Atheroma, thrombosis and embolism Flashcards
What is an atheroma?
Intimal lesion that protrudes into a vessel wall.
What are the 5 main steps of atheroma formation?
- Endothelial dysfunction
- Formation of lipid layer or fatty streak within the intima
- Migration of leukocytes and smooth muscle cells into the vessel wall
- Foam cell formation
- Degradation of extracellular matrix
What allows circulating LDLs into the intima?
Disruption of endothelial barrier due to endothelial dysfunction
When do macrophages become foam cells?
When monocytes enter the intima, they differentiate into phagocytic macrophages. These phagocytic macrophages may become foam cells when they absorb lipoproteins
What does an atheroma lesion consist of?
A raised lesion with a soft core of lipid (mainly cholesterol and cholesterol esters) and is covered by a fibrous cap.
What does the fibrous cap of an atheroma consist of?
Smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin
What does the central necrotic core of an atheroma consist of?
Cell debris, cholesterol crystals, foam cells, calcium
Diagram of atherosclerosis
Why are sites of birfucation common for atheromas?
Blood flow is often turbulent here
- E.g. abdominal aorta; particularly around branches
What vessels are commonly affected by atheromas?
- Abdominal aorta
- Coronary arteries
- Popliteal arteries
- Carotid vessels
- Circle of Willis
What are the non-modifiable risk factors for atheroma?
- Increasing age
- Male gender
- Family history
- Genetic abnormalities
What are the modifiable risk factors for atheroma?
- Hyperlipidemia (LDL:HDL)
- Hypertension
- Cigarette smoking
- Diabetes
- CRP (inflammation)
These factors can damage endothelium and cause an influx of lipids
How does atherosclerosis begin?
Starts with damage or injury to the inner layer of an artery
What may cause damage to inner layer of an artery?
- High blood pressure
- High cholesterol
- An irritant, such as nicotine
- Certain diseases, such as diabetes
How does atherosclerosis then develop in response to the endothelial injury?
Response to injury hypothesis:
- Atherosclerosis develops as a chronic inflammatory response
- Lesion progression occurs through interactions of modified lipoproteins, monocyte-derived macrophages, T-lymphocytes, and the normal cellular constituent of the arterial wall.
Describe mechanism of how atheroma forms
- Damage allows influx of lipids into intima
- Marcophages recruited and activated to try and engulf lipid –> forming foam cells
- Sometime die which causes an excess of extracellular lipid
- Smooth muscle cells infiltrate and proliferate and try to lay down collagen –> conenctive tissue forms a thin fibrous cap on the surface
What are foam cells?
A type of macrophage that localise to fatty deposits on blood vessel walls, where they ingest low-density lipoproteins and become laden with lipids, giving them a foamy appearance.
I.e. foam cells are fat-laden macrophages containing LDLs
How does the fibrous cap on the atheroma form?
Smooth muscle cells laying down collagen –> connective tissue forms fibrous cap
Basic response to injury hypothesis for atheroma?
- Chronic endothelial injury
- Endothelial dysfunction (increased permeability, monocyte adhesion and emigration)
- Smooth muscle emigration from media to intima, macrophage activation
- Macrophages and smooth muscle cells engulf lipid
- Smooth muscle proliferation, collagen and other ECM deposition, extracellular lipid
What is the earliest lesion in atherosclerosis?
Fatty streak
What is a fatty streak composed of?
Lipid filled foamy macrophages (i.e. macrophages that have ingested fat)
Describe appearance of fatty streaks
These lesions are not significantly raised and do not cause flow disturbance
Do all fatty streaks progress to atheromatous plaques?
No - but coronary fatty streaks begin to form in adolescence at the same anatomical sites that later tend to develop plaques
What does a fatty streak then progress to?
What does an atherosclerotic plaque consist of?
Intimal thickening and lipid accumulation
Describe appearance of an atheroslerotic plaque
Appears white and yellow raised plaques which often have superimposed thrombus on the plaque that appear red
Does an atherosclerotic plaque impinge on the vessel lumen? What is effect of this?
Yes - causes turbulent blood flow:
- There may be damage to overlying endothelium and thrombus can start to appear on surface
- Causes stenosis (narrowing) of vessel lumen
Diagram of atherosclerosis development
- Initial lesion
- Fatty streak
- Intermediate lesion
- Atheroma
- Fibroatheroma
- Complicated lesion
How does an initial lesion mainly progress to an atheroma?
Growth mainly by lipid addition
How does an atheroma progress to a fibroatheroma?
Increased smooth muscle and collagen (cap forms and core of extracellular lipid)
How does a fibroatheroma progress to a complicated lesion?
