Presented by

Dr SHARMILA G S
INTRODUCTION
Coagulation is a complex process by which blood
forms clot. It is an important part of hemostasis(the
cessastion of blood loss from damaged vessels)
wherein a damaged blood vessel wall is covered by a
platelet and fibrin containing clot to stop bleeding
and begin the repair of damaged vessels.
INTRODUCTION
When blood is shed out or collected in a container,it
looses its fluidity and jelly like mass after few
min’s.this process is called coagulation or clotting of
blood.
The clot is a mesh of thin fibrils entangling the blood
cells.these fibrils consist of fibrin .the fibrin is formed
from fibrinogen.
Basis
Blood flows through intact vessels
Resting state is designed to keep blood flowing
Arteries: rapid flow. Injury requires a plug
 Rapid, localised, controlled.
 minimise blood flow compromise

Veins: slower, intermittent flow

 Systemic anticoagulant
 clot dissolving system
Complex activating and inhibition system

Five components
Vessels
Platelets
Coagulation factors (clot forming)
Coagulation inhibitors (clot controlling)
Fibrinolysis (clot dissolving)
Haemostasis
1. Vasoconstriction
2. Platelets activated by thrombin form a platelet plug
3. Fibrin mesh forms via activation of the coagulation
system to strengthen the clot
4. Clot dissolution via plasmin
5. Normal blood flow past the clot
HISTORY
JOHANNES MULLER(180 1-1858) described
fibrin,substance of thrombus.
RUDOLF VIRCHOW(1821-1902) named fibrinogen
and it was isolated chemically by PROSPER SYLVIAN
DENIS.
ALEXANDER SCHIMOIT suggested

fibrinogen fibrin is a enzymatic

process and labelled hypothetical enzyme thrombin
and its precurssor prothrombin
ARTHUS in 1890 discovered ca is essential for
coagulation.
Platlets ---------1865 & their functions were
explained by GIULIO BIZZOZERO in 1882
The theory thrombin is generated by presence of
tissue factors was consolidated by PAUL MORAWITZ
IN 1905
NOMENCLATURE
The usage of roman numerals rather than eponyms or
systamatic names was agreed upon during annual
conferences(starting 1955)of hemostasis experts.
In 1962 consensus was achieved on the numbering of
factors I-XII.
This committee evolved into the present day
international committee on thrombosis and
hemostasis
Assignement of numerals ceasedin 1963.
 General concepts
Coagulation factors act as proteases when
activated (serine proteases)
Zymogens (inactive eg fibrinogen) converted
to enzymes/proteins by limited proteolysis
Complex formation requiring calcium,
phospholipid surface, cofactors
Thrombin converts fibrinogen to fibrin
monomer
Fibrin monomer crosslinked to fibrin
Forms "glue" for platelet plug
FACTORS INVOLVED IN BLOOD
CLOTTING
I FIBRINOGEN
II PROTHROMBIN
III THROMBOPLASTIN
IV CALCIUM
V LABILE /PROACCELERIN/ACCELATOR
GLOBULIN
VI presence has not been proved
VII STABLE FACTOR
VIII ANTIHEMOPHILIC FACTOR
IX CHRISTMAS FACTOR
X STUART POWER FACTOR
XI PLASMA THROMBOPLASTIN ANTECEDENT
XII HEGMAN FACTOR
XIII FIBRIN STABALIZING FACTOR
I FIBRINOGEN
Soluble plasma protien
Globulin in nature
Mol.wt is 3,40,000 dalton
Synthesized in liver
6 polypeptide chain
Plasma concen 0.3gm/100ml
Converted into fibrin in the presence of enzyme
thrombin
II PROTHROMBIN
Alpha 2 globulin,plasma protien
Inactive precursor of thrombin
Mol.wt is 69,000dalton
Synthesized in liver in the presence of vit k
Concen in adult is 40mg/100ml,in new born babies is
low, lower in liver diseases
III THROMBOPLASTIN
Tissue factor
Released by extrinsic pathway of formation of
prothrombin activator

