Hemostasis

HEMOSTASIS
By,
. Aishwarya S Nair
. Post Graduate student
. Oral Medicine & radiology
CONTENTS
1. Introduction
2. Definition of Hemostasis
3. Phases of Hemostasis
i. Phase of Vasoconstriction
ii. Phase of Temporary Platelet Plug
formation
iii. Phase of Fibrin Clot formation.
4. Platelets in Hemostasis.
5. Mechanism of Blood Coagulation
6. Regulation of Blood Coagulation
7. Fibrinolysis
8. Conclusion
9. References
INTRODUCTION
The word Haemostasis originates from two ancient Greek

words Haima meaning blood and stasis meaning
standing.1
DEFINITION
Hemostasis is
The process of forming clots in the blood vessels and
preventing blood loss while maintaining blood in a fluid
state within the vascular system. 2
1. Understanding Medical Physiology: A Textbook for Medical Students. R. L. Bijlani, S. Manjunatha, Pg 96

2. Ganongs Review of Medical Physiology, 24th edition Pg 565
EVENTS IN HEMOSTASIS
EVENTS IN HEMOSTASIS
The term hemostasis means prevention of blood loss.
Whenever a vessel is severed or ruptured, hemostasis is

achieved by several mechanisms:
i. Vascular spasm
ii. Formation of a platelet plug
iii. Formation of a blood clot as a result of blood
coagulation
iv. Eventual growth of fibrous tissue into the
blood
clot to close the hole in the blood vessel permanently 3
3. Guyton & Hall. Textbook of Medical Physiology, 10 th edition, Pg 419
i. VASCULAR CONSTRICTION
Immediately after a blood vessel has been cut or ruptured
Trauma itself causes the vessel wall to contract
Thus, the flow of blood from the ruptured vessel reduces

instantaneously.
How does the contraction occur?

Nervous reflexes
Local Myogenic spasm
Local humoral factors from traumatized tissues and blood
platelets.3
i. VASCULAR CONSTRICTION- Nervous Reflexes

> Initiated by pain nerve impulses or other impulses
that
originate from the traumatized vessel or from
nearby
tissues.
ii. VASCULAR CONSTRICTION- Local Myogenic Spasm
>
Most of the vasoconstriction results from local
myogenic contraction of blood vessel .
> Initiated by direct damage to the vascular wall.
iii. VASCULAR CONSTRICTION- Local Humoral Factors
> For smaller vessels, platelets are responsible for much
of
the vasoconstriction by releasing
vasoconstrictor substances such as Thromboxane A2 3
i. VASCULAR CONSTRICTION
> Trauma : > Degree of spasm.
Vascular spasm can last for many minutes or even hours
During that time, platelet plugging and blood coagulation can
take place.
VALUE OF VASCULAR SPASM is demonstrated by the fact
that
People whose lower legs have been completely severed
sometimes have such intense spasm in vessels as large as the
anterior tibial artery that there is no lethal loss of blood. 3
ii. FORMATION OF PLATELET PLUG

If the rent in the vessel wall is small sealed by a PLATELET
PLUG.
Platelets accumulate as a result of reactions triggered by

endothelial cells of the vessel wall that are disrupted +
platelets come into contact with the sub-endothelial tissues. 3
After they adhere, they undergo activation adhere to each
other forms a growing compacted mass PLATELET
HEMOSTATIC PLUG

4. Zucker, M.B. The functioning of blood platelets. Sci Am. 242 : 86 -103, 1980

Mechanism of the Platelet Plug
Platelet repair of vascular openings is based on several
important functions of the platelet itself.
When come in contact with damaged surface
Platelets change their characteristics drastically

Swell up, assume irregular shapes
Numerous pseudopods protruding from their surface. 3

Contractile proteins contract
Release of granules
They contain active factors
Become sticky so they can adhere to the
collagen in tissues + von Willebrand factor
Secrete large quantities of ADP and thromboxane A2.

ADP & thromboxane in turn act on nearby platelets to
activate them as well as to adhere to the original platelets. 3

Therefore at any damaged site
Activation of several other platelets
Thereby forming a PLATELET PLUG. 3
iii. COAGULATION PROCESS

Third mechanism for Hemostasis
Clot formation begins 15-20 seconds after trauma occurs.

May take 1 minute if the trauma is minor
Initiating factors:- Activating factors from
Traumatized vascular wall
Platelets and
Blood proteins adhering to the traumatized vascular wall.
iii. COAGULATION PROCESS

Third mechanism for Hemostasis
Within 3-6 minutes afte rupture of a vessel, if the vessel
opening is not too large,
The entire opening is filled with clot.
After 20 minutes to 1 hour, the clot retracts
This closes the vessel still further.
Platelets play an important role in this clot retraction. 3

iv. FIBROUS ORGANISATION (or) DISSOLUTION of

BLOOD CLOT
Once a blood clot is formed, it can follow one of the two
courses:
Can be invaded by fibroblasts
which
subsequently
form
Connective tissue.
Usual course for a clot formed
in a small hole in the vessel
It can DISSOLVE
Excess blood leaked into the
tissues forms clots & special
substances within the clot
become
activated.
This
function to dissolve the clot.
3
PLATELETS IN HEMOSTASIS
Characteristics of Platelets.
Platelets play an important role in the process of hemostasis.
Thus, to understand the role of platelets the characteristics
of platelets must be understood.
Thrombocytes
Round/ oval discs 3
Non- nucleated cells
2-4m in diameter
1,50,000- 4,00,000 cells/ l. 5
Formed from Megakaryocytes large cells in the bone
marrow.
Megakaryocytes Fragment into minute platelets either in
bone marrow or soon after entering blood. 3
5.Best And Taylors Physiological Basis of Medical Practice. 11th edition, Pg 410.
Characteristics of Platelets.
Lifespan = 10 days
About 1/3rd of the circulating platelets are present at any time

within the red pulp of the spleen; a substantial marrow
reserve of platelets does not exist.
Thus, if circulating platelets are suddenly depleted, about 5

days are required for new platelet production to restore the
count to normal. 5
Functions of Platelets.
Platelets have many functional characteristics of whole cells
CONTRACTILE PROTEINS
Actin,
Myosin
Thrombesthenin
STORAGE OF VARIOUS ENZYMES & LARGE QUANTITIES
OF Ca +2 IONS
Residuals of Endoplasmic Reticulum &
Golgi apparatus.3
Platelets have many functional characteristics of whole cells
PRODUCE ADP & ATP
Presence of mitochondria and

