BLOOD

It is a liquid connective tissue that consists of

cells surrounded by a liquid extracellular
matrix.
The extracellular matrix is called blood
plasma, and it suspends various cells and cell
fragments.

FUNCTIONS OF BLOOD
Transports oxygen, carbon
dioxide, nutrients, hormones,
heat, and wastes.
Regulates pH, body temperature,
and water content of cells.
Protects against blood loss through clotting,
and against disease through phagocytic white
blood cells and proteins such as antibodies,
interferons, and complement.
RED BLOOD CELLS / ERYTHROCYTES
-

a.
b.
a.
b.

Contain the oxygen-carrying protein

hemoglobin, which is a pigment that gives
whole blood its red color
Normal Value:
a. Male: 5.5x108L
b. Female: 4.7x108L
Biconcave disk having a mean of diameter of
about 7.8m and a thickness of 2.5m at the
thickest point and 1m or less in the center.
Average Volume: 90-95m3
Your RBC is a bag that can be deformed into
any almost shape because the normal cells
has a great excess of a cell membrane for the
quantity of the material inside. (Hindi sila
marupture dahil strong ang plasma
membrane nila at saka flexible pa ito)
Concentration of RBC in blood
Male: 5,200,000 mm3
Female: 4,700,000 mm3
RBCs can concentrate hemoglobin in the cell
uid up to about 34g in each 100mm of cells.
Hemoglobin: Red Blood Cell
Hematocrit(Hct): Volume of Percentage of
the Red Blood Cells
When it is in Normal Level
The whole blood of men contains an average
of 15g of hemoglobin per 100 mL
The whole blood of men contains an average
of 14g of hemoglobin per 100mL

FUNCTIONS:

Carries O2 from lungs to the tissues.

Transport Hemoglobin
Can concentrate Hemoglobin
Contain a large quantity of carbonic
anhydrase, an enzyme that catalyzes the
reversible reaction between carbon
dioxide (CO2) and water to form carbonic
acid (H2CO3), increasing the rate of this
reaction several thousand-fold.

PRODUCTION OF THE RED BLOOD CELLS

Early Weeks of Embryonic Life: Nucleated
RBC are produced in the yolk sac; Yolk Sac is
also the 1st site of blood formation.
Middle Trimester of Gestation: Liver is the
main organ to produce RBC but reasonable
numbers are also produced by spleen and
lymph nodes.
Last month of Gestation and After Birth:
RBC are produced exclusively in the Red Bone
Marrow.
At 5 years of Age: All bones of your body will
produce RBC
At 20 years of Age: The marrow of the long
bones, except for the proximal portions of the
humeri and tibiae, becomes quite fatty and
produces no more RBCs
At 20 years of Age Beyond: most RBCs
continue to be produced in the marrow of the
membranous bones, such as the vertebrae,
sternum, ribs, and ilia. Even in these bones,
the marrow becomes less productive as age
increases
GENESIS OF BLOOD CELLS
1. PLURIPOTENTIAL HEMATOPOIETIC STEM
CELL
- AKA: Hemocytoblasts
- It is where all the cells of the circulating blood
are eventually derived.

2.
-

3.
4.
5.
6.
-

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
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
When cultured, it will produce colonies of
specific types of blood cells
COLONY FORMING UNITS-ERYTHROCYTES
A committed stem cells that produced
erythrocytes.
GROWTH INDUCERS
Controlled growth and reproduction of the
dierent stem cells
INTERLEUKINS-3
Promotes growth and reproduction of
virtually all the dierent 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. 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)
4. 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 kidneys oxygen
consumption occurs
*Renal Tissue Hypoxia: Tissue Level HIF1; 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
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
eect 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 dierent
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 dierent 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,

in which the basic abnormality is an atrophic
gastric mucosa that fails to produce normal
gastric secretions.
The parietal cells of the gastric glands secrete
a glycoprotein called intrinsic factor, which
combines with vitamin B12 in food and
makes the B12 available for absorption by the
gut.

MECHANISM
Intrinsic factor binds tightly with the vitamin
B12. In this bound state, the B12 is protected
from digestion by the gastrointestinal
secretions.
Still in the bound state, intrinsic factor binds
to specific receptor sites on the brush border
membranes of the mucosal cells in the ileum
Vitamin B12 is then transported into the
blood during the next few hours by the
process of pinocytosis, carrying intrinsic
factor and the vitamin together through the
membrane.
(-) Intrinsic Factor = decreases availability of
vitamin B12 because of faulty absorption of the
vitamin.
Maturation Failure Caused by Folic Acid
(Pteroylglutamic Acid) Defciency

 Folic acid is a normal constituent of green

vegetables, some fruits, and meats
(especially liver). However, it is easily
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

Normal: 4-5g
65%: Hemoglobin
4%: Myoglobin
1%: Various Heme Compounds that promote
intracellular oxidation
0.1%: Combined with the protein transferrin
in the blood plasma
15-30%: Stored for later use, mainly in the
reticuloendothelial system and liver
parenchymal cells, principally in the form of
ferritin.

