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.
 - 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
- As these cells reproduce, a small portion of cytoplasmic organelles
them remains exactly like the original - During this reticulocyte stage, the cells pass
pluripotential cells and is retained in the bone from the bone marrow into the blood
marrow to maintain a supply of these, capillaries by diapedesis (squeezing through
although their numbers diminish with age the pores of the capillary membrane)
- Most of these cells undergo differentiation to 6. MATURE ERYTHROCYTES
form other cell type - The remaining basophilic material in the
2. COMMITED STEM CELLS reticulocyte normally disappears within 1 to
- They are intermediate stage cells are very 2 days
much like the pluripotential stem cells, even - Because of the short life of the reticulocytes,
though they have already become committed their concentration among all the RBCs is
to a particular line of cells normally slightly less than 1 percent
3. When cultured, it will produce colonies of
specific types of blood cells ERYTHROPOIETIN
4. COLONY FORMING UNITS-ERYTHROCYTES
- A circulating hormone that regulates Red
- A committed stem cells that produced
Blood Cell Production
erythrocytes.
- Transports oxygen to the tissue
5. GROWTH INDUCERS/ GROWTH AND
- (-) Erythropoietin = Hypoxia (little or no
REPRODUCTION INDUCER
effect in RBC production)
- Controlled growth and reproduction of the
- (+) Erythropoietin System is Functional =
different stem cells
Hypoxia causes a marked increase in
6. INTERLEUKINS-3
erythropoietin production and the
- Promotes growth and reproduction of
erythropoietin, in turn, enhances RBC
virtually all the different types of committed
production until the hypoxia is relieved.
stem cells
- Low Oxygen (primary stimulus) = RBC
STAGES OF DIFFERENTIATION OF RED BLOOD Production
CELLS - Formed mainly by your kidneys (90%) and
liver (10%)
1. PROERYTHROBLASTS - Erythropoietin is secreted mainly by
- Under appropriate stimulation, large fibroblast-like interstitial cells surrounding
numbers of these cells are formed from the the tubules in the cortex and outer medulla,
CFU-E stem cells where much of the kidney’s oxygen
2. BASOPHIL ERYTHROBLASTS consumption occurs
- Formed when your proerythroblasts starts to - *Renal Tissue Hypoxia: ↑ Tissue Level HIF-
divide multiple times. 1; HIF-1 will binds to a hypoxia response
- 1st Generation of the cells. element will reside in the erythropoietin gene
- Accumulates very little hemoglobin and it will increase erythropoietin synthesis.
3. POLYCHROMATOPHIL ERYTHROBLAST
 - Removal of Kidney or destruction of kidney = - Rapid Production of the RBC continues as
anemic; because the 10 percent of the normal long as the person remains in low oxygen
erythropoietin formed in other tissues state or until enough RBC have been
(mainly in the liver) is sufficient to cause only produced to carry adequate amounts of
one third to one half the RBC formation oxygen to the tissues despite the low level of
needed by the body oxygen
- When sufficient amount is oxygen is
NEUTRANSMITTER FOR NON-RENAL SENSOR
established = erythropoietin production
HYPOXIS
decreases to a level that will maintain the
1. Epinephrine required number of RBCs but not an excess
2. Norepinephrine - (-) Erythropoietin = RBC are formed by the
3. Prostaglandin bone marrow
- (+) Large amount Erythropoietin together
MOST COMMON HEMOGLOBIN CHAIN with iron = RBC production can rise to
- Alpha and Beta perhaps 10 or more times normal.

FACTORS THAT DECREASE OXYGENATION Maturation of Red Blood Cells Requires

Vitamin B12 (Cyanocobalamin) and
- Low Blood Volume Folic Acid
- Anemia
- Low Hemoglobin - Important for final maturation of the RBCs
- Poor Blood Flow are two vitamins, vitamin B12 and folic acid
- Pulmonary Disease - Both of these vitamins are essential for the
synthesis of DNA because
STORED IRON each, in a different way, is required for the
formation of thymidine triphosphate, one of
- AKA: FERRITIN
the essential building blocks of DNA.