Enzyme systems
LOCAL HORMONE PRODUCTION
Enzyme system that produce Prostaglandins. 3
PRODUCTION OF FIBRIN- STABILIZING FACTOR
Important protein for blood coagulation. 3
GROWTH FACTOR
Causes
Vascular endothelial cells
TO MULTIPLY &
Vascular smooth cells
GROW TO REPAIR
Fibroblasts
DAMAGED VASCULATURE
GLYCOPROTEINS & ADHERENCE
Glycoproteins on the surface repulses adherence to

normal endothelium
Causes adherence to injured vessels.
PHOSPHOLIPIDS
Platelet membrane contains several phospholipids that

play several activating roles at multiple points in the
clotting process. 3
Properties of Platelets : Platelet Structure
Electron microscopy reveals, complex structure.
Unstimulated platelet appears as a flattened disk.
Microtubules are present below its surface membrane.
Organelles are distributed throughout the platelet
granules
Lysosomal granules called dense bodies
Occasionally, mitochondria + fine granules of glycogen. 5
Two internal membranous systems can be recognised.
Open Canalicular System:
Sponge-like invaginations of the platelet surface
membrane
Provides with multiple channels through which the
activated platelets can both
+
secrete the contents of its
take up external Ca +2 ions
granules
Dense Tubular System
Channels of smooth endoplasmic reticulum
Does not communicate with the exterior of the cell
Intracellular storage site for Ca +2 ions. 5
Surface membrane consists of
Outer coat rich in carbohydrate ( glycocalix)
Underlying trilaminar unit membrane made up of lipids and
proteins. 3 types of lipids are present.
Phospholipids
Cholesterol
Glycolipids ( small amounts). 5
Membrane phospholipids are important both as a
Source of lipid activity for coagulation reactions
Source of arachidonic acid ( Precursor of Thromboxane
A2). 5
Three glycoproteins ( GP) have been identified namely GPI, GP
II, GPIII.
Individual molecular species in these 3 have been identified
example, GPIa, GPIb.
Receptor sites for hemostasis have been identified on GPIb
and in a complex formed by GPIIb- GPIIIa.
GPIb contains receptor for Fc fragment of IgG. 5
Properties of Platelets : Platelet Metabolic Processes
Glucose taken up by the cell or breakdown of intracellular
glycogen provides the main source of energy for the platelet.
Can synthesize both glycogen and fatty acids.
They contain neither DNA nor RNA and so are unable to
synthesize proteins. 5
On exposure to aspirin COX enzyme is irreversibly
inactivated Platelets cannot produce new enzyme due to
lack of DNA or RNA. 5
Properties of Platelets : Platelet Contractile System
Platelets contain large amounts of a contractile protein called
ACTIN and small amounts of Myosin.
Actin exists in 2 forms
G actin :- monomeric form
F actin :- double-helical filament
Activated platelets : contain large amounts of F actin.
Globular heads of MYOSIN bind to activated ACTIN filaments. 5
Properties of Platelets : Platelet Contractile System
2 proteins stabilize actin filaments
Actin binding protein cross-links actin filaments
- actinin Anchors filaments to inner surface of the
platelet membrane
Also contain Gelsolin Destabilizes actin filaments. 5
in free Ca +2 ions Ca +2 binds to Calmodulin Cacalmodulin complex activates enzyme Myosin light chain
kinase Phosphorylates light chain of MYOSIN this
permits actin- myosin interaction activates Myosin ATPase
Generation of CONTRACTILE FORCE. 5
Formation of Hemostatic Plugs: Adherence to Subendothelium
When vascular endothelium is disrupted, platelets adhere to
collagen in the exposed subendothelium.
Leads to formation of Hemostatic Plug.
A plasma protein von Willebrand factor is required for this
reaction.
von Willebrand factor: binds to both
Collagen in vessel wall
2 receptors on platelets. 5
In inactive stage, von Willebrand factor binds only to GPIb

receptor of platelets.
Second receptor GPIIb- IIIa does not form until the platelet is
activated.
Plasma source of this factor are the endothelial cells. 5
High molecular weight multimers of von Willebrand factor must

be present for effective adhesion of platelets to collagen.
Megakaryocytes can also synthesize this factor which is a
constituent of - granules and is secreted during platelet
activation. 5
Formation of Hemostatic Plugs: Platelet Activation
As platelets adhere to exposed collagen, they get activated.
Platelets arriving subsequently at the injury site also begin to
activate. Thus, a platelet mass starts to grow.
Platelet activation consists of a series of progressive,
overlapping events.
1. Platelet shape change
2. Cohesion of platelets
3. Liberation & oxidation of ARACHIDONIC ACID
4. Secretion of - granule & dense granule contents. 5
Platelet activation consists of a series of progressive,
overlapping events.
5. Secretion of lysosomal granule contents
6. Re-organization of the platelet membrane results in
blood coagulation & formation of fibrin on the platelet
surface.
7. An oriented centripetal contraction of actomyosin that
consolidates the mass of aggregated platelets. 5
Platelet activation is marked by
Reorganization of platelet membrane which results in
Coagulation
Formation of fibrin on platelet surface.
An oriented centripetal contraction of actomyosin
Consolidates the mass of aggregated platelets.
Hence, a stable platelet hemostatic plug is formed. 5
What triggers platelet activation????\
Contact with collagen
Initial thrombin that is formed.
What maintains & amplifies the activation???
ed concentration of THROMBIN
Substances liberated by activated platelets
ADP
THROMBOXANE A2
SEROTONIN
5
THROMBIN reacts with 2 platelet surface membrane glycoproteins:

GPV & GP Ib
Specific receptors are also present for

Collagen ADP Serotonin Epinephrine PGs 5
PGI2
PGD2
Formation of Hemostatic Plugs: Coupling of platelet
stimulation to response
COUPLING OF PLATELET STIMULATION TO RESPONSE

Stimuli that cause platelet activation cause
in Ca 2+ ions in the cytosol of the platelets

By uptake of Ca 2+ ions from the exterior
By release of Ca 2+ ions from vesicles in the dense tubular
system. 5
5.Best And Taylors Physiological Basis of Medical Practice. 11th edition, Pg 413

As Ca 2+ ions es
Ca 2+ - Calmodulin complexes are formed.
Bind to platelet enzymes
This causes ACTIVATION.
Ca 2+ dependent platelet protease is activated. This causes
activation of other platelet enzymes by PROTEOLYSIS. 5
Ca 2+ several platelet responses are stimulated.
Contraction of Platelet Actomyosin:
Ca 2+ - Calmodulin complex activates Myosin light chain
kinase enzyme.
Arachidonic Acid Release & Oxidation:
Activation of Phospholipase A2.
Secretion of granules from the Platelet. 5
Platelet c-AMP levels influence responsiveness of platelets to
inducing agents
How????
By regulation of Calcium pump that lowers cytoplasmic
calcium ion levels.
(i) PGI2 secreted by endothelial cells, activates ADENYL
CYCLASE c-AMP levels.
(ii) PGD2 may also play a role in this. 5
5.Best And Taylors Physiological Basis of Medical Practice. 11th edition, Pg 414
c-AMP
PHOSPHODIESTERASE
inactivated
c-AMP
Agents that block this enzyme cause an in c- AMP levels

thereby causing activation of Ca2+ pump.
For example, DYPYRIDAMOLE.
Alterations of platelet membrane lipids affect platelet
responsiveness. 5
Formation of Hemostatic Plugs: Platelet Cohesion
Platelet Cohesion is required to form aggregates
It needs formation of a receptor GpIIb-IIIa
Receptor for fibrinogen. 5
T
P
T
Platelet
GPIIb-IIIa receptor
T
Thrombospondin
F Fibrinogen
Release of subs. from platelet granules.
Formation of Hemostatic Plugs: Lipid Mediators of
Platelet Responses
Platelet stimulation activates 2 phospholipases
Phospholipase A
Phospholipase C
Phospholipase enzyme releases ARACHIDONIC ACID from platlet
membrane. 5
Platelet Responses
ARACHIDONIC ACID
Cyclo-oxygenase
PGG2 (endoperoxidase)
Lipoxygenase
12- Hydroperoxyeicosatetraenoic acid ( HPETE)
PGH2
IUM se
EL theta
TH
DO syn
EN clin
y
tac
PGD2 + Thromboxane A2
s
Pro
12- hydroxy- eicosatetraenoic acid

(HETE)
ET etase
L
E
T
th
PLA ne syn
oxa
b
om
Thr
PGI2
Platelet Responses
Thromboxane A2: Potent mediator of
Platelet aggregation
Vasoconstriction
Because of ability of TA2 to mobilize Ca2+ from dense tubular
system Release of granules
Secretion of ADP, serotonin & thrombospondin & other
constituents
in cAMP levels
ed responsiveness of
platelets to activating agents. 5
Platelet Responses
PGI2: Potent inhibitor of Platelet aggregation.
Therefore, suppresses overgrowth of hemostatic plugs
When activated platelets come in contact with undamaged
endothelium Endothelial cells secrete PGI2
Prevents formation of platelet plug over undamaged surfaces.
AGEPC :- Acetyl Glycerol Ether Phosphocholine
Potent mediator of inflammation.
Activates platelets and induces aggregation & secretion. 5
Platelet Secretion
Granules move to centre of platelet
Membranes fuse with membrane of

OPEN CANALICULAR SYSTEM
Contents are secreted. 5
Platelet Secretion
- GRANULE
necti
Fibro
n
oge
n
i
r
Fib n
Platelet
factor-4
PDGF
vWF
Thr
o
Albumin
mbo
n
spo
n di
Factor
V
buli
o
l
g
o
mb
Thro
n
Platelet Secretion
Thrombospondi
n
Binds to GPIIbIIIa receptor 7
fibrinogen
Platelet
cohesion
PDGF
Platelet factor-4
Brings
stimulator of
(SMOOTH
MUSCLE CELL)
+ (Fibroblast)
proliferation to
where it is
needed.
Neutralizes
anticoagulant
activity of
Heparin.
Binds to GAG,
Heparan
sulfate.
Thromboglobuli
n
Possesses
weak heparinneutralizing
activity.
CHEMOATTRACTANTS
Platelet Secretion
DENSE GRANULES
NI
O
T
O
SER N
AD
P
ATP
2+
Ca s
ion
Platelet Secretion
Serotonin
Vasoconstrictor
Platelet activating
factor
ADP
Amplifies platelet
activation
Primary aggregating
agent
Also synergistically acts
with Thrombin +
Collagen enhances
their effects.
MECHANISM OF BLOOD COAGULATION

INTRODUCTION
Coagulation mechanism is one of the componentss of hemostatic
mechanism.
It comprises of 3 separate though related, systems:
COAGULATION SYSTEM
COAGULATION- INHIBITORY SYSTEM
FIBRINOLYTIC SYSTEM
The essential role of coagulation mechanism is carried out by

coagulation factors. 6
6. De Gruchys Clinical Haematology in Medical Practice, 5 th edition. Pg 406

