2nd Year Pathology 2010

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

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 wallb) plateletsc) proteins of coagulation and fibrinolytic cascades

2nd Year Pathology 2010

Normal Haemostasis

1. Arteriolar vasoconstriction 2. Primary haemostasis temporary platelet plug

a) Platelet adhesionb) 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

1. Counter-regulatory mechanisms restrict plug to site of injury

2nd Year Pathology 2010

Haemostatic Mechanisms - 1

1. Arteriolar vasoconstrictiona) Exposure of subendothelial nerve fibres – reflexb) Endothelial damage endothelin secretion

2. Primary haemostasisa) Von Willebrand factor binds to exposed collagenb) Platelets bind to vWFc) 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

Platelets1. Glycoprotein receptors (integrins) on surface

a) GpIb: binds vWF important in plt adhesionb) 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

2. Alpha granulesa) Adhesion molecules (P-selectin, vWF)b) Coagulation factors (fibrinogen, fibronectin, factor V and vWF)c) Growth factors (PDGF, TGF-beta)

3. Dense bodiesa) ADP, ATP, calciumb) Vasoactive molecules (histamine, serotonin, adrenalin)

4. Other enzymesa) Thromboxane synthetase TXA2

Bleeding disorders

2nd Year Pathology 2010

Haemostatic Mechanisms - 2

3. Secondary haemostasisa) 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

Haemostatic Mechanisms - 3

4. Counter-regulatory mechanismsa) Fibrinolytic pathway (Plasminogen activation

formation of plasmin)a) Coagulation cascadeb) Circulating urokinase-like plasminogen activator (u-PA)c) Release of tissue-type plasminogen activator (t-PA) from

endothelium

b) Anticoagulant pathwaysa) Heparin-like molecules on endothelial surface

antithrombin III activationb) Endothelial synthesis of Protein Sc) Thrombin thrombomodulin activation Protein C

activation

Fibrin and fibrinogen degradation

Inhibition of coagulation

2nd Year Pathology 2010

VIIaVII

Tissue Factor

Extrinsic pathway

XII

XIIa

XI

XIa

IX

IXa +VIIIa

Collagen

Intrinsic pathway

XIII

X Xa

Prothrombin

Va V

Thrombin

Cross-linked fibrin

Fibrinogen Fibrin

Inhibitors

Fibrinolytic cascade

Tissue factor pathway inhibitor

Antithrombin III

Protein C + Protein S

Positive Feedback

2nd Year Pathology 2010

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 wall2. changes in blood flow3. 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– 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

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 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 plaque1. initial fatty streak2. plaque enlarges (smoking/hyperlipidaemia)3. turbulence (due to protrusion into lumen)4. loss of endothelium & exposure of collagen5. platelet adherence & activation6. fibrin meshwork deposition with RBC entrapment7. more turbulence, more platelet adherence, more fibrin

deposition8. 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

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

a b

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. Embolization4. 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 dissolvedOlder 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 pulmonary circulation

2nd Year Pathology 2010

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

Fat emboli in the lung

2nd Year Pathology 2010

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