Cardiovascular Flashcards
(219 cards)
1
Q
What is normal haemostasis (3)
A
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.
2
Q
What are platelets
A
Anuclear discs produced by cytoplasmic fragmentation of megakaryocytes in the bone marrow.
3
Q
How long is the lifespan of platelets
A
7 days
4
Q
What is the sequence of responses platelets show to vascular injury (3)
A
adhesion
activation
aggregation
3 As
5
Q
What is platelet adhesion
A
When the endothelial monolayer is damaged, platelets adhere strongly to the exposed ECM proteins, especially collagens
mediated by vWF
6
Q
What is vWF
A
von Willebrand factor (vWF)
mediates adhesion of platelets following vascular injury
bridges between glycoprotein IB (GpIb) on the platelet surface and the exposed collagen.
7
Q
What follows adhesion of platelets following adhesion
what does this involve
A
activation
i) shape change and ii) chemical secretion
8
Q
Describe the platelet shape change involved in activation following vascular injury
what is the purpose
A
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
9
Q
Name 3 chemicals released from platelets during activation
A
thomboxane A2 (TxA2) vasoactive amines eg 5HT and ADP
10
Q
Platelets release ADP during activation. What does this do?
what else is released here and what does this do?
A
ADP activates more platelets, increasing their recruitment to the region of vascular injury,
TxA2: induces platelet aggregation.
11
Q
What is platelet aggregation initially mediated by?
A
y the soluble plasma protein fibrinogen bridging between platelets via the GpIIb/IIIa complex.
12
Q
What is formed by fibrinogen bridging between platelets via GpIIb/IIIa
What is important about the structure formed
A
a primary haemostatic plug
plug has sufficient internal cohesion to temporarily resist the force of the streaming blood
13
Q
What does the production of thrombin cause (2)
A
□ 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
14
Q
When are the primary and secondary haemostatic plugs formed
A
primary: fibrinogen bridging between platelets via the GpIIb/IIIa complex.
secondary: fibrinogen converted to fibrin by thrombin, binding platelets in place
15
Q
What is the range of effects of reduced platelet count/function on haemostasis
A
range from purpura (bleeding from skin capillaries) to spontaneous haemorrhage.
16
Q
What 3 things comprise each proteolytic reaction in coagulation
A
□ An enzyme (an activated coagulationfactor)
□ The substrate (a pro-enzyme)
□ A co-factor to accelerate the reaction
17
Q
How can you speed up most of the reactions in the coagulation cascade
A
if carried out on a phospholipid-rich surface
e.g. on platelets or ‘microparticles’ (fragments of monocyte or platelet plasma membrane).
18
Q
What is the most important stimulus to start the coagulation cascade in vivo
A
initiation of the extrinsic pathway by tissue factor derived from damaged tissues.
19
Q
What is the penultimate step in the coagulation cascade
what are 4 functions of this product
A
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)
20
Q
What is the inactive precursor of the fibrinolytic system
when is this system activated
A
plasminogen
activated to accompany laying down of fibrin in order to dissemble the plug
21
Q
How is plasminogen activated
A
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)
22
Q
How do endothelial cells prevent haemostasis in healthy blood vessels (3)
A
Coagulation inhibition
Platelet inhibition
Activation of fibrinolysis
23
Q
How do endothelial cells inhibit coagulation in healthy blood vessels (5)
A
□ physical barrier against tissue factor □ tissue factor pathway inhibitor (TFPI) which inhibits tissue factor/VIIa complexes. □ thrombomodulin □ endothelial protein C receptor □ heparin-like molecules
24
Q
What is thrombomodulin
A
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.
25
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
26
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.
27
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
28
How do vascular endothelial cells activate fibrinolysis
□ production of tissue plasminogen activator(tPA)
29
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
30
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).