Thrombosis and/or hermatoma
What are the 4 seque of atherosclerotic plaques?
- Rupture, ulceration or erosion of the plaque
- Haemorrhage into plaque
- Atheroembolism
- Aneurysm formation
The plaque is at danger of rupturing, ulcerating or eroding. What would this cause?
This will expose the blood to highly thrombogenic substances (cholesterol and tissue that was under the fibrous cap) and induce thombosis –> blood clots which can block flow in the artery
What can cause a haemorrhage into a plaque?
If there is damage to one of the blood vessels feeding the plaque or the overlying endothelium
What happens during haemorrhaging into a plaque?
Blood rapidly enters plaque and expands it –> can lead to occlusion
What is atheroembolism?
Damage to overlying surface, bits of atheroma can break off and travel in the bloodstream as emboli
How can atherosclerotic plaques lead to aneurysm formation?
Over time, plaques may cause the artery wall to weaken due to atrophy –> can lead to an aneurysm
What does sequelae mean?
a condition which is the consequence of a previous disease or injury.
What is a thrombus?
A blood clot that occurs inside the vascular system
What are the 2 types of thrombosis?
- Arterial
- Venous
How does arterial thrombosis typically occur?
Usually occurs after the erosion or rupture of an atherosclerotic plaque
What is venous thrombosis most commonly due to?
Stasis
What is Virchow’s Triad?
Describes 3 factors that are ciritical important in the development of venous thrombosis:
- Stasis of blood flow
- Hypercoagulability
- Endothelial injury
How can endothelial injury lead to thrombosis?
Expose blood to factors within the underlying tissue which promote clotting cascade to cause a thrombus to form
How can abnormal blood flow lead to thrombosis?
Prothrombotic factors are able to build up and antithrombotic factors may not be abel to be brought into the area
How can hypercoagulabiliy lead to thrombosis?
A hypercoagulable state is the medical term for a condition in which there is an abnormally increased tendency toward blood clotting (e.g. Factor V Leiden)
Difference in cause of arterial and venous thrombosis?
Arterial: typically from rupture of atheromatous plaque
Venous: typically from combination of factors from Virchow triad
Difference in location between arterial and venous thrombosis?
Arterial: left heart chambers, arteries
Venous: venous sinusoids (a small irregularly shaped blood vessel) of muscle and valves of veins
Why does venous thrombosis typically appear near valves and sinusoids?
Sinusoids –> allow pooling of blood
Valves –> areas of turbulence
What diseases can arterial thrombosis lead to?
What diseases can venous thrombosis lead to?
Arterial:
- Acute coronary syndrome
- Ischaemic stroke claudication
Venous:
- Deep vein thrombosis
- Pulmonary embolism
What is claudication?
a condition in which cramping pain in the leg is induced by exercise, typically caused by obstruction of the arteries.
Difference in composition of arterial and venous thrombus?
Arterial: mainly platelets
Venous: mainly fibrin
How is arterial thrombosis treated?
Anti-platelet agents (e.g. clopidogrel)
How is venous thormbosis treated?
Anticoagulants e.g. warfarin, rivaroxaban
Components of Virchow’s Triad
What are the risk factors for endothelial damage?
Endothelial dysfunction (endothelium usually helps regulate clotting and vascular relaxation so dysfunction can lead to problems)
- Smoking
- Hypertension
Endothelial damage
- Surgery
- Catheter (PICC line)
- Trauma
What are the 2 categories of hypercoagulability?
- Hereditary
- Acquired
What are the hereditary factors of hypercoagulability\?
- Factor V Leiden
- Prothrombin
- Protein C and S deficiency
What is Factor V Leiden?
An inherited disorder of blood clotting –> a specific gene mutation that results in thrombophilia
This mutation means that Factor V (a cofactor of the clotting cascade) is resistant to inhibition by protein C
What is normal effect of Factor V?
Is a procoagulant molecule that interacts with other clotting proteins including activated factor X and PT to increase the production of thrombin
I.e. helps convert prothrombin into thrombin
What is Factor V normally degraded by?
Protein C
What can a deficiency in Factor V lead to?
Predisposition for haemorrhage (lack of clotting)
What is Prothrombin G20210A?
Mutation in the prothrombin gene causes people to produce more prothrombin than is normal which increases conversion of fibrinogen to fibrin
A genetic condition that increases the risk of blood clot
How can a Protein C and S deficiency lead to clotting?
Protein S and Protein C are both natural anticoagulants:
- Protein C: regulates activities of Factor VIIIa and Factor Va (cofactors in the activation of factor X and prothrombin respectively)
- Protein S: functions as cofactor to protein C in th inactivation of Factor VIIIa and Factor Va
What are protein C and S dependent on?
