ANTI HAEMOSTATIC

MECHANISM
DR ARPANA HAZARIKA
WHY BLOOD DOES NOT CLOT IN
CIRCULATION?
1.ENDOTHELIAL FACTORS
[a] Smoothness of endothelial lining prevents platelet
adhesion and extension of clot into blood vessel

[b]Negatively ,charged particle such as glyocalyx , a muco

polysaccharide present over endothelial lining ,repel the clotting
factors that are proteins ,anions ,thereby prevent clotting.

2FACTORS PREVENTING PLATELET AGGREGATION

Prostacyclin is an endogenous factor which prevents platelet
aggregation by inhibiting thromboxane A2 formation which
promotes platelet aggregation]
3VELOCITY OF CIRCULATION-Blood is pumped into the
vessels and circulated at a constant velocity which
contributes to its fluidity if decreases in certain condition it
leads to clotting.
4NATURAL ANTI COAGULANT in the blood also prevent
clotting.eg Heparin,Antithrombin III and protein C

5All endothelial cells except those in the cerebral micro

circulation produce thrombomodulin , a thrombin
binding protein that converts thrombin to protein C
activator.This activates protein C with its co factor Protein S
[6]ProteinC is a naturally occuring anticoagulant
Inactivates factorV and VIII and also inactivate an
inhibitor of tissue plasminogen activator increasing
the formation of plasmin
[7]Simultaneous activation of fibrinolytic system along
with clotting mechanism
.[8]In the event of clot formation ,liver removes the
activated clotting factors from the circulation
 THE CLOTTING MECHANISM
INTRINSIC EXTRINSC
Collagen Tisue Thromboplastin
XII
XI VII
IX
VIII
X

V FIBRINOGEN
(I)

PROTHROMBIN THROMBIN
(II) (III) FIBRIN
FIBRINOLYTIC SYSTEM
Fibrinolysis refers to the process that brings about
dissolution of blood clot
The important component of the fibrinolytic system is
plasmin or fibrinolysin which is present in the blood in
an
inactive inhibits thrombin to form plasminogen which
gets converted to plasmin
by the action of thrombin and tissue plasminogen
activator-TPA.
Plasmin lyses fibrin and fibrinogen with the production
of fibrin degradation product that inhibits thrombin
PLASMINOGEN-plasminogen is a ß-globulin produced
by the liver.Structurally human plasminogen
Consist of a heavy chain of 500 amino acids and a light
chain of 241 amino acids.The heavy chain at its amino
terminal is folded into five loops which are held
together by disulphide bonds.These loops are called
kringles.The kringles are the binding site by which
molecules attaches to fibrin and other clotting protein
and also to prothombin.Plasminogen is activated
by plasminogen activator system to produce
plasmin.The receptors of plasminogen are located
mainly on the surface of endothelial cell and also on
different type of cells
PLASMIN-is a powerful protease formed from its
precursor,the plasminogen.It lyses fibrin and fibrinogen
into fragments known as fibrin degradation
product[FDP] that inhibits thrombin
Thus there is a negative feedback which controls
plasmin generation .There are two plasminogen
activator system in the body -Intrinsic and Extrinsic
Plasminogen Activator System it operates in the following
Way
EXTRINSIC PATHWAY
Tissue plasminogen activator also called vascular
plasminogen activator is released from vascular
endothelium.The release of TPA from the vessel wall depends
on the release of serotonin from platelets and also release of
adrenaline
When there is physical and mental stress or exercise or
liberation of adrenalin on sympathetic stimulation,the
TPA is released vigorously and this removes fibrin so
that bleeding tends to prolong.In violent death the
blood is fluid and incoagulable due to fibrinolysis.This is
due to fibrinolysis.This is due to large amount of
adrenaline released into the blood before death
Given to patients soon after the onset of myocardial
infraction
UROKINASE-type plasminogen activator.The UPA is
Found in a number of tissues including endothelial
cell,renal cells and tumour cells
Note;Streptokinase and staphylokinase are bacterial
enzymes known to produce activation of plasmin like
TPA and UPA.Streptokinase is a protein produced
 ß hemolytic streptococci.It forms streptokinase
plasminogen complex which produce a conformational
change that expose active sites on plasminogen molecule
and lyse to form plasmin.There fore they are
in the treatment of early myocardial infraction to lyse
thrombin
INTRINSIC PLASMINOGEN ACTIVATOR SYSTEM
Contact factors[XIIa and kallikrin] that initiate clotting
mechanism also stimulate the dissolution of clots by
activating plasminogen and constitute the
Intrinsic plasminogenactivator system
FIBRINOLYSIS INHIBITORS-The rate of fibrinolysis is
influenced by the promoters and inhibitor.Fibrinolysis
inhibitor are present in plasma,blood cells,tissues and
Extracellular matrix.these inhibit plasmin or activation
of plasminogen
PHYSIOLOGICAL ROLE OF FIBRINOLYTIC
SYSTEM

1.CLEANING THE MINUTE CLOTS OF TINY VESSEL.