INTRODUCTION
Components of the system are:
Plasma protein coagulation factors, Calcium, Platelets

Certain surfaces not normally in contact with circulating blood
Lipoprotein derived from injured tissue cells called Tissue
Factor. 6
6. De Gruchys Clinical Haematology in Medical Practice, 5 th edition. Pg 407

INTRODUCTION
Numbers, letters & names are used to identify different components
of blood coagulation.
Some years ago, an international committee assigned Roman
numerals to the clotting factors.
This nomenclature is used for some but not all clotting factors. For
example,
Fibrinogen is not commonly called Factor I. 5

INTRODUCTION
2 proteins participating in coagulation havent been given
Roman numeral names. They are
Prekallikrein
HMW- kininogen
2 recently identified Vit-K dependent proteins were called
C, S.
Activated forms of these coagulation factors is identified by adding
lower case letter a .
For e.g. Activated Factor X will be noted as Factor Xa. 5

BASIC THEORY
There are > 50 substances that have been found in blood which
effects coagulation.
Promote Coagulation:-
PROCOAGULANTS
Inhibit Coagulation:- ANTICOAGULANTS.

Anticoagulants usually predominate.
But when vessel ruptures Procoagulants in the localised area of
tissue become activated 7 override the anticoagulants.
Thus, CLOT forms. 3

GENERAL MECHANISM
Clotting takes place in 3 essential steps
1. In response to ruptured vessel a cascade of reactions

occur results
in formation of PROTHROMBIN
ACTIVATOR.
2.
Prothrombin
Thrombin.
3.
Fibrinogen
Fibrin 3

Initiation of Coagulation- Formation of PROTHROMBIN
ACTIVATOR
?????? Which are the mechanisms which set
the coagulation
process into play?????

Trauma to vessel or adj. tissues
Trauma to blood
Contact of blood with
Damaged endothelial cells or with
Collagen & other tissue elements outside the vessel. 5
5. Best And Taylors Physiological Basis of Medical Practice. 11th edition, Pg 415.

ACTIVATOR
CLOTTING FACTORS & THEIR SYNONYMS
CLOTTING FACTOR
SYNONYMS
FACTOR I
FIBRINOGEN
FACTOR II
PROTHROMBIN
FACTOR III
TISSUE FACTOR
FACTOR IV
CALCIUM
FACTOR V
PROACCELERIN
FACTOR VI ( No more considered

a separate factor.).
Was previously called Accelerin

but is now known to be the
activated form of Factor V
FACTOR VII
PROCONVERTIN
FACTOR VIII
ANTI- HEMOPHILIC FACTOR A

ACTIVATOR
CLOTTING FACTORS & THEIR SYNONYMS
CLOTTING FACTOR
SYNONYMS
FACTOR IX
ANTI HEMOPHILIC FACTOR B
FACTOR X
STUART- PROWER FACTOR
FACTOR XI
PLASMA THROMBOPLASTIN
ANTECEDENT
FACTOR XII
HAGEMAN FACTOR
FACTOR XIII
FIBRIN STABILIZING FACOTR
PREKALLIKREIN
Fletcher factor
High- molecular- weight

kininogen
FITZGERALD FACTOR; HMWK
PLATELETS

ACTIVATOR
?????? How is it formed ?????

It is formed in 2 ways that interact with each other
1. EXTRINSIC PATHWAY
2. INTRINSIC PATHWAY. 5
In both pathways series of blood clotting factors play a major role. 3

ACTIVATOR: Extrinsic Pathway
Extrinsic pathway is called so because initiation of formation of

prothrombin activator begins after trauma to vascular wall or
extravascular tissues come into contact with blood. 5

(i) Exposure of blood to tissue factor

TF activity is a property of a specific membrane lipoprotein
moeity present to a varying degree on all cells after cell
membrane has been damaged.
Endothelial cells possess a low level of tissue factor activity not
normally available to react with plasma coagulation factors.
Alterations of endothelial cells makes Tissue factor available. 5

(ii) Tissue factor functions as a Co- factor for Factor VII

Factor VII must bind to tissue factor for initiation of blood
coagulation via extrinsic pathway
(iii) Tissue factor + Phospholipids
Called Tissue thromboplastin. 5
Factor IX
TT
F VII
Factor X
This complex then helps in activation of


Factor XIIa
Thrombin
a
Factor IX
Facto
r
Xa
Ca2+,
Phospholipids
1- chain Factor VII
2- chain Factor
VIIa
TF+ Factor VIIa
25
TF+ Factor VII

ACTIVATOR: Intrinsic Pathway
Called so because all the factors required for initiation are present
in plasma
Also called Contact- adhesion pathway as the initiation of reaction
depends on contact of Factor XII with damaged vessel wall
Exposure of blood to collagen initiates reactions involving 4
plasma proteins
Factor XII
Prekallikrein
Factor XI
HMW-- kininogen.5

Factor XII gets activated when there is

Trauma to vessel
Trauma to blood
Contact of blood with damaged endothelial cells or with
collagen & other tissue elements outside the vessel.
Factor XII becomes susceptible to limited cleavage by kallikrein to
form Factor XIIa.

Reciprocal activation occurs wherein

Factor XII
Factor XIIa
Kallikrein
Prekallikrein

Two forms of activated Factor XII exist

- XIIa:
Cleavage of 1 peptide bond
Effective in activation of Factor XI
Retained on surfaces.
- XIIa:
Cleavage of 2 peptide bonds
Effective in activation of Prekallikrein to kallikrein
NOT retained on surfaces.

