INTRODUCTION

Blood; Is a body fluid in human and other animals that delivers necessary substances such as
nutrients and oxygen to the cells and transport metabolic wastes product away from those
some cells.
Approximately 8% of an adult’s body weight is made up of blood. Females have around 4-5
liters, while males have around 5-6 liters. This difference is mainly due to the differences in
body size between men and women. Its mean temperature is 38 degrees Celsius. It has a pH of
7.35-7.45, making it slightly basic (less than 7 is considered acidic).
Whole blood is about 4.5-5.5 times as viscous as water, indicating that it is more resistant to
flow than water. This viscosity is vital to the function of blood because if blood flows too easily
or with too much resistance, it can strain the heart and lead to severe cardiovascular problems.
Blood in the arteries is a brighter red than blood in the veins because of the higher levels of
oxygen found in the arteries. An artificial substitute for human blood has not been found.

Functions of blood

Blood has three main functions: transport, protection and regulation.

1. Transport

Blood transports the following substances: Gases, namely oxygen (O2) and carbon dioxide
(CO2), between the lungs and rest of the body Nutrients from the digestive tract and storage
sites to the rest of the body Waste products to be detoxified or removed by the liver and
kidneys Hormones from the glands in which they are produced to their target cells Heat to the
skin so as to help regulate body temperature

2. Protection

Blood has several roles in inflammation: Leukocytes, or white blood cells, destroy invading
microorganisms and cancer cells Antibodies and other proteins destroy pathogenic substances
Platelet factors initiate blood clotting and help minimize blood loss
 3. Regulation

Blood helps regulate :pH by interacting with acids and bases ,Water balance by transferring
water to and from tissues

COMPOSITION OF BLOOD

Blood is classified as a connective tissue and consists of two main components: Plasma, which is
a clear extracellular fluid, formed elements (solid part), which are made up of the Red blood
cells(RBCs), White blood cell, and platelets. The formed elements are so named because they
are enclosed in a plasma membrane and have a definite structure and shape. All formed
elements are cells except for the platelets, which are tiny fragments of bone marrow cells.
Leukocytes are further classified into two subcategories called granulocytes which consist of
neutrophils, eosinophil and basophils; and granulocytes which consist of lymphocytes and
monocytes.

The formed elements (solid part) can be separated from plasma by centrifuge, where a blood
sample is spun for a few minutes in a tube to separate its components according to their
densities. RBCs are denser than plasma, and so become packed into the bottom of the tube to
make up 45% of total volume. This volume is known as the hematocrits. WBCs and platelets
form a narrow cream-coloured coat known as the buffy coat immediately above the RBCs.
Finally, the plasma makes up the top of the tube, which is a pale yellow colour and contains just
fewer than 55% of the total volume.

CLASIFICATIONS OF SOLID PART AND THEIR FUNCTION

1. Red blood cells, also called erythrocytes,

are the most abundant cell type in the blood. Other major blood components include plasma,
white blood cells, and platelets. The primary function of red blood cells is to transport oxygen
to body cells and deliver carbon dioxide to the lungs.

A red blood cell has what is known as a biconcave shape. Both sides of the cell's surface curve
inward like the interior of a sphere. This shape aids in a red blood cell's ability to maneuver
through tiny blood vessels to deliver oxygen to organs and tissues.

Red blood cells are also important in determining human blood type. Blood type is determined
by the presence or absence of certain identifiers on the surface of red blood cells. These
identifiers, also called antigens, help the body's immune system to recognize its own red blood
cell type.
Red Blood Cell Structure

Erythrocytes have a large surface for gas exchange and high elasticity to navigate through
capillary vessels.

Red blood cells have a unique structure. Their flexible disc shape helps to increase the surface
area-to-volume ratio of these extremely small cells. This enables oxygen and carbon dioxide to
diffuse across the red blood cell's plasma membrane more readily. Red blood cells contain
enormous amounts of a protein called hemoglobin. This iron-containing molecule binds oxygen
as oxygen molecules enter blood vessels in the lungs. Hemoglobin is also responsible for the
characteristic red color of blood.
Unlike other cells of the body, mature red blood cells do not contain a nucleus, mitochondria,
or ribosomes. The absence of these cell structures leaves room for the hundreds of millions of
hemoglobin molecules found in red blood cells. A mutation in the hemoglobin gene can result
in the development of sickle-shaped cells and lead to sickle cell disorder.