31
When does thrombosis occur
when the physiological mechanisms of haemostasis are activated inappropriately. It is a pathological process that may have serious consequences
32
Define 'thrombus'
‘a mass formed from blood constituents within the circulation during life’
33
What comprises a thrombus
fibrin and platelets, with entrapped red and white blood cells.
34
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).
35
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.
36
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
37
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)
38
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
39
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.
40
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
```
41
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
42
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.
43
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.
44
Why are the tails of venous thrombi red
The tail is red due to many enmeshed red cells.
45
What is the possible fate of thrombi (6)
```
lysis
propagation
stenosis/ occlusion
organisation
infection
embolization
```
46
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
47
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.
48
Do thrombi propagate towards or away from the heart
Propagates in a long tail along the vein, towards the heart.
49
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
50
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).
51
How can a thombus become infected?
during a transient bacteraemia or from an infection in an adjacent tissue.
52
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
53
Give 6 types of emboli
```
thrombus (thromboembolism),
fat,
air,
atheromatous debris, bone marrow,
amniotic fluid.
```
54
What are the effects of thromboemboli primarily due to
stenosis or occulsion of vessel at site of impaction, leading to ischaemia/ infarction
55
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.
56
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.
57
What are the 3 layers of the arterial wall
tunica intima, media, and adventitia
58
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
59
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).
60
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.
61
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.
62
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
63
give an example of a medium sized artery
eg coronary artery
64
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.
65
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
66
What is atherosclerosis a disease of
disease of the intima of large and medium sized arteries
67
What are the lesions in atherosclerosis
focal thickenings of the intima called plaques, which are deposits of fibrous tissue, lipids and cells.
68
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.
69
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
70
What do lipoproteins do
carry hydrophobic lipids in the aqueous environment of the plasma
71
Describe the structure of a lipoprotein
consist of a lipid core (triglycerides, cholesterol, cholesterol esters and phospholipids) surrounded by apolipoproteins.
72
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.
73
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
74
Why are macrophages which have accumulated masses of cholesterol called foam cells
named for their foamy appearance in paraffin-embedded tissue sections
75
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).
76
Which particular types of dyslipoproteinaemia increase the risk of atherosclerosis?
□ increased levels of: cholesterol; low density lipoproteins; lipoprotein a
□ decreased levels of: high densitylipoproteins
77
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)
78
What are high levels of blood HDL linked to
□ exercise
| □ modest alcohol consumption (~2 units/day)
79
What is the blood composition of an obese person usually (3)
□ lower levels of HDL
□ increased levels oftriglycerides
□ (also hypertension and diabetesmellitus)
80
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.
81
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
82
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.
83
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
84
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.
85
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
86
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.
87
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).
88
What happens to lipoproteins in atherosclerotic plaques
Lipoproteins, especially LDL, become modified (oxidised) in plaques by ROS and enzymes released by macrophages, endothelial cells and platelets.
89
Give 6 facts about oxidised lipoproteins in atherosclerosis
Oxidised lipoproteins:
□ are chemoattractant formonocytes
□ are phagocytosed by macrophages (which become foam cells)
□ induce dysfunction / apoptosisin smooth muscle, macrophages, endothelium
□ stimulate release of cytokines and growth factors from smooth muscle, macrophages, endothelium
□ may be immunogenic
□ inhibit plasminogen activation
90
Give evidence of the importance of oxidised lipoproteins in atherosclerosis
cholesterol-lowering drugs (e.g. statins, which reduce liver synthesis of cholesterol) decrease the frequency of coronary artery atherosclerosis.
91
How are T cells involved in atherogenesis
migrate to the plaque
T-lymphocytes may recognise antigens (e.g. oxidised lipoproteins) and subsequently activate immune responses and cytotoxic killing of cells in the plaque.
92
What happens to platelets in early and late atherosclerotic lesions
In early lesions, platelets adhere transiently to the injured or dysfunctional endothelial cells and release PDGF, which can activate smooth muscle cells.
