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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
Normal Haemostasis
Normal Haemostasis
1.
2.
3.
1.
2nd Year Pathology 2010
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)
2nd Year Pathology 2010
Platelets
1.
2.
Alpha granules
a)
b)
c)
3.
Other enzymes
a)
Dense bodies
a)
b)
4.
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
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)
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
2nd Year Pathology 2010
Protein C +
Protein S
Fibrinolytic
cascade
Thrombosis
Definition:
Virchows triad:
1. changes in the vessel wall
2. changes in blood flow
3. changes in the blood constituents
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
2nd Year Pathology 2010
Production of vWF
Production of tissue factor
Binding of factors IXa and
Xa
Turbulence
Eddy currents with local pockets of stasis
Promote endothelial cell injury
e.g. ulcerated atherosclerotic plaque
Hyperviscosity
predisposes to stasis in small vessels
polycythaemia) / deformed RBCs (sickle cell anaemia)
Anti-phospholipid
syndrome
Factor V Leiden
mutation
Protein C, Protein S,
antithrombin III
deficiencies
Homocystinemia
Prothrombin mutation
Plasminogen
abnormalities
Thrombus Formation
Atherosclerotic plaque
1.
2.
3.
4.
5.
6.
7.
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
Arterial Thrombi
Arterial Thrombi
Arterial Thrombi
Venous Thrombi
Consequences:
Rarely cause ischaemia if affect arterial supply
More commonly embolize
Fate of Thrombi
1. Dissolution
by fibrinolysis
2. Propagation
3. Embolization
4. Recanalization
5. Organization
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
Embolization
Thrombi at or above knee pulmonary emboli
Consequences of Thrombosis
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
Pulmonary Thromboembolism
Arise from thrombi in systemic venous circulation
leg veins (95%)
pelvic veins
intracranial venous sinuses
Pulmonary Thromboembolism
Pulmonary Thromboembolism
Pulmonary Thromboembolism
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
Systemic Thromboembolism
Arise in arterial system (heart/large arteries)
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)
Systemic Thromboembolism
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
Disseminated Intravascular
Coagulation
Thrombotic disorder
Sudden / insidious onset of widespread fibrin thrombi in
microcirculation
Diffuse circulatory insufficiency
Brain, lungs, heart, kidneys
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
2nd Year Pathology 2010
Consequences of Vascular
Insufficiency
Number of determining factors
Summary
Thrombosis
Embolism
Types of embolus
Systemic vs Pulmonary Embolism