Red Blood Cell Production

Red blood cells are derived from stem cells in red bone marrow. New red blood cell production,
also called erythropoiesis, is triggered by low levels of oxygen in the blood. Low oxygen levels
can occur for various reasons including blood loss, presence in high altitude, exercise, bone
marrow damage, and low hemoglobin levels.

When the kidneys detect low oxygen levels, they produce and release a hormone called
erythropoietin. Erythropoietin stimulates the production of red blood cells by red bone
marrow. As more red blood cells enter blood circulation, oxygen levels in the blood and tissues
increase. When the kidneys sense the increase in oxygen levels in the blood, they slow the
release of erythropoietin. As a result, red blood cell production decreases.

Red blood cells circulate on average for about four months. Adults have around 25 trillion red
blood cells in circulation at any given time. Due to their lack of a nucleus and other organelles,
adult red blood cells can not undergo mitosis to divide or generate new cell structures. When
they become old or damaged, the vast majority of red blood cells are removed from circulation
by the spleen, liver, and lymph nodes. These organs and tissues contain white blood cells called
macrophages that engulf and digest damaged or dying blood cells. Red blood cell degradation
and erythropoiesis typically occur at the same rate to ensure homeostasis in red blood cell
circulation.

Red Blood Cells and Gas Exchange

Gas exchange is the primary function of red blood cells. The process by which organisms
exchange gases between their body cells and the environment is called respiration. Oxygen and
carbon dioxide are transported through the body via the cardiovascular system. As the heart
circulates blood, oxygen-depleted blood returning to the heart is pumped to the lungs. Oxygen
is obtained as a result of respiratory system activity.In the lungs, pulmonary arteries form
smaller blood vessels called arterioles. Arterioles direct blood flow to the capillaries
surrounding lung alveoli. Alveoli are the respiratory surfaces of the lungs. Oxygen diffuses
across the thin endothelium of the alveoli sacs into the blood within the surrounding capillaries.
Hemoglobin molecules in red blood cells release the carbon dioxide picked up from body
tissues and become saturated with oxygen. Carbon dioxide diffuses from the blood to the
alveoli, where it is expelled through exhalation.

Consider the diagram below which show gaseous exchange between alveoli and capillaries

Then now oxygen-rich blood is returned to the heart and pumped to the rest of the body. As
the blood reaches systemic tissues, oxygen diffuses from the blood to surrounding cells. Carbon
dioxide produced as a result of cellular respiration diffuses from the interstitial fluid
surrounding body cells into the blood. Once in the blood, carbon dioxide is bound by
hemoglobin and returned to the heart via the cardiac . Diagram shows gaseous exchange in
human

Red Blood Cell Disorders

Diseased bone marrow can produce abnormal red blood cells. These cells may be irregular in
size (too large or too small) or shape (sickle-shaped). Anemia is a condition characterized by the
lack of production of new or healthy red blood cells. This means that there are not enough
functioning red blood cells to carry oxygen to body cells. As a result, individuals with anemia
may experience fatigue, dizziness, shortness of breath, or heart palpitations. Causes of anemia
include sudden or chronic blood loss, not enough red blood cell production, and the destruction
of red blood cells. Types of anemia include:

Aplastic anemia: A rare condition in which insufficient new blood cells are produced by bone
marrow due to stem cell damage. Development of this condition is associated with a number of
different factors including pregnancy, exposure to toxic chemicals, the side effect of certain
medications, and certain viral infections, such as HIV, hepatitis, or Epstein-Barr virus.
Iron-deficiency anemia: A lack of iron in the body leads to insufficient red blood cell
production. Causes include sudden blood loss, menstruation, and insufficient iron intake or
absorption from food.

Sickle cell anemia: This inherited disorder is caused by a mutation in the hemoglobin gene that
causes red blood cells to take on a sickle shape. These abnormally shaped cells get stuck in
blood vessels, blocking normal blood flow.

Normocytic anemia: This condition results from a lack of red blood cell production. The cells
that are produced, however, are of normal size and shape. This condition may result from
kidney disease, bone marrow dysfunction, or other chronic diseases.