In advanced lesions, platelets are also involved in thrombosis secondary to plaque ulceration or rupture
93
Together, the processes involved in atherogenesis result in a range of intimal lesions. List them in order of increasing severity (4)
(i) Isolated monocytes / macrophages can be found in the intima soon after birth.
(ii) Fatty streaks or fatty dots
(iii) Fibro-fatty atherosclerotic plaques.
(iv) Complicated plaques
94
How common are fatty streaks
is this dangerous?
common:
By the second decade of life these lesions can be found throughout the vascular tree but especially at branch points.
They cause no significant pathological effects themselves. Their relationship to subsequent atherosclerosis remains controversial.
95
What do atherosclerotic fatty dots/ streaks look like
Macroscopically they are pale yellow streaks or dots.
| Microscopically they are clusters of lipid-laden smooth muscle cells and macrophages (foam cells).
96
Where are fibro-fatty atherosclerotic plaques primarily seen
when do they usually appear
y in the abdominal aorta, coronary arteries, carotid arteries, the
circle of Willis, and at arterial branch points
by the third or fourth decade in men and later in women
97
how do fibro-fatty atherosclerotic plaques appear macro and microscopically
Macroscopically they are raised white-yellow plaques that may coalesce.
Microscopically, the media may appear thinned (atrophic). In the intima there are three regions:
fibrous cap, lipid core, should of cap
98
Describe the fibrous cap of fibro-fatty atherosclerotic plaques.
On the extreme intimal surface of the plaque, composed of collagen, smooth muscle cells, macrophages and T-lymphocytes.
99
Describe the lipid core of fibro-fatty atherosclerotic plaques.
Contains foam cells, and in more advanced lesions necrotic debris and extracellular lipid (particularly cholesterol).
100
Describe the shoulder of fibro-fatty atherosclerotic plaques.
Contains foam cells, smooth muscle cells, T-lymphocytes and new blood vessels (angiogenesis).
101
How can atherosclerotic plaques become complicated (4)
□ may become calcified.
□ may expand due to haemorrhage from new vessels.
□ may rupture / ulcerate, particularly if they are rich in leucocytes or show
haemorrhage.
This may lead to thrombosis and embolisation of plaque fragments.
□ An aneurysm is a localised abnormal dilatation of an artery or cardiac chamber.
Atherosclerosis causes an increased diffusion distance between the arterial lumen and the arterial wall, leading to thinning of the media and fragmentation of the
elastic laminae.
102
How much of human deaths does atherosclerosis account for
Atherosclerosis and its complications account for approximately 50% of human deaths in the Western world.
103
How does atherosclerosis present clinically
clinically silent until it reaches the stage when it causes symptoms and signs.
Often symptoms appear suddenly due to rupture, haemorrhage or thrombosis.
104
how does the progression of atherosclerosis differ between larger and smaller arteries
In smaller arteries, atherosclerosis causes gradual stenosis or occlusion due to plaque progression, haemorrhage, rupture or thrombosis.
In larger arteries embolisation of thrombus formed on the plaque and aneurysm formation are common consequences ofatheroma.
105
Give 3 clinical sequels of atherosclerosis
□ ischaemic heart disease (leading to angina, myocardial infarction and heart failure)
□ peripheral vascular disease (leading to gangrene)
□ cerebrovascular disease (leading to cerebral infarction/stroke)
106
What is ischaemia
inadequate local blood supply to an organ, i.e. an insufficient quantity of blood.
107
Is ischaemia based off quality of blood?
no
□ inadequate oxygen carrying capacity of blood in anaemia
□ inadequate oxygenation in heart / lung failure
are not ischaemia although often worsens it
108
What is infarction
define infarct
necrosis due to ischaemia.
The localised area of necrosis is an infarct
109
Give 5 causes of ischaemia
□ External narrowing or occlusion of vessels, e.g. tumours, compression (bed sores)
□ Internal narrowing or occlusion of vessels, e.g. atherosclerosis, thrombosis, embolism
□ Spasm of vessel, e.g. because of cold(‘frost-bite’)
□ Capillary blockage, e.g. sickle cell disease, cerebral malaria
□ Shock
110
Define shock
Circulatory failure with low arterial blood pressure, which causes impaired perfusion of tissues.