SICKLE CELL ANEMIA
(-) Vitamin B12 and Folic Acid: Failure of nuclear
- Pinalitan si Amino Acid Valine into maturation and cell division ↣ production of
Glutamic Acid macrocytes (flimsy membrane often irregular,
- Pwede niya marupture si blood vessels large and oval shaped; they are capable of carry
oxygen kaso they are very fragile kaya short life
ERYTHROPOIETIN STIMULATES PRODUCTION OF lang sila); Maturation failure of the RBC to be
PROERYTHROBLASTS FROM HEMATOPOIETIC mature.
STEM CELLS.
TISSUE OXYGENATION
- ↓ Low Oxygen Supply: Erythropoietin begins
to formed within minutes to hours until it - ↓Oxygen Level to tissue = ↑ RBC production
reaches to its maximum production in 24 - Anemia = Bone Marrow starts to produce
hours. large quantities of RBC production.
- No new RBCs appear in the circulating blood - Destruction of Bone Marrow due to X-ray
until about 5 days later Therapy = causes hyperplasia of the
- It has been determined that the important remaining bone marrow, to supply the
effect of erythropoietin is to stimulate the demand for RBCs in the body.
production of proerythroblasts from - High Altitude, where quantity of Oxygen
hematopoietic stem cells in the bone marrow decreases = Oxygen transported to the tissues
- once the proerythroblasts are formed, the decreases = RBC decreases
erythropoietin causes these cells to pass
Maturation Failure Caused by Poor Absorption
more rapidly through the different
of Vitamin B12 from the Gastrointestinal Tract—
erythroblastic stages than they normally do,
Pernicious Anemia.
further speeding up the production of new
RBCs
 - 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 - Iron Absorption from the intestine is
transferrin, which is transported in the
extremely slow
plasma.
- Even when tremendous quantities of iron are
- This iron is loosely bound. Excess iron in the
present in the food, only small proportions
blood is deposited in liver hepatocytes and in
can be absorbed
reticuloendothelial cells of the bone marrow.
- Once inside the cell's cytoplasm, iron LIFE SPAN OF RED BLOOD CELLS IN 120 DAYS
combines with the protein apoferritin to form
ferritin.
- RBCs do not have a nucleus, mitochondria, or
endoplasmic reticulum, they do have
- Varying quantities of iron can combine in cytoplasmic enzymes that are capable of
clusters of iron radicals in the ferritin. metabolizing glucose and forming small
- When the quantity of iron in the plasma amounts of adenosine triphosphate
decreases to less than normal, iron is DESTRUCTION OF HEMOGLOBIN BY
removed from ferritin quite easily and MACROPHAGES.
transported by transferrin in the plasma to
the portions of the body where it is needed.  When RBCs burst and release their
hemoglobin, the hemoglobin is phagocytized
- A unique characteristic of the transferrin
almost immediately by macrophages in
molecule is its ability to bind strongly with
many parts of the body, but especially by the
receptors in the cell membranes of the
Kupffer cells of the liver and macrophages of
erythroblasts and bone marrow.
the spleen and bone marrow.
- Transferrin is ingested via endocytosis into  During the next few hours to days, the
the erythroblasts along with the bound iron. macrophages release iron from the
- Transferrin delivers the iron directly to the hemoglobin and pass it back into the blood, to
mitochondria, where heme is synthesized. be carried by transferrin either to the bone
marrow for the production of new RBCs or to
- When red blood cells have reached the end of the liver and other tissues for storage in the
their life span and are destroyed, the form of ferritin.
hemoglobin released is ingested by cells of  The porphyrin portion of the hemoglobin
the monocyte-macrophage system. molecule is converted by the macrophages,
- The free iron that is liberated can be stored in through a series of stages, into the bile
the ferritin pool or reused for formation of pigment bilirubin, which is released into the
hemoglobin. blood and later removed from the body by
secretion through the liver into the bile; this
- A man excretes about 0.6 mg of iron
process
each day, mainly into the feces. Additional
quantities of iron are lost when bleeding CLINICAL NOTES
occurs. For a woman, additional menstrual
ANEMIA
loss of blood brings long term iron loss to an
average of about 1.3 mg/day
- Means a deficiency of red blood cells and can
ABSORPTION OF IRON FROM INTESTINAL TRACT be caused by rapid loss of red blood cells or
slow production of red blood cells.
