
trypsin.
 Plasmin digests the fibrin threads as well as
other clotting factors.
 Plasminogen becomes trapped in the clot
along with other plasma proteins.
 The injured tissues and vascular endothelium
slowly release a powerful activator called
tissue plasminogen activator (t-PA), which
converts plasminogen to plasmin
and removes the clot.
 Plasmin not only destroys fibrin fibers but
also functions as a proteolytic enzyme to
digest fibrinogen and a number of other
clotting factors.
 Small amounts of plasmin are continuously
formed in the blood.
  The blood also contains another factor, a2-
antiplasmin, which binds with plasmin and
causes inactivation; the rate of plasmin
formation must rise above a certain critical
level before it becomes effective
CLINICAL NOTES
- Excessive bleeding can result from a
deficiency of vita min K, from hemophilia, or
from thrombocytopenia
(platelet deficiency).
- Vitamin K is necessary for the formation of
five important clotting factors: prothrombin,
factor VII, factor IX, factor X, and protein C.
- In the absence of vitamin K, insufficiency of
these coagulation can lead to bleeding
1. HEMOPHILIA IS CAUSED BY A DEFICIENCY
OF FACTOR VIII OR IX AND OCCURS
ALMOST EXCLUSIVELY IN MALES
- Hemophilia A, or classic hemophilia, is caused
by a deficiency of factor VIII and accounts for
about 85% of cases.
- The other 15% of cases of hemophilia are the
result of a deficiency of factor IX.
- Both of these factors are transmitted
genetically via the female chromosome as a
recessive trait; women almost never have
hemophilia because at least one of their two X
chromosomes has the appropriate genes.
2. THROMBOCYTOPENIA IS A DEFICIENCY OF
PLATELETS IN THE CIRCULATORY SYSTEM
- People with thrombocytopenia have a
tendency to bleed from small vessels or
capillaries.
- As a result, small punctate hemorrhages
occur throughout the body tissues.
- The skin of such a person displays many
small, purplish blotches, giving the disease
the name thrombocytopenic purpura
THROMBOEMBOLIC CONDITIONS IN THE HUMAN
BEINGS
- An abnormal clot that develops in a blood
vessel is called a thrombus.
- An embolus is a free-flowing thrombus.
Emboli generally do not stop flowing until
they come to a narrow point in the circulatory
system.
- Thromboembolic conditions in human beings
are usually the result of a roughened
endothelial surface or sluggish blood flow.
- The rough endothelium can initiate the
clotting process.
- When blood flow is too slow, the
concentration of procoagulant factors often
rises high enough in a local area to initiate
clotting
ANTICOAGULANTS FOR CLINICAL USE
1. Heparin
- It is extracted from several animal tissues and
can be prepared in almost pure form.
- It increases the effectiveness of antithrombin
III.
- The action of heparin in the body is almost
instantaneous, and at normal dosages (0.5 to
1.0 mg/kg) it can increase the
clotting time from about 6 minutes to 30
minutes or longer.
- If too much heparin is given, a substance
called protamine can be administered, which
combines electrostatically with heparin to
cause its inactivation.
2. Coumarins such as warfarin cause the
plasma levels of prothrombin and factors
VIII, IX, and X to fall.
- Warfarin causes this effect by competing with
vitamin K for reactive sites in the enzymatic
processes for the formation of prothrombin
and the other three clotting factors.
BLOOD TYPING
ANTIGENICITY CAUSES IMMUNE REACTIONS TO
BLOOD
- Bloods of different people have different
antigenic and immune properties so that
antibodies in the plasma of one blood type
will react with antigens on the surfaces of the
rbc’s of another blood type
- When blood transfusions from one person to
another were first attempted, immediate or
delayed agglutination and hemolysis of the
 red blood cells (RBCs) often occurred, a. Type O Allele: either functionless or almost
resulting in typical transfusion reactions that functionless, so it causes no signifcant type O
frequently led to death agglutinogen on the cells.
MULTIPLICITY OF ANTIGENS IN THE BLOOD - The O allele is recessive to both the A and B
CELLS alleles, which show co-dominance.
b. Type A and B Allele: cause strong
- Two particular types of antigens are much agglutinogens on the cells
more
There are 6 possible alleles in your blood
likely than the others to cause blood
typing
transfusion reactions.
- They are the O-A-B system of antigens and the
Rh system
O-A-B SYSTEM
A AND B ANTIGENS—AGGLUTINOGENS
 Two antigens—type A and type B—occur on
the surfaces of the RBCs in a large proportion
of human beings
 It is these antigens (also called agglutinogens
because they often cause blood cell
agglutination) that cause most blood SINO KAYA MAS MARAMI? OBVIOUS NAMAN DBA
transfusion reactions
 Because of the way these agglutinogens are
inherited, people may have neither of them
on their cells, they may have one, or they may
have both simultaneously
MAJOR O-A-B BLOOD TYPES

- In transfusing blood from one person to

another, the bloods of donors and recipients
are normally classified into four major O-A-B
blood types,
- Depending on the presence or absence of the
two agglutinogens, the A and B agglutinogens
a. Blood Type O: When neither A nor B
agglutinogen is present
b. Blood Type A: Agglutinogen A is present only
c. Blood Type B: Agglutinogen B is present only
d. Blood Type AB: Agglutinogen A and B are
both present.
GENETIC DETERMINATION OF THE
AGGLUTINOGEN

