dr M.

Arman Nasution SpPD

Suatu keseimbangan
TROMBOSIS
= Pembentukan massa bekuan darah intravaskuler,
yang berasal dari komponen darah, pada orang
yang masih hidup
Bekuan darah = trombus

Lepas ke sirkulasi = tromboemboli

Gangguan keseimbangan antara sistem koagulasi dan

sistem fibrinolisis
Patogenesis Trombosis
1 2 3
KERUSAKAN PERUBAHAN ALIRAN PERUBAHAN DAYA
DINDING PEMBULUH DARAH BEKU DARAH
DARAH

(Endothelial injury/ (stasis / turbulence) (hypercoagulable

dysfunction) state)

www.themegallery.com
TRIAD OF VIRCHOW
R. Ross. Atherosclerosis. NEJM 340:115-126, 1999
TROMBOSIS
Trombosis Arteri Trombosis Vena

- Jenis white thrombus red thrombus

- Komponen Utama Trombosit + fibrin Eritrosit + fibrin

- Lokalisasi Percabangan vaskuler Daerah stasis

- Aliran darah Cepat Lambat

- Patogenesis Kerusakan vaskuler + Hiperkoagulabel +

aktivasi trombosit stasis

- Akibat -Infark miokard -DVT

-Trombosis serebri -Emboli paru
Faktor risiko trombosis
Faktor Risiko
Trombosis Arteri:
-Keadaan yang merusak
endotel pembuluh darah
(hipertensi, perokok,
hiperkolesterolemia, dll)
-Keadaan dengan trombosit
atau aktifitas trombosit
(polisitemia, DM, dll)
Trombosis Vena:
-Keadaan yang menimbulkan
stasis (immobilisasi)
- Keadaan yang menimbulkan
hiperkoagulabel
(pasca bedah, keganasan,
kontrasepsi oral, dll)
Trombosis
TES SKRINING TROMBOSIS
1. Darah rutin