Hemolytic anemia: Red blood cells are prematurely destroyed, typically as a result of an
infection, autoimmune disorder, or blood cancer.

Treatments for anemia vary based on severity and include iron or vitamin supplements,
medication, blood transfusion, or bone marrow transplantation.

2. White blood cells

White blood cells, A type of blood cell that is made in the bone marrow and found in the blood
and lymph tissues. White blood cell, Circulate around the blood and help the immune system
fight off infections and other diseases. Stem cells in the bone marrow are responsible for
producing white blood cells. The bone marrow then stores an estimated 80–90% of white blood
cells. When an infection or inflammatory condition occurs, the body releases white blood cells
to help fight the infection.

Structure of white blood cell

Types of White blood cells and functions

Health professionals have identified three main categories of white blood cell: granulocytes,
lymphocytes, and monocytes. The sections below discuss these in more detail.

 Granulocytes

Granulocytes are white blood cells that have small granules containing proteins. There are
three types of granulocyte cells:

I. Basophils: These represent less than 1% of white blood cells in the body and are
typically present in increased numbers after an allergic reaction.

II. Eosinophil: These are responsible for responding to infections that parasites cause. They
also play a role in the general immune response, as well as the inflammatory response,
in the body.

III. Neutrophils: These represent the majority of white blood cells in the body. They act as
scavengers, helping surround and destroy bacteria and fungi that may be present in the
body.
  Lymphocytes

These white blood cells include the following: B cells: Also known as B-lymphocytes, these cells
produce antibodies to help the immune system mount a response to infection. T cells: Also
known as T-lymphocytes, these white blood cells help recognize and remove infection-causing
cells. Natural killer cells: These cells are responsible for attacking and killing viral cells, as well
as cancer cells.

 Monocytes

Monocytes are white blood cells that make up around 2–8% of the total white blood cell count
in the body. These are present when the body fights off chronic infections. They target and
destroy cells that cause infections.

High white blood cell count

If a person’s body is producing more white blood cells than it should be, doctors call this
leukocytosis. A high white blood cell count may indicate the following medical conditions:
allergic responses, such as due to an asthma attack those that may cause cells to die, such as
burns, heart attack, and trauma inflammatory conditions, such as rheumatoid arthritis,
inflammatory bowel disease, or vacuities infections, such as with bacteria, viruses, fungi, or
parasites leukemia Surgical procedures that cause cells to die can also cause a high white blood
cell count.

Low white blood cell count

If a person’s body is producing fewer white blood cells than it should be, doctors call this
leukopenia. Conditions that can cause leukopenia include: autoimmune conditions such as
lupus and Hipbones marrow damage, such as from chemotherapy, radiation therapy, or
exposure to toxins bone marrow disorders leukemia lymphoma sepsis, which is a severe type of
infection vitamin B-12 deficiencies
Doctors may continually monitor white blood cells to determine if the body is mounting an
immune response to an infection.

3. Blood Platelets.

Platelets are tiny blood cells that help your body form clots to stop bleeding. If one of the
blood vessels gets damaged, it sends out signals to the platelets. The platelets then rush to the
site of damage and form a plug (clot) to fix the damage. The process of spreading across the
surface of a damaged blood vessel to stop bleeding is called adhesion. This is because when
platelets get to the site of the injury, they grow sticky tentacles that help them stick (adhere) to
one another. They also send out chemical signals to attract more platelets. The additional
platelets pile onto the clot in a process called aggregation.

Platelets are made in bone marrow along with white and red blood cells. Bone marrow is the
spongy center inside the bones. Another name for platelets is thrombocytes. Once platelets are
made and circulated into bloodstream, they live for 8 to 10 days. Under a microscope, a platelet
looks like a tiny plate. A normal platelet count is 150,000 to 450,000 platelets per microliter of
blood. risk for bleeding develops if a platelet count falls below 10,000 to 20,000. When the
platelet count is less than 50,000, bleeding is likely to be more serious if you're cut or bruised.

Structure of blood platelets

Conditions linked due to normal platelets or abnormal platelet counts are as follows:
a) Thrombocytopenia.