111
What are the different types of shock
cardiogenic
septic
hypovolaemic
anaphylactic
112
Give 4 causes of cardiogenic shock
□ myocardial infarction
□ arrythmia
□ outflow obstruction (pulmonary embolus)
□ external compression
113
2 causes of hypovolaemic shock
□ haemorrhage
| □ severe burns
114
What causes septic shock
Gram positive and negative bacteria
115
What causes anaphylactic shock
□ generalized type 1 hypersensitivity
116
Give 3 consequences of ischaemia
what do these changes lead to
□ Hypoxia
□ Poor supply of nutrients, e.g. glucose and amino acids
□ Failure to remove waste products of metabolism
These changes lead to reduced aerobic respiration and also reduced anaerobic respiration.
117
Give 6 effects of ischaemia on cells
□ Damage to mitochondria
o Depletion of cellular ATP
o Accumulation of reactive oxygenspecies
□ Dysfunction and damage to cell membranes, causing defects in permeability:
o Plasma membrane
o Lysosomal membranes
□ Influx of calcium ions
□ Damage to cytoskeleton
□ Protein mis-folding
□ Damage to DNA
118
True or false
| Loss of cell function may occur rapidly and long before morphological changes appear
true
myocardial cells stop contracting 1 minute after their blood supply is occluded.
In contrast, ultrastructural changes take 30 minutes to develop and histological changes 4-12 hours
119
How do morphological changes occur during ischaemia
sequentially, at a rate that depends on the susceptibility of the cells affected
120
Describe the reversible and irreversible changes that occur in ischaemic tissue (3)
□ Reversible changes will revert to normal if the cause of the ischaemia is resolved.
□ Irreversible changes indicate impending cell death. In ischaemia, death occurs mainly by necrosis, although apoptotic pathways may also be activated.
□ The ‘point of no return’, between reversible and irreversible injury is ill-defined but relates to the severity of damage to mitochondria and cell membranes.
121
What does reversible cell injury after ischaemia look like on ultrasound (5)
□ Cell swelling
□ Plasma membrane blebs (rounded outpouchings)
□ Swellingof organelles, e.g. endoplasmic reticulum, mitochondria
□ Nuclear chromatin clumping
□ May be lipid vacuoles in cytoplasm (fatty change), if the cell metabolises fat (e.g. hepatocytes, myocardial cells)
122
What does reversible cell injury after ischaemia look like histologically
□ Cell swelling
| □ Fatty change
123
What are the 2 key morphological features of necrosis
what causes these changes (2)
denaturation of cytoplasmic proteins and enzymatic digestion of the cell contents.
□ Breakdown of lysosomal membranes, allowing enzymes to leak into the cytoplasm
□ Breakdown of the cell membrane, leading to extra-cellular leakage of cell contents.
In due course, these can induce acute inflammation. The inflammatory cells introduce more lysosomal enzymes, which enter the dying cells through the disrupted cell membrane.
124
What can be seen on ultrasound to indicate necrosis (4)
□ Breakdown of the plasma membrane
□ Breakdown of the nuclear membrane
□ Breakdown of organelle membranes, including lysosome rupture
□ Mitochondrial disruption and deposits of electron-dense material (proteins and calcium)
125
What can be seen histologically in necrotic tissue
□ Increased cytoplasmic eosinophilia, due to loss of RNA (reduced binding of haematoxylin) and denaturation of proteins (increased binding of eosin).
□ Cytoplasm may appear ‘moth eaten’ (reflecting enzymatic digestion)
□ Nuclei may be shrunken (pyknosis), pale (karyolysis) or fragmented (karyorrhexis)
126
Why can necrotic tissue preserve its architecture for several days
what is this called
In necrosis caused by ischaemia, protein denaturation in the cytoplasm is typically more prominent than enzymatic digestion
coagulative necrosis.