2. Jumlah trombosit

3. Fibrinogen

4. PT, APTT, TT

5. FDP dan D-Dimer

 HEMOSTASIS:
Mekanisme perlindungan tbh dr kehilangan drh
Aktivitas pembuluh darah
Fungsi trombosit
pembekuan darah
PEMBEKUAN DRH
Proses kimia dimana protein plasma berinteraksi
utk mengubah fibrinogen fibrin
Pemeriksaan Khusus
D-Dimer
Fibrinogen
Protein S
Protein C
Antitrombin III
 Kegagalan hemostasis PERDARAHAN
Kegagalan mempertahankan fluiditas darah
TROMBOSIS
ISTILAH ~ HEMOSTASIS
Trombosit
Trombus
Emboli
Tromboemboli
ANTIKOAGULAN
MENCEGAH PEMBEKUAN DRH
IND: INH TROMBUS & EMBOLI
INH DRH BEKU IN VITRO
PEMBAGIAN:
1. HEPARIN
2. AK ORAL :
- DERIVAT 4 HIDROKSIKUMARIN
- DERIVAT INDAN 1,3 DION
3. AK IKAT ION Ca
ANTITROMBOSIT
INH AGREGASI TROMBOSIT
EX : ASPIRIN
DIPIRIDAMOL
SULFINPIRAZON
DEKSTRAN
TROMBOLITIK
INDIKASI :
- INFARK MIOPCARK AKUT
- TROMBOSIS VENA DALAM
- EMBOLI PARU
- TROMBOEMBOLI
EX:
- STREPTOKINASE
- UROKINASE (ANTIDOT: AS
AMINOKAPROAT)
- RT-PA
HEMOSTATIK
LOKAL
- HEMOSTATI SERAP ( SPON GEALTIN, OKSISEL, BUSA FIBRIN
INSANI)
- ASTRIGEN ( FERI KLORIDA, AS TANAT, NITRAS ARGENTI)
- KOAGULAN ( TROMBIN, AKTIVATOR PROTROMBIN)
- VASOKONSTRITOR( EPI, NE)
SISTEMIK
-DESMOPRESIN
- VIT K
- AS AMINOKAPROAT
- AS TRANEKSAMAT
- FIBRINOGEN INSANI
Thromboembolic events
Activation of coagulation system Solid mass
of blood constituents formed within the
vasculature
Thrombosis formation of blood clot at site of
coagulation system activation
Embolism migration through the vasculature
to a distant site
Cause tissue damage by occlusion of blood
vessels
Result in ischaemia and infarction
Thromboembolic events
ischaemia
lack of oxygen due to impaired blood supply
results in reversible cell injury or irreversible injury
and necrosis (infarction)
depends on duration & tissues metabolic needs
infarction
tissue necrosis due to ischaemia
Major causes of morbidity & mortality
myocardial infarction, stroke, pulmonary embolism
Normal Haemostasis
Maintains blood in fluid state in normal vessels
Induces rapid, localized plug at site of vascular
injury
Complex set of activators & inhibitors
(procoagulant & anticoagulant influences)
3 components
a) endothelium and vascular wall
b) platelets
c) proteins of coagulation and fibrinolytic cascades
Normal Haemostasis
1. Arteriolar vasoconstriction
2. Primary haemostasis temporary platelet plug
a) Platelet adhesion
b) Platelet activation (shape change & granule release)
c) Platelet aggregation
3. Secondary haemostasis solid permanent plug
a) Activation of coagulation cascade
b) Conversion of fibrinogen to insoluble fibrin
c) Aggregates of polymerized fibrin & platelets
4. Counter-regulatory mechanisms restrict plug to site
of injury
2nd Year Pathology 2010
Haemostatic Mechanisms - 1
1. Arteriolar vasoconstriction
a) Exposure of subendothelial nerve fibres reflex
b) Endothelial damage endothelin secretion
2. Primary haemostasis
a) Von Willebrand factor binds to exposed collagen
b) Platelets bind to vWF
c) Platelets activated on contact & release granule
contents, including ADP and thromboxane (TXA2)
d) Platelet aggregation stimulated by ADP and TXA2
e) Autocatalytic cascade of plt adhesion, activation
and aggregation (ADP and TXA2)
2nd Year Pathology 2010
Platelets
1. Glycoprotein receptors (integrins) on surface
a) GpIb: binds vWF important in plt adhesion
b) GpIIb-IIIa: binds fibrinogen important in secondary
haemostasis
GpIb deficiency Bernard-Soulier syndrome
vWF deficiency von Willebrands disease
GpIIb-IIIa deficiency Glanzmanns Thombasthenia Bleeding
2. Alpha granules disorders
a) Adhesion molecules (P-selectin, vWF)
b) Coagulation factors (fibrinogen, fibronectin, factor V and vWF)
c) Growth factors (PDGF, TGF-beta)
3. Dense bodies
a) ADP, ATP, calcium
b) Vasoactive molecules (histamine, serotonin, adrenalin)
4. Other enzymes
a) Thromboxane synthetase TXA2
Haemostatic Mechanisms - 2
3. Secondary haemostasis
a) Tissue factor released from damaged endothelium
b) Tissue factor and secreted plt factors activate
coagulation cascade
c) Activation of thrombin
Conversion of fibrinogen to insoluble fibrin fibrin
deposition
Autocatalytic activation of coagulation cascade
Binding to plt surface receptors further plt aggregation
and activation
Fibrin deposition stabilizes and anchors aggregated plts
Haemostatic Mechanisms - 3
4. Counter-regulatory mechanisms
a) Fibrinolytic pathway (Plasminogen activation
formation of plasmin)
a) Coagulation cascade
b) Circulating urokinase-like plasminogen activator (u- Fibrin and
PA) fibrinogen
degradation
c) Release of tissue-type plasminogen activator (t-PA)
from endothelium
b) Anticoagulant pathways
a) Heparin-like molecules on endothelial surface
antithrombin III activation
Inhibition
b) Endothelial synthesis of Protein S of
c) Thrombin thrombomodulin activation Protein C coagulation
activation

