Tujuan Pembelajaran

• Memahami trombosis dan

perkembangan trombus pada
pembuluh darah yang terjejas
• Mendeskripsikan perubahan
struktur platelet dan pembentukan
cangkang fibrin selama agregasi
• Mendeskripsikan koagulasi darah
pada post mortem
• Memahami nasib trombi;
embolisme, fibrinolisis,
organisasi
• Memahami faktor klinis yang
berhubungan dengan respon
thrombosis
Dr. dr. Awal Prasetyo, M.Kes, Sp.THT-KL, MMRS • Mendeskripsikan agregasi
 S.Ked (FK UNDIP); dr (FK UNDIP)
M.Kes (Patobiologi) (FK UNDIP)
THT-KL (FK UNDIP)
Dr (Ilmu Kedokteran) (FKKMK UGM)
MM (Administrasi Rumah Sakit) (Pasca UMS)
WD 3 FK UNDIP (2016-2019)
Dekan FKIK UNIB (2019-sekarang)
Dewan Pakar PB IDI (2018-2021)
Ketua PMI Kota Semarang (2021-2026)
HAK CIPTA & PATEN = 10 Judul
HAK PATEN MERK = 1 Judul

Awal Prasetyo
 Thrombosis

• Can develop in arteries or veins, in large or small vessels,

can fill up thewhole lumen of a vessel (occlusive
thrombosis) or only part of it (mural or parietal
thrombosis).
• A thrombus that develops as a result of vessel wall trauma
usually consists of a small central platelet aggregate
that causes the precipitation of a huge mass of fibrin around
it, which millions of red cells & leukocytes are trapped.

• Fibrin can also materialize without platelets aggregates when

they are caused by forces other than vessel wall trauma,
particularly in microvessels & venous.
 Thrombus & Coagula

• Trombus is reserved for blood clots that develop in living

animals & in streaming blood.
• Coagula is blood clots that materialize postmortem in
stagnant blood have different features from the thrombi
that develop in vivo.
 Thrombosis Response
1) Development of A Thrombus in An Injured Vessel
• Platelet Aggregation
• Stuctural Changes of Platelets During Aggregation
• Formation of a Fibrin Shell Around the Platelet Aggregate
Post Mortem Blood Coagulation
Fates of Thrombi
• Embolism Thrombolysis Organization
2) Summary of All Clinically Relevant Thrombogenic Factors
• Wall Damage
• Changes in Blood Composition – Chemical Hypercoagulability
• Changes in Blood Composition – Platelets
• Hemodynamic Changes
• Infections Endotoxin
3) In Vitro Platelet Aggregation
• Endogenous Agents Exogenous & Manmade Agents
 1) Development of A Thrombus in
An Injured Vessel
a) Platelet Aggregation
b) Stuctural Changes of Platelets During Aggregation
c) Formation of a Fibrin Shell Around the Platelet Aggregate
 a) Platelet Aggregation
• In a normal, uninjured vessels, platelets do not stick to
one another & to the vessel wall to form a thrombus
because the 3 following forces keep them apart & away
from the wall.
1) Platelet, blood cells & endothelial surface are coated by an
electronegative sialic-acid containing carbohydrate layer that
makes all repel one another & also produce a mutual repulsion
between blood cells & vessel wall.
2) In straight vessels, in laminar flow, all cells tend to concentrate
towards the central axis of bloodstream, leaving a cell-free
marginal plasma zone between themselves & the wall lining.

3) Normal endothelium produce a special prostaglandin, prostacyclin

(PGI2), inhibits aggregation of platelets & causes relaxation of
smooth muscle.
 Normal Endothelium#1
Produces 2 substances that activate certain anticoagulant plasma
proteins (proteins that inhibit fibrin-producing enzyme cascade);
1) Heparinoids (activate antithrombin III)
2) Thrombomodulin (activate protein C)
If fibrin deposits on endothelium, thrombomodulin can help
dissolve the fibrin by producing plasminogen activating factor
(PAF), an agent that activates the fibrin-dissolving enzyme plasmin
(fibrinolysin).
Fibrinolysin prevent the blood from clothing in normal
endothelium, by 3 ways;
1) Inhibits platelet aggregation
2) Opposes fibrin generation
3) Degrade fibrin that already formed.
Normal Endothelium#2
 Thrombosis Response

• Is the solidification of flowing blood within a blood vessel.