Secretion of moderate amount of apotransferrin in
the bile from the liver↣Apotransferrin binds with the - Blood loss anemia occurs after significant
free iron and certain iron compounds such as hemorrhage. The body is able to replace the
hemoglobin and myglobin↣Transferrin↣Transferrin plasma within 1 to 3 days; however, the
will bind with receptors in the membranes of the concentration of red blood
intestinal epithelial cell↣Release in to the blood cells remains low.
capillaries in the form of plasma transferrin.
 - After significant hemorrhage, a period of 3 to polycythemia as a result of the thin
atmosphere.
4 weeks is required to return the number of
red blood cells to normal levels. - Polycythemia can also occur in individuals
1. APLASTIC ANEMIA with cardiac failure because of decreased
- It is the result of nonfunctioning bone delivery of oxygen to the tissues.
a. Polycythemia vera
marrow, which may be due to exposure to
gamma radiation for cancer treatment or - It is a genetic aberration in the
toxic chemicals such as insecticides or hemocytoblastic cell line.
benzene in gasoline. - The blast cells continue to produce red blood
- Autoimmune disorders such as lupus cells even though too many blood cells are
erythematosus result in an immune system present in the circulation. The hematocrit can
attack on the healthy cells of the bone rise to 60% to 70%.
marrow, which destroys stem cells and may - Polycythemia greatly increases the viscosity
lead to aplastic anemia.
of the blood; as a result, blood flow through
- Individuals with severe aplastic anemia the vessels is often sluggish.
usually die unless they are treated with blood
HEMOSTASIS AND BLOOD COAGULATION
transfusions or bone marrow transplants.
2. MEGALOBLASTIC ANEMIA HEMOSTASIS
- It is the result of a lack of vitamin B12, folic
acid, or intrinsic factor. Lack of these - Means prevention of blood loss.
substances leads to slow reproduction of the - Whenever a vessel is severed or ruptured,
erythrocytes in the bone marrow. As a result, hemostasis is achieved by several
these erythrocytes grow into large, odd- mechanisms:
shaped cells called megaloblasts.  Vascular constriction,
 Formation of a platelet plug,
3. HEMOLYTIC ANEMIA  Formation of a blood clot as a result of blood
- It is the result of fragile red blood cells that coagulation,
rupture as they pass through the capillaries.  Eventual growth of fibrous tissue into the
blood clot to close the hole in the vessel
- With hemolytic anemia, the number of red permanently
blood cells that form is normal or in excess of 1. VASCULAR CONSTRICTION
normal; however, because these cells are
extremely fragile, their life span is very short. - Blood vessel has been cut or ruptured or
trauma will result smooth wall muscle
- Sickle cell anemia is a type of hemolytic contraction; reduction of blood flow
anemia caused by an abnormal composition
of the globin chains of hemoglobin. - Contraction results from
 Local Myogenic Spasm (aid in the loss of
- When this abnormal hemoglobin is exposed
blood by briefly constricting the muscle
to low concentrations of oxygen, it where the broken blood vessel is located)
precipitates into long crystals inside the red  Local Autacoid Factors from the
blood cell. This causes the cell to have an traumatized tissues and blood
abnormal sickle shape and to be extremely platelets
fragile.  Nervous Reflexes (initiated by pain
Polycythemia nerve impulses or other sensory impulses
that originate from the traumatized vessel
- It is a condition in which the number of red or nearby tissues)
blood cells in the circulation increases owing - The more severely a vessel is traumatized,
to hypoxia or genetic aberration. Individuals the greater the degree of vascular spasm.
who live at high altitudes have physiologic
 - The spasm can last for many minutes or even adherence to injured areas of the vessel wall,
especially to injured endothelial cells and
hours, during which time the processes of
even more so to any exposed collagen from
platelet plugging and blood coagulation can
deep within the vessel wall
take place.
PHYSICAL AND CHEMICAL CHARACTERISTIC - Life Cycle: 8-12 days only
OF PLATELETS

- AKA: Thrombocytes - Can be eliminated from the circulation mainly

by tissue macrophage system.