Factor XI with HMW-K in the presence of Factor XIIa

Activated Factor XIa
K
HMWFactor XI
Factor
XIIa
Factor X
Ia

Activation of Factor IX, X
(i) Activation of Factor IX :
Requires both
Factor XIa
TF-Factor VII complex for activation
Proteolysis results in formation of ACTIVATION PEPTIDE from
native molecule.

2 ways in which Activation of Factor IX can occur.
Factor XIa
In fluid state
Requires on presence of Ca2+
ions
Factor XIa binds to native
Factor IX molecule alters its
configuration.
TF- Factor VIIa

Factor IX binds to complex on
cell surface
And Factor IX is activated on
cell surface & presumably then
released.

It has been noted that Factor XI deficiency causes mild bleeding
disorder while Factor IX deficiency causes severe bleeding.
This leads one to believe that

A reaction independent of Factor Xia activation might be
important for normal hemostasis. 5

(i) Activation of Factor X :
Can take place via 2 ways:
Direct activation through TF- Factor VIIa complex.
Factor IXa + Platelet procoagulant phospholipid + Factor
VIIIa This complex causes activation of Factor X
Factor Xa. 5

Activation of Prothrombin
Prothrombin is converted into thrombin in the presence of Factor
Xa, Va, phospholipids and Ca2+ ions. 5
Pr
-Phospholipid
Xa
-Ca2+ ions
sites
Va
Pr
-Prothrombin
Xa
-Factor Xa
-GIa receptor
Pr
Va
Va
-Factor Va
-Platelet

Activation of PROTHROMBIN
Prothrombin
Xa1
NH2
GIa
COOH
Va
Prethrombin
Thrombin
Xa1
NH2
GIa
COOH
Va
Xa2
Prethrombin

Activation of PROTHROMBIN
Thrombin
COOH
Thrombin cleaves the substrate

NH2
GIa
Va
This prevents prothrombin from subsequently forming thrombin

After formation of thrombin it moves off platelet surface &
diffuses into surrounding plasma.
CK
A
B
D
EE
F
e
v
)
(ISM
N
A
H
MEC

Formation & Stabilization of Fibrin
Fibrinogen is a dimeric protein which contains 1 pair each of , ,

chains.
Central nodule & 2 distal nodules.
Central nodule is made up of (-NH2) terminals of all 6 chains.
Each distal nodule is made up of (-COOH) groups of these chains.5

Thrombin cleaves small peptides from (-NH2) terminal of - chain

& each - chain.
Exposes new amino acid groups functions as polymerization
sites form non- covalent bonds.
Thrombin activates Factor XIII. 5

Thrombin activates Factor XIII.
Factor XIII has 2 alpha and 2 beta chains.
- chain: Enzymatic site
Thrombin cleaves a polypeptide from - chain Ca2+ ion
binds to that site - chain separates.
Resultant - chain acts as a TRANSGLUTAMINASE. 5

To catalyze formation of amide bonds between cross-linking sites in
chain.
Thus, FIBRIN molecules POLYMERIZE.
???? Due to covalent bonds formed between adjacent molecules.
- chain:- 1. Cross-link Fibrin --- Fibronectin
Fibrin---- - Plasmin inhibitor. 5

Factor XIIIa:- 1. Covalent bonds Fibronectin---Collagen

Also binds Actin, MyosinF
Helps in a.) Strengthening the bond
b.) Clot retraction
c.) Prevent excessive FIBRINOLYSIS.5
REGULATION OF BLOOD COAGULATION
Circulating blood doesnt clot because it is not normally exposed to

materials capable of initiating blood coagulation. 5
Should activated CF intermediates enter circulation Rapidly

cleared by cellular mechanisms. 7
However, in some clinical conditions coagulation may occur due to
stasis of blood. 5
5. Best And Taylors Physiological Basis of Medical Practice. 11th edition, Pg 425
7. SpaetTH, HI Horowitz, D. Zucker- Franklin, J. Cintron & JJ Biezenski. Reticuloendothelial clearance of blood
thromboplastin by rats. Blood 17: 196-205, 1961
Small clot may be formed.

Majority of people the thrombi fail to enlarge due to LOCAL
SUPPRESSION by plasma inhibitors such as
Antithrombin- III
Activated protein-C. 5

ANTITHROMBIN-III
Primary inhibitor of
Thrombin
Factor Xa
Factor Ixa
Serine proteases of INTERMEDIATE & TERMINAL steps
of Blood Coagulation
NOT primary inhibitor of
Serine proteases which INITIATE blood coagulation. 5

ANTITHROMBIN-III
AT-3 takes several minutes to inactivate THROMBIN. However, in

the presence of HEPARIN instantaneously inactivates
THROMBIN.
HEPARIN- SULFATE: Weak heparin-like anticoagulant activity.
Present on endothelial surfaces.
2- Macroglobulin cant compensate completely for a reduced
plasma AT-3. 5

Inactivation of Factor VIII & V by THROMBIN
Proteolysis of Factor VIII & V require thrombin

Activated forms are unstable.
THROMBIN binds to a molecule on endothelial cells
THROMBOMODULIN
Changes specificity of thrombin Activates protein C cleaves
& inactivates Factor VIII & V. 5
FIBRINOLYSIS
Just as prothrombin is inert precursor of thrombin

PLASMINOGEN is inert precursor of PLASMIN
INSOLUBLE FIBRIN ---------------- FIBRIN DEGRADATION PRODUCTS.
Plasmin catalyzes several cleavages in fibrin thereby producing

many small soluble products.
2 activated forms: Vascular Plasminogen Activator (vPA)
Urokinase. 5
FIBRINOLYSIS
(vPA):-
Major activator
Released by endothelium
Urokinase:- Released by epithelial cells

such as Kidney epithelium.
Factor XIIa, kallikrein, Factor Xia also function as weak
plasminogen activators. Little physiological significance.
5. Best And Taylors Physiological Basis of Medical Practice. 11th edition, Pg 426, 427
FIBRINOLYSIS
Inhibition of PA by inhibitors is also imortant in modulating
FIBRINOLYSIS.
2 mechanisms: vPAs: need for it to bind to FIBRIN to enhance its specific
activity.
Rapid blood clearance.
2- antiplasmin inactivates PLASMIN very rapidly. (10s)
Thus, inhibition by 2- antiplasmin
represents a crucial
mechanism in preventing excessive fibrinolysis. 5