- The ABO blood group genetic locus has three

alleles, which means three different forms of AGGLUTININS
the same gene.
- (-)Type A Agglutinogen = (+) Anti agglutinins
- These three alleles, IA, IB, and IO, determine A develop in plasma
the three blood types.
 - (-)Type B Agglutinogen= (+) Anti agglutinins
B develop in plasma
- (-) Type O Agglutinogen = Both A and B Anti-
agglutinins are present
- (+) Type AB Agglutinogen = (-) Both A and B
Anti-Agglutinins are absent.
TITER OF THE AGGLUTININS AT DIFFERENT
AGES.
 At Birth: Quantity of Agglutinins is nearly
zero
 2-8 months: an infant begins to produce
agglutinins—anti-A agglutinins when
type A agglutinogens are not present in
the cells, and
anti-B agglutinins when type B
agglutinogens are not in the cells
 8-10 years of Age: Maximum titer is
ofagglutinins
 10 Above/Remaining Years of Life:
Decreases as we grow older.
ORIGIN OF AGGLUTININS IN THE PLASMA
 The agglutinins are gamma globulins, as are
almost all antibodies, and they are produced
by the same bone marrow and lymph gland
cells that produce antibodies to any other
antigens.
 Most of them are IgM and IgG
immunoglobulin molecules.
But why are these agglutinins produced in people
who do not have the respective agglutinogens in
their RBCs?
 The answer to this question is that small
amounts of type A and B antigens enter the
body in food, in bacteria, and in other ways,
and these substances initiate the
development of the anti-A and anti-B
agglutinins.
 For instance, infusion of group A antigen into
a recipient having a non-A blood type causes
a typical immune response with formation of
greater quantities of anti-A agglutinins than
ever. Also, the neonate has few, if any,
agglutinins, showing that agglutinin
formation occurs almost entirely after birth
AGGLUTINATION PROCESS IN TRANSFUSION
REACTIONS
- When bloods are mismatched so anti-A or
anti-B plasma agglutinins are mixed with red
blood cells containing A or B agglutinogens,
the red blood cells agglutinate into clumps.
- These clumps can plug small blood
vessels throughout the circulatory system. In
some cases, the antibodies induce lysis of red
blood cells through activation of the
complement system
ACUTE HEMOLYSIS OCCURS IN SOME
TRANSFUSION REACTIONS.
 One of the most lethal effects of transfusion
reactions is renal failure.
 The excess hemoglobin from the
hemolyzed red blood cells leaks through the
glomerular membranes into the renal tubules.
 Reabsorption of water from the tubules
causes the hemoglobin concentration to rise,
resulting in hemoglobin precipitation and
subsequent blockade of the tubules.
BLOOD TYPING
 The RBCs are first separated from the plasma
and diluted with saline solution.
 One portion is then mixed with anti-A
agglutinin and another portion with anti-B
agglutinin
 If the RBCs have become clumped—that is,
“agglutinated”—one knows that an antibody-
antigen reaction has resulted
RH BLOOD TYPES
- There are six common types of Rh antigens,
each of which is called an Rh factor
- Designated as C, D, E, c, d, and e
- A person who has a C antigen does
not have the c antigen, but the person missing the C
antigen always has the c antigen.
- The same is true for the D-d and E-e antigens. Also,
because of the manner of inheritance of these factors,
each person has one of each of the three pairs of
antigens
- The type D antigen is widely prevalent in the
population and considerably more antigenic than the
other Rh antigens
 - Anyone who has this type of antigen is said to
be Rh positive, whereas a person who does not have
type D antigen is said to be Rh negative
- However, it must be
noted that even in Rh-negative people, some of the
other Rh antigens can still cause transfusion
reactions, although the reactions are usually much
milder

Rh Immune Response
Formation of Anti-Rh Agglutinins

- When RBCs containing Rh factor are injected

into a person whose blood does not contain
the Rh factor—that is, into an Rh-negative
person—anti-Rh agglutinins develop slowly,
reaching maximum concentration of
agglutinins about 2
to 4 months later.
- This immune response occurs to a much
greater extent in some people than in others.
- With multiple exposures to the Rh factor, an
Rh-negative person eventually becomes
strongly “sensitized” to Rh factor
CHARACTERISTICS OF RH TRANSFUSION
REACTIONS.

1. If an Rh-negative person has never before

been exposed to Rh-positive blood,
transfusion of Rh-positive blood into that
person
- It will likely cause no immediate reaction.
However, anti-Rh antibodies can develop in
sufficient quantities during the next 2 to 4
weeks to cause agglutination of the
transfused cells that are still circulating in the
blood.
- These cells are then hemolyzed by the tissue
macrophage system. Thus, a delayed
transfusion reaction occurs, although it is
usually mild.
- Upon subsequent transfusion of Rh-positive
blood into the same person, who is now
already immunized against the Rh factor, the
transfusion reaction is greatly enhanced and
can be immediate and as severe as a
transfusion reaction caused by mismatched
type A or B blood