11 - Hemostasis & Blood Coagulation

Hemostasis & Blood
Coagulation
BY
IDIONGO O. UMOH
20-Feb-18 Hemostasis & Blood coagulation 1

Platelets
Platelets are small granulated
bodies
2 - 4m in diameter
Have half life of about 8 – 12 days
There are about 150,000 to
300,000/L of blood
About 30 – 40% of circulating
platelets are found in spleen
Platelets
Megakaryocytes form platelets by
Pinching off bits of cytoplasm and
extruding them into circulation
The formation of platelets is
controlled by
• Colony stimulating factors
– The GM – CSF, IL-1, IL-3, IL-6
• Thrombopoietin
– Facilitate megakaryocyte maturation

Platelets
Platelets membrane contain
Glycoproteins
• Prevents adherence of platelets to
endothelium
Microtubules
• Provides structural support to the cells
Phospolipids
• Accelerates clotting reactions

Their cytoplasm contain
Proteins:Contractile proteins, Actin,
myosin, von Willebrand factor, Fibrin-
stabilizing factor, Platelet-activating factor
(PAF), Thrombospondin
Enzymes: ATPase, Enzymes necessary
for synthesis of prostaglandins.
Hormonal Substances: Adrenaline2. 5-
hydroxytryptamine (5-HT; serotonin),
Histamine

Platelets
Their Cytoplasm also contain
thrombosthenin
• Cause the platelets to contract
Glycogen, lysosomes
Two types of granules
• Dense granules contain
– Serotonin, ADP, calcium, Lysosomes
•  - Granules which contain
– Clotting factors (fibrinogen, V and XIII)
– Platelet derived growth factor (PDGF)

Functions Of Platelets
BLOOD CLOTTING
formation of intrinsic prothrombin activator. This
substance is responsible for the onset of blood clotting
PREVENTION OF BLOOD LOSS (HEMOSTASIS)

Vasoconstriction, platelet plug, coagulation of blood
REPAIR OF RUPTURED BLOOD VESSEL

By Secreting PDGF to repair damaged vessels
DEFENSE MECHANISM
By the property of agglutination, platelets encircle the
foreign bodies and destroy them

Physiological variations
Age: Platelets are less in infants (100,000 to 150,000/cu
mm) and reaches normal level at 3rd month after birth.
Sex: There is no difference in the platelet count

between males and females. In females, it is reduced
during menstruation.
High altitude: Platelet count increases.
After meals: After taking food, the platelet count

increases.

Platelet Disorders
Thrombocytopenia; Decrease in platelet
count is called thrombocytopenia. It leads to
thrombocytopenic purpura
Thrombocytosis; Increase in platelet count
is called thrombocytosis. Thrombocytosis
occurs in the following conditions: Allergic
conditions, Asphyxia, Hemorrhage, Bone
fractures, Surgical operations
Thrombocythemia; Thrombocythemia is
the condition with persistent and abnormal
increase in platelet count. Thrombocythemia
occurs in the following conditions: Carcinoma,
Chronic leukemia
20-Feb-18 9
Hemostasis & Blood coagulation
(II) Haemostasis
Haemostasis
Is the arrest or stoppage of bleeding
It is achieved by
• Vasoconstriction
• Formation of platelet plug
• Formation of blood clot

Vascular Constriction
After blood vessel injury
Walls of the vessel contract due to
• Nervous reflex initiated by
– Pain or other tissue factors
• When blood vessels are cut, endothelium is
damaged, and collagen exposed.
• Platelets adhere to collagen and get
activated
• Also secreting serotonin and other
vasoconstrictor substances which causes
vasoconstriction
• Adherence of platelets to collagen is
accelerated by Von willebrand Factor.
Platelet Plug
When platelets come in contact
with damaged vascular surface
They become activated
• Contractile protein contract causing
– Release of granules
• They become sticky and stick to collagens
• They release large quantities of
Thromboxane A2 and ADP which
– Enhance platelets aggregation