- They are minute discs 1 to 4 μm in diameter
- Formed in the bone marrow from - ½ of platelets are removed by the
megakaryocytes macrophages from the spleen.
a. MEGAKARYOCYTES
- Extremely large hematopoietic cells in the
marrow
- The megakaryocytes fragment into the MECHANISM OF PLATELET PLUG FORMATION
minute platelets either in the bone marrow or
soon after entering the blood, especially as - It only happens when there is a very small
they squeeze through capillaries. vascular hole from the body
1. Platelets come in contact with a damaged
- Normal Value: 150-450x103 per μL vascular surface
STRUCTURES INSIDE THE CYTOPLASM OF - Platelets rapidly change their own
PLATELETS characteristics drastically
2. SWELLING
1. Actin and Myosin and thrombosthenin
(cause platelets to contract) - Assume irregular forms with numerous
2. Residuals of both the endoplasmic irradiating pseudopods protruding from their
reticulum and the Golgi apparatus surfaces
3. CONTRACTION OF CONTRACTILE
- Synthesize various enzymes and especially
PROTEINS
store large quantities of Ca2+
3. Mitochondria and Enzyme Systems - It will release a granules that contains
multiple active factors
- Capable of forming ATP and ADP
4. Enzyme Systems that synthesize - They will become sticky so that they adhere
prostaglandins to collagen and to a protein called Willeband
Factor (that leaks into the traumatized tissue
- Which are local hormones that cause many
from the plasma; they secrete large quantities
vascular and other local tissue reactions
of ADP; and their enzymes form thromboxane
5. FIBRIN-STABILIZING FACTOR
A)
6. GROWTH FACTOR
4. ADP and THROMBOXANE ACT ON NEARBY
- Causes vascular endothelial cells, vascular PLATELETS
smooth muscle cells, and fibroblasts to - Stickiness of these additional platelets causes
multiply and grow, thus causing cellular
them to adhere to the original activated
growth that eventually helps repair damaged
platelets
vascular walls
5. AT THE SITE OF A PUNCTURE IN A BLOOD
VESSEL WALL, THE DAMAGED VASCULAR
WALL ACTIVATES SUCCESSIVELY
- On your platelet cell membrane surface is a
coat of glycoproteins that repulses adherence
to normal endothelium and yet causes
 - Increasing numbers of platelets that attract - Procoagulants: Promote Coagulation
more and more additional platelets, thus - Anticoagulants: Inhibit Coagulation
forming a platelet plug
- This plug is loose at first, but it is usually Clotting takes place in three essential steps:
successful in blocking blood loss if the 1. In response to rupture of the vessel or
vascular opening is small. damage to the blood itself, a complex cascade
- During the subsequent process of blood of chemical reactions occurs in the blood
coagulation, fibrin threads form. involving more than dozen blood coagulation
factors. The net result is formation of a
- These threads attach tightly to the platelets,
complex of activated substances collectively
thus constructing an unyielding plug. called prothrombin activator
IMPORTANCE OF THE PLATELET MECHANISM 2. The prothrombin activator catalyzes
FOR CLOSING VASCULAR HOLES conversion of prothrombin into thrombin.
3. The thrombin acts as an enzyme to convert
 Extremely important for closing minute fibrinogen into fibrin fibers that enmesh
ruptures in very small blood vessels that platelets, blood cells, and plasma to form the
occur many thousands of times daily. clot.