VI CALCIUM
ionic calcium is essential for blood coagulation
V PROACCELERIN
Unstable factor
Required for formation of prothrombin activator &
thus conversion of prothrombin to thrombin in both
extrinsic as well as intrinsic mech of bllod
coagulation.
Is consumed during clotting hence absent in serum.
VII STABLE FACTOR/
AUTOPROTHROMBIN I
Stable protien synthesized in liver in the presence of
vit k
Required for activation of fac x in extrinsic pathway.
It is not consumed during clotting and therefore
present in serum as well as plasma.
VIII ANTI HEMOPHILIC FACTOR
Protien of beta 2 globulin synthesized in liver
Required for activation of x &formation of
prothrombin activator in intrinsic pathway.
Consumed during clotting and therefore absent from
the serum.
Congenital deficiency causes classical hemophilia.
Clotting time is prolonged.
IX CHRISTMAS FACTOR
Also called plasma thromboplastin component./auto
prothrombin 2
Protien synthesized in liver independent of vit k.
It is activated by active factor xi in the presence of
calcium.
Essential for formation of prothrombin activator in
intrinsic pathway.
Deficiency causes hemophilia B
X STUART POWER FACTOR
Protein plasma & synthesized in liver
Activated by fac ix in the presence of VIII,Ca,&
phospholipids.
Activated factor X along with active factor V ,Ca, and
pospholipids forms a complex called prothrombin
activator in both pathways.
XI PLASMA THROMBOPLASTIN
ANTECEDENT
Activated by factor XII required for activation of factor
IX in the presence of calcium in intrinsic pathway.
Deficiency causes hemorrhagic state.

XII HAGEMAN FACTOR

Is activated to XII a when it comes in contact wirh
negatively charged surface,foreign substance or rough
surface.
Its activation in the blood initiates intrinsic pathwayby
activating XI to Xia
Activated factor XII also activates prekallikrein to
kellikerin which in turn activates XII to XIIa(feedback
activations)

XIII FIBRIN STABALIZING FACTOR

 Ca2+
Plasma protein stabilization fibrin
polymers
PLATLATLET
PHOSPHOLIPIDS(PPL)
Essential for clotting in the absence of tissue extract

 intrinsic pathway
MECHANISM OF
COAGULATION
Clot formation is initiated under following situations
1. Trauma to the vascular wall and adjacent tissues
2. Trauma to blood
3. Contact of blood with damaged endothelial cells or
collagen or other tissue elements outside the vessel.
the process of coagulation involves a cascade of
reactions in which activation of one factor leads to
activation of next clotting factor.
The process can be divided into three steps
Formation of prothrombin activator
Conversion of prothrombin to thrombin
Conversion of fibrinogen into fibrin
FORMATION OF
PROTHROMBIN ACTIVATOR
EXTRINSIC PATHWAY
INTRINSIC PATHWAY
Extrinsic Pathway Intrinsic Pathway
Tissue trauma Blood trauma/ contact with collagen

Leakage of Tissue Factor Activation of factor

Ca+2, factor VII XII, IX, VIII

X Xa X Xa
Ca+2 Ca+2

Prothrombin activator
Prothrombin
Ca+2 activator
Prothrombin Thrombin Prothrombin Thrombin
(factor II) (factor II)

Activation of certain factors (VII, II, X and protein C and S) is

essential for coagulation. This activation requires vit K (reduced
form)
 Thrombin

Fibrinogen Fibrin Monomers

Ca+2, factor XIII

Fibrin threads
EXTRINSIC PATHWAY
It includes following 3 basic steps
Release of tissue thromboplastin

X Xa
Effect of activated factor X to form prothrombin
activator
INTRINSIC PATHWAY
IT BEGINS IN THE BLOOD ITSELF
Activation of factorXII
Activation of factorXI
ACTIVATION OF FACTOR IX
Activation of factor X
Formation of prothrombin activator
CONVERSION OF
PROTHROMBIN TO THROMBIN
Caused by prothrombin activator in the presence of
calcium
Surface of platelets which forms platelet plug
at the site of injury
The rate of formation of thrombin is directly
proportional to quantity of prothrombin activator
available which in turn is proportional to the degree
of trauma to the vessel wall or blood
THROMBIN
Proteolytic enzyme
Amt of thrombin produced during clotting of 1ml of blood is
sufficient to coagulate 3 lt of blood
FUNCTIONS
Conversion of fibrinogen to fibrin
Positive feedback role of thrombin
accelarate the rate of formation of prothrombin activator by
activating factor VIII,V,XIII.in this way thrombin itself can
cause further conversion of thrombin to
prothrombin(amplification affect)
Activates protien c(anticoagulant)
Conversion of fibrinogen to
fibrin
1. Proteolysis
 Thrombin(proteolytic enzyme)
removes

fibrinogen(4 low mol wt peptide chains)

fibrin monomer
2. Polymerization
fibrin monomer
polymerizes
long fibrin threads

which forms reticulum of the clot

Initially the clot is weak because the fibrin threads are
not crosslinked with each other
3. stabilization of fibrin polymers
Fibrin stabalizing factor (XIII) is activated by thrombin
in the presence of calcium,which causes formation of
covalent crosslinkages between fibrin threads adding
strength to fibrin meshwork.the fibrin meshwork
trapes remaining components of plasma and blood
cells to form solid mass called clot.
BLOOD CLOT RETRACTION
Blood clot meshwork of fibrin threads

