Cardiovascular Flashcards
What is normal haemostasis (3)
A physiological response of blood vessels to injury, to prevent blood loss.
□ Accomplished by co-operation between platelets, the coagulation system and endothelial
cells.
□ Limited and controlled by feedback loops and natural antagonists.
What are platelets
Anuclear discs produced by cytoplasmic fragmentation of megakaryocytes in the bone marrow.
How long is the lifespan of platelets
7 days
What is the sequence of responses platelets show to vascular injury (3)
adhesion
activation
aggregation
3 As
What is platelet adhesion
When the endothelial monolayer is damaged, platelets adhere strongly to the exposed ECM proteins, especially collagens
mediated by vWF
What is vWF
von Willebrand factor (vWF)
mediates adhesion of platelets following vascular injury
bridges between glycoprotein IB (GpIb) on the platelet surface and the exposed collagen.
What follows adhesion of platelets following adhesion
what does this involve
activation
i) shape change and ii) chemical secretion
Describe the platelet shape change involved in activation following vascular injury
what is the purpose
from discs to flat plates with long processes.
associated with changes that increase interactions with the coagulation system:
□ modified conformation of GpIIb/IIIa
□ movement of negatively-charged phospholipids to the cell surface
Name 3 chemicals released from platelets during activation
thomboxane A2 (TxA2) vasoactive amines eg 5HT and ADP
Platelets release ADP during activation. What does this do?
what else is released here and what does this do?
ADP activates more platelets, increasing their recruitment to the region of vascular injury,
TxA2: induces platelet aggregation.
What is platelet aggregation initially mediated by?
y the soluble plasma protein fibrinogen bridging between platelets via the GpIIb/IIIa complex.
What is formed by fibrinogen bridging between platelets via GpIIb/IIIa
What is important about the structure formed
a primary haemostatic plug
plug has sufficient internal cohesion to temporarily resist the force of the streaming blood
What does the production of thrombin cause (2)
□ platelet contraction, where the platelet membranes are drawn into close apposition, with eventual fusion to form a solid mass.
□ conversion of fibrinogen to insoluble fibrin strands, which bind the platelets in place. This creates the stable secondary haemostatic plug, which traps red and white blood cells
When are the primary and secondary haemostatic plugs formed
primary: fibrinogen bridging between platelets via the GpIIb/IIIa complex.
secondary: fibrinogen converted to fibrin by thrombin, binding platelets in place
What is the range of effects of reduced platelet count/function on haemostasis
range from purpura (bleeding from skin capillaries) to spontaneous haemorrhage.
What 3 things comprise each proteolytic reaction in coagulation
□ An enzyme (an activated coagulationfactor)
□ The substrate (a pro-enzyme)
□ A co-factor to accelerate the reaction
How can you speed up most of the reactions in the coagulation cascade
if carried out on a phospholipid-rich surface
e.g. on platelets or ‘microparticles’ (fragments of monocyte or platelet plasma membrane).
What is the most important stimulus to start the coagulation cascade in vivo
initiation of the extrinsic pathway by tissue factor derived from damaged tissues.
What is the penultimate step in the coagulation cascade
what are 4 functions of this product
activation of the multi-functional protease thrombin
□ Cleaves soluble fibrinogen into insoluble fibrin monomers
□ Activates factor XIII, which cross-links the fibrin monomers to form polymers (strands)
□ Activates other coagulation factors, e.g. XI, V, VIII, thereby producing positive feedback loops
□binds to various cell receptors, leading to activation of platelets, endothelial cells and leukocytes (neutrophils and monocytes)
What is the inactive precursor of the fibrinolytic system
when is this system activated
plasminogen
activated to accompany laying down of fibrin in order to dissemble the plug
How is plasminogen activated
plasminogen is precipitated along with fibrin in the anterior of the thrombus and is converted to plasmin there
Important mediators of this process include: factor XIIa and plasminogen activators (e.g. tissue plasminogen activator and urokinase)
How do endothelial cells prevent haemostasis in healthy blood vessels (3)
Coagulation inhibition
Platelet inhibition
Activation of fibrinolysis
How do endothelial cells inhibit coagulation in healthy blood vessels (5)
□ physical barrier against tissue factor □ tissue factor pathway inhibitor (TFPI) which inhibits tissue factor/VIIa complexes. □ thrombomodulin □ endothelial protein C receptor □ heparin-like molecules
What is thrombomodulin
expressed on endothelial cell surfaces in healthy vessels
changes the conformation of thrombin so it is less able to activate coagulation factors and platelets. In the presence of thrombomodulin, thrombin becomes able to activate protein C.