In physiological condition the clotting system of the
plasma is continually forming small amount fibrin
Which are deposited to form a thin layer on vascular
endothelium and the fibrinolytic system is constantly
In action to prevent excessive fibrin formation
2-PROMOTE NORMAL HEALING PROCESS.
Lysis of clot formed as a result of tissue injury helps
to promote normal healing process
3LIQUEFACTION OF MENSTURAL BLOOD CLOT
In the vagina is carried out by fibrinolytic system
4LIQUEFACTION OF SPERMS IN THE EPIDIDYMIS
When seminal ejaculation does not occur is caused by
the fibrinolytic system
5]ROLE IN INFLAMMATORY RESPONSE
In addition to its fibrinolytic activity , plasmin can
form plasma kinins and thus contribute to the vascular
and sensory features of inflammatory to injury
ANTICOAGULANTS
Anticoagulants refer to the substances which delay or prevent
the process of coagulation of blood .In vitro ,
blood clotting can be prevented by substances which
sequester calcium e.g sodium citrate or oxalate ,sodium
edetate .
In vivo,the tendency of thrombosis can be inhibited by
1Antagonizing clotting factor
2By destruction of the key substance fibrinogen
3By inhibiting the synthesis of factors II,VII,IX and X
TYPES
Anticoagulant may be divided into endogenous and
exogenous anticoagulant
ENDOGENOUS ANTICOAGULANTS
Endogenous anticoagulant are those which are present
Inside the blood naturally
Heparin
Antithrombin III
Protein C
EXOGENOUS ANTICOAGULANT
Exogenous anticoagulant are administred from outside
These include
Heparin and its derivatives
Calcium sequesters
Vitamin K antagonist
Defibrination substances
1.HEPARIN-Heparin a naturallly acting anticoagulant,it
can also be synthesized.It inhibits blood coagulation
both in vivo and vitro
For commercial use heparin is extracted from certain
animal tissue.Synthesised form has longer life,therefore
its action last for 4-5 hrs.It mainly inhibits activated
factors of intrinsic and common pathway.including
Xa,IXa.
Clinical use-Due to its rapid action heparin can be used
to treat thrombosis and pulmonary emboli
initial management of patient with `unstable angina,
Acute myocardial infraction[MI] and during cardiac
Bypass surgery
In selected patient with dissiminated intravascular
coagulation
2DANAPAROID is a mixture of non heparin glycosamine
isolated from procine intestinal mucosa.It
mainly cause inhibition of factorXa by antithrombin but
does not prolong PTT
3LEPIRUDIN is a recombinant derivative of hirudin
present in salivary gland of medicinal leech.It is a direct
inhibitor of thrombin
4]CALCIUM SEQUESTER OR DECALCIFYING AGENTS
In vitro blood clotting can be prevented by substances
Which sequester calcium from blood.These include two
types of agents
Substances which form insoluble salts with calcium
such as sodium citrate and sodium oxalate
6]CALCIUM CHELLATORS which bind calcium such as
ethylene diaminitetraacetic acid[EDTA]
7]VITAMIN K AGONIST–These are used orally and can
prevent coagulation in vivo.These agents occupy
Vitamin K receptor sites in the liver and prevent vitamin
K from carrying out its normal physiological
function,These substances inhibit synthesis of vitamin K
dependent factors VII,IX and X.These include coumarin
derivatives dicumarol,warfarin,phenindon and
nicumalone
8DICUMAROL is an first original oral anticoagulant
isolated for clinical use because of its slow absorption
9WARFARIN-For synthesis of vitamin k dependent
coagulation factors.Vitamin K act as cofactor for
formation of Ý gluatamil carboxylase and epoxide
reductase are responsible for formation of metabolism
of vit K.Warfarin acts by inhibiting enzyme epoxide
reductase complex.This enzyme converts inactive
form of vitamin k into active form
[4.]Thrombolytic drug include plasminogen
activtor,streptokinase and urokinase
[5]Anti platelet drug like aspirin prevent platelet
formation
[6.]Defrbinating substances-defibrination substance are
those which cause destruction of fibrin.These include
[7.]Malaysian pit viper venom-It is a type of snake venom
which in vivo acts as anticoagulant by causing
defibrination
MALASYIAN PIT VIPER VENOM -It is a type of snake
venom which in vivo acts as anticoagulant by causing
defibrination and also stimulating fibrinolytic system.
ARVIND or ANCORD–It is a purified preparation of
snake venom.It is a glycoprotein in nature and is
administered by injection.It acts as anticoagulant by
causing defibrination and thus producing imperfect
fibrinogen polymer
Cold-keeping blood cold [5to 6c] can retard coagulation
but cannot absolutely prevent.For this reason blood is
stored in blood banks at low temperature but some
anticoagulant is always used