BLOOD & CLOTTING FACTORS

CONTENTS

INTRODUCTION

FUNCTIONS

CONSTITUENTS OF BLOOD

GENESIS OF RBC

RED BLOOD CORPUSCLES

ANAEMIA

POLYCYTHEMIA

WHITE BLOOD CORPUSCLES

LEUKEMIA

CLOTTING FACTORS

CLOTTING CASCADE

BLEEDING DISORDERS
INTRODUCTION;

Blood is a specialized bodily fluid that delivers necessary substances to the body's
cells – such as nutrients and oxygen – and transports waste products away from those
same cells.

It is composed of blood cells suspended in a liquid called blood plasma. Plasma,

which constitutes 55% of blood fluid, is mostly water (92% by volume) & contains
dissipated proteins, glucose, mineral ions, hormones, carbon dioxide ,platelets and
blood cells themselves. The blood cells present in blood are mainly red blood cells
(also called RBCs or erythrocytes) and white blood cells, including leukocytes and
platelets. The most abundant cells in blood are red blood cells. These contain
hemoglobin, an iron-containing protein, which facilitates transportation of oxygen by
reversibly binding to this respiratory gas and greatly increasing its solubility in blood.
In contrast, carbon dioxide is almost entirely transported extracellularly dissolved in
plasma as bicarbonate ion.

Blood is bright red when its hemoglobin is oxygenated. Blood is circulated around
the body through blood vessels by the pumping action of the heart. In lungs, arterial
blood carries oxygen from inhaled air to the tissues of the body, and venous blood
carries carbon dioxide, a waste product of metabolism produced by cells, from the
tissues to the lungs to be exhaled.

FUNCTIONS;

Blood performs many important functions within the body including:

 Supply of oxygen to tissues (bound to hemoglobin, which is carried in red

cells)
 Supply of nutrients such as glucose, amino acids, and fatty acids (dissolved in
the blood or bound to plasma proteins (e.g., blood lipids))
 Removal of waste such as carbon dioxide, urea, and lactic acid
 Immunological functions, including circulation of white blood cells, and
detection of foreign material by antibodies
 Coagulation, which is one part of the body's self-repair mechanism (blood
clotting after an open wound in order to stop bleeding)
 Messenger functions, including the transport of hormones and the signaling of
tissue damage
 Regulation of body pH
 Regulation of core body temperature
  Hydraulic functions

Constituents of blood

Blood accounts for 8% of the human body weight, with an average density of
approximately 1060 kg/m3, very close to pure water's density of 1000 kg/m3.The
average adult has a blood volume of roughly 5 liters (1.3 gal), composed of plasma
and several kinds of cells (occasionally called corpuscles); these formed elements of
the blood are erythrocytes (red blood cells), leukocytes (white blood cells), and
thrombocytes (platelets). By volume, the red blood cells constitute about 45% of
whole blood, the plasma about 54.3%, and white cells about 0.7%.

Whole blood (plasma and cells) exhibits non-Newtonian, viscoelastic fluid dynamics;
its flow properties are adapted to flow effectively through tiny capillary blood vessels
with less resistance than plasma by itself. In addition, if all human hemoglobin were
free in the plasma rather than being contained in RBCs, the circulatory fluid would be
too viscous for the cardiovascular system to function effectively.

CELLS;

 4.7 to 6.1 million (male), 4.2 to 5.4 million (female) erythrocytes:

In most mammals, mature red blood cells lack a nucleus and organelles.
They contain the blood's hemoglobin and distribute oxygen. The red blood
cells (together with endothelial vessel cells and other cells) are also marked by
glycoproteins that define the different blood types. The proportion of blood
occupied by red blood cells is referred to as the hematocrit, and is normally
about 45%. The combined surface area of all red blood cells of the human
body would be roughly 2,000 times as great as the body's exterior surface.

 4,000–11,000 leukocytes:

White blood cells are part of the immune system; they destroy and
remove old or aberrant cells and cellular debris, as well as attack infectious
agents (pathogens) and foreign substances. The cancer of leukocytes is called
leukemia.

200,000–500,000 thrombocytes:

thrombocytes, also called platelets, are responsible for blood clotting

(coagulation). They change fibrinogen into fibrin. This fibrin creates a mesh onto
which red blood cells collect and clot, which then stops more blood from leaving the
body and also helps to prevent bacteria from entering the body.

Plasma

About 55% of whole blood is blood plasma, a fluid that is the blood's liquid medium,
which by itself is straw-yellow in color. The blood plasma volume totals of 2.7–3.0
liters (2.8–3.2 quarts) in an average human. It is essentially an aqueous solution
containing 92% water, 8% blood plasma proteins, and trace amounts of other
materials. Plasma circulates dissolved nutrients, such as glucose, amino acids, and
fatty acids (dissolved in the blood or bound to plasma proteins), and removes waste
products, such as carbon dioxide, urea, and lactic acid.

Other important components include:

 Serum albumin
 Blood-clotting factors (to facilitate coagulation)
 Immunoglobulins (antibodies)
 lipoprotein particles
 Various other proteins
 Various electrolytes (mainly sodium and chloride)

The term serum refers to plasma from which the clotting proteins have been removed.
Most of the proteins remaining are albumin and immunoglobulins.

Red Blood Cells (Erythrocytes)

The major function of red blood cells, is to transport hemoglobin, which in turn
carries oxygen from the lungs to the tissues.
The red blood cells are responsible for most of the acid-base buffering power of
whole blood.
Shape and Size of Red Blood Cells.
Normal red blood cells, are biconcave discs having a mean diameter of about 7.8
micrometers and a thickness of 2.5 micrometers at the thickest point and 1
micrometer or less in the center. The average volume of the red blood cell is 90 to 95
cubic micrometers.
Concentration of Red Blood Cells in the Blood.
In normal men, the average number of red blood cells per cubic millimeter is
5,200,000 (±300,000); in normal women, it is 4,700,000 (±300,000). Persons living at
high altitudes have greater numbers of red blood cells.
Quantity of Hemoglobin in the Cells.
Red blood cells have the ability to concentrate hemoglobin in the cell fluid up to
about 34 grams in each 100 milliliters of cells.

Production of Red Blood Cells

Areas of the Body That Produce Red Blood Cells.