What does endothelial protein C receptor do
binds protein C on the cell surface. In turn, protein C binds its co-factor protein S and together they inhibit the activation of Va and VIIIa
What do the heparin like molecules from endothelial cells in healthy blood vessels do
bind anti-thrombin III and inhibit activation of thrombin, IXa and Xa.
How do vascular endothelial cells inhibit platelets normally
□ physical barrier against vWF and extra-cellular matrix
□ prostacyclin (PGI2) and nitric oxide (NO), potent platelet inhibitors
How do vascular endothelial cells activate fibrinolysis
□ production of tissue plasminogen activator(tPA)
What is the dual role of endothelial tissue in haemostasis
Normal healthy blood vessels - prevents haemostasis
After injury to a blood vessel - Activated endothelial cells promote haemostasis
How do activated endothelial cells promote haemostasis after injury to the vessel
□ Breach of the physical barrier exposes vWF, extra-cellular matrix, tissue factor, etc.
□ The cells down-regulate production of anti-haemostatic molecules (e.g. TFPI, thrombomodulin, protein C receptor, tPA, etc.) and upregulate pro-haemostatic molecules, e.g. plasminogen activator inhibitors (PAI).
When does thrombosis occur
when the physiological mechanisms of haemostasis are activated inappropriately. It is a pathological process that may have serious consequences
Define ‘thrombus’
‘a mass formed from blood constituents within the circulation during life’
What comprises a thrombus
fibrin and platelets, with entrapped red and white blood cells.
Where can thrombi form and how can they cause further damage
may form in a cardiac chamber or blood vessel (artery, vein or capillary)
may cause further damage by obstructing the lumen of vessels in which they form, or by breaking off, traveling in the circulation and obstructing a vessel elsewhere (embolism).
How does a blood clot differ from a thrombus
a blood clot, in contrast to a thrombus, is:
□ is formed in static blood
□ involves primarily the coagulation system, without interaction of platelets with the vessel wall, e.g. in vitro when blood is placed in a test tube, or post mortem.
□ is soft, jelly-like and unstructured. It is composed of a random mixture of blood cells suspended in serum proteins.
What can be used to summarise the predisposing factors for thrombosis
Virchow’s Triad (1856):
(i) changes in vessel wall
(ii) changes in blood flow
(iii) changes in the constituents of blood
What causes changes to a blood vessel’s wall, leading to a predisposition to thrombosis (5)
These changes are due to endothelial cell injury or activation, for example due to:
□ ischaemic hypoxia, (e.g. in the endothelium lining the cardiac chamber in coronary artery disease)
□ infection (of blood vessel or adjacent tissues)
□ physical damage (e.g. rupture of atherosclerotic plaques, crushing of veins)
□ chemical damage (e.g. lipids, bacterial lipopolysaccharide, toxins from cigarettes)
□ immunological damage (e.g. deposition of immunecomplexes)
How does changes to blood flow predispose to thrombosis (4)
Disruption of laminar flow can cause:
□ platelets to come into contact with endothelium
□ impaired removal of pro-coagulant factors
□ impaired delivery of anti-coagulant factors
□ direct injury or activation of endothelium
How do the causes of changes in blood flow differ between vessel types (3 each)
Arteries or cardiac chambers: An important cause is turbulence, e.g. due to:
□ narrowing (caused by atherosclerosis)
□ aneurysms (abnormal dilations)
□ infarcted myocardium
Veins: An important cause is stasis, e.g. due to:
□ failure of the right side of the heart
□ immobilization
□ compressed veins (e.g. long flights orbed-rest)
The veins most commonly affected are the pelvic veins and the deep and superficial leg veins.
Give examples of how changes to the constituents of blood can predispose to thrombosis (5)
congenital: Specific genetic causes include deficiency of antithrombin III or protein C.
acquired: □ tissue damage (e.g. trauma, myocardial infarction) □ cigarette smoking □ elevated blood lipids □ oral contraceptive therapy
How does the structure and appearance of thrombi change
depends on rate of flow at the site of formation
(i) Arteries or cardiac chambers
□ Thrombi are compact masses, granular and firm.
□ They contain laminations (lines of Zahn)
(ii) Veins
□ Thrombi often have a pale head with a long red tail.
□ There is often little evidence of lamination
What are the lines of Zahn
laminations in arterial thrombi composed of pale branching layers of fibrin and
platelets and darker layers with more erythrocytes.
Do arterial or venous thrombi show lines of Zahn
arterial
There is often little evidence of lamination, but thrombi in veins still have fibrin and platelets, especially in the head.