CONCLUSION
REFERENCES
1. Understanding Medical Physiology: A Textbook for Medical Students. R. L. Bijlani,

S. Manjunatha, Pg 94.
2. Ganongs Review of Medical Physiology, 24th edition Pg 565
CONTENTS- PART 2
HAEMORRHAGIC DISORDERS
Vascular defects
Platelet disorders
CONTENTS- PART 3
COAGULATION DISORDERS
DENTAL CONSIDERATIONS
THANK
HEMORRHAGI
C DISORDERS
By,
. Aishwarya S Nair
. Post Graduate student
. Oral Medicine & radiology
CONTENTS- PART 2
HAEMORRHAGIC DISORDERS
Vascular defects
Platelet disorders
VESSEL WALL DISORDERS

CONGENITAL
HEREDITARY
HEMORRHAGIC
TELANGECTASIA
CONNECTIVE
TISSUE DISORDERS:
1. Ehlers- Danlos
syndrome
2. Osteogenesis
Imperfecta
3. Marfan syndrome
4. Cushings
syndrome
ACQUIRED
1. Severe
infections
2. Allergic
manifestations
3. Drugs
4. others: scurvy,
senile purpura
Infections
Microbe induce damage to vessel wall (vasculitis)

and DIC
Septicemia, meningococcaemia, infective
endocarditis and ricketssiosis
Induce petechial and purpuric hemorrhages
Drug reactions
Vascular injury mediated by deposition of drug

induced immune complexes in vessel walls, which
leads to hypersensitivity (leukocytoclastic) vasculitis
Induce cutaneous petechiae and purpura without
causing thrombocytopenia
Scurvy and Ehler Danlos

syndrome
Defect in collagen that weakens the vessel wall
Induce microvascular bleeding
Cushing syndrome
Protein wasting effects of excessive corticosteroids
Loss of perivascular supporting tissue
Purpura and skin hemorrhages
Henosch schnolein purpura

Systemic hypersensitivity disease
Resulting from deposition of immune complexes within vessels and glomerular
mesangial regions
Characterized by purpuric rash, colicky abdominal pain, polyarthralgia and acute
glomerulonephritis
Hereditary hemorrhagic telangiectasia

Also called Weber-Osler-Rendu syndrome
Autosomal dominant disorder
Dilated tortous vessels with thin walls that can bleed easily
Perivascular amyloidosis
Weaken blood vessels and cause bleeding
Manifest as mucocutaneous petechiae
SCURVY
- Results from vitamin C deficiency
- scurvy results when dietary vitamin C falls below 10mg/d
Manifestations :
- Vascular fragility leads to bleeding tendency which manifest as petechiae
and ecchymoses
- Hematuria, epistaxis,subperiosteal bleeding, heamarthrosis may occur
- Hemorrhage under nails
- Hair follicles may be hyperkeratotic with vascular congestion -> perifollicular
hemorrhages
- Increased susceptibility to infections
- Manifest in gingival and periodontal tissues :

Interdental and marginal
gingiva bright red with
swollen, smooth , shiny
surface
gingiva becomes boggy,

ulcerates and bleeds. Color
changes to violaceous red
- Gingival ulcers show typical microorganism- fusospirochete, patients have

typical foul breath (putrid gums)
-
In severe cases, hemorrhage into and swelling of the periodontal

membrane occur, followed by loss of bone and loosening of the teeth,
which eventually exfoliates
Management
- dose of 250mg vitamin C, 8 hourly orally
EHLERS DANLOS SYNDROME

- Congenital disorder
- Collagen synthesis is impaired
-
Joint
hyperextensibility,
skin
extensibility, tissue fragility

- Capillaries are poorly suppported by
subcutaneous collagen leading to
ecchymosis
CLASSIFICATION OF EHLERS DANLOS SYNDROME
The extraoral manifestations :

the presence of scarring on the chin and forehead, a history of repeated
luxations of the TMJ, epicanthus, hypertelorism, a narrow curved nose, sparse
hair and hyperelasticity of the skin.
The intraoral manifestations:
Mucosa
As fragile as the skin, the mucosa tears easily when touched by instruments.
Sutures do not hold.
Periodontal Tissues
-The fragility of the gingiva can be detected following treatments such
as prophylaxis, periodontal surgery or extraction.
-Hemorrhage may be difficult to control during surgical procedures.
-Early-onset generalized periodontitis is one of the most significant oral
manifestations of the syndrome : can lead to the premature loss of
deciduous and permanent teeth.
The Teeth
-Hypoplasia of the enamel is commonly seen.
-
Premolar and molar teeth can present with deep fissures and long cusps.
- The teeth seem to be fragile and microdontia is sometimes present.