In this condition, bone marrow makes too few platelets or platelets are destroyed. If platelet
count gets too low, bleeding can occur under the skin as a bruise or it can happen inside the
body as internal bleeding or it can happen outside the body through a cut that won't stop
bleeding or from a nosebleed. Thrombocytopenia can be caused by many conditions. These
include several medicines, cancer, liver disease, pregnancy, infections, and an abnormal
immune system.

b) Essential thrombocythemia.

In this condition, bone marrow makes too many platelets. People with this condition may have
platelet counts of more than 1 million, which can lead to bleeding. Other symptoms can include
blood clots that form and block blood supply to the brain or the heart. Doctors don't fully know
what causes this type of thrombocythemia, but changes in bone marrow cells (called
mutations) can lead to some cases.
 c) Secondary thrombocytosis.

This is another condition caused by too many platelets, Secondary thrombocytosis is more
common. It's not caused by a bone marrow problem instead caused by other disease or
condition stimulates the bone marrow to make more platelets. Causes include infection,
inflammation, some types of cancer, and reactions to medicines. Symptoms are usually not
serious. The platelet count goes back to normal when the other condition gets better.

d) Platelet dysfunction.

Many rare diseases are linked to poor platelet function, this means the number of platelets is
normal, but the platelets don't work as they should. Medicines such as aspirin can cause these
conditions to happen. It's important to know which medicines affect platelets and Know that
while taking these medicines you have an increased risk of bleeding.

Platelets are tiny but important cells in blood that help the body control bleeding. If you have
symptoms such as easy bruising, a cut that keeps bleeding, or frequent nosebleeds.

CLASSIFICATION OF LIQUID PART (BLOOD PLASMA) AND THEIR FUNCTION

plasma is a yellowish liquid component of blood that holds the blood cells of whole blood in
suspension. It is the liquid part of the blood that carries cells and proteins throughout the body.
It makes up about 55% of the body's total blood volume. It is the intravascular part of
extracellular fluid (all body fluid outside cells). It is mostly water (up to 95% by volume), and
contains important dissolved proteins (6–8%) (example, serum albumins, globulins, and
fibrinogen), glucose, clotting factors, electrolytes (Na+, Ca2+, Mg2+, HCO3−, Cl−.), hormones,
carbon dioxide (plasma being the main medium for excretory product transportation), and
oxygen. It plays a vital role in an intravascular osmotic effect that keeps electrolyte
concentration balanced and protects the body from infection and other blood disorders.

Blood plasma is a mixture of proteins, enzymes, nutrients, wastes, hormones and gases. Blood
plasma is separated from the blood by spinning a tube of fresh blood containing an
anticoagulant in a centrifuge until the blood cells fall to the bottom of the tube. The blood
plasma is then poured or drawn off. For point-of-care testing applications, plasma can be
extracted from whole blood via filtration or via agglutination to allow for rapid testing of
specific biomarkers. Blood plasma has a density of approximately 1025 kg/m3, or 1.025 g/ml.
Blood serum is blood plasma without clotting factors.

Components of blood plasma and their functions

 Plasma Proteins

These are the most abundant substance in plasma by weight and play a part in a variety of roles
including clotting, defense and transport. Collectively, they serve several functions:

i. They are an important reserve supply of amino acids for cell nutrition. Cells called
macrophages in the liver, gut, spleen, lungs and lymphatic tissue can break down plasma
proteins so as to release their amino acids. These amino acids are used by other cells to
synthesize new products.

ii. Plasma proteins also serve as carriers for other molecules. Many types of small
molecules bind to specific plasma proteins and are transported from the organs that
absorb these proteins to other tissues for utilization.

iii. The proteins also help to keep the blood slightly basic at a stable pH. They do this by
functioning as weak bases themselves to bind excess H+ ions. By doing so, they remove
excess H+ from the blood which keeps it slightly basic.

iv. The plasma proteins interact in specific ways to cause the blood to coagulate, which is
part of the body’s response to injury to the blood vessels (also known as vascular injury),
and helps protect against the loss of blood and invasion by foreign microorganisms and
viruses.

v. Plasma proteins govern the distribution of water between the blood and tissue fluid by
producing what is known as a colloid osmotic pressure.
There are three major categories of plasma proteins, and each individual type of proteins has
its own specific properties and functions in addition to their overall collective role:

 Albumins,

These are the smallest and most abundant plasma proteins. Reductions in plasma albumin
content can result in a loss of fluid from the blood and a gain of fluid in the interstitial space
(space within the tissue), which may occur in nutritional, liver and kidney disease. Albumin also
helps many substances dissolve in the plasma by binding to them, hence playing an important
role in plasma transport of substances such as drugs, hormones and fatty acids.

