Thrombosis and Embolism

dr. Gusti Hariyadi Maulana, MSc, SpPD

2nd Year Pathology 2010

 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

2nd Year Pathology 2010

 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 & tissue’s metabolic needs
• infarction
– tissue necrosis due to ischaemia
• Major causes of morbidity & mortality
– myocardial infarction, stroke, pulmonary embolism

2nd Year Pathology 2010

 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

2nd Year Pathology 2010

 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
• 1. Arteriolar vasokonstriksi

• Paparan serabut saraf subendotelial - refleks

• Kerusakan endotel → sekresi endotelin

• 2. Hemostasis primer
• Faktor Von Willebrand mengikat pada kolagen yang terbuka
• Trombosit mengikat ke vWF
• Platelet diaktifkan pada kontak & melepaskan isi granul, termasuk ADP dan
tromboksan (TXA2)
• Agregasi platelet distimulasi oleh ADP dan TXA2
• Kaskade autocatalytic dari adhesi plt, aktivasi dan agregasi (ADP dan TXA2)
 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 Willebrand’s disease
• GpIIb-IIIa deficiency → Glanzmann’s 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

2nd Year Pathology 2010

 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

2nd Year Pathology 2010

3) Hemostasis sekunder
a) Faktor jaringan dikeluarkan dari endothelium yang rusak
b) Faktor jaringan dan faktor-faktor plt yang disekresikan mengaktifkan
kaskade koagulasi
c) Aktivasi trombin
Konversi fibrinogen menjadi fibrin yang tidak larut → deposisi fibrin
Aktivasi autokatalitik dari kaskade koagulasi
Mengikat reseptor permukaan plt → lanjut agregasi dan aktivasi
Deposisi fibrin menstabilkan dan jangkar agregat
 Haemostatic Mechanisms - 3
4. Counter-regulatory mechanisms
a) Fibrinolytic pathway (Plasminogen activation →
formation of plasmin)
a) Coagulation cascade Fibrin and
b) Circulating urokinase-like plasminogen activator (u-PA) fibrinogen
c) Release of tissue-type plasminogen activator (t-PA) from degradation
endothelium
b) Anticoagulant pathways
a) Heparin-like molecules on endothelial surface →
antithrombin III activation Inhibition of
b) Endothelial synthesis of Protein S coagulation
c) Thrombin → thrombomodulin activation → Protein C
activation

2nd Year Pathology 2010

4) Mekanisme penanggulangan peraturan
a) Fibrinolytic pathway (Aktivasi Plasminogen → pembentukan plasmin)
Kaskade koagulasi
Beredar seperti aktivator plasminogen urokinase (u-PA)
Pelepasan aktivator plasminogen tipe jaringan (t-PA) dari endotelium

b) Jalur antikoagulan
Molekul mirip heparin pada permukaan endotel → aktivasi antitrombin
III
Sintesis endotel Protein S
Trombin → aktivasi trombomodulin → Aktivasi Protein C
 Extrinsic pathway Intrinsic pathway Inhibitors

Tissue factor
Tissue Factor
pathway 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
Cross-linked fibrin Fibrinolytic
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
• Virchow’s triad:
1. changes in the vessel wall
2. changes in blood flow
3. changes in the blood constituents

2nd Year Pathology 2010

 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

2nd Year Pathology 2010

 Endothelium
• Antithrombotic functions • Procoagulant functions
– Antiplatelet
• Adenosine diphosphatase
(↓ ADP)
• Prostacyclin and nitric – Production of vWF
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

2nd Year Pathology 2010

 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

2nd Year Pathology 2010

 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 (Trousseau’s syndrome)
• tissue damage – surgery, trauma, burns
• Hyperviscosity
– predisposes to stasis in small vessels
• polycythaemia) / deformed RBC’s (sickle cell anaemia)
• Presence of endothelial cell toxins
– toxins in cigarette smoke, high levels of lipid or cholesterol
– predispose to endothelial cell injury

2nd Year Pathology 2010

 Anti-phospholipid • autoantibodies bind plasma proteins with affinity for
syndrome phospholipid surfaces, including coagulation factors
• associated with SLE
Factor V Leiden mutation • most common inherited form of hypercoagulability
• 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 syndrome • autosomal dominant disorder, precipitated by stress

2nd Year Pathology 2010

 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

2nd Year Pathology 2010

 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 RBC’s
• 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

2nd Year Pathology 2010

 Arterial Thrombi

Non-occlusive thrombi in wall of atherosclerotic aorta

2nd Year Pathology 2010
 Arterial Thrombi

Occlusive thrombus in wall of atherosclerotic coronary artery

2nd Year Pathology 2010
 Arterial Thrombi

a b

Alternating layers of a) platelets and fibrin and b) red blood cells

2nd Year Pathology 2010
 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

2nd Year Pathology 2010

 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
 Consequences of Thrombosis

Acute myocardial infarct secondary to coronary artery thrombosis

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

2nd Year Pathology 2010
pulmonary circulation
 Pulmonary Thromboembolism

Saddle embolus in branching main pulmonary artery

2nd Year Pathology 2010
 Pulmonary Thromboembolism

Small pulmonary embolus in branch of pulmonary artery

2nd Year Pathology 2010
 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

 Systemic Thromboembolism

Renal infarct secondary to systemic thromboembolism

2nd Year Pathology 2010
 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

2nd Year Pathology 2010

Fat emboli in the lung
 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

 Other Forms of Embolism

Kidney showing cholesterol embolism from an atherosclerotic plaque

2nd Year Pathology 2010
 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

 Non-thromboembolic Vascular
Insufficiency
• Atheroma
– M.I., hypertension due to renal artery stenosis
• Spasm
– angina, Raynaud’s phenomenon
• External Compression
– surgery, torsion, tumour
• Steal syndrome
– Blood diverted to one organ or tissue due to increased demands,
compromising the supply of another
• Hyperviscosity
– Sickle cell disease → splenic infarcts

2nd Year Pathology 2010

 Consequences of Vascular
Insufficiency
• Number of determining factors
– Size of vessel and size of vascular territory
– Partial / total vascular occlusion
– Duration of ischaemia
– Metabolic needs of tissue involved
– Presence or absence of alternative (collateral)
circulation
• Most important consequence = Infarction
• Commonest cause of death in western world

2nd Year Pathology 2010

 Summary
• Thrombosis
– Normal haemostatic mechanisms
– Pathogenesis: Virchow’s 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