127
What is coagulative necrosis.
In necrosis caused by ischaemia, protein denaturation in the cytoplasm is typically more prominent than enzymatic digestion.
As a result, the necrotic tissue preserves its architecture and firmness for several days
128
What is usually detectable first indicating necrosis in the body
give an example
Damage to the plasma membrane of necrotic cells allows the cell contents to leak into the blood.
Elevated levels of cell-specific proteins are typically detectable before morphological changes appear and can be used clinically to provide early evidence of cell death.
For example, in myocardial infarction:
□ histological changes do not appear for 4-12hours
□ elevated levels of enzymes specific to cardiac muscle are detectable in the blood after 2
hours.
129
Give the factors that affect the outcome of ischaemia (8)
(i) Susceptibility of cells
(ii) Susceptibility of organs
(iii) Size of block
(iv) Degree of block (stenosis or occlusion)
(v) Demand oftissue
(vi) General adequacy of the circulatory system
(vii) Speed of onset
(viii) Persistence of the block
130
What determines the susceptibility of cells to ischaemia
use stars to indicate how susceptible different cells are (with ***** being the highest sensitive)
Determined by cellular metabolic rate and oxygen demand, e.g. (in decreasing order of sensitivity):
□ Neurones - very sensitive *****. Irreversibly damaged by only 3 minutes of anoxia.
□ Renal proximal tubular epithelium - sensitive ****. Ion reabsorption function is rapidly impaired.
□ Myocardium - sensitive ***. Irreversible damage after 20 minutes anoxia, but functional impairment (with risk of arrhythmia) within one minute.
□ Skeletal muscle - less sensitive **. Capable of anoxicwork.
□ Fibroblasts and macrophages – insensitive *.
131
What deteremines the Susceptibility of organs to ischaemia
Determined largely by the anatomy of the blood supply to the organ:
□ Collateral circulation - may reduce susceptibility
□ Organs with dual blood supply - if one supply is blocked the other may suffice
□ Single vessel
132
Give 3 examples of organs with dual blood supplies
o lungs are supplied by pulmonary and bronchial arteries (and by alveolar air)
o liver is supplied by hepatic portal vein and hepatic artery
o brain is supplied by circle of Willis
133
Which organs are most susceptible to ischaemia
Organs supplied from a single vessel, so-called functional end arteries, are very susceptible to ischaemia, e.g. kidney,spleen
134
How does demand of the tissue affect the outcome of ischaemia
□ blood supply may become inadequate on exertion, e.g. heart or leg muscles
□ experimentally, induced hypothermia can reduce the effects of brain ischaemia
135
How does the adequacy of the circulatory system affect the outcome of ischaemia
□ outcome may be worse if there is co-existing anaemia, heart failure, impaired oxygenation of the blood, etc.
136
How does rate of onset of ischaemia affect outcome
□ slow onset may allow development of collateral circulation (e.g. coronaries)
□ sudden ischaemia leaves no time for adaptation and causes infarction
137
How persistent is ischaemia
□ some thrombi may be unstable, leading to transient ischaemia, e.g. in brain
□ other blockages may be stable giving persistent ischaemia
138
Why must you be careful when restoring blood flow to previously ischemic tissue
some cells reversible injury may become irreversible.
139
How can successful reperfusion following coronary artery occlusion be achieved
thrombolysis (e.g. using
| streptokinase), angioplasty, coronary artery bypass grafting.
140
Give 2 mechanisms thought to underlie reperfusion injury
□ Generation of fresh mediators of cell injury, e.g.: free radicals, calcium overload
□ Initiation of acute inflammation, by delivery of neutrophils and complement proteins
141
Give 3 key aspects of the microscopic appearance of an infarct
(i) Infarcted tissues show coagulative necrosis.
