Vascular Disturbances II

Thrombosis and Embolism

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 & tissues metabolic needs

infarction
tissue necrosis due to ischaemia

Major causes of morbidity & mortality

myocardial infarction, stroke, pulmonary embolism
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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

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Normal Haemostasis
1.
2.

3.

1.
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Arteriolar vasoconstriction
Primary haemostasis temporary platelet plug
a) Platelet adhesion
b) Platelet activation (shape change & granule release)
c) Platelet aggregation
Secondary haemostasis solid permanent plug
a) Activation of coagulation cascade
b) Conversion of fibrinogen to insoluble fibrin
c) Aggregates of polymerized fibrin & platelets
Counter-regulatory mechanisms restrict plug to site of
injury

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)
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Platelets
1.

Glycoprotein receptors (integrins) on surface

a)
b)

GpIb: binds vWF important in plt adhesion

GpIIb-IIIa: binds fibrinogen important in secondary haemostasis

2.

Alpha granules
a)
b)
c)

3.

ADP, ATP, calcium

Vasoactive molecules (histamine, serotonin, adrenalin)

Other enzymes
a)

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Adhesion molecules (P-selectin, vWF)

Coagulation factors (fibrinogen, fibronectin, factor V and vWF)
Growth factors (PDGF, TGF-beta)

Dense bodies
a)
b)

4.

GpIb deficiency Bernard-Soulier syndrome

vWF deficiency von Willebrands disease
GpIIb-IIIa deficiency Glanzmanns Thombasthenia

Thromboxane synthetase TXA2

Bleeding
disorders

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

2nd Year Pathology 2010

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-PA)
c) Release of tissue-type plasminogen activator (t-PA) from
endothelium

Fibrin and
fibrinogen
degradation

b) Anticoagulant pathways
Heparin-like molecules on endothelial surface
antithrombin III activation
b) Endothelial synthesis of Protein S
c) Thrombin thrombomodulin activation Protein C
activation
a)

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Inhibition of
coagulation

Extrinsic pathway

Intrinsic pathway

Tissue Factor
XII

XI

IX

Inhibitors
Tissue factor
pathway inhibitor

Collagen

VII

VIIa

XIIa XIa

IXa
+
VIIIa

Xa
Va

Prothrombin

Positive Feedback

Antithrombin
III

Thrombin

Fibrinogen

Fibrin

XIII
Cross-linked fibrin
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Protein C +
Protein S

Fibrinolytic
cascade

Thrombosis

Inappropriate activation of haemostatic

mechanisms

Definition:

E.g. uninjured vessel or very minor injury

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

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:

2nd Year Pathology 2010

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 functions

Procoagulant functions

Antiplatelet
Adenosine diphosphatase
( ADP)
Prostacyclin and nitric
oxide (also vasodilation)

Anticoagulant
Heparin-like molecules
(activate antithrombin III)
Thrombomodulin
(activates protein C)
Protein S synthesis

Fibrinolytic
t-PA
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Production of vWF
Production of tissue factor
Binding of factors IXa and
Xa

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 (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

2nd Year Pathology 2010

Anti-phospholipid
syndrome

autoantibodies bind plasma proteins with affinity for

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,
antithrombin III
deficiencies

autosomal dominantly inherited deficiencies of

anticoagulant factors

Homocystinemia

elevated plasma homocysteine levels

also increased rick of atherosclerosis

Prothrombin mutation

increases the level and activity of prothrombin

Plasminogen
abnormalities

Plasminogen or tissue plasminogen activator

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.
2.
3.
4.
5.
6.
7.

initial fatty streak

plaque enlarges (smoking/hyperlipidaemia)
turbulence (due to protrusion into lumen)
loss of endothelium & exposure of collagen
platelet adherence & activation
fibrin meshwork deposition with RBC entrapment
more turbulence, more platelet adherence, more fibrin
deposition
8. thrombus of alternating layers of platelets, fibrin and red
blood cells
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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

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Arterial Thrombi

Non-occlusive thrombi in wall of atherosclerotic aorta

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Arterial Thrombi

Occlusive thrombus in wall of atherosclerotic coronary artery

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Arterial Thrombi

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

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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

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Consequences of Thrombosis

Acute myocardial infarct secondary to coronary artery thrombosis

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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

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Pulmonary Thromboembolism

Embolus migrates from deep leg veins through venous system to

pulmonary circulation

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Pulmonary Thromboembolism

Saddle embolus in branching main pulmonary artery

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Pulmonary Thromboembolism

Small pulmonary embolus in branch of pulmonary artery

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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)
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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

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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

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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

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Other Forms of Embolism

Kidney showing cholesterol embolism from an atherosclerotic plaque

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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, Raynauds 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
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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: 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