Can be extremely useful, for;
• Life-saving.
• Reaction when it develops in response to trauma of small vessels
in the somatic periphery & plugs them.
• Preventing us from bleeding to death.
IN FACT
• The whole thrombotic process have invented by
evolution as an automatic self-sealing mechanism
for traumatized vessels.
BUT, IT CAN ALSO
• Be very harmful & lethal when it occludes major
visceral vessels in the body, causing necrosis of parts
of vital viscera (heart, brain) & often death.
 The dramatic changes materialize which
cause platelets to adhere to the injured wall:

The local loss of endothelium leads to

1) Local loss of electronegative platelet-repelling charge
that resides in sialic acid coat of endothelium.
2) Local loss of endothelium-produced inhibitor of
platelet aggregation prostacyclin (PGI2).
3) Local loss of disruption of smooth laminar flow of blood
& the emergence at the site of trauma.
4) Exposes blood & platelet to underlying subendothelial
collagen fibers that always surround the endothelial
tube of any vessel, large or small, normal or diseased.
The exposure of platelets to subendothelial collagen
constitute the
most powerful stimulus
not only for platelet adherence to the traumatized wall
but also for the subsequent aggregation & other changes
of platelets over the trauma site).
• The sudden exposure of platelets to subendothelial collagen caused
by vessel trauma represents the principal physiological
signal that “tells” platelets to adhere to & aggregate over the
injured wall segment.
• When platelets encounter collagen, they would “know”
that the vessel wall is broken & needs plugging.
• Naturally, more collagen in vessel wall, the stronger its platelet-
aggregating capacity would be; thus breaks in a highly collagenized
atherosclerotic arterial wall initiate much larger & much more
occlusive thrombi than breaks through normal arterial walls.
• The binding of platelets to the exposed collagen
fibers appears to be promoted by von
Willebrand factor, a substance produced by
the endothelial cells.
The endothelium
• Proves to be functionally very
disperse & adaptable to the
needs of the moment.
• It opposes the initiation of a
thrombus under normal
circumstances, but it produces
factors that help its
development when it is needed,

as after
vessel wall injury.
 The AGGREGATION PROCESS
is induced by 3 factors:

1. Adenosine diphosphate (ADP)

(A nucleotide derived from adenosine triphosphate (ATP) by loss of one
phosphate & it exists within practically all cells of the body).
2. Thrombin
(Is produced from plasma protein prothrombin by action of another plasma
principle, the Hageman factor).
3. Thromboxane
(A short-lived product that depresses cyclic AMP consentration within the
platelets & causes them to aggregate).
 The AGGREGATION PROCESS
is induced by 3 factors:

1. Adenosine diphosphate (ADP)

2. Thrombin
3. Thromboxane
 The AGGREGATION PROCESS that
is induced by ADP

• A severely injured, ADP leaks out of destroyed myocytes & extravasated

erythrocytes at site of injury & promotes aggregation of platelets with help of
calcium & fibrinogen.
• ADP also stimulate ATP synthesis in platelets , promotes contraction
& pseudopod formation by these cells.
• ADP is powerful stimulant of aggregation in vivo (when infused into blood
vessels) & in vitro (when added to a suspension of platelets-rich plasma).
• The aggregating platelets, contract & shoot out pseudopods, release
vasoactive amines (serotonin, histamine & epinephrine), which stimulate
vessel constraction & contribute to hemostasis.
• ADP promote more platelet aggregation, in a self-amplification of
this process.
• Platelet derived growth factor (PDGF), which stimulate fibroblast
& smooth muscle mitosis & therefore furthers the organization of thrombus
by granulation tissue with arterioles & venules.
 The AGGREGATION PROCESS
is induced by 3 factors:

1. Adenosine diphosphate (ADP)

2. Thrombin
3. Thromboxane
 The aggregation process that
is induced by Thrombin
• Is activated as soon as plasma contacts the rough & blood-foreign
surfaces & cell breakdown products created by severe vascular injury
at the trauma site.
• At small concentration levels, thrombin promotes platelet
aggregation through a not clearly elucidated mechanism.
 The AGGREGATION PROCESS
is induced by 3 factors:

1. Adenosine diphosphate (ADP)

2. Thrombin
3. Thromboxane
 The aggregation process that
is induced by Thromboxane
• The exposure of platelets to sub-endothelial collagen causes
them to synthesize prostaglandins PGG2 & PGH2 (from
arachidonic acid, a polyunsaturated fatty acid), and these
prostaglandins are transformed by peroxidations in the dense
tubular system of platelets
into thromboxane A2.