 blood cells platelets plasma

The fibrin threads adhere to damaged surface of blood

vessels.
Clot begins to contract and squeeze out most of the
fluid called serum(plasma- fibrinogen and other clotting
factors)---------- 30-60mins
Platelets are essential for clot retraction.
platelet thrombosthenin
Actin, myosin contractile protiens

present in cytoplasm of platlets causes strong

contraction of platlet spicules attached to fibrin fibres
Activated by thrombin and calcium ions
ROLE OF CALCIUM IN BLOOD
COAGULATION
REQUIRED FOR PROMOTION OF ALL THE
REACTION except 1st two reactions in intrinsic
pathway.
ROLE OF VITAMIN K
Complex naphthoquinone deravative
Source
 absorbed
Food bacterial flora gut liver
ade amt
of bile salts
small intestine
In liver synthesis of following factors are dependent
on vit k
Coagulant like prothrombin
VII,IX,X
Circulatory anticoagulant protien
VITAMIN K DEFICIENCY
EFFECTS
Prothrombin time and blood clotting time is
prolonged.
CAUSES
Obstructive jaundice
New born babies
Chronic diarrhoea
Side effects of antibiotics
ROLE OF LIVER
Plays a significant role
1. Synthesis of procoagulants V,VII,IX,X,Prothrombin
&fibrinogen
2. Removal of activated procoagulant
3. Synthesis of anticoagulants like heparin,antithrombin
III &protein c
Liver failure causes
1. Bleeding disorders due to hypocoagubility of the
blood.
2. Uncontrolled extensive clotting inside the blood
vessels
Role of blood vessels
Endothelium plays both anticoagulatry as well as
coagulatory roles.
Anticoagulatory roles
1. Acts as a barrier between the thrombogenic
subendothelial tissue and the blood.
2. Produce heparin and alpha 2 macroglobulin which are
coagulation inhibitors
3. Smoothness of uninjured endothelial cells prevents
platelet aggregation
4. Produce prostaglandin which opposes platelet aggregation
Clotting mechanism
1. Secreates von willebrands factor it initiates platlet
aggregation and hemostasis.
2. Tissue factors released during trauma initiates the
extrinsic pathway
Subendothelial tissue
Collagen fibers
Platlet aggregation is initiated when blood comes in
contact with
Intrinsic coagulation pathway is initiated when
factor XII is activated.
VASCULAR SMOOTH MUSCLE
Causes vasoconstriction initiated by mechanical
injuries to muscle.
Circulating blood does not clot
Velocity of circulation
constant velocity.
decrease in velocity causes intravascular clotting.
Surface effects of endothelium
1. Smoothness of endo lining inhibits platlet adeshion
2. A layer of glycocalyx absorbed to the inner surface of
endothelium being negatively charged repels clotting
factors and platlets and thereby prevents clotting.
Intact endothelium acts as a barrier between the
thrombogenic subendothelial collageneous tissue
and the blood.
CIRCULATORY ANTICOAGULANTS
Natural anticoagulant present in the blood they are
1. Heparin
2. Antithrombin III
3. Alpha 2 macroglobulin
4. Protein c
Fibrinolytic mechanism
Protein c is naturally occurring anticoagulant which
inactivates factor V ,VII also inactivates an inhibitor
of tissue plasminogen activator increasing the
formation of plasmin which acts as fibrinolytic.
Removal of activated clotting factors
liver plays a important role
ANTIHEMOSTATIC
MECHANISMS
The factors which balance the tendency of the blood
to clot invivo constitute the antihemostatic factors.
These can be grouped as
1. Factors preventing platelet aggregation
2. Factors preventing coagulation
3. Factors causing fibrinolysis
Factors preventing platelet
aggregation
Prostacyclin
Is a endogenous factor which inhibit platelet
aggregation by inhibiting thromboxane A 2 formation
CIRCULATORY ANTICOAGULANTS
Heparin
Anti thrombin III
PROTEIN C
anticoagulants
Substance which delay or prevent the coagulation of
the blood
TYPES
ENDOGENOUS
EXOGENOUS
Endogenous are those present inside the body naturally
Heparin
Antithrombin III
Protein c
 Exogenous anticoagulant
Heparin
Calcium sequesters
Vitamin k antagonist
Defibrination substance
 HEPARIN
Powerful naturally acting anticoagulant
First isolated from liver
Polysaccharide containing many sulphate groups
Mol wt is 15,000-18,000 dalton
SECRETION
Secreated by basophils and mast cells
 Mechanism of action
Present on luminal surface of endothelium it acts by
following mechanism
Prevents of activation of prothrombin to thrombin
Inhibits the action of thrombin on fibrinogen
Facilitates the action of anti thrombin III ,i.e. acts as
its cofactor and thereby inhibits the active forms of
clotting factors IX, X,XI,XII
Calcium sequesters/decalcyfing agents
Invitro blood clotting can be prevented by substance
which remove calcium from the blood.these include
Substance which forms insoluble salts with calcium
such as sodium citrate and sodium oxalate
Calcium chelators which bind calcium such as
ethylene diaminetetraacetic acid(EDTA)
Vitamin k antagonist
Used orally and thus can prevent coagulation
effectively. these include
Coumarian derivatives,e.g. dicoumarol and warfarin
Mechanism of action
These agents occupy vitamin k receptor sites in the
liver and prevent vitamin k to carry out its normal
physiological functions.thus these substance inhibit
synthesis of vit k dependent factor,i.e. factors VII,IX,
AND X
DEFIBRINATION SUBSTANCE
Destruction of fibrinogen . These include
Malaysian pit viper venom.
Arvin or ancord-purified preparation of snake venom.
It is a glyco protien and is administered by injections.
COLD
Temp maintained is 5-10 degree c
Inhibitors: ANTI-coagulants
Antithrombin III
Directly inactivates serine proteases
Thrombin and Xa. Also: IXa and Xia
Potentiated by heparin
Protein C
Inhibits (cleaves) the cofactors VIIIa and Va
Significantly decreases the rate of clot formation
Needs to be activated
Protein S:
Enhances activity of protein C
Thrombomodulin
Activated by thrombin
Binds to thrombin to alter its conformation
Complex activates protein C
Tissue pathway factor inhibitor
Inhibits FVIIa-tissue factor complex
Anticoagulants
Too little or ineffective
Extensive clot
Too much
Bleeding