Platelet Plug
Aggregated platelets form
Platelet plug which at first
• Is loose but can block blood loss
Subsequently fibrin threads develop
• Attach to platelets
• Construct a tight plug
Platelet aggregation is accelerated by
platelet activating factor (PAF).
Platelet Plug
If the vessel damage is small
Platelet plug is enough to block blood
loss
But if the hole is big then
• Blood clot formation is required to block
blood loss

Platelet Plug
If a person has few platelets then
Plug formation is impaired
Develops small bleeding spots under
the skin and through out internal
tissues
• Thrombocytopenic purpura

Formation of Blood Clot
Clot formation
Begins 15 to 20 sec after injury
Activator substances
From traumatized vessel,
• Increase Platelet aggregation
– Fibrinogen converted to fibrin fibres
– Clot formation, and retraction

Formation of Clot
Platelets attach to fibrin fibres
Release fibrin stabilizing factor
Cause more fibrin fibres to attach to
one another
Platelets also activate
Actin, myosin, thrombosthenin
• Cause contraction of platelets together
with the attached fibres

Formation of Clot
This causes compression of fibrin
mesh into smaller mass
• This squeezes most of the fluid out
(serum)

Factors Involved in Blood
Clotting
Coagulation of blood occurs through a series
of reactions due to the activation of a group
of substances.
Substances necessary for clotting are
called clotting factors.
Thirteen clotting factors are identified in
Humans;

Clotting Factors
Nomenclature
Factor synonym
I Fibrinogen
II Prothrombin
III Tissue factor, tissue thromboplastin
IV Ca++
V Proaccelerin, labile factor, accelerator – Globulin (Ac-G)
VII Stable factor

Clotting Factors
Nomenclature
Factor synonym
VIII Anti-hemophilic factor (AHF),anti-hemophilic globulin,

anti-hemophilic factor A
IX Plasma thromboplastin component (PTC), Christmas factor,
anti-hemophilic factor B
X Stuart factor, Stuart Prower factor
XI Plasma thromboplastin antecedent (PTA), anti-hemophilic

factor C
XII Hageman factor
XIII Fibrin stabilizing factor

Clotting Factors
Nomenclature
Factor Synonym
Prekalikrein Fletcher factor
HMWK High molecular weight Kininoggen, Fitzgerald factor
Platelets Platelets phospholipids
Vitamin K is essential for the formation of various clotting

factors, namely II, VII, IX
and X.

Initiation of Coagulation
In both the extrinsic and intrinsic
pathways
Different plasma proteins ( 
globulins)
• Called blood clotting factors
• Play major role in the formation of
prothrombin activator

Initiation of Coagulation
The blood clotting factors are
Inactive proteolytic enzymes
When activated they cause
Cascading reactions leading to the
• Activation of the various factors and
• Formation of prothrombin activator

Stages Of Blood Clotting
In general, blood clotting occurs in
three stages:
1. Formation of prothrombin
activator
2. Conversion of prothrombin into
thrombin
3. Conversion of fibrinogen into
fibrin.
Formation Of Prothrombin
Activator (Stage 1)
Blood clotting commences with the
formation of a substance called
prothrombin activator, which
converts prothrombin into
thrombin.
Its formation is initiated by substances
produced either within the blood or
outside the blood.

