Group 1 Presentation On Haem and Thromb

GROUP 1 1
PRESENTATION
HAEMOSTASIS
AND
THROMBOSIS
Friday, February
16, 2018
Haemostasis • Definition;
Comprises a series of regulated processes
that maintain blood in a fluid, clot free
state in normal vessels while rapidly
forming a localized haemostatic plug at
site of vascular injury.
Counterpart of this process is thrombosis
which involves formation of blood clots
(thrombus) within intact vessels.
2
Friday, February 16, 2018
• Normal haemostasis and its regulation:
Steps involved
I. Arteriolar vasoconstriction; following
vascular injury augmented local
secretion of endothelin (endothelium
derived vasoconstrictor).
II. Primary haemostasis; formation of
initial platelet plug . Brought by
platelet adherence, activation and
aggregation to the extracellular matrix.
III. Activation of thrombin; endothelial
injury exposes tissue factor iii (
thromboplastin) which act in
conjugation with factor vi triggering
coagulation cascades and activation of
thrombin 3
iv. Secondary haemostasis; activated
thrombin promotes formation of
insoluble fibrin clot by cleaving fibrinogen.
Thrombin also is a potent activator of
additional platelets which serve to
reinforce the haemostatic plug.
v. As bleeding is controlled counter
regulatory mechanisms ( e.g. factors
that produce fibrinolysis such as tissue
type plasminogen activator ) are set
into motion to insure that clot
formation is limited to the site of injury
4
ENDOTHELIUM Refers to the cells that line the interior
surfaces of blood vessels and lymphatic
vessels forming an interface between
circulating blood or lymph in the lumen
and the rest of vessel walls, it’s the thin
layer of simple squamous cells called
endothelial cells.
It acts as central regulator of hemostasis,
when the endothelial cells are in normal
state they express anti-coagulant factors
that inhibit platelet aggregation,
coagulation and promotes fibrinolysis.
5
Antithrombotic Inhibitory Effects on Platelets. Intact
endothelium prevents
Properties of platelets (and plasma coagulation
Normal factors) fromengaging the highly
thrombogenic subendothelial ECM.
Endothelium Nonactivated platelets do not adhere to
normal endothelium;even with activated
platelets, prostacyclin (i.e.,
prostaglandin I2 [PGI2]) and nitric oxide
produced by endothelium impede their
adhesion. Both mediators also are potent
vasodilators and inhibitors of platelet
aggregation;
their synthesis by endothelial cells is
stimulated by a number of factors
6
factors such as thrombin and cytokines produced during coagulation.
Endothelial cells also produce adenosine
Diphosphatase(ATPase), which degrades adenosine diphosphate(ATP) and
further inhibits platelet aggregation.
7
Inhibitory These actions
Effects on
are mediated by factors expressed on
endothelial surfaces,
Coagulation particularly heparin-like molecules,
Factors.
thrombomodulin, and
tissue factor pathway inhibitor. The
heparin-like
molecules act indirectly; They are
cofactors that greatly
enhance the inactivation of thrombin (and
other coagulation factors) by the plasma
protein antithrombin III. Thrombomodulin
also acts indirectly; It binds to thrombin,
thereby modifying the substrate specificity
of thrombin. 8
Prothrombotic Activation of Platelets. Endothelial injury brings
platelets
Properties of into contact with the subendothelial ECM, which

includes
Injured or among its constituents von Willebrand factor, a

large
activated multimeric protein that is synthesized by
endothelium
extracellular matrix. Von Willebrand Factor(vWF)
is held
fast to the ECM through interactions with collagen
and also
binds tightly to Gp1b, a glycoprotein found on the
surface
of platelets. These interactions allow vWF to act as
a sort
of molecular glue that binds platelets tightly to
denuded
vessel walls. 9
Activation In response to cytokines such as tumor
necrosis factor [TNF] or interleukin-1 [IL-
of Clotting 1]) or
Factors certain bacterial products including

endotoxin, endothelial
cells produce tissue factor, the major in
vivo activator of
coagulation, and downregulate the
expression of thrombomodulin.
Activated endothelial cells also bind
coagulation
factors IXa and Xa, which enhances the
catalytic activities of these factors.
10
Antifibrinolytic Activated endothelial cells secrete
Effects plasminogen activator inhibitors (PAIs),
which limit fibrinolysis
and thereby favouring thrombosis.
11
THE ROLE • Platelets are anucleated cell
OF fragments shed into bloodstream