BLOOD COAGULATION CONVERSION OF PROTHROMBIN TO THROMBIN

- 3rd Mechanism for blood clotting 1. PROTHROMBIN ACTIVATOR

a. Severe Trauma: 15-20 seconds clotting - It is formed as a result of rupture of a blood
b. Minor Trauma: 1-2 minutes clotting vessel or as a result of damage to special
- Within 3 to 6 minutes after rupture of a substances in the blood
vessel, the entire opening or broken end of 2. THE PROTHROMBIN ACTIVATOR, IN THE
the vessel is filled with clot if the vessel PRESENCE OF SUFFICIENT AMOUNTS OF
opening is not too large. IONIC CALCIUM
- After 20 minutes to an hour, the clot retracts, - Causes conversion of prothrombin to
which closes the vessel still further. thrombin
3. THE THROMBIN CAUSES
FIBROUS ORGANIZATION OR DISSOLUTION OF POLYMERIZATION OF FIBRINOGEN
THE BLOOD CLOT MOLECULES INTO FIBRIN FIBERS WITHIN
ANOTHER 10 TO 15 SECONDS
- Once a blood clot has formed, it can follow
one of two courses:
- The rate limiting factor in causing blood
 It can become invaded by fibroblasts, coagulation is usually the formation of
which subsequently form connective tissue prothrombin activator and not the
all through the clot subsequent reactions beyond that point
 It can dissolve - Platelets also play an important role in the
- Most Common in small hole in the blood conversion of prothrombin to thrombin
vessel: Invasion by Fibroblasts 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.
MECHANISM OF BLOOD COAGULATION
- It can be split into thrombin
GENERAL MECHANISM
 - Formed continually by the liver, and it - The fibrin fibers also adhere to damaged
is continually being used throughout the body surfaces of blood vessels; therefore, the blood
for blood clotting clot becomes adherent to any vascular
- Vitamin K: required by the liver for normal opening and thereby prevents further blood
loss.
activation of prothrombin, as well as a few
other clotting factors CLOT RETRACTION AND EXPRESSION OF SERUM
- (-) Vitamin K or Liver Disease: Decrease  Within a few minutes after a clot is formed, it
prothrombin level. begins to contract and usually expresses most
CONVERSION OF FIBRINOGEN TO FIBRIN— of the fluid from the clot within 20 to 60
FORMATION OF THE CLOT minutes
 Serum cannot clot because it fibrinogen and
FIBRONOGEN most other blood clotting factors
 Platelets are necessary for clot retraction to
- Formed in the liver, and liver disease can occur.
decrease the concentration of circulating  Platelets entrapped in the clot continue to
fibrinogen release procoagulant substances, one of the
- Due to its molecular size, it normally leaks most important of which is fibrin-stabilizing
from the blood vessels into the interstitial factor, which causes more and more cross-
fluids, linking bonds between adjacent fibrin fibers.
 Platelets contribute directly to clot
- When the permeability of the capillaries contraction by activating platelet
becomes pathologically increased, fibrinogen thrombosthenin, actin, and myosin molecules,
does leak into the tissue fluids in sufficient which are all contractile proteins in the
quantities to allow clotting of these fluids in platelets and cause strong contraction of the
much the same way that plasma and whole platelet spicules attached to the fibrin (This
blood can clot. action also helps compress the fibrin
ACTION OF THROMBIN ON FIBRONOGEN TO meshwork into a smaller mass)
FORM FIBRIN  The contraction is activated and accelerated
by thrombin, as well as by calcium ions
 The fibrin monomer molecule polymerizes released from calcium stores in the
with other fibrin monomer molecules to form mitochondria, endoplasmic reticulum, and
the long fibrin threads that produce the Golgi apparatus of the platelets.
reticulum of the clot.  As the clot retracts, the edges of the broken
 The newly formed fibrin reticulum is blood vessel are pulled together, thus
strengthened by a substance called fibrin- contributing still further to hemostasis
stabilizing factor, which normally is present
in small amounts in plasma. POSITIVE FEEDBACK OF CLOT FORMATION
 This substance is also released from  Once a blood clot has started to develop, it
platelets entrapped in the clot. normally extends within minutes into the
 Fibrin-stabilizing factor, an enzyme, causes surrounding blood—that is, the clot initiates
covalent bonding between the fibrin a positive feedback to promote more clotting
monomer molecules and adjacent fibrin  Most important causes of this clot promotion
threads, thereby strengthening the fibrin is that the proteolytic action of thrombin
meshwork. allows it to act on many of the other blood
BLOOD CLOT clotting factors in addition to fibrinogen.
 Once a critical amount of thrombin is formed,
- Composed of a meshwork of fibrin fibers a positive feedback develops that causes still
running in all directions and entrapping more blood clotting and more and more
blood cells, platelets and plasma. thrombin to be formed; thus, the blood clot
 continues to grow until blood leakage - Within a few seconds this splits prothrombin
ceases
to form thrombin, and the clotting process
proceeds as previously described.