Formation Of Prothrombin
Activator
Thus Prothrombin activator can be
formed by two ways
Intrinsic pathway
• In this pathway, the formation of
prothrombin activator is initiated by
platelets, which are within the blood itself
Extrinsic Pathway
• In this pathway, the formation of
prothrombin activator is initiated by the
tissue thromboplastin, which is formed from
the injured tissues

Intrinsic Pathway
Begins when
Exposure of collagen in traumatized blood vessel
Causes
Activation of Inactive factor XII (Hageman Factor)
In the Presence of Kallikrein and High Molecular
weight Kinogen (HMWK)
Activated factor XII in the presence of HMWK

Activates factor XI

Intrinsic Pathways
Activated factor XI together with
platelets phospholipids, Ca++
Activates factor IX
Activated factor IX together with
VIII, platelets phospholipids, Ca++
• Activates factor X
After the activation of factor X
the activated factor X reacts with platelet
phospholipid and factor V to form
prothrombin activator.
• In the Presence of Ca++

Intrinsic Pathways
Blood trauma VIII
HMWK,
XII XIIa prekalikrein
VIIIa, platelets
phospholipids,
XI XIa Ca++
Thrombin IX IXa
X Xa
V,
phospholipids,
Prothrombin
Ca++ Platelets
activator
phospholipids,
Ca++
Prothrombin Thrombin

The Extrinsic Pathways
Begins with traumatized vascular
walls or extra vascular tissue
The Injured tissue release
Tissue factor (tissue thromboplastin)
• Composed of phospholipids
– Lipoproteins complex containing
proteolytic enzymes

The Extrinsic Pathways
Glycoprotein and phospholipid
components of thromboplastin
convert factor X into activated factor X,
in the presence of factor VII and Ca++.

The Extrinsic Pathway
Activated factor X
Combine with tissue phospholipids,
platelets phospholipids, factor V, Ca++
To form the complex known as prothrombin
activator

Extrinsic Pathway
Trauma
Tissue factors VIIa,

Ca++
Tissue factor,
Ca++, factor V,
X Xa thrombin
Platelet Prothrombin
phospholipids, activator
Ca++
Prothrombin Thrombin

Prothrombin & Thrombin
Prothrombin is a plasma protein
 2 globulin, MW 68,700
conc in plasma = 15 mg/dl
It is an unstable compound
Splits easily to smaller compounds
• Thrombin being one of them
It is formed by the liver
Require vitamin K for the formation

Conversion Of Prothrombin To
Thrombin (Stage 2)
Blood clotting is all about thrombin
formation. Once thrombin is formed, it
definitely leads to clot formation.
Prothrombin activator that is formed

in intrinsic and extrinsic pathways
converts prothrombin into
thrombin in the presence of
calcium (factor IV).

Conversion Of Prothrombin To
Thrombin (Stage 2)
Once formed thrombin initiates the
formation of more thrombin
molecules.
The initially formed thrombin activates
Factor V. Factor V in turn accelerates
formation of both extrinsic and intrinsic
prothrombin activator, which converts
prothrombin into thrombin.
This effect of thrombin is called
positive feedback effect

Conversion of Fibrinogen to
Fibrin (Stage 3)
Fibrinogen is a high mol wt protein, MW
340,000
Found in plasma at a conc 100 - 700 mg/dl
It is also formed in the liver
Because of its high MW
It does not leak into interstitial space

Conversion of Fibrinogen
Into Fibrin (Stage 3)
Thrombin acts on fibrinogen to convert it into
fibrin
Removes 4 low mol wt peptides from each mol of
fibrinogen
• Forms molecules of fibrin monomers which
polymerize to form
– Fibrin fibres
Fibrin activating factor, released by platelets
Activated by thrombin
Converts fibrin molecules into cross linked
meshwork of fibrin fibres

Intra-vascular
Anticoagulants
Factors involved in the prevention of
Coagulation in the normal vascular system
include
Endothelial surface factors
Smoothness of the endothelium prevent
• Contact activation of the intrinsic pathway
Layer of glycocalyx
• Present in the endothelium
– Repels clotting factors, platelets
– Prevents activation of clotting

Intra-vascular
Anticoagulants
Presence of thrombomodulin in endothelium
Bind thrombin
Combination of thrombin & thrombomodulin
• Slows clotting
• Activate plasma protein C
– Inactivates factor V, VII
Action of fibrin and Antithrombin III
Fibrin fibres
• Thrombin becomes attached to fibrin fibres
• This prevent spread of thrombin to neighbouring
regions