In the early weeks of embryonic life, primitive, nucleated red blood cells are
produced in the yolk sac. During the middle trimester of gestation, the liver is the
main organ for production of red blood cells, but reasonable numbers are also
produced in the spleen and lymph nodes. Then, during the last month or so of
gestation and after birth, red blood cells are produced exclusively in the bone marrow.
The bone marrow of essentially all bones produces red blood cells until a person is 5
years old. The marrow of the long bones, except for the proximal portions of the
humeri and tibiae, becomes quite fatty and produces no more red blood cells after
about age 20 years. Beyond this age,most red cells 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 RBC
Proerythroblast ------Basophil erythroblast --------Polychromatophil erythroblast
--------------Orthochromatic erythroblast ----------Reticulocyte -----------
Erythrocytes

Stages of Differentiation of Blood Cells

Life Span and Destruction of Red Blood Cells

When red blood cells are delivered from the bone marrow into the circulatory system,
they normally cir culate an average of 120 days before being destroyed. Even though
mature red cells 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. These enzymes also (1) maintain pliability
of the cell membrane, (2) maintain membrane transport of ions, (3) keep the iron of
the cells’ hemo- globin in the ferrous form rather than ferric form, and (4) prevent
oxidation of the proteins in the red cells. Even so, the metabolic systems of old red
cells become progressively less active, and the cells become more and more fragile,
presumably because their life processes wear out.
Once the red cell membrane becomes fragile, the cell ruptures during passage through
some tight spot of the circulation. Many of the red cells self-destruct in the spleen,
where they squeeze through the red pulp of the spleen. When the spleen is removed,
the number of old abnormal red cells circulating in the blood increases considerably.

Destruction of Hemoglobin.

When red blood cells burst and release their hemoglobin, the hemoglobin is
phagocytized almost immediately by macrophages in many parts of the body, but
especially by the Kupffer cells of the liver and macrophages of the spleen and bone
marrow. During the next few hours to days, the macrophages release iron from the
hemoglobin and pass it back into the blood, to be carried by transferrin either to the
bone marrow for the production of new red blood cells 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;

Anemias
Anemia means deficiency of hemoglobin in the blood, which can be caused by either
too few red blood cells or too little hemoglobin in the cells. Some types of anemia and
their physiologic causes are the following.

Blood Loss Anemia. After rapid hemorrhage, the body replaces the fluid portion of
the plasma in 1 to 3 days, but this leaves a low concentration of red blood cells. If a
second hemorrhage does not occur, the red blood cell concentration usually returns to
normal within 3 to 6 weeks.
In chronic blood loss, a person frequently cannot absorb enough iron from the
intestines to form hemo- globin as rapidly as it is lost. Red cells are then pro- duced
that are much smaller than normal and have too little hemoglobin inside them, giving
rise to microcytic, hypochromic anemia, which is shown in
Aplastic Anemia. Bone marrow aplasia means lack of functioning bone marrow. For
instance, a person exposed to gamma ray radiation from a nuclear bomb blast can
sustain complete destruction of bone marrow, followed in a few weeks by lethal
anemia. Likewise, excessive x-ray treatment, certain industrial chemicals, and even
drugs to which the person might be sensitive can cause the same effect

Megaloblastic Anemia
The red cells grow too large, with odd shapes, and are called
megaloblasts. Thus, atrophy of the stomach mucosa, as occurs in pernicious anemia,
or loss of the entire stomach after surgical total gastrectomy can lead to megaloblastic
anemia. Also, patients who have intes- tinal sprue, in which folic acid, vitamin B12,
and other vitamin B compounds are poorly absorbed, often develop megaloblastic
anemia. Because in these states the erythroblasts cannot proliferate rapidly enough to
form normal numbers of red blood cells, those red cells that are formed are mostly
oversized, have bizarre shapes, and have fragile membranes. These cells rupture
easily, leaving the person in dire need of an adequate number of red cells.

Hemolytic Anemia.
Different abnormalities of the red blood cells, many of which are hereditarily
acquired, make the cells fragile, so that they rupture easily as they go through the
capillaries, especially through the spleen. Even though the number of red blood cells
formed may be normal, or even much greater than normal in some hemolytic diseases,
the life span of the fragile red cell is so short that the cells are destroyed faster than
they can be formed, and serious anemia results. Some of these types of anemia are the
following.
In hereditary spherocytosis, the red cells are very small and spherical rather than
being biconcave discs. These cells cannot withstand compression forces because they
do not have the normal loose, baglike cell membrane structure of the biconcave discs.
On passing through the splenic pulp and some other tight vas- cular beds, they are
easily ruptured by even slight compression.
In sickle cell anemia, which is present in 0.3 to 1.0 per cent of West African and
American blacks, the cells have an abnormal type of hemoglobin called hemo- globin
S, containing faulty beta chains in the hemo- globin molecule, as explained earlier in
the chapter. When this hemoglobin is exposed to low concentra- tions of oxygen, it
precipitates into long crystals inside the red blood cell. These crystals elongate the
cell and give it the appearance of a sickle rather than a bicon- cave disc. The
precipitated hemoglobin also damages the cell membrane, so that the cells become
highly fragile, leading to serious anemia. Such patients fre- quently experience a
vicious circle of events called a sickle cell disease “crisis,” in which low oxygen
tension in the tissues causes sickling, which leads to ruptured red cells, which causes
a further decrease in oxygen tension and still more sickling and red cell destruction.
Once the process starts, it progresses rapidly, eventu- ating in a serious decrease in
red blood cells within a few hours and, often, death.
In erythroblastosis fetalis, Rh-positive red blood cells in the fetus are attacked by
antibodies from an Rh-negative mother. These antibodies make the Rh-positive cells
fragile, leading to rapid rupture and causing the child to be born with serious anemia.
This is discussed in Chapter 35 in relation to the Rh factor of blood. The extremely
rapid formation of new red cells to make up for the destroyed cells in erythro-
blastosis fetalis causes a large number of early blast forms of red cells to be released
from the bone marrow into the blood.