by marrow megakaryotes.
PLATELETS • They are important in normal
hemostasis by forming a
hemoststic plug that seals
vascular defects, and by
providing a surface that recruits
and concentrates activated
coagulation factors.
12
• Their function depends on several
components such as integrin family of
glycoprotein receptorss, a contractory
cytosketon and two types of
cytoplasmic granules which are alpha
granules and dense bodies.
13
• After vascular injury, platelets
encounter extracellular components
and initiate the following events.
14
i. Platelet adhesion
ii. Platelet activation
iii. Platelet aggregation
15
Platelet • Platelet adhesion initiates clot
formation and depends on von
adhesion willebrand factor and platelet
glycoprotein Gp1b
• The vWF undergoes confirmational
change allowing it to bind
simulteneously to collagen in ECM
and Gp1b on platelets.
• The adhesion of the two is very
important in clotting
16
Platelet • Refers to an irreversible shape change of
the platelets and release reaction of both
activation granules.
• The change in shape enhances subsquent
aggregation and increase surface area
available for interaction with coagulation
factors.
• The dense bodies releases calcium and
ADP which are important in susquent
reactions.
• The alpha granules releases fibrinogen,
fibronectin and other coagulating factors.
• Activated platelets also synthesize
thromboxane A2 which activates
additional nearby platelets and plays a
role in platelet aggregation 17
Platelet • This follows platelet adhesion and
activation and is stimulated by some of
aggregation the same factors that induced platelet
activation such as thromboxane.
• It is promoted by the bridging
interaction between fibrinogen and
GpIIb/IIIa receptor on adjacent platelets.
• The inherited deficiency of GpIIb/IIIa
results in bleeding disorder and inability
of plateletes to aggregate a condition
known as glanzmann thrombasthenia
18
COAGULATI 19
ON CASADE
Friday, February
16, 2018
• By dfn; Coagulation cascade is a series
of amplifying enzymatic reactions.At
each step in the process a proenzyme is
proteolysed(activated) to become an
active enzyme which inturn proteolyze
next proenzyme in the series eventually
leading to activation of thrombin.
• Thrombin is responsible for
proteolyzing fibrinogen into fibrin
20
• Blood coagulation is traditionally
categorized into twopathways;
• 1.extrinsic pathway and
• 2.intrinsic pathway
21
EXTRINSIC• EPC is initiated by tissue factor which
activate factor VII and forms a tissue
PATHWAY OF factor-factor VIIa.
COAGULATION• The complex initiates coagulation via

activation of factor X to factor Xa.Factor
Xa converts prothrombin(factor II) to
thrombin (facto IIa).Factor Va is a
cofactor that act as coenzyme required
in conversion of prothrombin to
thrombin.
22
EXT • Thrombin proteolyzes fibrinogen into
fibrin
PATHWAY • The thrombin-mediated cleavage of
CONT……. fibrinogen results in a fibrin monomer,
which is polymerized and stabilized by
factor VIIa, thus forming the fibrin clot.
• The extrinsic pathway is clinically
assesed by the prothrombin time
which is a measure of factor II,V,VII,X
and fibrinogen
23
Classical presentation of the
coagulation cascade
24
INTRINSIC • It involve activation of all clotting
factors with the exception of factor VII
COAGULATION and XII.
PATHWAY • >This pathway may involve contact

activation with the interaction of what
is so called contact factors: factor XII,
prekallikrein, and high-molecular
weight kininogen(HMWK) as well
asfactor XI. Contact activation is
important in invitro clotting in glass
containers and in laboratory testing, but
its physiological role has been questined
because a deficiency of contact factor is
not associated with abnormal bleeding
25
INT • >The process is probably initiated by the
tissue factor-factor VIIa Complex,
COAGULATION activating factor IX to factor IXa.Factor
PATHWAY IXa in turn leads to the conversion of
CONT…….
factor X to Xa catalyzed by factor VIIa.
• >Thrombin production further
stimulates the pathway by the
activation of factor XI to factor XIa and
by the activation of the cofactors, factor
V to factor Va and factor VIII To factor
VIIa.
26
INT• The intrinsic pathway is clinically
evaluated by the partial
COAGULATION thromboplastin time which is a
PATHWAY measure of factors II,V,VII,IX,X,XI and