 Globulins,

This is second most common type of protein in the blood plasma Which can be subdivided into
three classes from smallest to largest in molecular weight which are alpha, beta and gamma
globulins. The globulins include high density lipoproteins (HDL), an alpha-1 globulin, and low
density lipoproteins (LDL), a beta-1 globulin. HDL functions in lipid transport carrying fats to
cells for use in energy metabolism, membrane reconstruction and hormone function. HDLs also
appear to prevent cholesterol from invading and settling in the walls of arteries. LDL carries
cholesterol and fats to tissues for use in manufacturing steroid hormones and building cell
membranes, but it also favors the deposition of cholesterol in arterial walls and thus appears to
play a role in disease of the blood vessels and heart. HDL and LDL therefore play important
parts in the regulation of cholesterol and hence have a large impact on cardiovascular disease.

 Fibrinogen,

Fibrinogen proteins make up most of the remaining proteins in the blood. Fibrinogens are
responsible for clotting blood to help prevent blood loss which is a soluble precursor of a sticky
protein called fibrin, which forms the framework of blood clot, Fibrin plays a key role in
coagulation of blood.

MECHANISM OF BLOOD CLOTING

Blood clotting also known as coagulation which is defined as the process by which blood
changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the
cessation of blood loss from a damaged vessel, followed by repair. The mechanism of
coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and
maturation of fibrin.

Coagulation begins almost instantly after an injury to the endothelium lining a blood vessel.
Exposure of blood to the sub endothelial space initiates two processes: changes in platelets,
and the exposure of sub endothelial tissue factor to plasma factor VII, which ultimately leads to
cross-linked fibrin formation. Platelets immediately form a plug at the site of injury; this is
called primary hemostasis. Secondary hemostasis occurs simultaneously: additional coagulation
(clotting) factors beyond factor VII (listed below) respond in a cascade to form fibrin strands,
which strengthen the platelet plug.

Coagulation is highly conserved throughout biology. In all mammals, coagulation involves both
a cellular (platelet) and a protein (coagulation factor) component. The system in humans has
been the most extensively researched and is the best understood

When the endothelium is damaged, the normally isolated, underlying collagen is exposed to
circulating platelets, which bind directly to collagen with collagen-specific glycoprotein Ia/IIa
surface receptors. This adhesion is strengthened further by von Will brand factor (vWF), which
is released from the endothelium and from platelets; vWF forms additional links between the
platelets' glycoprotein Ib/IX/V and A1 domain. This localization of platelets to the extracellular
matrix promotes collagen interaction with platelet glycoprotein VI. Binding of collagen to
glycoprotein VI triggers a signaling cascade that results in activation of platelet integrins.
Activated integrins mediate tight binding of platelets to the extracellular matrix. This process
adheres platelets to the site of injury.

Activated platelets release the contents of stored granules into the blood plasma. The granules
include ADP, serotonin, platelet-activating factor ,vWF, platelet factor 4, and thromboxane A2 ,
which in turn activate additional platelets. The granules' contents activate a Gp-linked protein
receptor cascade, resulting in increased calcium concentration in the platelets' cytosol. The
calcium activates protein kinase C which in turn activates phospholipase A2 (PLA2 ).PLA2 then
modifies the integrin membrane glycoprotein IIb/IIIa, increasing its affinity to bind fibrinogen.
The activated platelets change shape from spherical to stellate and the fibrinogen cross-links
with glycoprotein IIb/IIIa aid in aggregation of adjacent platelets (completing primary
hemostasis).