(ii) Acute inflammation develops at the viable margins within 24 hours.
(iii) Some tissues (e.g. liver) may attempt regeneration, although usually the infarct becomes organised. By around three to five days macrophages start to appear and granulation tissue begins to develop. Over the following six to eight weeks the infarct is replaced by a non-functional fibrous scar.
142
When do histological changes appear in an infarct
□ Histological changes usually appear after 4-12hours.
| There may be earlier biochemical evidence of cell damage
143
Give 7 macroscopic aspects of an infarct's appearance
(i) In acute tissue anoxia there may be capillary dilation, even haemorrhage. Hence the infarct is red (and poorly defined) in the early stages.
(ii) In solid tissue (e.g. heart, kidney, spleen), the infarct becomes pale and well demarcated quite rapidly (usually within 24 hours). These are pale infarcts.
(iii) Some infarcts may remain red due to haemorrhage (red infarcts)
(iv) The shape of the infarct is determined by the blood supply to the tissue
(v) In the early stages the margins of pale infarcts may appear red
(vi) In some tissue (e.g. lung) there is a risk of secondary infection, leading to one type of septic
infarct, which in turn may progress to an abscess.
(vii) In brain, infarcts undergo liquefactive necrosis
144
What are red infarcts
infarcts which remain red due to haemorrhage eg:
□ Arterial occlusion
o in spongy tissue, such as the lung
o in tissues with collateral blood supplies e.g. gut
□ Venous occlusion
145
What shapes are infarcts usually
cone-shaped, with the apex at the point of occlusion and the base at the organ surface.
Such infarcts are wedge-shaped in two dimensions.
146
Why do the margins of pale infarcts appear red early on
what else may be present
what happens to the infarct eventually
represents acute inflammation and/or granulation tissue
there may be a fibrinous exudate on the surface of the organ.
Eventually the infarct is replaced by grey scar tissue
147
What happens to infarcts in the brain
undergo liquefactive necrosis.
The necrotic cells are digested quickly and form a cyst containing liquid, surrounded by reactive glial cells.
The mechanisms underlying this process are poorly understood
148
What causes MI
Usually coronary artery atherosclerosis, complicated by thrombosis.
Predominantly affects the left ventricle
149
Give 8 effects of myocardial infarction
□ dysrhythmia
□ sudden death
□ cardiogenic shock
□ rupture of theinfarct
□ mural thrombosis on the endocardium lining the infarct
□ scarring may lead to cardiac aneurysm, which often contains mural thrombus
□ adaptation to inadequate cardiac output, e.g. dilatation, hypertrophy
□ heart failure
150
What generally causes a pulmonary infarction
give 4 possible effects of this
thromboembolism from pelvic or leg veins
□ may be silent, e.g. ifsmall
□ impaired lung function
□ pressure overload on right heart and possibly right heart failure
□ infection - septic infarcts,abscess
151
Give 3 possible causes of cerebral infarction
□ cerebral artery thrombosis
□ embolism: from the heart (thrombus) or from atheroma, usually in common carotid arteries (thrombus or plaque)
□ shock - common in the elderly
152
What are 2 effects of a cerebral infarction
□ liquefactive necrosis and cyst formation
| □ clinically there is sudden onset of inadequate cerebral function (a stroke)
153
Define anaemia
A reduction in the total circulating RBC mass, with reduced oxygen carrying capacity of the blood
154
How is anaemia usually measured
as a reduction in haemoglobin concentration of the blood
155
why does anaemia arise
because of an imbalance between the rate of production of RBCs and the rate of loss or destruction
156
What are Erythroid progenitors called
erythroblasts (normoblasts) and reticulocytes.