Polycythemia
Secondary Polycythemia. Whenever the tissues become hypoxic because of too little
oxygen in the breathed air, such as at high altitudes, or because of failure of oxygen
delivery to the tissues, such as in cardiac failure, the blood-forming organs
automatically produce large quantities of extra red blood cells. This condition is
called secondary polycythemia, and the red cell count commonly rises to 6 to 7
million/mm3, about 30 per cent above normal.
A common type of secondary polycythemia, called physiologic polycythemia, occurs
in natives who live at altitudes of 14,000 to 17,000 feet, where the atmos- pheric
oxygen is very low. The blood count is generally 6 to 7 million/mm3; this allows
these people to perform reasonably high levels of continuous work even in a rarefied
atmosphere.
Polycythemia Vera (Erythremia). In addition to those people who have physiologic
polycythemia, others have a pathological condition known as polycythemia vera, in
which the red blood cell count may be 7 to 8 million/mm3 and the hematocrit may be
60 to 70 per cent instead of the normal 40 to 45 per cent. Poly- cythemia vera is
caused by a genetic aberration in the hemocytoblastic cells that produce the blood
cells. The blast cells no longer stop producing red cells when too many cells are
already present. This causes excess pro- duction of red blood cells in the same manner
that a breast tumor causes excess production of a specific type of breast cell. It usually
causes excess production of white blood cells and platelets as well.
In polycythemia vera, not only does the hematocrit increase, but the total blood
volume also increases, on some occasions to almost twice normal. As a result, the
entire vascular system becomes intensely engorged. In addition, many blood
capillaries become plugged by the viscous blood; the viscosity of the blood in poly-
cythemia vera sometimes increases from the normal of 3 times the viscosity of water
to 10 times that of water.

Leukocytes (White Blood Cells)

The leukocytes, also called white blood cells, are the mobile units of the body’s
protective system. They are formed partially in the bone marrow (granulocytes and
monocytes and a few lymphocytes) and partially in the lymph tissue (lym- phocytes
and plasma cells).
The real value of the white blood cells is that most of them are specifically
transported to areas of serious infection and inflammation, thereby providing a rapid
and potent defense against infectious agents.
General Characteristics of Leukocytes
Types of White Blood Cells.

Six types of white blood cells are normally present in the blood. They are
polymorphonuclear neutrophils, polymorphonuclear eosinophils, polymorphonuclear
basophils, monocytes, lymphocytes, and, occa- sionally, plasma cells. In addition,
there are large numbers of platelets, which are fragments of another type of cell
similar to the white blood cells found in the bone marrow, the megakaryocyte. The
first three types of cells, the polymor- phonuclear cells, all have a granular
appearance.

Life Span of the White Blood Cells

The life of the granulocytes after being released from the bone marrow is normally 4
to 8 hours circulating in the blood and another 4 to 5 days in tissues where they are
needed.
The monocytes also have a short transit time, 10 to 20 hours in the blood.
Lymphocytes enter the circulatory system continually, along with drainage of lymph
from the lymph nodes and other lymphoid tissue. After a few hours, they pass out of
the blood back into the tissues by diapedesis. The lymphocytes have life spans of
weeks or months.
The platelets in the blood are replaced about once every 10 days.
Neutrophils and Macrophages Defend Against Infections
It is mainly the neutrophils and tissue macrophages that attack and destroy invading
bacteria, viruses, and other injurious agents in the circulating blood. Conversely, the
tissue macrophages begin life as blood monocytes, which are immature cells while
still in the blood and have little ability to fight infectious agents at that time. However,
once they enter the tissues, they begin to swell—sometimes increasing their diameters
as much as fivefold—to as great as 60 to 80 micrometers, a size that can barely be
seen with the naked eye. These cells are now called macrophages, and they are
extremely capable of combating intra-tissue disease agents.
White Blood Cells Enter the Tissue Spaces by Diapedesis.
Neutrophils and monocytes can squeeze through the pores of the blood capillaries by
diapedesis. That is, even though a pore is much smaller than a cell, a small portion of
the cell slides through the pore at a time; the portion sliding through is momentarily
constricted to the size of the pore, White Blood Cells Move Through Tissue Spaces
by Ameboid Motion. Both neutrophils and macrophages can move through the tissues
by ameboid motion, Some cells move at velocities as great as 40 mm/min, a distance
as great as their own length each minute.
White Blood Cells Are Attracted to Inflamed Tissue Areas by Chemotaxis.
Many different chemical substances in the tissues cause both neutrophils and
macrophages to move toward the source of the chemical. This phe- nomenon, is
known as chemotaxis. When a tissue becomes inflamed, at least a dozen different
products are formed that can cause chemotaxis toward the inflamed area. They
include (1) some of the bacterial or viral toxins, (2) degenerative products of the
inflamed tissues themselves, (3) several reaction products of the “complement
complex” activated in inflamed tissues, and (4) several reaction products caused by
plasma clotting in the inflamed area, as well as other substances.
Phagocytosis
The most important function of the neutrophils and macrophages is phagocytosis,
which means cellular ingestion of the offending agent. Whether phagocytosis will
occur depends especially on three selective procedures.
1.most natural structures in the tissues have smooth surfaces, which resist
phagocytosis. But if the surface is rough, the likelihood of phagocytosis is increased.
2. most natural substances of the body have protective protein coats that repel the
phagocytes. Conversely, most dead tissues and foreign particles have no protective
coats, which makes them subject to phagocytosis.
3. the immune system of the body develops antibodies against infectious agents
such as bacteria. The antibodies then adhere to the bacterial membranes and thereby
make the bacteria especially susceptible to phagocytosis. To do this, the antibody
molecule also combines with the C3 product of the complement cascadeThe C3
molecules, in turn, attach to receptors on the phagocyte membrane, thus initiating
phagocytosis. This selection and phagocytosis process is called opsonization.

Inflammation: Role of Neutrophils and Macrophages

Inflammation
When tissue injury occurs, whether caused by bacteria, trauma, chemicals, heat, or
any other phenomenon, multiple substances are released by the injured tissues and
cause dramatic secondary changes in the sur- rounding uninjured tissues. This entire
complex of tissue changes is called inflammation.
“Walling-Off” Effect of Inflammation. One of the first results of inflammation is to
“wall off” the area of injury from the remaining tissues. The tissue spaces and the
lymphatics in the inflamed area are blocked by fibrinogen clots so that after a while,
fluid barely flows through the spaces. This walling-off process delays the spread of
bacteria or toxic products.