- Radiographic examination often reveals pulp stones and roots that are short
and deformed
The Tongue
The tongue is very supple. Approximately 50% of those with the syndrome
can touch the end of their nose with their tongue compared to 8-10% of
the population.
The Palate
The palate is commonly vaulted.
MARFANS SYNDROME
- Autosomal dominant
- caused by mutation in fibrillin gene
- characterized by :
1.skeletal disproportion (arm span more than height ) ,
2.Arachnodactyly (long,thin spider like fingers),
3.Generalized hypermobility of joints and
4.CVS anomalies like mitral valve prolapse, aortic incompetence
- Oral manifestation : high arched palate, bifid uvula, malocclusion and
multiple odontogenic cyst of maxilla and mandible and gingival hemorrhage
HEREDITARY HEMORRHAGIC TELANGIECTASIA

- Autosomal dominant
- Dilatation of capillaries and small arterioles produce characteristic small red
spots that blanch on pressure in the skin and mucous membranes, particularly
the nose and GI tract
- Recurrent epistaxis and chronic GI bleeding lead to anemia
- Perioral and intraoral angiomatous nodules or telangectasia ( lips, tongue and
palate )
PLATELET DISORDERS
THROMBOCYTOPATHIC
CONGENITA
L
1. Storage
pool
disease
2. Bernard
soulier
syndrome
3.
Glanzmann
s
thromboast
henia
ACQUIRED
1. Drug
induced
( aspirin )
2. Renal and
liver disease
3.
Myeloprolife
rative
disorder
THROMBOCYTOPENIC
CONGENIT
AL
1. May
hegglin
anomaly
ACQUIRED
1. Impaired production :
a. Bone marrow failure
b. Leukemia
c. Aplastic anemia
2. Excessive
destruction :
a. Immune
b. Idiopathic
thrombocytopenic purpura
3. Dilutional
a. Massive transfusion
4. Others
a. DIC
b. Thrombotic
thrombocytopenic purpura
Thrombocytopathic disorders
- defect in platelet function
- Excessive bruising and gingival bleeding
- platelet count is normal or increase
- bleeding time is prolonged
- platelet function is abnormal :
1. Defect in adhesion
2. Defect in aggregation
3. Defect in release of active substances
Condition
Defect
Glanzmans
Deficiency in platelet membrane
thromboasthenia
glycoprotein -> failure of platelet

aggregation
Bernard soulier
Deficiency in platelet membrane
syndrome
glycoprotein -> failure of platelet

aggregation,
Large platelets -> epistaxis,
mennorhagia and prolonged bleeding
from tooth extractions
Storage pool disease
Inherited disorder, lack of storage pool
Thrombocytopenic disorders
- Reduced platelet production or excessive peripheral destruction
Condition
Defect
Idiopathic
-Immune mediated destruction of platelets
thrombocytope
mediated by platelet autoantibodies
nic purpura
- in children it may follow viral infection

- characteristically seen in women
- easy bruising, purpura, epistaxis and
menorrhagia
- orally : hematomas and hemorrhagic bullae
Condition
Defect
Thrombotic
-Underlying cause unknown
thrombocytope
- excessive platelet destruction because of
nic purpura
endothelial damage
- characterized by complex of fever, florid
purpura, fluctuating cerebral dysfunction and
hemolytic anemia
- orally : microvascular infarcts in gingiva and
oral mucosa
May hegglin
anomaly
- Rare hereditary condition

- triad of thrombocytopenia, giant platelets
and inclusion bodies in leukocytes
INHERITED ABNORMALITIES OF THE PLATELET

MEMBRANE.
Glanzmann Thrombasthenia
Bernard-Soulier Syndrome
Collagen Receptor Deficiency
ADP & other Primary Receptor Deficiency
Scott Syndrome
GLANZMANN THROMBASTHENIA
Described by Glanzmann in 1918 as Hereditary Hemorrhagic
Thrombasthenia.
Autosomal recessive inheritance
Clinical variability ranges from only minimal bruising to
potentially fatal hemorrhages.

: Platelet Functional Abnormality
(i) Platelet Aggregation
Absence of platelet aggregation in response to all
PHYSIOLOGICAL AGONISTS hallmark of GT.
GPIb dependent binding to vWF is normal.
(ii) Platelet adhesion, secretion & procoagulant activity
P binding to collagen: normal
Spreading over defect is defective.
In GPIIb/IIIa deficiency, follower platelet interactions werent
seen.

(i) Platelet Fibrinogen & -granule proteins
Platelet fibrinogen: acquired through endocytosis GPIIb/IIIa
receptors Stored in - granules.
In GT P lack FIBRINOGEN through the plasma levels are
normal.
Type I:- unable to transport fibrinogen
Type II:-express 5-15% of GPIIb/IIIa : - granules detectable.
Clot retraction is affected.

: Clinical Manifestations
(i) Patient

: Classification
Type I:
Variant disease:
No platelet aggregation
No fibrinogen in -granules
No clot retraction
<5% GPIIb/IIIa levels.
Type II:
No platelet aggregation
Subnormal levels of fibrinogen
in -granules
Residual clot retraction
5% -15% : GPIIb/IIIa levels.
No/
abnormal
platelet
aggregation
Fibrinogen storage & clot
retraction are affected.
GPIIb/IIIa gene defects
expression of protein but
prevents ligand binding.

BERNARD- SOULIER SYNDROME

BSS was 1st described in 1948 with the report of an infant who
had severe mucocutaneous bleeding, prolonged BT,normal PC,
giant platelets.
Additional patients were reported over the foll. Years and the
initial diagnostic criteria was established as
Prolonged BT
Thrombocytopenia in most patients
Defective ristocetin- induced platelet agglutination
Normal clot retraction. 1
1. Hemostasis and Thrombosis By, Robert W. Coleman et al, 5 th edition, Pg 998.

: Platelet Structural Abnormality
Large platelets, as large as 20 m in diameter.
Large platelet size possibly due to ed content of protein &
dense granules.
Spheroid in shape rather than discoid.
More deformable due to deficiency of membrane GPIb/IX
complexes less attachment of the surface membrane to the
membrane cytoskeleton. 1
1. Hemostasis and Thrombosis By, Robert W. Coleman et al, 5 th edition, Pg 998.