fibrinogen.
CONT……
27
• Concurrent activation of the
coagulation cascade generates
thrombin, which stabilizes the
platelet plug through two
mechanisms.
28
i. Thrombin activates platelet surface
receptor(Protease Activated
Receptor [PAR]) which in concert
with ADP and thromboxane further
increases platelet aggregation, then
platelet contraction follows creating
the secondary hemostatic plug.
ii. Thrombin converts fibrinogen to
fibrin within the vicinity of the plug,
cementing the plug in place.
29
This is marks the end of part one of our presentation
5 sec break to review blood supply of the body
30
Part two
31
THROMBOSIS 32
Friday, February
16, 2018
Thrombosis
Is the process of formation of solid mass in
circulation from the constituents of flowing blood.
The solid mass is called a thrombus.
This is different from blood clot,
Blood clot
Is the mass of coagulated blood formed in vitro e.g. in
a test tube.
Before moving on there are some few important related

definitions to understand below;
33
Haematoma
is the extravascular accumulation of blood clot e.g. into the
tissues.
Haemostatic plugs
Are the blood clots formed in healthy individuals at the site of
bleeding e.g. in injury to the blood vessel. Haemostatic plugs
are
useful as they stop the escape of blood and plasma, whereas
thrombi developing in the unruptured cardiovascular system
may
be life-threatening by causing one of the following harmful
effects;
34
Ischaemic injury.
Thrombi may decrease or stop the blood
supply to part of an organ or tissue and cause
ischaemia which may subsequently result in
infarction.
Thromboembolism
The thrombus or its part may get
dislodged and be carried along in the bloodstream
as embolus
to lodge in a distant vessel.
35
36
PATHOGENESIS OF THROMBOSIS
(VIRCHOW’S TRIAD)
Friday, February
16, 2018
ENDOTHELIAL • Definition:Destruction of normal
INJURY architecture of endotheal cells lining the

blood vessels.
• Endotheal dysfunction can result from
 hypertension,bacterial
products,radiation,toxins from
cigarette smoke
• How this event can lead to
thrombosis
 Exposure of subendothelial collagens
37
EI cont.....  Release of von Willebrand`s factor
 Production of thromboxane A2 by
activated platelets
 Reduction of lumen of blood
vessels[Congestion-Stasis-
THROMBOSIS]
38
ABNORMAL BLOOD FLOW
In the body blood flow is laminar, however under conditions of 39
high flow, laminar flow can be disrupted and

become turbulent meaning that the blood does not flow linearly
and smoothly, instead the velocity component of the blood
randomly fluctuates.
The process of slowing down of blood flow is known as STASIS.
-Turbulence contributes to arterial and cardiac thrombosis by
forming endothelia injury where as stasis form venous thrombosis
even without endothelial injury.
-During the condition of normal blood flow platelets and other
cells are found in the centre of vessel lumen separated from
endothelium by slower moving layer of plasma.
Friday, February
16, 2018
• In both turbulence and stasis, the blood
flow is
distorted, platelets and leukocytes come
into with the endothelium providing
endothelial cell activation and enhanced
pro-coagulant activity.
• *Due to stasis, also the inhibitors of

coagulation fail to reach the site of
thrombus, and impedes the inflowing of
clotting factor inhibitors resulting in the
enlargement of thrombus.
40
Cardiac -form in any chamber of the heart or valve
thrombi cusps.
The left ventricular thrombi (LVT) is a
blood clot
the left ventricle of the heart and is a
common
complication of acute myocardial
infarction.the
clot is a mural thrombus meaning it is on
the
wall of the ventricle.
41
42
Arterial -Arterial thrombi are formed in the rapid
flowing
and venous blood and venous thrombi are formed in
thrombi slowly
moving blood
Arterial thrombus is dangerous as it can
block
Blood flow in major organs such as the
heart
and brain.
43
Common type of venous thrombosis is a
deep
Vein thrombosis occuring in deep veins of
the
Legs and other parts of the body.
44
45
46
Capillary • Thrombi occuring in the blood
capillaries
thrombi • Mostly seen in some types of vasculitis
and
• Disseminated intravascular
coagulopathy[DIC].
• The thrombi are not visible by the naked
eyes
• but are appaent microscopically.
47
 Refers to alteration of coagulation
pathway.Predisposes affected person to
thrombosis.
 Can be divided into Primary
secondary .
 This occur as a result of mutation in