Macrophage and Neutrophil Responses During Inflammation

Tissue Macrophage Is a First Line of Defense Against Infection.
Within minutes after inflammation begins, the macrophages already present
in the tissues, whether histiocytes in the subcutaneous tissues, alveolar macrophages
in the lungs, microglia in the brain, or others, immediately begin their phagocytic
actions.
Neutrophil Invasion of the Inflamed Area Is a Second Line of Defense.
Within the first hour or so after inflammation begins, large numbers of
neutrophils begin to invade the inflamed area from the blood. This is caused by
products from the inflamed tissues that initiate the fol- lowing reactions: (1) They
alter the inside surface of the capillary endothelium, causing neutrophils to stick to the
capillary walls in the inflamed area. This effect is called margination.(2) They cause
the intercellular attachments between the endothelial cells of the capillaries and small
venules to loosen, allowing openings large enough for neu- trophils to pass by
diapedesis directly from the blood into the tissue spaces. (3) Other products of inflam-
mation then cause chemotaxis of the neutrophils toward the injured tissues.
Second Macrophage Invasion into the Inflamed Tissue Is a Third Line of Defense.

Along with the invasion of neutrophils, monocytes from the blood enter the
inflamed tissue and enlarge to become macrophages. However, the number of
monocytes in the circulating blood is low: also, the storage pool of monocytes in the
bone marrow is much less than that of neutrophils. There- fore, the buildup of
macrophages in the inflamed tissue area is much slower than that of neutrophils,
requiring several days to become effective.

Increased Production of Granulocytes and Monocytes by the Bone Marrow Is a

Fourth Line of Defense. The fourth line of defense is greatly increased
production of both gran- ulocytes and monocytes by the bone marrow. This results
from stimulation of the granulocytic and mono- cytic progenitor cells of the marrow.

The Leukemias
Uncontrolled production of white blood cells can be caused by cancerous mutation of
a myelogenous or lymphogenous cell. This causes leukemia, which is usually
characterized by greatly increased numbers of abnormal white blood cells in the
circulating blood.
Types of Leukemia. Leukemias are divided into two general types: lymphocytic
leukemias and myeloge- nous leukemias. The lymphocytic leukemias are caused by
cancerous production of lymphoid cells, usually beginning in a lymph node or other
lymphocytic tissue and spreading to other areas of the body. The second type of
leukemia, myelogenous leukemia, begins by cancerous production of young
myelogenous cells in the bone marrow and then spreads throughout the body so that
white blood cells are produced in many extramedullary tissues—especially in the
lymph nodes, spleen, and liver.
In myelogenous leukemia, the cancerous process occasionally produces partially
differentiated cells, resulting in what might be called neutrophilic leukemia,
eosinophilic leukemia, basophilic leukemia, or monocytic leukemia. More frequently,
however, the leukemia cells are bizarre and undifferentiated and not identical to any
of the normal white blood cells. Usually, the more undifferentiated the cell, the more
acute is the leukemia, often leading to death within a few months if untreated. With
some of the more dif- ferentiated cells, the process can be chronic, some- times
developing slowly over 10 to 20 years. Leukemic cells, especially the very
undifferentiated cells, are usually nonfunctional for providing the normal pro- tection
against infection.
Effects of Leukemia on the Body
The first effect of leukemia is metastatic growth of leukemic cells in abnormal areas
of the body. Leukemic cells from the bone marrow may reproduce so greatly that they
invade the surrounding bone, causing pain and, eventually, a tendency for bones to
fracture easily.
Almost all leukemias eventually spread to the spleen, lymph nodes, liver, and other
vascular regions, regardless of whether the origin of the leukemia is in the bone
marrow or the lymph nodes. Common effects in leukemia are the development of
infection, severe anemia, and a bleeding tendency caused by thrombo- cytopenia (lack
of platelets). These effects result mainly from displacement of the normal bone
marrow and lymphoid cells by the nonfunctional leukemic cells.
Finally, perhaps the most important effect of leukemia on the body is excessive use of
metabolic substrates by the growing cancerous cells. The leukemic tissues reproduce
new cells so rapidly that tremendous demands are made on the body reserves for
foodstuffs, specific amino acids, and vitamins. Con- sequently, the energy of the
patient is greatly depleted, and excessive utilization of amino acids by the leukemic
cells causes especially rapid deterioration of the normal protein tissues of the body.
Thus, while the leukemic tissues grow, other tissues become debili- tated. After
metabolic starvation has continued long enough, this alone is sufficient to cause
death.

CLOTTING FACTORS

Factor I- FIBRINOGEN

FactorII- PROTHROMBIN

Factor III- TISSUE THROMBOPLASTIN

Factor IV- CALCIUM

Factor V- FACTOR LABILE

Factor VII- STABLE FACTOR

Factor VIII- ANTIHAEMOPHILIC

Factor IX- CHRISTMAS

Factor X- STUART PROWER

Factor XI-PTA

Factor XII- HAGEMAN

Factor XIII- FIBRIN STABILISING FACTO

CASCADE OF BLOOD CLOTTING;
 BLEEDING DISORDERS AND MANAGEMENT

Causes for postoperative hemorrhage

Combination of factor
Local systemic

Defects in coagulation

Defect vascular bed defect in platelets

It is essential to differentiate all these causes & act quickly & decisively in
event of complication.

There are many unexpected & undesirable postoperative complications. These

can be grouped under two major categories.

Those related to bleeding & those related to delayed wound healing & infection.

Laboratory tests of haemostasis.

There is multitude of lab tests of platelet function & of the coagulation cascade.
The surgeon must often decide which of these tests to obtain to maximize the
probability of detecting occult haemostatic defect.

1) Bleeding time : - (BT)

BT is the single best screening test for platelet function, but it has been criticized
because in some studies it does not correlate with surgical bleeding. But some authors
recommend this as a routine preoperative test because it screens for von willibrand’s
disease & platelet dysfunction. BT is useful in detecting vascular disorder i.e.
ontogenesis imperfecta, hereditary hemorrhagic telengiectasia). The test is performed
by inflating a BP cuff of 40 mm of Hg & then making a standard cut on inner surface
of forearm. Blood is removed from edge of the drop using filter paper until bleeding
has stopped

2) Prothrombin test

But screening test for abnormalities of the extrinsic, common limbs of the
coagulation the clotting time of plasma with ideal concentration of tissue
thromboplastin. Decreased level of factor 1 (afbrinogenemia), II, V

(Parahaemophilia) VII (hypoproconvertinemia) & X result in prolonged PT.