Vitamin K
What are the acquired causes of hypercoagulability?
- Cancer
- Chemotherapy
- HRT
- High oestrogen states (e.g. the pill)
- Pregnancy
- Obesity
- HIT
How can high oestrogen lead to increased risk of clots?
Oestrogen, like many lipophilic hormones, affects the gene transcription of various proteins. Thus, oestrogen increases plasma concentrations of these clotting factors by increasing gene transcription
What is HIT?
Heparin induced thrombocytopenia - the development of thrombocytopenia (a low platelet count), due to the administration of various forms of heparin, an anticoagulant.
Heparin is a blood thinner used to prevent blood clots. With HIT, your body reacts to heparin in a way that may cause clots instead of preventing them.
Thrombocytopenia means you have a low level of platelets, which are blood cells that help your blood clot. Usually, low platelets would cause you to bleed. But the reaction to heparin may cause clots instead.
How can HIT lead to thrombosis?
Patient may develop antibodies to heparin which in turn leads to thrombosis
These antibodies bind to heparin and activate platelets –> prothrombotic
What are the causes of stasis?
- Immobility
- Polycythaemia
How can immobility lead to thrombosis?
Using muscles less, less squeezing of venous blood back to heart
What is polycythaemia? How can it lead to thrombosis?
An increase in the number of red blood cells. The extra cells cause the blood to be thicker, and this, in turn, increases the risk of other health issues, such as blood clots
Are platelets involved in a clot?
No
Where can clots occur?
Outside a vessel (test tube or hematoma) or inside but only postmortem
What colour is a clot?
Red
Is a clot attached to a vessel wall?
No
describe appearance of clot
Red, gelatinous
Are platelets involved in a thrombus?
Yes
Where does a thrombus occur?
Only inside a vessel
Describe colour of a thrombus in an artery and vein
Red –> venous
Pale –> arterial
Is thrombus attached to vessel wall?
Yes
What are the sequelae of thrombosis?
- Occlusion of vessel (can cause downstream ischaemia or infarction)
- Dissolution (may be broken down and resolves itself)
- Incorporation into vessel wall (may lead to narrowing of vessel lumen)
- Recanalisation (new blood vessels grow into thrombus)
- Embolisation (part of thrombus can break up and travel to another organ where it can cause blockage of a vessel)
What is an embolus?
A mass of material in the vascular system able to become lodged in the vessel and block its lumen
Where are most emboli derived from?
Thrombi - most common are pulmonary embolus derived from DVT which breaks off, travels through venous system into pulmonary arteries
Types of emboli:
- Thrombus derived
- Atheromatous plaque material (bits can break off if overlying fibrous cap is damaged OR if there is haemorrhage into plaque)
- Vegetation on heart valves
- Fragments of tumour (causing metastasis)
- Amniotic fluid
- Gas
- Fat
How can vegetation on heart valves lead to emboli?
If heart valves are damaged then this can predispose to thrombi forming on surface as endothelium is damaged and due to turbulent blood flow.
These thrombi can sometimes become infected –> causes infective carditis, become fragile and can break off
What does the effect of a pulmonary embolus depend on?
The size of the embolus
How can a small emboli lodge?
Can lodge in pulmonary vasculature –> causes increased pressure and therefore pulmonary hypertension
This means right hand side of heart has to work harder –> can get heart failure secondary to lung disease, this is called ‘cor pulmonale’
What is ‘cor pulmonale’?
An alteration in the structure and function of the right ventricle (RV) of the heart caused by a primary disorder of the respiratory system. Pulmonary hypertension is often the common link between lung dysfunction and the heart in cor pulmonale
What are dangers of large pulmonary emboli?
Can lodge in bifurcation of pulmonary artery and blocks it entirely –> sudden death
Where do pulmonary emboli tend to arise/go?
Arise from thrombi that form in the venous system that travel through the veins, into the right side of the heart, through the pulmonary artery and lodge in a smaller vessel
Where do systemic emboli tend to arise from?
Not from veins but from arterial system - generally originate from the heart (left side) or atheromatous plaque
How can systemic emboli be a sequelae of myocardial infarction?
Death of myocardium and overlying endocardium –> predisposes to thrombosis due to damage
Also, part of the heart is no longer functioning correctly which can cause turbulence –> thrombus can form over area of myocardial infarction
How can atrial fibrillation lead to systemic emboli?
Turbulence and pockets of stasis due to mal coordination of atria –> thrombus formation
What is infective endocarditis? How can it lead to systemic emboli?