Why are the tails of venous thrombi red
The tail is red due to many enmeshed red cells.
What is the possible fate of thrombi (6)
lysis propagation stenosis/ occlusion organisation infection embolization
How can a thrombus be broken down
how can (why would) is be accelerated therapeutically
by the fibrinolytic system
in an attempt to restore blood flow, e.g. streptokinase therapy early after myocardial infarction
Where does propagation of a thrombus usually occur
in relatively stagnant blood beyond an occluded vein.
Propagates in a long tail along the vein, towards the heart.
Do thrombi propagate towards or away from the heart
Propagates in a long tail along the vein, towards the heart.
What is organisation (in the context of a thrombus) (5)
Thrombus induces an inflammatory reaction and subsequent organisation,
consisting of:
□ Partial digestion by enzymes released from leukocytes
□ Monocyte / macrophage phagocytosis of debris
□ Overgrowth and ingrowth of endothelium, with formation of new vascular channels
□ Migration of smooth muscle cells and fibroblasts
□ Synthesis of extra-cellular matrix, e.g.collagen
What can happen to an organised thrombus
may be incorporated into the vessel wall, narrowing the lumen.
Alternatively, the new vascular channels may anastomose and dilate, eventually restoring blood flow (recanalisation).
How can a thombus become infected?
during a transient bacteraemia or from an infection in an adjacent tissue.
What is an embolus
an intravascular mass (solid, liquid or gas) carried by blood flow from its point of origin to impact at a distant site
Give 6 types of emboli
thrombus (thromboembolism), fat, air, atheromatous debris, bone marrow, amniotic fluid.
What are the effects of thromboemboli primarily due to
stenosis or occulsion of vessel at site of impaction, leading to ischaemia/ infarction
What tends to lead to pulmonary embolism
what can this cause
Emboli from systemic veins (usually leg and/or pelvis) or right side of heart
hypoxia, reduced cardiac output, right heart failure and potentially death.
What happens to emboli from the left heart or aorta
enter the systemic arterial system and may pass to the brain, spleen, kidney, gut, legs, etc.
Results may include infarction with subsequent organ failure.
What are the 3 layers of the arterial wall
tunica intima, media, and adventitia
Describe the tunica intima
what functions does it perform (5)
Consists of endothelial cells (flattened cells linked by tight junctions) lying on a basement
membrane.
Endothelial cells perform many functions, including:
□ containment of the blood
□ selective transport of fluids, gases, ions and proteins into tissues
□ control of haemostasis
□ regulation of blood pressure
How long is the lifespan of endothelial cells in healthy adult blood vessels
have a long life (average > 5years)
and only rarely divide (< 1/10,000 dividing at any one time).
However they retain the latent capacity to proliferate (angiogenesis).
What does the tunica media consist of
layers of perforated elastic laminae with smooth muscle cells in between.
The intimal side of the media is bound by the internal elastic lamina and the adventitial side by the external elastic lamina.
What does the tunica adventitia consist of
connective tissue, and contains fibroblasts, leucocytes (mainly macrophages) and nerves, in addition to the lymphatic and blood vessels (vasa vasorum) supplying the artery wall.
describe the wall structure of large arteries
(e.g. aorta, common carotid, common iliac) have prominent elastic laminae in
their media, between the internal and external elastic laminae.
This leads to their classification as elastic arteries. They are exposed to high pulsatile pressures. Their elastic recoil assists the maintenance of continuous flow
give an example of a medium sized artery
eg coronary artery
What are muscular arteries
why are they called this
medium and small arteries
their media is composed largely of smooth muscle cells with fewer elastic fibres.
Separate internal and external elastic laminae are visible.
Contraction of the smooth muscle cells in the tunica media assists in the regulation of blood pressure.
True or false
the function of the entire vessel wall is more than the sum of its parts.
true
The multiple cell types in the vessel wall continually communicate to regulate one another’s fate and function. Therefore they form a system
What is atherosclerosis a disease of
disease of the intima of large and medium sized arteries
What are the lesions in atherosclerosis
focal thickenings of the intima called plaques, which are deposits of fibrous tissue, lipids and cells.
true or false
Arteriosclerosis is the same as atherosclerosis
false
arteriosclerosis implies loss of elasticity and physical hardening of the arterial wall from any cause.
Epidemiological studies have revealed a set of positive risk factors for atherosclerosis and its consequences.