Congenital low levels of factor I. II. VII, V & X are rare But acquired defects are
common & caused by liver disease, coumadin therapy, Vit K deficiency, disseminated
intravascular coagulation, high titer lupus anticoagulant & high dose of heparin therapy.

During anticoagulation therapy & monitoring aspects are taken

A) International normalized ratio (INR)

b) Patient’s self management

INR is the value calculated from the ratio of Patient’s prothrombin time (PT) to
mean of normal range. This value is then corrected by multiplication by the
international sensitivity index (ISI). The ISI is based on a quantitative assessment of
responsiveness of a thromboplastin. The INR system was established to standard
discrepancies in specific thromboplastin used in the PT test. ISI is performed against
different WHO reference materials.

Pt can also do self-assessment of PT.A portable monitor for measuring PT

called Coagu Check (Hoffman La Rache) now available. It measures the PT from a
capillary stick & expresses the result as INR within minutes. This is used in patients to
alter coumadin dosage.

Partial thromboplastin Time

The PTT is a test that measures abnormalities of intrinsic pathway of coagulation.
The test is performed by adding a platelet substitute (phospholipase A) so that platelet
activity is not tested. A modification of PTT is addition of an activator that maximizes
contact activation and increase sensitivity reproducibility of the test. The activated PTT
is more commonly used.

Abnormalities of the most common heritable coagulation cascade deficiencies are

measured by aPTT. Decreased levels of factor 1 (afbrinogenia) II, V (Parahemophilia)
VIII (hemophilia A) VWF(von Willebrand factor disease) IX (Christmas disease), X,
XI, and XII are all found in a PTT.

Although aPTT is the single most sensitive laboratory test for coagulation defects,
it must be interpreted with knowledge of its limitation. It lacks sensitivity to mild
deficiency of single clotting factors and to haemostatic defects due to coumadin. Slight
prolongation of a PTT is of no significance.
Thrombin Time: (TT)
It measures interaction between exogenously added thrombin and fibrinogen. It is
most commonly used in disseminated intravascular coagulation or in afbrinogenemia.
Platelet Counts - These are obtained on anticoagulated blood by using electronic
particles counter. The reference range being 150-450x10 3/mm3. Counts outside this
must be confirmed by using blood smear visual examination.
Activated clotting time:(aCT) It is used for assessing heparinisation of patients
intraoperatively. Whole blood is mixed with diatomaceous earth. aCT should be
prolonged by 3-4 times before cardiac bypass surgery begins.
Blood Smear - It assesses morphological abnormalities and quantitative platelet
disorder.
Mixes: - Mixing of patient plasma with an equal volume of normal plasma in a standard
test for identification of coagulation inhibitors such as lupus anticoagulants and for
confirming specific factor deficiency. If prolongation of a PTT or PT is due to specific
factor deficiency, the mix will correct to normal. If on the other hand inhibitors of
coagulation is responsible for prolonged aPTT or PT mix will not correct to normal.
Investigation Normal Range causes for
abnormality

1. Platelet counts 150-350x10 9/1 Thrombocytopenia

* Congenital
* Acquired

2. Bleeding Time Less than 8mm Thrombocytopenia

Thrombopathy
* Congenital
* Acquired
Von Willebrand's disease
3. Prothrombin time 12-14 sec Def. of factor
(INR value upto 3.5) II, V, VII, X
Or 1.5 - 3 times Liver disease
normal PT ) Warfarin therapy
DIC

4. Activated partial
Thromboplastin time 30-40 sec Def. of factor II,
V, VII, IX, X, XI, XII
(Hemophilia A, B,
Von Willebrands disease
DIC)

5. Fibrinogen 1.5 - 3.0g/dl Congenital

 hypofibrinogenemia
Haemostasis
The prevention of bleeding depends upon maintaining the integrity of blood vessel
walls by mechanism, which ensures that any breaches are rapidly sealed by deposition
of platelets and fibrin. This process can be arbitrarily divided as
a. Primary haemostasis- Blood vessel constricts

Activated platelets adhere to damaged wall

Aggregation of platelets

Platelet plug

Bleeding stopped

This is reinforced by deposition of network of fibrin. These 2 stages are clearly

interrelated.

Coagulation cascade has been given below which shows interrelationship between
coagulation factors and platelets.

Disorders can be classified as

Disorders of primary hemostasis

A.Vessel wall abnormalities
1. Inherited
Hereditary hemorrhagic telengictasia
Ehler Danlos syndrome
2. Acquired
Scurvy
Anaphylactoid secondary to drugs and chemicals.
B.Disorders of platelets
1. Inherited
Thrombostenia
Hereditary giant platelet
Platelet releasing defects
Congenital Thrombocytopenia
2. Acquired
Thrombocytopenia
Failure of platelet production
Aplasia of bone marrow
Drugs and chemicals
Leukemia
Secondaries of carcinoma
3. Reduced platelet survival
Chronic idiopathic thrombocytopenic purpura
Drug, food sensitivity
Acute infections
Auto immune
Disseminated lupus erythematosus
Thromboticthrombocytopenic purpura
4.Altered platelet function
Drugs like -
Aspirin,
Phenyl butasone,
High dose of penicillin
5. Disease like
myeloproliferative disease,
hyper gamma globulinemia
Disorders of secondary hemostasis.
Congenital-
 Hemophilia A
Hemophilia B
Von wiilebrand disease
Afibrinogenemia

Acquired-
Vit K deficiency
Liver disease

Combined defects
- Disseminated intravascular coagulation
-Primary fibrinolysis associated with prostatic
adenocarcinoma.