2nd Year Pathology 2010

Extrinsic pathway Intrinsic pathway Inhibitors

Tissue factor pathway

Tissue Factor
inhibitor
XII XI IX
Collagen
VII VIIa XIIa XIa IXa +

VIIIa
Protein C +
Protein S
X Xa

Va V Positive Feedback

Prothrombin Thrombin Antithrombin III

Fibrinogen Fibrin
XIII
Fibrinolytic
Cross-linked fibrin
2nd Year Pathology 2010
cascade
Thrombosis
Inappropriate activation of haemostatic
mechanisms
E.g. uninjured vessel or very minor injury
Definition:
formation of solid mass of blood constituents within
vascular system in life
Virchows triad:
1. changes in the vessel wall
2. changes in blood flow
3. changes in the blood constituents
Changes in the vessel wall
Primarily damage to intimal surface (endothelium)
Causes of endothelial cell injury:
ulcerated atherosclerotic plaques
scarred valves in endocarditis / prosthetic valves
radiation, cigarette smoke, cholesterol/lipids
Results of endothelial cell injury:
exposed subendothelial extracellular matrix
platelet activation
activation of coagulation cascade
depletion of antiplatelet, anticoagulant and fibrinolytic
functions
endothelial activation activation of procoagulant functions
Endothelium
Antithrombotic Procoagulant functions
functions
Antiplatelet
Adenosine diphosphatase
( ADP) Production of vWF
Prostacyclin and nitric
oxide (also vasodilation) Production of tissue factor
Anticoagulant Binding of factors IXa and
Heparin-like molecules Xa
(activate antithrombin III)
Thrombomodulin
(activates protein C)
Protein S synthesis
Fibrinolytic
t-PA
Changes in blood flow
Normal flow is laminar
cells in centre of blood stream
clear zone of plasma adjacent to endothelium
Disrupted flow is static or turbulent
Stasis
Platelets in contact with endothelium
Prevent dilution of clotting factors
Retard inflow of clotting factor inhibitors
e.g. myocardial infarct, aneurysm, atrial fibrillation,
hyperviscosity syndromes
Turbulence
Eddy currents with local pockets of stasis
Promote endothelial cell injury
e.g. ulcerated atherosclerotic plaque
Changes in blood constituents
Hypercoagulability
Leads to recurrent venous thrombosis, arterial thrombosis,
recurrent abortion and stillbirths
Inherited (see table overleaf) or Acquired (below)
oral contraceptive use
pregnancy / hyperoestrogenic states
malignancy - elaboration of a procoagulant factor, leading to arterial
and venous thrombosis (Trousseaus syndrome)
tissue damage surgery, trauma, burns
Hyperviscosity
predisposes to stasis in small vessels
polycythaemia) / deformed RBCs (sickle cell anaemia)
Presence of endothelial cell toxins
toxins in cigarette smoke, high levels of lipid or cholesterol
predispose to endothelial cell injury
Anti-phospholipid autoantibodies bind plasma proteins with affinity for
syndrome phospholipid surfaces, including coagulation factors
associated with SLE
Factor V Leiden most common inherited form of hypercoagulability
mutation present in 5% of Caucasians
mutant factor V resistant to protein C inactivation
Elevated factor VIII as common as factor V Leiden mutation
genetic and environmental factors including OCP use
Protein C, Protein S, autosomal dominantly inherited deficiencies of
antithrombin III anticoagulant factors
deficiencies
Homocystinemia elevated plasma homocysteine levels
also increased rick of atherosclerosis
Prothrombin mutation increases the level and activity of prothrombin