Therapeutics
Heparin
Activated protein C
TPFI inhibitor
Fibrinolysis
Prevents excessive fibrin deposition
Allows closely coupled with fibrin formation
Localised surface bound phenomenon that is
catalysed by fibrin formation
Components: fibrinolysis
Plasminogen -> plasmin

Plasminogen activators

Inactivators of plasminogen

Inhibitors of plasmin
 
                                                                        
PHYSIOLOGICAL ROLE OF
FIBRINOLYSIS SYSTEM
Plasmin play following role
Cleaning the minute clots of tiny vessels
Promote normal healing process
Liquefaction of menstrual clot
Liquefaction of sperms in epididymis
Role in inflammatory response
TESTS FOR COAGULATION
BLEEDING TIME
-the time lapse between the skin prick and arrest of
bleeding is known as bleeding time.
Normal range
By dukes method-1-6min’s
Prolonged BT occurs in purpura while its normal in
hemophilia
Clotting time
The time interval from oozing of blood after acut or
injury till the formation of clot is called clotting time
Normal range is 3-8min’s
Prolonged in hemophilia
 Intrinsic pathway
XII

XI
Extrinsic pathway
IX VII
APTT
VIII
X
PT
Prothrombin thrombin
V, Ca, P/L
(II)
fibrinogen fibrin
XIII
STABILISED FIBRIN
Intrinsic pathway test-PTT
Activated partial thromboplastin time
Max activation of contact factors
XII,XI, prekallirein,high mol.wt kinogen
More consistant and reproducable
Eliminates leangthy contact activation phase
Normal values
PTT-40-100sec(>120 abnormal)
aPTT-25-35sec
EXTRINSIC PATHWAY TEST
PROTHROMBIN TIME
Time required for blood to coagulate is called
PT
Performed by adding a mixture of calcium and
thromboplastin to citrated plasma
As a control, a normal blood sample is tested
continuously
PT ratio (PTR) = Patient’s PT
Control PT
PROBLEMS WITH PT/PTR
Thromboplastins are extracts from brain, lung or
placenta of animals
Thromboplastins from various manufacturers differ
in their sensitivity to prolong PT
May result in erratic control of anticoagulant therapy
REFERENCES
Guyton and hall; text book of medical physiology-10 th
edition.
Text book for human physiology for dental students-
indu khurana
Wright (1962) “the nomen clature of blood clotting
factors” can med assoc j86 373-4 PMID 14008442
Essential of medical physiology –k sembulingam
THANK YOU