Platelet disorder's and their treatment

Platelet is necessary to maintain vascular integrity and prevent haemorhage. They form
two important functions
1. Exposure to sub endothelial tissue, such as connective tissue, causes platelets to
adhere to the sets of injury. The plug formed depends on a protein expressed on the
cell surface of platelets known as von will brand’s factor VIII:VWF

2. Once exposed to sub endothelial tissue platelets release the stored contents of
granules from their cytoplasm to surrounding tissue. Granules contain many chemo
tactic factors as well as adenosine diphosphate, calcium, fibrinogen and epinephrine.
Calcium stimulates phospholipase to cleave phosopholipids providing building blocks
for prostaglandins Primary prostaglandin synthesized by platelets is thromboxane A2
that causes vasoconstriction.

3. Platelets form catalytic sources for coagulation cascade, which leads to deposition of
fibrin.

Disorders that affect total count of platelets and quality of platelets will be bound to
cause severe haemostatic defect. Following defects are discussed with management
1. Autoimmune Thrombocytopenia (AITP)
It was referred as idiopathic theombocytopenic purpura. This term is somewhat
outdated and less descriptive. Three categories of AITP are now recognized.

a. Idiopathic thrombocytopenic purpura (ITP)

- a chronic disease of unknown causes with an insidious onset affecting predominantly
young adults with 3:1 female predominance.

b. Secondary thrombocytopenic purpura, which resembles ITP but is

associated with an autoimmune disease, malignancy or other immunomodulatory
disease.
c. Acute post viral autoimmune thrombocytopenia - most commonly seen in children
following viral infection - lasting less than 6 months. Chronic form rarely occurs but
cannot be differentiated from ITP

Although it is only known that antibodies are produced against platelets, the
mechanism of formation of antibodies is not known. Various hypothesis include

a. Molecular mimicry - viral marker resembling platelet cell marker

b. Anti-idiotype antibodies -where secondary antibiotics are made to antibodies formed
against viral markers.
c. Exposure of previously hidden marker on the platelet surface

Clinical course
- Clinical features include
- Petechiae, cutaneous pupura
- Bleeding gums
- Epistaxis
- Haematuria
- Melena
- Menorrhagia

Severe complication like cerebral haemorhage can be seen.

 Diagnosis is primarily by clinical picture and lab findings- Thrombocytopenia,
normal PT and aPTT. Splenomegaly is not seen.
- Drug induced thrombocytopenia can be ruled out by history
- Post viral AITP has typical history of viral infection.

Treatment
Patient with chronic AITP are treated with steroids and spleenectomy - 80% of patient
will obtain permanent remission.

Intravenous lgG therapy is used- blocks reticuloendothelial system by competing for

binding sites on macrophages that would normally bind to destroy platelet covered in
antibodies.

If these measures do not improve their platelet infusion may be necessary

Acute post viral thrombocytopenia is managed differently because of excellent
prognosis.. The disease is of childhood in 90% of cases and usually follows viral
infection. The autoantibody responsible is IgM which explains the short duration of
illness that is 3 1/2 weeks. Because of benign nature it is managed by

a. Non interventional strategy with limitation of activity

b. Avoidance of NSAIDS
c. Weekly monitoring of platelet count.

However if the child has excessive haemorhage or child is above 10 years treatment
protocol of adult AITP can be used.
If surgery has to be carried out then intravenous lgG should be given.

2. Thrombotic Thrombocytopenic purpura (TTP)

It is a rare (1/10 6 population), life threatening characterized by
- Neurolgical abnormalities
- Microangeopathic hemolytic anemia
- Thrombocytopenia
- Fever
 - Renal dysfunction

Lab finding - Platelet count less than 40,000

-Rule out DIC with clinical features
- Biopsies of gingiva - 15% case
- Bone marrow - 30% cases is diagnostic

Pathological examination of tissue reveals small arterial and arteriolar thrombosis

composed mainly of platelets.
Coagulation factor levels are not abnormal distinguishing from DIC

Cause - Blood plasma have abnormal VIII VWF causing blood to form platelet clot
- Decreased synthesis of PGI2 (prostacyclin), which is most potent inhibitor of
platelet aggregation secreted by blood endothelium.
Treatment - 90% mortality rate.
Prognosis- poor
Treatment includes - Plasma transfusion.
- Plasma pheresis
Platelet infusion should not be done as it will worsen the condition

3. Platelet dysfunction and Renal disease

Uremic patients have varying levels of platelet dysfunction that is reversible on

hamodialysis. Serum levels of guandinosuccinic acid and hydroxyphenolic acid are
elevated in such patients and then decreased PF3 level (Phospholipid) on platelet
surface which are important for activation of coagulation cascade. A functional defect
in the interaction between proteins IIb and IIIa of VWF has also been implicated.

treatment- Dialysis
- DDAVP (1-diamino-8-D arginine vasopressin) has been effective -1-12hs of
improvement.
- Infusion of cryoprecipitate -24-36hs of improvement.
4. Drug induced Thrombocytopenia

NSAID's like - Aspirin, Indomethacin, Phenylbutazone, Sulphenpyrazone

Antibiotics - Penicillins, cephalosporin
Dextran
Heparin
beta-blockers
Over 100 drugs are implicated to cause thrombocytopenia

Pathogenesis is not clear. But due to interaction of drugs with platelet surface
membrane causes alteration of antigen and hence antibody production is triggered..
Atleast 6 day lag period is seen in cases without previous exposure.

- Clinical features - fever, chills, arthralgias abrupt onset of petechie, hematoma not
related to trauma.

- Rx includes immediate cessation of causative drug. Since antibodies are found in the
blood for many years, the causative drug should not be administered again.

- If severe and life threatening -Rx parallel to AITP should be carried out.

5) Ethanol induced
80% of chronic alcoholic have mild to moderate thrombocytopenia
Ethanol is directly toxic to platelets & megakaryocytes. It also causes decrease
qualitative function mainly due to decreased store production of theombaxane A2

6) Pregnancy associated – It is associated with increased platelet activation &

consumption accounting for thromocytopenia in about 8% of normal pregnant patient .
It is mild in nature with no thrombocytoperia in fetus

Dental Rx in Theombocytopenia
 Platelet count of 40,000/mm3 is called critical value. Usually a count of atleast
50,000 /mm3 is necessary for oral surgical procedures with conjunction of local
haemostatic measure.

Surgery can be carried out with use of DDAVP & IgG infusions as described
earlier.