157
What is the normal RBC size
from about 6.0 to 9.5 µm (av. 7.0 µm)
158
What is the lifespan of a RBC
~120 days, after which they are destroyed in the spleen
159
What is haemoglobin composed of
a tetramer of two pairs of polypeptides, each combined with a haem group
160
Give 3 types of symptom common to all forms of anaemia
□ Skin and nails thin, mucous membranes pale
□ Hypoxic damage in viscera (myocardium, kidney, liver, brain)
□ Compensatory changes
vary according to the severity of anaemia
161
Give 3 symptoms of hypoxic damage in viscera in an anaemic patient
o weakness, malaise, easy fatigability
o angina pectoris
o headache, dimness of vision,faintness
162
What are the compensatory changes seen in anaemia (3)
o raised cardiac rate and output
o increased breathing rate (often breathlessness on mild exertion)
o hyperplasia of haematopoietic tissue in bonemarrow
163
Give 3 major causes of anaemia
□ Blood Loss (Haemorrhage)
□ Impaired Generation of RBC or Their Constituents (Dyserythropoiesis)
□ Increased Destruction of Red Cells (Haemolytic Anaemias)
164
Give reasons for dyserythropoiesis
o abnormalities of stem cells (aplastic anaemias)
o abnormalities of erythroblasts and red cell production
□ defective DNA synthesis (megaloblastic anaemia)
□ defective haemoglobin synthesis
□ defective haem synthesis (iron deficiency)
□ defective globin synthesis (thalassaemias)
165
What are 2 things that might increase destruction of RBCs
o intrinsic abnormalities of erythrocyte (usually hereditary)
o extrinsic abnormalities (usually acquired)
166
What causes megaloblastic anaemias
what happens to the RBCs
deficiency of vitamin B12 or folic acid (co-enzymes in synthesis of thymidine)
Cells show impaired DNA synthesis. Nuclear maturation is defective and the cell does not divide.
The cell continues to make RNA and protein and therefore enlarges.
167
Give 7 changes that occur in megaloblastic anaemias
□ Ineffective haemopoiesis (pancytopenia)
□ Expansion of haemopoietic tissue
□ RBC precursors enlarged (megaloblasts) and may appear in the blood
□ RBC enlarged (macrocytosis) and ovalshaped
□ RBC different sizes (anisocytosis) and shapes(poikilocytosis)
□ Iron cannot be utilised normally and is deposited in various organs
□ Effects in other cells and tissues, e.g.:
o neutrophils and megakaryocytes large with hyper-segmented nuclei
o enlarged nuclei in gut epithelial cells
168
What is Vit B12 required for
conversion of the transport form of folic acid, methyl-tetrahydrofolate (me-FH4), to tetrahydrofolate (FH4).
FH4 enables transfer of one-carbon units and is required for thymidine synthesis
169
Where is cobalamin absorbed and stored
□ absorbed in terminal ileum - requires intrinsic factor from gastric mucosa
□ storage in liver - normally provides for 5years
170
Why is B12 deficiency slow to develop
stores in liver
171
What are common causes of cobalamin deficiency
□ inadequate intake, e.g. vegans
□ increased requirements, e.g. pregnancy, anaemia, malignancy
□ malabsorption due to gastric causes
□ malabsorption due to pancreatic deficiency
□ malabsorption due to ileal disease
172
Give an example of cobalamin (B12) deficiency due to gastric causes
pernicious anaemia is intrinsic factor deficiency due to autoimmune destruction of gastric mucosa
173
True or false
| humans are entirely dependent upon dietary folate and cobalamin
true
□ humans are entirely dependent on dietary B12, all from animal sources
□ humans are entirely dependent on dietary folate, e.g. from vegetables, fruit
174
Where is folate absorbed
why are we often folate deficient
how long can folate be stored for
□ absorption in jejunum
□ average Western diet contains excess per day, but 90% destroyed by cooking
□ storage provides 100 daysreserve
175
Give 4 causes of folate deficiency
□ inadequate intake, e.g. the elderly, chronic alcoholics
□ increased requirements, e.g. pregnancy, anaemia, malignancy
□ inadequate absorption in small bowel disease, e.g. coeliac
□ impaired utilisation, e.g. folic acid antagonist methotrexate
176
What is the commonest anaemia in the UK
Iron deficiency anaemia
177
What is the commonest nutritional disease in the world?