Intra-vascular
Anticoagulants
Antithrombin III
Circulating protease inhibitor
• Binds to serine proteases in the coagulation
system
• Blocking their activity as coagulating factors
• Binding is facilitated by heparin
Factors inhibited include
– IX, X, XI, XII
It also binds and inactivates thrombin

Intra-vascular
Anticoagulants
Heparin
Powerful anticoagulant
Present in blood in small amounts
In combination with antithrombin III
• Form powerful inhibition of coagulation
Thrombin
Activates plasma protein C which
• Inactivates factor Va, VII, VIIIa

Clot Retraction
After the formation of clot, the blood clot
starts contracting.
And after about 30 to 45 minutes, the
straw-colored serum oozes out of the
clot.
The process involving the contraction of
blood clot and oozing of serum is called
clot retraction. Contractile proteins,
namely actin, myosin and
thrombosthenin in the cytoplasm of
platelets are responsible for clot
retraction Hemostasis & Blood coagulation 45
Fibrinolysis
Lysis of blood clot inside the blood

vessel is called fibrinolysis. It helps to
remove the clot from lumen of the
blood vessel.
This process requires a substance called
plasmin or fibrinolysin

Fibrinolytic System
Plasminogen Function to dissolve
activator
Fibrin ,
the clot after it has
Thrombin been formed
Consist of
Plasminogen Plasmin
proenzyme
plasminogen
Which is converted to
Fibrin Soluble fibrin plasmin by
Plasminogen activator
• Tissue plasminogen
activator (t-PA)

Fibrinolytic System
Plasminogen Plasmin digest
activator
Fibrin , Fibrin and
Thrombin fibrinogen
• Dissolve the
Plasminogen Plasmin
clot
Fibrin Soluble fibrin

Fibrinolytic System
Plasminogen
activator
Plasminogen
Fibrin , activator
Thrombin
Tissue
Plasminogen Plasmin plasminogen
activator (t-PA)
Secreted by
endothelial cells

Fibrinolytic System
Plasminogen
activator
During the clotting
Fibrin , process
Thrombin
Plasminogen & t-PA
Plasminogen Plasmin bind to fibrin
Increases the ability
to generate plasmin

Inhibition of Fibrinolytic
System
Plasminogen
activator
Plasmin inhibitor
Fibrin ,
Thrombin 2 antiplasmin
2 -antiplasmin
Binds with plasmin
Plasminogen Plasmin
To inhibit its
function

Inhibition of Fibrinolytic
System
Plasminogen
activator
Plasminogen
Fibrin ,
- activator inhibitor
Thrombin PAI -1
type 1
Plasminogen Plasmin PAI-1
2 antiplasmin
Inhibit plasminogen
activation
Slows formation of
plasmin

Tests For Blood Clotting
Blood clotting tests are used to
diagnose blood disorders.
Some tests are also used to monitor the
patients treated with anticoagulant
drugs such as heparin and warfarin.
Types of Tests Include:
1. Bleeding time
2. Clotting time
Hemostasis & Blood coagulation 53

Bleeding Time
Bleeding time (BT) is the time
interval from oozing of blood after
a cut or injury till arrest of
bleeding.
Usually, it is determined by Duke
method using blotting paper or filter
paper method.
Its normal duration is 3 to 6 minutes.
It is prolonged in purpura.

Clotting Time
Clotting time (CT) is the time
interval from oozing of blood after
a cut or injury till the formation of
clot.
It is usually determined by capillary
tube method. Its normal duration is 3 to
8 minutes. It is prolonged in
hemophilia.

Applied Physiology
BLEEDING DISORDERS
Bleeding disorders are the conditions
characterized by prolonged bleeding
time or clotting time.
Bleeding disorders are of three types:
1. Hemophilia.
2. Purpura.
3. von Willebrand disease.