Block injections are contra indicated inpatient below 30,000/mm3

Defects in coagulation
Hemophilia A-
- bleeding disorder caused by deficiency of clotting factors VIII.
- accounts for 80% of al hemophilia .
Incidence 1:10,000 of male population
Severe hemophilia with activity less than 1%
Moderate with activity less than 3-5%
Mild with activity less than 5-12%
Severity of symptoms can vary. prolonged bleeding is the hallmark of hemophilia
A and typically occurs when an infant is circumcised. Additional bleeding
manifestations when infant becomes mobile.
Mild cases may go unnoticed .Men are affected as it is due recessive gene.
However women can be carrier.
Symptoms include
- Haemarthrosis.
- Haermatomas
- Haematuria
- Bleeding from mucosal surfaces of nose and mouth.
Lab Diagnosis
Clinically patient will have increased apt but normal PT.
The factor VIII is preset in the form of complex
VIII: c – procoagulant activity of factor VIII
Complex - deficient in hemophilia
VIII : VWF – Von willebrand activity of factor VIII
complex that is deficient in Von Willebr
 and’s disease

VIII : Ag – Antigenic property – responsible for

coagulant property of VIII
VIII: VWF Ag – Antigenic property VWF.
VIII R: RCO - Activity of the factor VIII Complex that supports
aggregation of platelets by the
presence of antibiotic ristocetin

Hemophilia B
It is called as Christmas disease, but clinically indistinguishable from
hemophilia A.
- Incidence is 1:100000 .
- Found in males but females can be carriers
- Only testing for specific factor activity distinguishes hemophilia B from
hemophilia A.
- As with factor VIII, 30 % of IX activity is required for normal hemostasis
following surgery or trauma..

Management :-
Patient treatment should be based on following principles.
- Control of bleeding
- Minimum hospitalization
- Minimum chances of viral infection
- Low expenditure

As a dentist our role will be to educate patient and parents for bringing the
child to the dental clinic for preventive measures, rather than wait for extensive
procedure which require elevated factor levels & as well as hospitalization. Patient
should be taken into confidence & good rapport established.

Dental Management
- Pain Control – Intra pulpal anaesthesia is safe & can be effectively used for pulp
extirpation. Intra ligamentary injection even though not contraindicated might be
painful. Buccal, labial & palatal infiltration can be done but with caution & local
pressure applied for atleast 3-4min.
- Blocks given – Like inferior alveolar nerve block require atleast 30% of factor
level as these injections are usually given in highly vascular areas with no distinct
boundaries & filled with loose connective tissue Extravasation of blood into
oropharyngeal region can cause dysphagia, Pain, respiratory obstruction.

* use of NSAIDS should be strictly avoided

* General anaesthesia with tracheal intubation or laryngeal mask might induce
laryngeal haematoma & these forms are very difficult to control
* Extra muscular injections are also to be avoided
Conscious sedation, nitrous oxide / Oxygen analgesia intravenous sedation with
diazepam are always to be encouraged.

Restorative & prosthodontic procedue

Generally these procedure do not cause any significant bleeding & hence can
safely be carried out.
Rubber dam with correctly applied clamps to prevent any injuries that might
induce bleeding.
Restorative procedure must be encouraged in patient with blood coagulopathies
as they will be least invasive & bloodless.

Periodontal procedures
It can be safely carried out provided scaling is supra gingival .
Deep subgingival scaling might have to be carried out quadrant wise with
adequate local pressure application .
Once gross scaling done subgingival scaling has to be postponed to later date
as gingiva will become the inflamed & be hyperemic – so less bleeding
- Subgingival calculus gets exposed as enlarged gingiva shrinks.
Periodontal parks can be used to as it prevents bleeding & protect the exposed areas.

Endodontic therapy:-
It is often treatment of choice as it involves minimal bleeding . care should be taken to
prevent over instrumentation.Pulpal bleeding is not a problem & stops on extirpation /
local presence.

Pedodontic Patient therapy:-

Exfoliation of tooth might cause bleeding but local pressure usually stops such
bleeding. Moss advocates extraction of mobile primary tooth with infiltration to
periodontal space without factor replacement & two days of vigorous oral prophylaxis
to prevent inflammation.

Topical fluoride application & use of pit and fissure sealants should be
encouraged.

Stainless steel crown should be given ensuring that gingival margins are taken
care of .

Orthodontic Therapy
It can be safely carried out. But appliances should not cause any trauma.
Bleeding from minor cuts usually responds to local pressure. The use of extra oral force
& shorter treatment duration further decrease the potential of bleeding complications.

Oral Surgery Procedure:-

It has the greatest potential for hemorrhage of all dental procedure. Appropriate
pucautionary measures allow surgical procedure to be performed safely. Factor levels
will have to be raised to 50 – 100% of level But this is not easy. plasma half life of
Factor VIII is 8 – 12 hrs & Factor IX is 18 – 24 hrs. Additional factor maintainence
may be indicated post operatively.