DURING THE INITIATION OF COAGULATION, - Activated factor X is the protease that causes
PROTHROMBIN ACTIVATOR IS FORMED IN TWO splitting of prothrombin to thrombin.
BASIC WAYS. THE INTRINSIC MECHANISM FOR INITIATING THE
FORMATION
- Via the extrinsic pathway, which begins with OF PROTHROMBIN ACTIVATOR
trauma to the vascular wall and surrounding
tissue, - Begins with trauma to the blood or exposure
- Via the intrinsic pathway, which begins in the of the blood to collagen in the traumatized
blood itself. vascular wall.
- Both pathways involve a series of b-globulin - This occurs via the following cascade of
plasma proteins. reactions:
1. Activation of factor XII and release of
- These blood clotting factors are proteolytic
platelet phospholipids
enzymes that induce the successive cascading
reactions of the clotting process. - Through trauma, factor XII is activated to
form a proteolytic enzyme called activated
THE EXTRINSIC MECHANISM FOR INITIATING factor XII.
THE FORMATION OF PROTHROMBIN ACTIVATOR
- Simultaneously, the blood trauma damages
- Begins with trauma to the vascular wall or blood platelets, which causes the release of
extravascular tissues and occurs according to platelet phospholipids containing a
the following three steps: lipoprotein called platelet factor III, which
1. RELEASE OF TISSUE THROMBOPLASTIN plays a role in subsequent clotting reactions.
2. ACTIVATION OF FACTOR XI
- Traumatized tissue releases a complex of
several factors called tissue thromboplastin; - The activated factor XII acts enzymatically on
these factors include phospholipids from the factor XI to activate factor XI.
membranes of the traumatized tissue and a - This second step in the intrinsic pathway
lipoprotein complex that functions as a requires high-molecular-weight kininogen.
proteolytic enzyme. 3. ACTIVATION OF FACTOR IX BY ACTIVATED
2. ACTIVATION OF FACTOR X TO FORM FACTOR XI
ACTIVATED FACTOR X
- The activated factor XI then acts
- The lipoprotein complex of tissue enzymatically on factor IX to activate it.
thromboplastin complexes with blood 4. ACTIVATION OF FACTOR X
coagulation factor VII and in the presence of
tissue phospholipids and calcium ions acts
- The activated factor IX, acting in concert with
factor VIII and with platelet phospholipids
enzymatically on factor X to form activated
and factor III from the traumatized platelets,
factor X
activates factor X. When either factor VIII or
3. EFFECT OF ACTIVATED FACTOR X TO
platelets are in short supply, this step is
FORM PROTHROMBIN ACTIVATOR
deficient.
- The activated factor X immediately forms
- Factor VIII is the factor that is missing in the
a complex with the tissue phospholipid
person who has classic hemophilia. Platelets
released as part of the tissue thromboplastin
are the clotting factor lacking in the bleeding
and with factor V to form a complex called
disease called thrombocytopenia
prothrombin activator.
5. ACTIVATION OF ACTIVATED FACTOR X TO
FORM PROTHROMBIN ACTIVATOR.
 - the same as the last step in the extrinsic thrombomodulin layer are lost, which
activates factor XII and platelets and initiates
pathway (i.e., activated factor X combines
the intrinsic pathway of clotting.
with factor V and platelets or tissue
phospholipids to form the complex called - Agents that remove thrombin from blood,
prothrombin activator). such as the fibrin threads that form during
- The prothrombin activator in turn initiates the process of clotting and an a-globulin
called antithrombin III, are the most
cleavage of prothrombin to form thrombin,
important anticoagulants in the blood.
thereby setting into motion the final clotting
process. - Thrombin becomes absorbed to the fibrin
threads as they develop; this prevents the
CALCIUM IONS ARE REQUIRED FOR BLOOD
spread of thrombin into the remaining blood
CLOTTING
and prevents excessive spread of the clot.
 Except for the first two steps in the intrinsic - The
pathway, calcium ions are required for thrombin that does not adsorb to the fibrin
promotion of all the reactions; in the absence threads combines with antithrombin III,
of calcium ions, blood clotting does not occur. which inactivates the thrombin.