Hemophilia
Hemophilia is a group of sex-linked
inherited blood disorders,
characterized by prolonged
clotting time.
However, the bleeding time is

normal.
Usually, it affects the males, with the
females being the carriers.

Hemophilia
Because of prolonged clotting time,
even a mild trauma causes excess
bleeding which can lead to death.
Damage of skin while falling or

extraction of a tooth may cause excess
bleeding for few weeks.
Easy bruising and hemorrhage in

muscles and joints are also common in
this disease. Hemostasis & Blood coagulation 58
Causes of Hemophilia
Hemophilia occurs due to lack of

formation of prothrombin
activator.
That is why the coagulation time is
prolonged.
The formation of prothrombin
activator is affected due to the
deficiency of factor VIII, IX or XI.

Types of Hemophilia
Hemophilia A or classic hemophilia:
Due to the deficiency of factor VIII.
85% of people with hemophilia are
affected by hemophilia A.
Hemophilia B or Christmas disease:
Due to the deficiency of factor IX. 15%
of people with hemophilia are affected
by hemophilia B.
Hemophilia C or factor XI deficiency:
Due to the deficiency of factor XI. It is a
very rare bleeding disorder
Symptoms of Hemophilia
Spontaneous bleeding.
Prolonged bleeding due to cuts, tooth
extraction and surgery.
Hemorrhage in gastrointestinal and
urinary tracts.
Bleeding in joints followed by swelling
and pain
Appearance of blood in urine

Treatment of Hemophilia
Effective therapy for classical
hemophilia involves replacement of
missing clotting factor.

Purpura
Purpura is a disorder characterized by

prolonged bleeding time. However, the
clotting time is normal.
Feature of this disease is spontaneous
bleeding under the skin from
ruptured capillaries.
It causes small tiny hemorrhagic
spots in many areas of the body.

Purpura
The hemorrhagic spots under the skin
are called purpuric spots (purple
colored patch like appearance).
That is why this disease is called
purpura.
Blood also sometimes collects in large

areas beneath the skin which are called
ecchymoses.

Von Willebrand Disease
Its a bleeding disorder, characterized by
excess bleeding even with a mild injury.
It is due to deficiency of von
Willebrand factor, which is a protein
secreted by endothelium of damaged
blood vessels and platelets.
This protein is responsible for
adherence of platelets to endothelium
of blood vessels during hemostasis after
an injury and also for the survival and
maintenance of factor VIII in plasma.
Von Willebrand Disease
Deficiency of von Willebrand factor
suppresses platelet adhesion. It also
causes deficiency of factor VIII.
This results in excess bleeding, which
resembles the bleeding that occurs
during platelet dysfunction or
hemophilia.

11 - Hemostasis & Blood Coagulation

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Hemostasis & Blood

20-Feb-18 Hemostasis & Blood coagulation 1

20-Feb-18 Hemostasis & Blood coagulation 3

20-Feb-18 Hemostasis & Blood coagulation 4

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PREVENTION OF BLOOD LOSS (HEMOSTASIS)

REPAIR OF RUPTURED BLOOD VESSEL

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Sex: There is no difference in the platelet count

High altitude: Platelet count increases.

After meals: After taking food, the platelet count

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III Tissue factor, tissue thromboplastin

V Proaccelerin, labile factor, accelerator – Globulin (Ac-G)

VII Stable factor

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VIII Anti-hemophilic factor (AHF),anti-hemophilic globulin,

XI Plasma thromboplastin antecedent (PTA), anti-hemophilic

XIII Fibrin stabilizing factor

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Prekalikrein Fletcher factor

HMWK High molecular weight Kininoggen, Fitzgerald factor

Platelets Platelets phospholipids

Vitamin K is essential for the formation of various clotting

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Activated factor XII in the presence of HMWK

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Tissue factors VIIa,

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Prothrombin activator that is formed

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Lysis of blood clot inside the blood

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Fibrin Soluble fibrin

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