BS platelets aggregate normally in response to ADP,
epinephrine & collagen but, FAILED TO AGGREGATE in
presence of FIBRINOGEN.
therefore, either GPIb receptor or GPIIb/IIIa receptor are
defective.
Also, lack of binding of vWF in presence of RISTOCETIN
was noted.
A1 domain of vWF expresses epitopes which can react with
GPIb receptors. 1
1. Hemostasis and Thrombosis By, Robert W. Coleman et al, 5 th edition, Pg 998, 999

These domains are inaccessible. RISTOCETIN mimics the
adhesion process by making these epitopes on vWF
accessible.
vWF binding stimulated by ADP or thrombin, which occurs
on GPIIb/IIIa receptors is normal.
Therefore, ADP, collagen & arachidonic acid can stimulate
BS platelets to aggregate and secrete their granules. 1
1. Hemostasis and Thrombosis By, Robert W. Coleman et al, 5 th edition, Pg 999

: Platelet Membrane Glycoprotein Abnormality
A specific decrease of platelet membrane
GPIb
concentration.
BS platelets also deficient in GP IX & V.
4 distinct genes are necessary to produce 1 unit of GPIb- I,
I, IX & V.
Variant BSS has qualitative defects non- functional GP
Ib/IX/V complex.
GP defects characteristic of BS platelets also extend to the
MK. 1

: Clinical Manifestations
Both sexes are equally affected.
Bleeding
symptoms:
Purpura,
epistaxis,
gingival
hemorrhage and menorrhagia.

Unpredictable severity of bleeding.
Presence of severe thrombocytopenia ( < 20,000/ l) doesnt
appear to cause a > risk of bleeding. 1

: Current Diagnostic Criteria
The diagnostic criteria for BSS are:
Bleeding symptoms : Purpura, epistaxis, gingival bleeding,
menorrhagia without hemarthroses & deep visceral hematomas.
Moderate- severe thrombocytopenia.

Large platelets- a heterogenous size.
Abnormal bleeding time- longer than predicted.
Normal platelet aggregation: ADP, collagen, epinephrine.
Absent platelet agglutination by ristocetin & vWF not
corrected by normal plasma. 1

: Differential Diagnosis
May-Hegglin Syndrome
Epstein Syndrome
Fechtner Syndrome
Sebastian Platelet Syndrome
Montreal Platelet Syndrome

: Treatment
Local Measures for bleeding episodes.
Platelet transfusions invasive procedures.
If auto-antibodies present- Plasma exchange Platelet
transfusion.
Desmopressin, r Factor VIIa.

Hemostasis

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HEMOSTASIS

The word Haemostasis originates from two ancient Greek

1. Understanding Medical Physiology: A Textbook for Medical Students. R. L. Bijlani, S. Manjunatha, Pg 96

The term hemostasis means prevention of blood loss.

Whenever a vessel is severed or ruptured, hemostasis is

3. Guyton & Hall. Textbook of Medical Physiology, 10 th edition, Pg 419

Immediately after a blood vessel has been cut or ruptured

Trauma itself causes the vessel wall to contract

Thus, the flow of blood from the ruptured vessel reduces

How does the contraction occur?

i. VASCULAR CONSTRICTION- Nervous Reflexes

ii. FORMATION OF PLATELET PLUG

Platelets accumulate as a result of reactions triggered by

3. Guyton & Hall. Textbook of Medical Physiology, 10 th edition, Pg 419

ii. FORMATION OF PLATELET PLUG

When come in contact with damaged surface

Platelets change their characteristics drastically

3. Guyton & Hall. Textbook of Medical Physiology, 10 th edition, Pg 420

ii. FORMATION OF PLATELET PLUG

Contractile proteins contract

Secrete large quantities of ADP and thromboxane A2.

ii. FORMATION OF PLATELET PLUG

Therefore at any damaged site

Activation of several other platelets

Thereby forming a PLATELET PLUG. 3

3. Guyton & Hall. Textbook of Medical Physiology, 10 th edition, Pg 420

iii. COAGULATION PROCESS

Clot formation begins 15-20 seconds after trauma occurs.

3. Guyton & Hall. Textbook of Medical Physiology, 10 th edition, Pg 420

iii. COAGULATION PROCESS

The entire opening is filled with clot.

After 20 minutes to 1 hour, the clot retracts

This closes the vessel still further.

Platelets play an important role in this clot retraction. 3

iv. FIBROUS ORGANISATION (or) DISSOLUTION of

3. Guyton & Hall. Textbook of Medical Physiology, 10 th edition, Pg 420

About 1/3rd of the circulating platelets are present at any time

Thus, if circulating platelets are suddenly depleted, about 5

Presence of mitochondria and

Glycoproteins on the surface repulses adherence to

Platelet membrane contains several phospholipids that

Collagen in vessel wall

In inactive stage, von Willebrand factor binds only to GPIb

High molecular weight multimers of von Willebrand factor must

THROMBIN reacts with 2 platelet surface membrane glycoproteins:

Specific receptors are also present for

COUPLING OF PLATELET STIMULATION TO RESPONSE

in Ca 2+ ions in the cytosol of the platelets

COUPLING OF PLATELET STIMULATION TO RESPONSE

Agents that block this enzyme cause an in c- AMP levels

Release of subs. from platelet granules.

12- hydroxy- eicosatetraenoic acid

Granules move to centre of platelet

Membranes fuse with membrane of

Contents are secreted. 5

MECHANISM OF BLOOD COAGULATION

MECHANISM OF BLOOD COAGULATION

The essential role of coagulation mechanism is carried out by

6. De Gruchys Clinical Haematology in Medical Practice, 5 th edition. Pg 406

MECHANISM OF BLOOD COAGULATION

Plasma protein coagulation factors, Calcium, Platelets

6. De Gruchys Clinical Haematology in Medical Practice, 5 th edition. Pg 407

MECHANISM OF BLOOD COAGULATION

MECHANISM OF BLOOD COAGULATION

MECHANISM OF BLOOD COAGULATION

Inhibit Coagulation:- ANTICOAGULANTS.

3. Guyton & Hall. Textbook of Medical Physiology, 10 th edition, Pg 420