Kaneda & colleagues have reported that factor levels of 25% for deciduous &
20% for permanent teeth healing post extraction phase. 3 modalities are advocated
- continuous infusion
- Intermittent infusion
- Single concentrate infusion with antifibrinolytic agent .
 Recently it was shown that post operative bleeding & the need or transfusion
after oral surgery were significantly reduced with tranexamic acid being used as a
mouthwash .
The tranexamic acid binds to lysine binding sites on plasminogen & plasmin .
This mechanism blocks the binding of plasmin to fibrin, thus acting as a potent inhibitor
of fibrinolysis .The efficiency of local antifibrinolytic Rx has been proved by
observation, that the concentration of tranexamic acid mouthwash in saliva remains
sufficiently high to suppress fibrinolysis for several house after use, while only
insignificant levels was demonstrated in plasma at the same time.
The concentration used is 5% solution poured into 5 ml + 5ml of water is used
for local irrigation & mouth wash.
Suturing with non resorbable suture can be effectively done. Resorbable
suture might cause inflammatory responses & hence increase bleeding.
Fibrin glue is hotly debated as currently used fibrin glue which mimics final
stage of blood clotting .
Because of possibility of spreading viral infection, it is not used.
- Factor VIII C replacement therapy can be calculated as 1 unit of VIII C per Kg of
body weight results in increase of 0.02 units /mm. For major surgeries value should be
0.8 – 1.0 Units /mm (80 –100%) & then maintaining at 0.3 – 0.5 units /mm
- Alternate therapy for mild & moderate hemophiliacs include the use of desmopressin
(DDAVP) – 1 deamino – 8 – d – arginine vasopressin . In hemophilic patent it is found
to increase factor VIII : C & factor VIII VWF .
The mechanism of action is unclear. The release of stored factors in vascular
endothelial cells and endogenous stores are believed to be the cause for the increase.
Current recommendation is 0.3 micro g /kg of desmopressin diluted in 50ml of normal
saline ,slow infusion over 15-30mm. The maximum raise occurs at about 90-120
minutes & persistent activity for 6 or more hours.
Side effects are mild headache, flushing & are due to increase volume & can be
usually controlled by fluid restriction.
Currently gene therapy being investigated for treatment of hemophiliacs & it is
an excellent candidate for several reasons .
- Involved proteins are delivered into circulation by a variety of cell types &
low levels of expression lead to significant improvement in management of bleeding
episodes.
 - Excellent animal models exist & therapy can be easily tested
- Present gene therapy shows partial correction of hemophilia in dog & mouse
models
- Epsilon – amino capric acid (EACA or Tranexamic acid – oral dose) can also
be used.
The standard dose is 4 gm of EACA by mouth every 4-6 hrs for 7-10 days or
0.25mg/kg body weight post operatively 3-4times a day. Contraindicated in patient
with hematuria due to association with upper urinary tract obstruction.

Von willebrand’s disease :-

Clinically patient present with a congenital (autosomal dominant) bleeding disorder
with increased activated partial thromboplastin time & increase bleeding time &
decreased plasma conc. of VIII : C & VIII : VWF.
Administration of NSAID’s will sometimes cause the first clinical symptom in
patients with mild disease and should be avoided due to increased hemorrhagic risk.
Based on multimeres of VWF it is classified as
- Ia, Ib, Ic,
- IIa, IIb, IIc, IId
-III.
Type I VW disease accounts for 70-80% of patients
In this all multimeres of VWF are present but at decreased level.

Type II VWF accounts 10-15% of patient – here high molecular weight

multimers are low.
Type III VWD is almost complete absence of VWF.
Clinical feature are same as hemophilia but increased bleeding tendency.
Mangament includes
- Cryoprecipitate
- DDAVP – Rx of choice in Type I
- Human – P – factor VIII concentrate for type II & type III VWD.
Dissseminated intra vascular coagulation
It is by far most frequent & serious acquired defect. Excessive surgical bleeding
in patient without coagulation defects is due to DIC. In DIC the usual balance between
coagulation & fibrinolysis is lost . coagulation under some circumstances results is
consumption of coagulation factors & platelets due to widespread formation of fibrin –
thrombus formation throughout the microcirculation

Causes are
*Thromboplastin release
-Sepsis
- Malignancies (adenocarcinoma)
- Haemolysis
- Fat emboli
- Placental absorption
- Amniotic fluid bolus

* Endothelial damage (intrinsic)

- Sepsis
- - Anaphylaxis
- Acidosis
- Crush injuries
- Vasculitis
- - Ricketsial diseases
- Burns
* Directly conversion of fibrinogen to fibrin
- Snake venom
- Bacterial toxins.
* Contact of blood with foreign meterials

Clinical manifestations include

Early – hypotension due to obstruction of microcirculation
- Vasoconstriction
-Fever
- Bleeding – petechiae purpura venupuncture bleeding
Late –
Ischemic degeneration of organ resulting in organ failure secondary to
obstruction of microcirculation lungs, Kidney, brain , pancreas , heart & GIT
are affected .
Diagnosis
- All factor level decreased
-Increased PT & increased aPTT
-Blood smear examination

Management
– Prognosis poor

-Aggressive Rx required. Patient may survive early complications but may end up with
late complication

Rx comprises of cryoprecipitate infusion and increased factor levels . Platelet

concentrate should be increased. Underlying cause should be managed.

Abnormal lab test.

Disease PT PTT BT
Von willebrand disease N Increase increase
Hemophilia N increase N
Liver disease increase increase varies
CoumadinTherapy Increase N varies
Heparin Therapy varies increase varies

Anti coagulation & Minor Oral surgery

The risk of post operative hemorrhage from office oral surgical procedures has
been a concern for longtime. However little current information is available regarding
the actual amount of bleeding encountered in out patient oral surgery.

It has been suggested that in recent years in many patients oral surgical
procedures can be done without alteration of then regular oral anticoagulation therapy
(OAT).

The WHO recommends use of INR (International normalized Ratio) standardization

for monitoring.
 It has been recommended that INR values of 3.5 – oral surgical procedure can
be safely carried out.

Rebound phenomenon is a hyper coagulation and this condition occurring after

OAT withdrawl but it has been not well documented.

A survey conducted in USA has shown that 96% of oral surgeons prefer
alteration of anticoagulant in patients with low risk of thromboembolism .
It has been argued that oral anticoagulation regimen should be altered to low
molecular weight heparin (LMWH) used with postoperative management. The
advantage being in case of excessive bleeding there is antogonist – protamine sulphate
that could be used.

From oral surgeon’s point of view there are no

well –documented cases of serious bleeding problems after tooth removal in patients
receiving therapeutic levels of OAT, but there are several cases of embolic
complications described in patients whose therapy has been withdrawn.

CONCLUSION:-
Treatment of patients with bleeding disorders presents a unique challenge .
Knowledge of specific coagulation defect is essential for proper management and
requires close consultation and co-ordination with patients physician & hematologist.
The conservative approach in treatment & management is recommended. When
local anesthetic is used , bleeding risk only relates to surgical site & can be controlled
with local homeostasis – Thus replacement Therapy is not absolutely necessary .
Proper oral hygiene instructions , preventive therapy & conservative management are
key for treating patient with blood coagulopathies.
REFERENCES

1)Text Book of Oral Medicine, diagnosis & treatment - Burkits

2) Text book of Basic Pathology - Robbin’s

3) Davidson’s principle & practice of Medicine - Davidson
4) Text Book of Medical Physiology- Guyton & Hall
5) Text Book of Physiology for Dental students- A.K.Jain
6) Essentials of Pathology For Dental Students- Harsh Mohan.