 Fortunately, the calcium ion concentration
rarely falls sufficiently low to affect the HEPARIN
kinetics of blood clotting significantly.
 When blood is removed, it can be - In the presence of excess heparin, removal
prevented from clotting by reducing the of thrombin from the circulation is almost
calcium ion concentration below the instantaneous.
threshold level for clotting. - Mast cells located in the pericapillary
 This can be accomplished through either connective tissue throughout the body and
deionization of the calcium via reaction with the basophils of the blood produce heparin.
substances such as a citrate ion or
precipitation of the calcium with substances - These cells continually secrete small amounts
such as an oxalate ion. of heparin that diffuse into the circulatory
system.
PREVENTION OF BLOOD CLOTTING IN THE
NORMAL VASCULAR SYSTEM—INTRAVASCULAR LYSIS OF BLOOD CLOT
ANTICOAGULANTS  Plasminogen is a plasma protein that when
 The most important factors for the activated becomes a substance called
prevention of clotting in the normal vascular plasmin, a proteolytic enzyme that resembles
system are trypsin.
1. The smoothness of the endothelium  Plasmin digests the fibrin threads as well as
other clotting factors.
- Which prevents contact activation of the  Plasminogen becomes trapped in the clot
intrinsic clotting system; along with other plasma proteins.
2. A layer of glycocalyx in the endothelium  The injured tissues and vascular endothelium
- Which repels the clotting factors and platelets slowly release a powerful activator called
3. a protein bound with the endothelial tissue plasminogen activator (t-PA), which
membrane (called thrombomodulin) converts plasminogen to plasmin
and removes the clot.
- Which binds thrombin.
 Plasmin not only destroys fibrin fibers but
- The thrombomodulin-thrombin complex also also functions as a proteolytic enzyme to
activates a plasma protein called protein C, digest fibrinogen and a number of other
which inactivates activated factors V and VIII clotting factors.
 Small amounts of plasmin are continuously
- When the endothelial wall is damaged, its
formed in the blood.
smoothness and its glycocalyx-
  The blood also contains another factor, a2- they come to a narrow point in the circulatory
antiplasmin, which binds with plasmin and system.
causes inactivation; the rate of plasmin - Thromboembolic conditions in human beings
formation must rise above a certain critical
are usually the result of a roughened
level before it becomes effective
endothelial surface or sluggish blood flow.
CLINICAL NOTES - The rough endothelium can initiate the
clotting process.
- Excessive bleeding can result from a
deficiency of vita min K, from hemophilia, or - When blood flow is too slow, the
from thrombocytopenia concentration of procoagulant factors often
(platelet deficiency). rises high enough in a local area to initiate
clotting
- Vitamin K is necessary for the formation of
five important clotting factors: prothrombin, ANTICOAGULANTS FOR CLINICAL USE
factor VII, factor IX, factor X, and protein C.
1. Heparin
- In the absence of vitamin K, insufficiency of
- It is extracted from several animal tissues and
these coagulation can lead to bleeding
can be prepared in almost pure form.
1. HEMOPHILIA IS CAUSED BY A DEFICIENCY
OF FACTOR VIII OR IX AND OCCURS - It increases the effectiveness of antithrombin
ALMOST EXCLUSIVELY IN MALES III.
- Hemophilia A, or classic hemophilia, is caused - The action of heparin in the body is almost
by a deficiency of factor VIII and accounts for instantaneous, and at normal dosages (0.5 to
about 85% of cases. 1.0 mg/kg) it can increase the
clotting time from about 6 minutes to 30
- The other 15% of cases of hemophilia are the
minutes or longer.
result of a deficiency of factor IX.
- If too much heparin is given, a substance
- Both of these factors are transmitted
called protamine can be administered, which
genetically via the female chromosome as a
combines electrostatically with heparin to
recessive trait; women almost never have
cause its inactivation.
hemophilia because at least one of their two X
2. Coumarins such as warfarin cause the
chromosomes has the appropriate genes.
plasma levels of prothrombin and factors
2. THROMBOCYTOPENIA IS A DEFICIENCY OF
VIII, IX, and X to fall.