• It now appears that

only thromboxane, but most
agents that aggregate platelets
accomplish this by inhibiting intra-
platelet adenylcyclase &
decreasing intra platelet cyclic
AMP levels.
 Development of A Thrombus in
An Injured Vessel
• Platelet Aggregation
• Stuctural Changes of Platelets During Aggregation
• Formation of a Fibrin Shell Around the Platelet Aggregate
 Stuctural Changes of Platelets
During Aggregation
1. Contraction, outgrowth of filiform pseudopods &
development of multivesicular sac in association with
the pseudopods.
2. Loss of dense contents (degranulation of α-granules),
and loss of vesicles from multivesiculer sacs.
3. Vacuolation, blebbing & rupture.
 Stuctural Changes of Platelets
During Aggregation

1. Contraction
2. Loss of dense contents
3. Vacuolation, blebbing & rupture
Contraction, outgrowth of filiform pseudopods
& development of multivesicular sac in association
with the pseudopods

• These changes be linked to processes of adhesion & aggregation

(sticking of platelets to subendothelial collagen & one to another).
• The contraction is

effected through 8-20

nm contractile,
actomyosin-like
filaments, and it is also helped
by the
existence of two canalicular
system in platelets,
an open &
a closed one, as striated muscle.
 Stuctural Changes of Platelets
During Aggregation

1. Contraction
2. Loss of dense contents
3. Vacuolation, blebbing & rupture
 Loss of dense contents
(degranulation of α-granules), and loss of
vesicles from multivesiculer sacs.

• The dense cores of α-granules have been found to contain ADP,

acid lipid phosphatase, vasoactive amines, calcium & phospholipid
in different proportions.
• Their loss from the platelets be promoted by the platelet
contraction.
• The α-granules contents are squeezed by the contraction into the
platelets open canalicular system & released outward from there.
• The loss of vesicles from the multivesicular sacs that develop in
association with the filiform processes is as yet of obscure
significance.
 Stuctural Changes of Platelets
During Aggregation

1. Contraction
2. Loss of dense contents
3. Vacuolation, blebbing & rupture
 Vacuolation, blebbing & rupture

• This is terminal destructive change of platelets that begins and

is most pronounced in peripheral zone of platelet aggregate.
• It probbaly provides the streaming blood above the platelet
pile with additional granule contents and with membrane-
bound (structural) phospholipid from disintegrating platelets.
 Development of A Thrombus in
An Injured Vessel
• Platelet Aggregation
• Stuctural Changes of Platelets During Aggregation
• Formation of a Fibrin Shell Around the Platelet Aggregate
 Formation of a Fibrin Shell Around
the Platelet Aggregate#1
• The platelet aggregate is not a sufficiently strong seal for the vessel
trauma & reinforced by the formation of a layer of fibrin
over it.
• All aggregated platelets release materials from their cytoplasm
(ADP, serotonin, phospholipoproteins), but the platelets
at top of the pile release most abundant amount,
including phospholipoprotein rich in kephalin, into circulation &
platelet surfaces & also losing their α-granules.
• The membrane-bound part of this kephalin-rich phospholipoprotein
(platelet factor III) triggers in plasma the whole enzymatic chain
reaction that leads to the precipitation of fibrin
(“the clotting cascade”), that activates plasma clotting factors
V-XII to create thromboplastin, turns prothrombin into active
proteolytic enzyme thrombin, transforms soluble fibrinogen into
soluble fibrin.
 Formation of a Fibrin Shell Around the
Platelet Aggregate#2
• The whole process requires the presence of calsium ions &
be inhibited by; heparin, a natural antithrombin
substance, antithrombin III & protein C.
• Also be triggered by factors released from injured cells
(tissue thromboplatin activators) & by foreign surfaces.
• In normal; the endothelial cells oppose thrombosis by producing
plasminogen activator (PA), a factor that promotes the dissolution
of unwanted fibrin, but when vessel wall injured, the endothelial
cells protect the useful fibrin seal by producing plasminogen
activator inhibitor (PA-I).
• Other functional dualism of endothelium is its ability to cause
dilatation or constriction. The endothelium produce prostacyclin
(PGI2) that may cause vasodilatation (in order to inhibit platelet
aggregation), and also endothelin that cause powerfull constriction.
 Formation of a Fibrin Shell Around
the Platelet Aggregate#3