factor V and prothrombin Genes.
48
a. LEIDEN MUTATION.
 Refers to mutation of Factor V
Gene,cause alteration in amino acids
residue in it hence resistant to protein C.
(Anti-coagulant molecule)
 In Laiden Mutation Glutamine
substitutes Arginine.
B. Inherited deficiencies of Anti-thrombin
III,Protein C which are anticoagulants.
 This condition make the
thrombogenic activity to rise.
49
 This occur due to increased hepatic
synthesis of coagulation factors and
reduced synthesis of anti-thrombin III.
 The following are the major causes of
secondary hypercoagulability.
 Heparin inducedThrombocytopenia.
 Patient treated with unfractionated
heparin(Therapeutic anticoagulant).
50
 Marked by development of
autoantibodies that bind complexes of
heparin and platelet membrane(platelet
Factor 4)
 Result in platelet activation,aggregation
and consumption.(Hence cause
thrombocytopenia)
 Finally,lead into exacerbation of
prothrombotic state
51
 Antiphospholipid antibody syndrome.
 Associated with autoantibodies directed
against anionic phospholipids(i.e,
Cardiolipin).
 Thus plasma protein antigens that bind
to such phospholipids are not efficiently
carried.Example impaired carriage of
prothrombin.
 Finally,there will occur hypercoagulability
due to induced endothelial injury.
52
 OTHER FACTORS.
 Myocardial infarction
 Disseminated intravascular coagulation
 Prosthetic cardiac valves
 Prolonged bed rest
 Tissue injury
53
54
Predisposing • A number of primary (genetic) and
secondary (acquired) factors favour
factors for thrombosis.
thrombosis Primary (Genetic) factors:
i) Deficiency of antithrombin
ii) Deficiency of protein C or S
iii) Defects in fibrinolysis
iv) Mutation in factor V
55
• Secondary (acquired) factors:
i) Advanced age
ii) Prolonged bed-rest or immobilisation
iii) Cigarette smoking and obesity
iv) oral contraceptive use and
hyperestrogenic state of pregnancy.
v) cancer
vi) Vascular diseases
56
Morphological features of thrombosis
Thrombi can occur everywhere on the
cardiovascular system. It can be arterial
thrombi or venous thrombi.
Arterial thrombi arise at the site of

endothelial injury or turbulence, and it
grows in a retrograde direction from the
point of attachment.
Grossly they appear white and
mural.
57
Venous thrombi usually occur at the site
of stasis. Its growth is by extension
towards the blood flow.
Grossly they appear red and
occlusive.
The propagating portion of a thrombus

tends to be poorly attached and therefore
prone to fragmentation and migration
through the blood as an embolus.
58
Thrombi can have grossly (and
microscopically) apparent
laminations called lines of Zahn,
these represent pale platelets and
fibrin layers alternating with darker
red cells rich layer.
Their presence can therefore usually

distinguish antemortem thrombosis
from postmortem thrombosis
(bland nonlaminated clots)
59
• Postmortem clots can sometimes be
mistaken for venous thrombi. However,
the former are gelatinous and due to
red cell settling have a dark red
dependent portion and a yellow
“chicken fat” upper portion; they also
are usually not attached to the
underlying vessel wall. By contrast, red
thrombi typically are firm, focally
attached to vessel walls, and contain
gray strands of deposited fibrin
60
FATE OF • 1.Propagation: Thrombus my accumulate
more platelets and fibrin , eventually
THROMBUS leading to vessel obstruction.
• 2.Embolization: It may dislodge and travel

to other sites of the vessel.
• 3.Dissolution: occurs when the fibrinolytic

mechanisms break up the thrombus and
blood flow is restored to the vessel. This
may be aided by drugs (for example after
occlusion of a coronary artery). The best
response to fibrinolytic drugs is within a
couple of hours, before the fibrin
meshwork of the thrombus has been fully
developed 61
• 4.Organization and recanalization:
involves the ingrowth of smooth muscle
cells, fibroblasts and endothelium into
the fibrin-rich thrombus. If
recanalization proceeds it provides
capillary-sized channels through the
thrombus for continuity of blood flow
through the entire thrombus but may
not restore sufficient blood flow for the
metabolic needs of the downstream
tissue.
62
• Thank you
63

Group 1 Presentation On Haem and Thromb

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GROUP 1 1

Properties of into contact with the subendothelial ECM, which

Injured or among its constituents von Willebrand factor, a

Factors certain bacterial products including

OF fragments shed into bloodstream

COAGULATION• The complex initiates coagulation via

PATHWAY • >This pathway may involve contact

PATHWAY measure of factors II,V,VII,IX,X,XI and

5 sec break to review blood supply of the body

Before moving on there are some few important related

INJURY architecture of endotheal cells lining the

high flow, laminar flow can be disrupted and

• *Due to stasis, also the inhibitors of

 This occur as a result of mutation in

thrombosis Primary (Genetic) factors:

Arterial thrombi arise at the site of

The propagating portion of a thrombus

Their presence can therefore usually

• 2.Embolization: It may dislodge and travel

• 3.Dissolution: occurs when the fibrinolytic

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