What are these? (7)
(i) Acquired (modifiable) risk factors
□ Dyslipidaemia
□ Cigarette smoking
□ Hypertension
o both systolic and diastolic pressures are important
□ Diabetes mellitus
o via dyslipidaemia, elevated PAI-1 and other factors
(ii) Constitutive (non-modifiable) risk factors
□ Genetics
o A positive family history is a strong predictor of atherosclerotic disease.
o Inheritance is usually polygenic, involving genes affecting factors related to
atherogenesis (e.g. blood pressure, blood glucose regulation, inflammatory
response).
o Some single gene disorders also increase risk, e.g. mutations of the LDL
receptor (familial hypercholesterolaemia).
□ Advancing age
□ Male gender
o pre-menopausal femalesare protected, possibly by oestrogens
What do lipoproteins do
carry hydrophobic lipids in the aqueous environment of the plasma
Describe the structure of a lipoprotein
consist of a lipid core (triglycerides, cholesterol, cholesterol esters and phospholipids) surrounded by apolipoproteins.
What do LDL and HDL do
Low-density lipoproteins (LDL) deliver cholesterol to the peripheral tissues.
High-density lipoproteins (HDL) transport cholesterol from the peripheral tissues to the liver for excretion in the bile.
What are the 2 systems that LDLs transfer lipids into cells
□ The native LDL receptor pathway, which is responsible for cholesterol breakdown. Under-activity of this pathway leads to
hypercholesterolaemia.
□ The scavenger receptor pathway, used by macrophages to take up lipoproteins that have been modified, e.g. oxidised. The scavenger receptor pathway leads to uncontrolled accumulation of cholesterol, after which the macrophages are known as foam cells
Why are macrophages which have accumulated masses of cholesterol called foam cells
named for their foamy appearance in paraffin-embedded tissue sections
What is Dyslipoproteinaemia
an abnormality in the constitution / concentration of lipoproteins in the blood.
may be inherited (e.g. familial hypercholesterolaemia) or secondary to other diseases (e.g. diabetes mellitus).
Which particular types of dyslipoproteinaemia increase the risk of atherosclerosis?
□ increased levels of: cholesterol; low density lipoproteins; lipoprotein a
□ decreased levels of: high densitylipoproteins
What type of diets are high cholesterol blood levels linked to
diets high in:
□ cholesterol
□ saturated fats
□ trans-fats (unsaturated fats with double bonds in trans)
What are high levels of blood HDL linked to
□ exercise
□ modest alcohol consumption (~2 units/day)
What is the blood composition of an obese person usually (3)
□ lower levels of HDL
□ increased levels oftriglycerides
□ (also hypertension and diabetesmellitus)
Give an overview of pathogenesis of atherosclerosis
In atherogenesis, the cellular components of the vessel wall system are disrupted in a prolonged response to injury of endothelial cells.
This leads to a chronic inflammatory process.
What are the key changes to vessel walls in atherosclerosis (6)
(i) Endothelial cell ‘injury’ and dysfunction
(ii) Monocyte migration into the plaque and maturation into macrophages
(iii) Smooth muscle cell activation
(iv) Lipoprotein infiltration
(v) T-lymphocyte migration into the plaque
(vi) Platelet adherence
What is the importance of endothelial injury and dysfunction
This is the key initiator of atherosclerosis.
Endothelial injury leads to altered endothelial cell gene expression, which produces multiple dysfunctional changes in the intima.
Describe the involvement of monocytes in atherosclerosis
Circulating monocytes, recruited by chemotactic factors, adhere to endothelial cells and enter the lesion, where they mature into macrophages
What happens to macrophages once they have infiltrated a lesion after vascular endothelial injury
macrophages phagocytose oxidised lipoproteins to become foam cells.
Macrophage activation induces multiple changes that contribute to atherogenesis.
Macrophage activation after entering an endothelial lesion induces multiple changes that contribute to atherogenesis. What are these? (6)
give the molecules involved with each
activate endothelial cells (IL1; TNF alpha)
recruit and activate mono/lymphocytes (IL2, IL6, chemokines eg MCP1, MIP1 alpha)
Activate smooth muscle (PDGF, FGF, TGF beta)
Modify ECM (collagenase)
Oxidise/ ingest lipoproteins (ROS)
Present antigen to t cells
How are smooth muscles activated in atherogenesis
Macrophages, platelets and endothelial cells produce growth factors (e.g. PDGF and FGF) and reactive oxygen intermediates that activate vascular smooth muscle cells.
What happens to vascular smooth muscle once it is activated in atherogenesis (2)
the smooth muscle cells proliferate, migrate into the intima, change from a contractile phenotype to a synthetic phenotype.
They secrete ECM and release enzymes that assist in matrix remodelling (such as collagenase).