The speed of formation, size, composition & special

features of thrombus depend on:
• Amount of thrombus building materials (platelet &
clotting factors) in blood & the local type of blood
flow.
 Formation of a Fibrin Shell Around
the Platelet Aggregate#3

Factors that may diminish the speed of thrombus development;

• deficiency of thromboplastin precursor synthesis due to genetic
defect,
• lack of prothrombin & fibrinogen due to severe liver disease.
The rapid & strong laminar blood flow, as in straight aortic tube,
will rapidly wash away the locally formed thrombin.
Slow blood flow, as in veins, allows the forming thrombin.
Rapid turbulent blood flow, as in aortic aneurysma, produces through a not yet
completely understood mechanism thrombi with platelet & fibrin layers.

• The fibrin-forming coagulation process does not expand to freeze

all blood of body, because factors that trigger are progressively
diluted by blood flow as the distance from their generation site
increases, are removed by liver & checked by various circulating
inhibitors of coagulation.
 Thrombosis Response
Development of A Thrombus in An Injured Vessel
• Platelet Aggregation
• Stuctural Changes of Platelets During Aggregation
• Formation of a Fibrin Shell Around the Platelet Aggregate
Post Mortem Blood Coagulation
Fates of Thrombi
• Embolism Thrombolysis Organization
Summary of All Clinically Relevant Thrombogenic Factors
• Wall Damage
• Changes in Blood Composition – Chemical Hypercoagulability
• Changes in Blood Composition – Platelets
• Hemodynamic Changes
• Infections Endotoxin
In Vitro Platelet Aggregation
• Endogenous Agents Exogenous & Manmade Agents
FATES OF THROMBI

1)DETACH, make EMBOLISM

2)DISSOLVED, make TROMBOLYSIS
3)REPLACED, make ORGANIZATION
 Thrombosis Response
Development of A Thrombus in An Injured Vessel
• Platelet Aggregation
• Stuctural Changes of Platelets During Aggregation
• Formation of a Fibrin Shell Around the Platelet Aggregate
Post Mortem Blood Coagulation
Fates of Thrombi
• Embolism Thrombolysis Organization
Summary of All Clinically Relevant Thrombogenic Factors
• Wall Damage
• Changes in Blood Composition – Chemical Hypercoagulability
• Changes in Blood Composition – Platelets
• Hemodynamic Changes
• Infections Endotoxin
In Vitro Platelet Aggregation
• Endogenous Agents Exogenous & Manmade Agents
 Summary of All Clinically Relevant
Thrombogenic Factors

Factors promote (initiate or enhance)

Thrombogenesis
1) Vessel wall damage (physical, chemical, inflammatory,
degenerative vasculer disease)
2) Changes in the chemical or cellular composition of the blood
3) Hemodynamic changes (including stasis, increased blood
viscosity and turbulence)
4) Infections (bacteria, viruses and their products)
 Summary of All Clinically Relevant
Thrombogenic Factors

Factors promote (initiate or enhance)

Thrombogenesis
1) Vessel wall damage (physical, chemical, inflammatory,
degenerative vasculer disease)
2) Changes in the chemical or cellular composition of the blood
3) Hemodynamic changes (including stasis, increased blood
viscosity and turbulence
4) Infections (bacteria, viruses and their products)
 Wall Damage &
Chemical Damage
Physical wall damage
• Endothelial destruction by mechanical trauma
• Extreme heat (burns) or cold (freezing)
• Dehydration by air drying
• Electrical injury (positive or negative unipolar
electrode with current sufficient intensity)
• All types of ionizing radiation
 Wall Damage &
Chemical Damage