PLATELETS IN THE CIRCULATORY SYSTEM
- People with thrombocytopenia have a
- Warfarin causes this effect by competing with
vitamin K for reactive sites in the enzymatic
tendency to bleed from small vessels or
processes for the formation of prothrombin
capillaries.
and the other three clotting factors.
- As a result, small punctate hemorrhages
BLOOD TYPING
occur throughout the body tissues.
- The skin of such a person displays many ANTIGENICITY CAUSES IMMUNE REACTIONS TO
small, purplish blotches, giving the disease BLOOD
the name thrombocytopenic purpura
- Bloods of different people have different
THROMBOEMBOLIC CONDITIONS IN THE HUMAN antigenic and immune properties so that
BEINGS antibodies in the plasma of one blood type
will react with antigens on the surfaces of the
- An abnormal clot that develops in a blood rbc’s of another blood type
vessel is called a thrombus.
- When blood transfusions from one person to
- An embolus is a free-flowing thrombus. another were first attempted, immediate or
Emboli generally do not stop flowing until 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 - When bloods are mismatched so anti-A or
B develop in plasma anti-B plasma agglutinins are mixed with red
- (-) Type O Agglutinogen = Both A and B Anti- blood cells containing A or B agglutinogens,
the red blood cells agglutinate into clumps.
agglutinins are present
- (+) Type AB Agglutinogen = (-) Both A and B
- These clumps can plug small blood
vessels throughout the circulatory system. In
Anti-Agglutinins are absent.
some cases, the antibodies induce lysis of red
TITER OF THE AGGLUTININS AT DIFFERENT blood cells through activation of the
AGES. complement system
 At Birth: Quantity of Agglutinins is nearly ACUTE HEMOLYSIS OCCURS IN SOME
zero TRANSFUSION REACTIONS.
 2-8 months: an infant begins to produce
agglutinins—anti-A agglutinins when  One of the most lethal effects of transfusion
type A agglutinogens are not present in reactions is renal failure.
the cells, and  The excess hemoglobin from the
anti-B agglutinins when type B hemolyzed red blood cells leaks through the
agglutinogens are not in the cells glomerular membranes into the renal tubules.
 8-10 years of Age: Maximum titer is  Reabsorption of water from the tubules
ofagglutinins causes the hemoglobin concentration to rise,
 10 Above/Remaining Years of Life: resulting in hemoglobin precipitation and
Decreases as we grow older. subsequent blockade of the tubules.

ORIGIN OF AGGLUTININS IN THE PLASMA BLOOD TYPING

 The agglutinins are gamma globulins, as are  The RBCs are first separated from the plasma
almost all antibodies, and they are produced and diluted with saline solution.
by the same bone marrow and lymph gland  One portion is then mixed with anti-A
cells that produce antibodies to any other agglutinin and another portion with anti-B
antigens. agglutinin
 Most of them are IgM and IgG  If the RBCs have become clumped—that is,
immunoglobulin molecules. “agglutinated”—one knows that an antibody-
antigen reaction has resulted
But why are these agglutinins produced in people
who do not have the respective agglutinogens in RH BLOOD TYPES
their RBCs?
- There are six common types of Rh antigens,
 The answer to this question is that small each of which is called an Rh factor
amounts of type A and B antigens enter the - Designated as C, D, E, c, d, and e
body in food, in bacteria, and in other ways,
and these substances initiate the - A person who has a C antigen does
development of the anti-A and anti-B not have the c antigen, but the person missing the C
agglutinins. antigen always has the c antigen.
 For instance, infusion of group A antigen into - The same is true for the D-d and E-e antigens. Also,
a recipient having a non-A blood type causes because of the manner of inheritance of these factors,
a typical immune response with formation of each person has one of each of the three pairs of
greater quantities of anti-A agglutinins than antigens
ever. Also, the neonate has few, if any, - The type D antigen is widely prevalent in the
agglutinins, showing that agglutinin population and considerably more antigenic than the
formation occurs almost entirely after birth other Rh antigens

AGGLUTINATION PROCESS IN TRANSFUSION

REACTIONS
 - 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