The coagulation cascade of secondary hemostasis has two initial pathways which lead to fibrin
formation. These are the contact activation pathway (also known as the intrinsic pathway),
and the tissue factor pathway (also known as the extrinsic pathway), which both lead to the
same fundamental reactions that produce fibrin. It was previously thought that the two
pathways of coagulation cascade were of equal importance, but it is now known that the
primary pathway for the initiation of blood coagulation is the tissue factor (extrinsic) pathway.
The pathways are a series of reactions, in which a zymogen (inactive enzyme precursor) of a
serine protease and its glycoprotein co-factor are activated to become active components that
then catalyze the next reaction in the cascade, ultimately resulting in cross-linked fibrin.

The coagulation factors are generally serine proteases (enzymes), which act by cleaving
downstream proteins. The exceptions are tissue factor, FV, FVIII, FXIII. Tissue factor, FV and
FVIII are glycoproteins, and Factor XIII is a transglutaminase. The coagulation factors circulate as
inactive zymogens. The coagulation cascade is therefore classically divided into three pathways.
The tissue factor and contact activation pathways both activate the "final common pathway" of
factor X, thrombin and fibrin.

Tissue factor pathway (extrinsic)

The main role of the tissue factor pathway is to generate a "thrombin burst", a process by
which thrombin, the most important constituent of the coagulation cascade in terms of its
feedback activation roles is released very rapidly. FVIIa circulates in a higher amount than any
other activated coagulation factor. The process includes the following steps
  Following damage to the blood vessel, FVII leaves the circulation and comes into contact
with tissue factor expressed on tissue-factor-bearing cells (stromal fibroblasts and
leukocytes), forming an activated complex (TF-FVIIa).

 TF-FVIIa activates FIX and FX.

 FVII is itself activated by thrombin, FXIa, FXII, and FXa.

 The activation of FX (to form FXa) by TF-FVIIa is almost immediately inhibited by tissue
factor pathway inhibitor (TFPI).

 FXa and its co-factor FVa form the prothrombinase complex, which activates
prothrombin to thrombin. Thrombin then activates other components of the
coagulation cascade, including FV and FVIII (which forms a complex with FIX), and
activates and releases FVIII from being bound to vWF.

 FVIIIa is the co-factor of FIXa, and together they form the "tenase" complex, which
activates FX; and so the cycle continues. ("Tenase" is a contraction of "ten" and the
suffix "-ase" used for enzymes.)

Contact activation pathway (intrinsic)

The contact activation pathway begins with formation of the primary complex on collagen by
high-molecular-weight kininogen , prekallikrein, and FXII (Hageman factor). Prekallikrein is
converted to kallikrein and FXII becomes FXIIa. FXIIa converts FXI into FXIa. Factor XIa activates
FIX which with its co-factor FVIIIa form the tenase complex, which activates FX to FXa. The
minor role that the contact activation pathway has in initiating clot formation can be illustrated
by the fact that patients with severe deficiencies of FXII, HMWK, and prekallikrein do not have a
bleeding disorder. Instead, contact activation system seems to be more involved in
inflammation and innate immunity. Despite this, interference with the pathway may confer
protection against thrombosis without a significant bleeding risk.

Final common pathway

The division of coagulation in two pathways is arbitrary, originating from laboratory tests in
which clotting times were measured either after the clotting was initiated by glass, the intrinsic
pathway; or clotting was initiated by thromboplastin (a mix of tissue factor and phospholipids),
the extrinsic pathway.

Further, the final common pathway scheme implies that prothrombin is converted to thrombin
only when acted upon by the intrinsic or extrinsic pathways, which is an oversimplification. In
fact, thrombin is generated by activated platelets at the initiation of the platelet plug, which in
turn promotes more platelet activation.

Thrombin functions not only to convert fibrinogen to fibrin, it also activates Factors VIII and V
and their inhibitor protein C (in the presence of thrombomodulin); and it activates Factor XIII,
which forms covalent bonds that crosslink the fibrin polymers that form from activated
monomers.
Consider the diagram the summarize the mechanism of blood

Cofactors
Various substances are required for the proper functioning of the coagulation cascade:

 Calcium and phospholipid

Calcium and phospholipid (a platelet membrane constituent) are required for the tenase and
prothrombinase complexes to function. Calcium mediates the binding of the complexes via the
terminal gamma-carboxyl residues on FXa and FIXa to the phospholipid surfaces expressed by
platelets, as well as procoagulant micro particles or micro vesicles shed from them. Calcium is
also required at other points in the coagulation cascade.