Infective endocarditis is an infection in the heart valves or endocardium –> can cause thrombi
What 4 major issues can systemic emboli cause?
- CVA (Cerebrovascular accident - a stroke, emboli become lodged in circulation of brain)
- TIA (Transient Ischemic Attack - a temporary blockage of blood to the brain similar to a stroke (“mini-strokes)” but leave no lasting brain damage or residual symptoms
- Gangrene - eath of body tissue due to either a lack of blood flow, commonly affects extremeties
- Bowel necrosis - reduced flow to the GI tract (secondary to vascular occlusion)
What is paradoxical embolism?
A paradoxical embolism refers to an embolus which is carried from the venous side of circulation to the arterial side, or vice versa.
What is the response-to-injury hypothesis behind atherosclerosis?
Chronic inflammatory response to endothelial injury to the arterial wall
What causes endothelial injury?
- hyperlipidaemia
- high blood pressure
- immune reactions
- an irritant (e.g. nicotine)
- diabetes
What follows endothelial injury?
- Monocytes adhere and emigrate into lesion
- Smooth muscle emigrates from the media to the intima, leading to monocytes differentiating into macrophages
- Macrophages and smooth muscle cells engulf the lipid, macrophages become foam cells and a fatty streak appears on the lining
- Smooth muscle proliferation, collagen and other ECM deposition
- Extracellular lipid continues to develop, leading to a fibro-fatty atheroma
What causes macrophages to become foam cells?
They engulf the lipid
What is the earliest lesion in atherosclerosis?
Fatty streak - beginning as multiple minute yellow spots that coalesce into streaks
What is a fatty streak composed of?
Lipid filled foamy macrophages
How do fatty streaks affect flow?
Not significantly raised and do not cause flow disturbance.
What follows a fatty streak?
Atherosclerotic plaque
Appearance of an atherosclerotic plaque?
Appears white-yellow and superimposed thrombus on the plaque appears red
What does an atherosclerotic plaque consist of?
Intimal thickening and lipid accumulation
How do atherosclerotic plaques affect flow?
Impinges on the vessel lumen
What follows an atherosclerotic plaque?
Complicated lesion –> can lead to thrombosis
What are the possible sequelae of atherosclerosis?
- Rupture, ulceration or erosion of the intimal surface
- Haemorrhage into plaque
- Athero-embolism
- Aneurysm formation
What is result of rupture, ulceration or erosion of the intimal surface?
Exposes the blood to highly thrombogenic substances and induces thrombosis, lumen occlusion and maybe ischaemia
What is a thrombus?
A solid mass of blood constituents formed within the vascular system in vivo.
Where can a thrombus occur?
Can occur in the arterial system (most commonly superimposed on atheroma) or the venous system (most commonly due to stasis)
Arterial vs venous thrombosis
What are the 3 factors of Virchow’s Triad?
- Endothelial injury
- Hypercoagulability
- Stasis
What can cause endothelial damage?
smoking, hypertension, surgery, catheter, trauma
What can cause hypercoagulability?
can be hereditary (Factor V Leiden, Prothrombin G20210A, Protein C/S deficiency) or acquired (cancer, chemotherapy, pregnancy, obesity)
What can cause stasis?
immobility or polycythemia
What is polycythaemia?
an increase in the number of red blood cells in the body which causes the blood to be thicker
Once a thrombus develops, what can happen?
- Will occlude the vessel
- May dissolve
- May be incorporated into vessel wall –> causing recanalisation
- May embolise –> problem
What is an embolus?
- Mass of material in the vascular system able to become lodged in the vessel and block its lumen
- 99% are thomrbi derived
What else can form an embolus?
- Atheromatous plaque material
- Vegetation on heart valves (infective carditis)
- Fragments of tumour (causing metastasis)
- Amniotic fluid
- Gas
- Fat
What are the 2 types of emboli?
Systemic or pulmonary
What can a systemic embolus cause?
Generally originating from the heart (myocardial infarction/atrial fibrillation) or an atheromatous plaque. Can cause cerebral infarction, gangrene, bowel necrosis.
Why are areas of turbulent blood flow more vulnerable to atherosclerotic plaques?
Frictional force exerted on blood-vessel walls –> endothelial injury
What is thrombophilia?
A condition in which there’s an imbalance in naturally occurring blood-clotting proteins, or clotting factors
What is cor pulmonale?
The enlargement and failure of the right ventricle of the heart as a response to pulmonary hypertension
What can cause cor pulmonale?
Acute:
- Massive PE
- Injury due to mechanical ventilation
Chronic:
- COPD (most common)
- Chronic PE
What is the medical term for a stroke?
Cerebrovascular accident (CVA)