TRANSPORTATION OF IRON

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
to release this oxygen readily in the
peripheral tissue capillaries, where the
gaseous tension of oxygen is much lower than
in the lungs
-

HEMOGLOBIN FORMATION
a.
b.
-

Normal Value
Male: 15g/dL
Female: 14g/dL
Synthesis of hemoglobin begins in the
proerythroblasts It will continue in the
reticulocytes stageLeaving of erythrocytes
in the bone marrow and will pass to the
bloodstream Formation of Hemoglobin
until they become mature erythrocytes.

IRON METABOLISM
-

Iron is important for the formation of

hemoglobin
Also important for other essential elements

When iron is absorbed from the small

intestine it immediately combines with a bglobulin 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 liverApotransferrin binds with the
free iron and certain iron compounds such as
hemoglobin and myglobinTransferrinTransferrin
will bind with receptors in the membranes of the
intestinal epithelial cellRelease 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
Kuper 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, oddshaped 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
-

1.
-

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
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 m 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 L

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.

of platelets are removed by the

macrophages from the spleen.

MECHANISM OF PLATELET PLUG FORMATION

1.
2.
-

3.
-

4.
-

It only happens when there is a very small

vascular hole from the body
Platelets come in contact with a damaged
vascular surface
Platelets rapidly change their own
characteristics drastically
SWELLING
Assume irregular forms with numerous
irradiating pseudopods protruding from their
surfaces
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)
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
a.
b.
-

3rd Mechanism for blood clotting

Severe Trauma: 15-20 seconds clotting
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:

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.

1.

CONVERSION OF FIBRINOGEN TO FIBRIN

FORMATION OF THE CLOT
FIBRONOGEN
-

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.

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
uids,
When the permeability of the capillaries
becomes pathologically increased, fibrinogen
does leak into the tissue uids in sufficient
quantities to allow clotting of these uids 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 fibrinstabilizing 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 uid 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 crosslinking 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 bloodthat 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

1.

2.

3.

4.

5.

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:
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.
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.
ACTIVATION OF FACTOR IX BY ACTIVATED
FACTOR XI
The activated factor XI then acts
enzymatically on factor IX to activate it.
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
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 SYSTEMINTRAVASCULAR
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 glycocalyxthrombomodulin 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, a2antiplasmin, 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 dierent people have dierent

antigenic and immune properties so that
antibodies in the plasma of one blood type
will react with antigens on the surfaces of the
rbcs 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,
resulting in typical transfusion reactions that
frequently led to death

MULTIPLICITY OF ANTIGENS IN THE BLOOD

CELLS
-

Two particular types of antigens are much

more
likely than the others to cause blood
transfusion reactions.
They are the O-A-B system of antigens and the
Rh system

MAJOR O-A-B BLOOD TYPES

-

a.
b.
c.
d.

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
Blood Type O: When neither A nor B
agglutinogen is present
Blood Type A: Agglutinogen A is present only
Blood Type B: Agglutinogen B is present only
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 dierent forms of
the same gene.
- These three alleles, IA, IB, and IO, determine
the three blood types.
a. Type O Allele: either functionless or almost
functionless, so it causes no signifcant type O
agglutinogen on the cells.
- The O allele is recessive to both the A and B
alleles, which show co-dominance.
b. Type A and B Allele: cause strong
agglutinogens on the cells
There are 6 possible alleles in your blood
typing

O-A-B SYSTEM
A AND B ANTIGENSAGGLUTINOGENS
Two antigenstype A and type Boccur 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
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

SINO KAYA MAS MARAMI? OBVIOUS NAMAN DBA

AGGLUTININS
-

(-)Type A Agglutinogen = (+) Anti agglutinins

A develop in plasma
(-)Type B Agglutinogen= (+) Anti agglutinins
B develop in plasma
(-) Type O Agglutinogen = Both A and B Antiagglutinins are present
(+) Type AB Agglutinogen = (-) Both A and B
Anti-Agglutinins are absent.

AGGLUTINATION PROCESS IN TRANSFUSION

REACTIONS
-

TITER OF THE AGGLUTININS AT DIFFERENT

AGES.
At Birth: Quantity of Agglutinins is nearly
zero
2-8 months: an infant begins to produce
agglutininsanti-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

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 clumpedthat is,
agglutinatedone knows that an antibodyantigen 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 factorthat is, into an Rh-negative
personanti-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