Transcript Thrombosis-and

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 & tissue’s metabolic needs
• infarction
– tissue necrosis due to ischaemia
• Major causes of morbidity & mortality
– myocardial infarction, stroke, pulmonary embolism
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Normal Haemostasis
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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
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2.
3.
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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
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2.
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.
Bleeding
disorders
Alpha granules
a)
b)
c)
3.
GpIb deficiency  Bernard-Soulier syndrome
vWF deficiency  von Willebrand’s disease
GpIIb-IIIa deficiency  Glanzmann’s Thombasthenia
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
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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
X
IXa
+
VIIIa
Protein C +
Protein S
Xa
Va
Prothrombin
Positive Feedback
V
Antithrombin
III
Thrombin
Fibrinogen
Fibrin
XIII
Cross-linked fibrin
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Fibrinolytic
cascade
Thrombosis
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Inappropriate activation of haemostatic
mechanisms
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Definition:
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E.g. uninjured vessel or very minor injury
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
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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:
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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
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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
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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
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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
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Thrombus Formation
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Atherosclerotic plaque
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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 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
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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
a
b
Alternating layers of a) platelets and fibrin and b) red blood cells
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Venous Thrombi
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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
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Fate of Thrombi
1.
Dissolution
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Propagation
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along length of vessel  complete vessel occlusion
Embolization
Recanalization
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by fibrinolysis
capillaries invade thrombus to re-establish blood flow
Organization
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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)
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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
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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
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Systemic Thromboembolism
• Arise in arterial system (heart/large arteries)
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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)
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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
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Other Forms of Embolism
Fat emboli in the lung
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Other Forms of Embolism
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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
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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
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Consequences of Vascular
Insufficiency
• Number of determining factors
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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
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Summary
• Thrombosis
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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
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