Plasminogen Plasminogen or tissue plasminogen activator

abnormalities deficiency, plasminogen activator inhibitor excess
features resemble protein C or S deficiency
Sticky platelet autosomal dominant disorder, precipitated by stress
syndrome
Thrombus Formation
Atherosclerotic plaque
1. initial fatty streak
2. plaque enlarges (smoking/hyperlipidaemia)
3. turbulence (due to protrusion into lumen)
4. loss of endothelium & exposure of collagen
5. platelet adherence & activation
6. fibrin meshwork deposition with RBC entrapment
7. more turbulence, more platelet adherence, more
fibrin deposition
8. thrombus of alternating layers of platelets, fibrin and
red blood cells
Arterial Thrombi
Large vessels (aorta, heart) - nonocclusive / mural
Smaller vessels (coronary arteries, leg arteries) - often
occlusive
Classically have alternating white and red layers
called lines of Zahn
alternating layers of pale platelets and darker RBCs
e.g. aneurysmal sacs, infarcted left ventricle, damaged
heart valves, atherosclerotic plaques
Consequences:
Ischaemia in tissues distal to thrombus with possible necrosis
(infarction)
May embolize due to rapid flow
Arterial Thrombi

Non-occlusive thrombi in wall of atherosclerotic aorta

Arterial Thrombi

Occlusive thrombus in wall of atherosclerotic coronary artery

Venous Thrombi
Sites of stasis, commonly veins of lower extremity
Red - More enmeshed erythrocytes, less platelets
Occlusive
Predisposing factors
Bed rest, immobilization, heart failure, surgery, trauma,
pregnancy, hypercoagulable states
Consequences:
Rarely cause ischaemia if affect arterial supply
More commonly embolize
 Fate of Thrombi
1. Dissolution
by fibrinolysis
2. Propagation
along length of vessel complete vessel occlusion
3. Embolization
4. Recanalization
capillaries invade thrombus to re-establish blood flow
5. Organization
Inflammation and fibrosis replacement by scar, may
obliterate vessel lumen

Recent thrombi may be completely dissolved

Older thrombi more resistent to fibrinolysis
(extensive fibrin polymerization)

2nd Year Pathology 2010

Consequences of Thrombosis
Arterial Thrombosis
Obstruction:
Myocardial infarction due to coronary artery thrombosis
Cerebral infarction (Stroke) due to carotid artery thrombosis
Acute lower limb ischaemia & infarction due to femoral/popliteal artery
thrombosis
Embolization:
Cardiac/aortic mural thrombi emboli to brain, kidneys, spleen
Venous Thrombosis e.g. deep leg veins
Obstruction:
Local congestion, swelling, pain, tenderness
Oedema and impaired venous drainage
Infection & varicose ulcers
Embolization
Thrombi at or above knee pulmonary emboli

2nd Year Pathology 2010

Embolism
Any intravascular mass (solid, liquid or gas)
carried by blood to site distant from point of origin
Most derived from thrombi (thromboembolism)
Lodge in vessels too small to permit further
passage
partial / complete vascular occlusion
distal tissue ischaemia & infarction

2nd Year Pathology 2010

Pulmonary Thromboembolism
Arise from thrombi in systemic venous circulation
leg veins (95%)
pelvic veins
intracranial venous sinuses
Risk factors as for venous thrombosis
Effects are two-fold:
Possible infarction of lung tissue supplied by infarct
Interruption of oxygenation of blood within this area
Interruption of right ventricular outflow
Effects depend on size
2nd Year Pathology 2010
 Pulmonary Thromboembolism

Embolus migrates from deep leg veins through venous system to pulmonary
2nd Year Pathology 2010
circulation
Pulmonary Thromboembolism
Small:
silent due to collateral bronchial artery flow
organization with cumulative damage (idiopathic
pulmonary hypertension)
Medium:
pulmonary infarct with acute respiratory and cardiac
symptoms
Large:
right heart failure & collapse (>60% pulm circ)
Massive:
sudden death e.g. saddle embolus