 Vitamin K

Vitamin K is an essential factor to a hepatic gamma-glut amyl carboxylase that adds a carboxyl
group to glutamic acid residues on factors II, VII, IX and X, as well as Protein S, Protein C and
Protein Z. In adding the gamma-carboxyl group to glutamate residues on the immature clotting
factors, Vitamin K is itself oxidized. Another enzyme, Vitamin K epoxide reductase , reduces
vitamin K back to its active form. Vitamin K epoxide reductase is pharmacologically important
as a target of anticoagulant drugs warfarin and related coumarins such as acenocoumarol,
phenprocoumon, and dicumarol. These drugs create a deficiency of reduced vitamin K by
blocking VKORC, thereby inhibiting maturation of clotting factors. Vitamin K deficiency from
other causes (e.g., in malabsorption) or impaired vitamin K metabolism in disease (e.g., in liver
failure) lead to the formation of PIVKAs (proteins formed in vitamin K absence), which are
partially or totally non-gamma carboxylated, affecting the coagulation factors' ability to bind to
phospholipid.

Regulators

Five mechanisms keep platelet activation and the coagulation cascade in check. Abnormalities
can lead to an increased tendency toward thrombosis which are,

 Protein C

Protein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease

enzyme that is activated by thrombin into activated protein C (APC). Protein C is activated in a
sequence that starts with Protein C and thrombin binding to a cell surface protein
thrombomodulin. Thrombomodulin binds these proteins in such a way that it activates Protein
C. The activated form, along with protein S and a phospholipid as cofactors, degrades FVa and
FVIIIa. Quantitative or qualitative deficiency of either (protein C or protein S) may lead to
thrombophilia (a tendency to develop thrombosis). Impaired action of Protein C (activated
Protein C resistance), for example by having the "Leiden" variant of Factor V or high levels of
FVIII, also may lead to a thrombotic tendency.

 Ant thrombin

Ant thrombin is a serine protease inhibitor (serpin) that degrades the serine proteases:
thrombin, FIXa, FXa, FXIa, and FXIIa. It is constantly active, but its adhesion to these factors is
increased by the presence of heparan sulfate (a glycosaminoglycan) or the administration of
heparins (different heparinoids increase affinity to FXa, thrombin, or both). Quantitative or
qualitative deficiency of ant thrombin (inborn or acquired, e.g., in proteinuria) leads to
thrombophilia.

Tissue factor pathway inhibitor (TFPI)

Tissue factor pathway inhibitor (TFPI) limits the action of tissue factor (TF). It also inhibits
excessive TF-mediated activation of FVII and FX.

 Plasmin

Plasmin is generated by proteolysis cleavage of plasminogen, a plasma protein synthesized in

the liver. This cleavage is catalyzed by tissue plasminogen activator (t-PA), which is synthesized
and secreted by endothelium. Plasmin proteolytically cleaves fibrin into fibrin degradation
products that inhibit excessive fibrin formation.

 Prostacyclin
Prostacyclin (PGI2) is released by endothelium and activates platelet Gs protein-linked
receptors. This, in turn, activates adenylyl cyclase, which synthesizes cAMP. cCAMP inhibits
platelet activation by decreasing cytosolic levels of calcium and, by doing so, inhibits the release
of granules that would lead to activation of additional platelets and the coagulation cascade.

 Fibrinolysis

Is the breakdown of blood clots due to a medical disorders, medicine and other causes. It
prevents blood clot that occur naturally from growing and causing problems

Role in immune system

The coagulation system overlaps with the immune system. Coagulation can physically trap
invading microbes in blood clots. Also, some products of the coagulation system can contribute
to the innate immune system by their ability to increase vascular permeability and act as
chemotactic agents for phagocytic cells. In addition, some of the products of the coagulation
system are directly antimicrobial. For example, beta-lysine, an amino acid produced by platelets
during coagulation, can cause lysis of many Gram-positive bacteria by acting as a cationic
detergent. Many acute-phase proteins of inflammation are involved in the coagulation system.
In addition, pathogenic bacteria may secrete agents that alter the coagulation system, e.g.
coagulase and streptokinase
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