Chemical damage
• Numerous inorganic or organic chemicals
(including immune factors) of sufficiently
high concentration on the blood
• Arteritis
• Phlebitis
• Atherosclerosis
 Summary of All Clinically Relevant
Thrombogenic Factors

Factors promote (initiate or enhance)

Thrombogenesis
1) Vessel wall damage (physical, chemical, inflammatory,
degenerative vasculer disease)
2) Changes in the chemical or cellular composition of the blood
3) Hemodynamic changes (including stasis, increased blood
viscosity and turbulence
4) Infections (bacteria, viruses and their products)
 Changes in Blood Composition-Chemical
Hypercoagulability

Trombosis can be spontaneously initiated by;

• Activation of thromboplastic factors in blood through release of
thromboplastin activators from disintegrating cells
Cells (not only platelet) contain variable amount of thromboplastin-

activating phospholipoproteins.
In extensive cell disintegration;
• Sickle cell anemia
• Premature separation of the placenta
• Widespread malignant neoplasia

The development of multiple small fibrin thrombi in microsirculation of

several viscera (lungs, liver, kidneys and spleen), called DIC (disseminated
intravascular coagulation syndrome)
 Changes in Blood Composition-Chemical
Hypercoagulability

Some cells breakup that release thromboplastin-

activating phospholipoproteins would also

expected to release cytoplasmic (c-ADP) into blood
stream, so act as minor variable of platelet aggregation.

Several condition increase the number of platelets/mm3,

the adhesiveness to each other & to foreign surface;
1) Trauma associated with substantial blood loss
2) Certain high-fat diets
 Summary of All Clinically Relevant
Thrombogenic Factors

Factors promote (initiate or enhance)

Thrombogenesis
1) Vessel wall damage (physical, chemical, inflammatory,
degenerative vasculer disease)
2) Changes in the chemical or cellular composition of the blood
3) Hemodynamic changes (including stasis, increased blood
viscosity and turbulence
4) Infections (bacteria, viruses and their products)
Haemodynamic Changes
 Haemodynamic Changes

Haemodynamic condition promote thrombosis by enhancing the

speed of development and ultimate size of thrombi produced by
iniating factors;
• Stasis
• Increased blood viscosity
• Increased blood turbulence
Stasis, be caused by;
• All kinds of contrictions of vessel lumen
• Loss of competent valves
• Heart failure
• Debilitating condition
• Result in loss of the propulsion of venous blood by skeletal muscle contraction
 Haemodynamic Changes

One way stasis work by;

• Delaying the washing away any thrombin.
• Hypoxia induced by stasis can injure the
endothelium, causing swelling and vacuolation
• Sufficiently intensive and prolonged stasis could
produce trombogenic endothelial damage.
 Haemodynamic Changes
Increased viscosity can be caused by increased
blood concentration of small particles or cells.
• It probably works by slowing down blood flow and pomoting
stasis.
 Haemodynamic Changes

Increased turbulence of blood flow at all

vessel branchings and vessels narrow or
aneurysmal scas develop.
It seems to work in the following two ways;
1) Picking up platelets (and other blood cells)
2) Injuring endothelium
 Summary of All Clinically Relevant
Thrombogenic Factors

Factors promote (initiate or enhance)

Thrombogenesis
1) Vessel wall damage (physical, chemical, inflammatory,
degenerative vasculer disease)
2) Changes in the chemical or cellular composition of the blood
3) Hemodynamic changes (including stasis, increased blood
viscosity and turbulence
4) Infections (bacteria, viruses and their products)
Infections
 Thrombosis Response
Development of A Thrombus in An Injured Vessel
• Platelet Aggregation
• Stuctural Changes of Platelets During Aggregation
• Formation of a Fibrin Shell Around the Platelet Aggregate
Post Mortem Blood Coagulation
Fates of Thrombi
• Embolism Thrombolysis Organization
Summary of All Clinically Relevant Thrombogenic Factors
• Wall Damage
• Changes in Blood Composition – Chemical Hypercoagulability
• Changes in Blood Composition – Platelets
• Hemodynamic Changes
• Infections Endotoxin
In Vitro Platelet Aggregation
• Endogenous Agents Exogenous & Manmade Agents
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