Thrombosis, Embolism and Infarction

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Vascular Disturbances II Thrombosis and Embolism
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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

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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
• endothelium and vascular wall
• platelets
• proteins of coagulation and fibrinolytic cascades

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Normal Haemostasis

• Arteriolar vasoconstriction
• 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
• Counter-regulatory mechanisms ? restrict plug to
  site of injury

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Haemostatic Mechanisms - 1

• Arteriolar vasoconstriction
• Exposure of subendothelial nerve fibres reflex
• Endothelial damage ? endothelin secretion
• Primary haemostasis
• Von Willebrand factor binds to exposed collagen
• Platelets bind to vWF
• Platelets activated on contact release granule
  contents, including ADP and thromboxane (TXA2)
• Platelet aggregation stimulated by ADP and TXA2
• Autocatalytic cascade of plt adhesion, activation
  and aggregation (ADP and TXA2)

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Platelets

• Glycoprotein receptors (integrins) on surface
• GpIb binds vWF ? important in plt adhesion
• GpIIb-IIIa binds fibrinogen ? important in
  secondary haemostasis
• GpIb deficiency ? Bernard-Soulier syndrome
• vWF deficiency ? von Willebrands disease
• GpIIb-IIIa deficiency ? Glanzmanns Thombasthenia
• Alpha granules
• Adhesion molecules (P-selectin, vWF)
• Coagulation factors (fibrinogen, fibronectin,
  factor V and vWF)
• Growth factors (PDGF, TGF-beta)
• Dense bodies
• ADP, ATP, calcium
• Vasoactive molecules (histamine, serotonin,
  adrenalin)
• Other enzymes
• Thromboxane synthetase ? TXA2

Bleeding disorders
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Haemostatic Mechanisms - 2

• Secondary haemostasis
• Tissue factor released from damaged endothelium
• Tissue factor and secreted plt factors activate
  coagulation cascade
• 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

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Haemostatic Mechanisms - 3

• Counter-regulatory mechanisms
• Fibrinolytic pathway (Plasminogen activation ?
  formation of plasmin)
• Coagulation cascade
• Circulating urokinase-like plasminogen activator
  (u-PA)
• Release of tissue-type plasminogen activator
  (t-PA) from endothelium
• Anticoagulant pathways
• Heparin-like molecules on endothelial surface ?
  antithrombin III activation
• Endothelial synthesis of Protein S
• Thrombin ? thrombomodulin activation ? Protein C
  activation

Fibrin and fibrinogen degradation
Inhibition of coagulation
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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
• changes in the vessel wall
• changes in blood flow
• 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
• exposed subendothelial extracellular matrix
• platelet activation
• activation of coagulation cascade
• depletion of antiplatelet, anticoagulant and
  fibrinolytic functions
• endothelial activation ? activation of
  procoagulant functions

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Endothelium

• Antithrombotic 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

• Procoagulant functions
• Production of vWF
• Production of tissue factor
• Binding of factors IXa and Xa

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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

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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
  (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

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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

• Atherosclerotic plaque
• 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
• 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
a
b
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

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Fate of Thrombi

• Dissolution
• by fibrinolysis
• Propagation
• along length of vessel ? complete vessel
  occlusion
• Embolization
• Recanalization
• capillaries invade thrombus to re-establish blood
  flow
• 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)

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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 (gt60 pulm circ)
• Massive
• sudden death e.g. saddle embolus

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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)

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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

• 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 _at_
  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, 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

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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