2nd Year Pathology 2010

Systemic Thromboembolism
Arise in arterial system (heart/large arteries)
Atheromatous plaque with thrombus
Valve vegetation
Atrial thrombus (Atrial Fibrillation)
Old myocardial infarct (adynamic)
Recent myocardial infarct (loss of endothelium)

Rarely paradoxical embolus from venous system

(through septal defect in heart)

2nd Year Pathology 2010

Systemic Thromboembolism
Travel in systemic circulation
Cause arterial occlusion, distal ischaemia &
infarction
brain - stroke, neurological deficit / death
renal/splenic infarcts may be asymptomatic, seen as
ischaemic scars at autopsy
intestine - mesenteric emboli cause intestinal infarction,
can be lethal
limbs - ischaemic foot (dry gangrene)

2nd Year Pathology 2010

Hypercoagulability
Definition: Alteration in the hemostatic balance
between blood fluidity and clot formation. This is due
to genetic and acquired disorders which shift this
balance toward excessive or inappropriate platelet
aggregation and fibrin formation and predispose to
thrombosis.
Other Forms of Embolism
Fat embolism
Next most common after thromoemboli
Fracture of long bones / Burns / Trauma
Can cause severe pulmonary insufficiency
Air embolism
Gas bubbles obstructing vascular flow
Surgical /obstetric procedures / Chest wall injury
Decompression sickness
Gases dissolve in blood at high pressure
Come out as bubbles during rapid decompression
N2 bubbles remain - muscle, jts, lungs, brain, heart

2nd Year Pathology 2010

Other Forms of Embolism
Atheromatous plaque embolism
Platelet emboli
Infective emboli (infective endocarditis)
Tumour emboli
Foreign material (talc in IVDU)
Amniotic fluid embolism
amniotic fluid forced into uterine veins @ delivery,
causing respiratory distress

2nd Year Pathology 2010

Claudication
Ischemy perifer
1. Causes of acute leg ischemia.
2. How to differentiate causes of acute leg
ischemia.
3. Natural history of the disease.
4. Therapy.
Disseminated Intravascular
Coagulation
Thrombotic disorder
Sudden / insidious onset of widespread fibrin thrombi in
microcirculation
Diffuse circulatory insufficiency
Brain, lungs, heart, kidneys
Consumption of platelets and coagulation factors
Activation of fibrinolytic pathways

Severe bleeding disorder

Complication of any widespread activation of thrombin
Sepsis, Burns, Trauma, Extensive Surgery, Amniotic fluid
embolism, Carcinoma, Intravascular haemolysis
2nd Year Pathology 2010
Summary
Thrombosis
Normal haemostatic mechanisms
Pathogenesis: Virchows triad
Arterial vs Venous Thrombi
Fate of Thrombi
Embolism
Types of embolus
Systemic vs Pulmonary Embolism
Other Causes of Vascular Insufficiency
Consequences of Vascular Insufficiency

2nd Year Pathology 2010

Embolism angiographic picture.

Get better or worse with time?

Iliac stenosis

angioplasty
Iliac stenosis post angioplasty and stent
In situ thrombosis - aortic occlusion

Risk factors?

Symptoms?

Treatment?

Outcome?

Get better or worse with time?

 Multi-level peripheral vascular disease

External iliac Superficial femoral Tibial

 Embolism in situ thrombosis
History no claudication claudication

Embolic source yes no

Risk factors for atherosclerosis no yes

Contra-lateral pulses yes no

Murmur maybe no

Time for collaterals no yes

to develop

Natural history gets worse gets better

with time with time
Chronic ischemia and types of foot ulcers

Arterial Venous Neuropathic

Leg ulcers Arterial Venous Neuropathic

Location Distal Medial Pressure

malleolus point

Arterial disease Yes No No

and risk factors for
atherosclerosis

Contra-lateral No Yes Yes (maybe)

pulses

Skin changes of No Yes No

venous HTN

Neuropathy Maybe No Yes

Terima kasih
ASS WR WB