iron deficiency
178
True or false
| In Fe deficiency anaemia, RBCs and precursors are not microcytic and hypochromic
```
false
RBC (and precursors) are microcytic and hypochromic. May be poikilocytosis
```
179
What is the daily requirement and average daily intake of iron
□ daily requirement: 7mg for male, 15 mg for female
| □ average daily dietary intake15-20mg
180
What is the major source of iron for humans
□ major source is organic (haem) iron in animal produce (~25% absorbed)
□ also inorganic (non-haem) iron from vegetable produce (~5% absorbed)
181
Where is the iron storage pool
bound in ferritin, which is converted to haemosiderin if there is iron overload
182
How is iron balance maintained
through regulation of iron absorption in the duodenum
183
Describe regulation of iron absorption in the duodenum
There is negative feedback via hepcidin, which is released by the liver if hepatic iron levels rise and prevents iron absorption. Instead, iron is converted to ferritin in mucosal cells, which are shed.
184
Give 4 causes of iron deficiency
□ impaired absorption e.g. small boweldisease
□ increased demand e.g. pregnancy, childhood
□ chronic blood loss to exterior (gastro-intestinal e.g. peptic ulcer, malignancy; genito-urinary e.g. malignancy)
□ low dietary intake e.g. poverty, old age
185
Why can there be changes in nails, hair, tongue, etc in severe iron deficiency
loss of function of iron-containing enzymes (e.g. cytochromes, catalase)
186
What are the 2 types of anaemias due to red cell destruction?
□ extravascular - removal by macrophages, largely in spleen (which enlarges)
□ intravascular - lysis within the circulation
187
What is included in the response to haemolytic anaemia
what will the blood contain
increased erythropoiesis, with expansion of red marrow and extra-medullary haematopoiesis.
increased numbers of reticulocytes and may contain erythroblasts.
188
which causes of haemolytic anaemia are usually a) intrinsic to RBC and b) extrinsic to RBC
a) hereditary
eg
□ Structural defects e.g. hereditary spherocytosis - defects in red cell skeleton produces
deformed spheroidal cells
□ Enzyme defects e.g. pyruvate kinase deficiency - reduced ATP from glycolysis
□ Abnormalities of haemoglobin (haemoglobinopathies)
```
b) acquired
eg:
□ Immune e.g. haemolytic disease of the newborn (Rhesus incompatibility)
□ Physical e.g. valve replacements
□ Chemical e.g. lead poisoning
□ Infection e.g. malaria
```
189
What is the most common haemoglobinopathy
what is it caused by
sickle cell disease
SNV causing a2b2 6 glu -> val (polar to non-polar) on external surface of beta globin protein
190
What happens to HbS homozygotes
dehydration, infection, decreased pO2,decreased pH cause HbS to aggregate and polymerise
This causes distortion of red cells (e.g. sickle or holly leaf shapes), which is initially reversible but becomes irreversible.
191
What are the consequences of sickle cell
□ Haemolysis, mostly in the spleen.
□ Occlusion of small blood vessels with reduced O2 delivery to organs (and more sickling).
□ Tissue hypoxia/infarction can cause pain (e.g. bones, lungs, brain)
□ May also be chronic tissue hypoxia (e.g. affecting growth, kidneys, heart, lungs, etc.)
192
Which small blood vessels are most affected by sickle cell crisis
The microvascular beds most likely to be occluded are those where flow is slow, e.g. spleen, bone marrow, sites of inflammation.
193
What is Hb like in HbS heterozygotes
In heterozygotes (sickle cell trait) only 40% of Hb is HbS - sickling only occurs if severe decreased pO2, decreased pH, etc.
194
How common can heterozygous HbS be
why is this
s up to 30% in some African populations.
A/S children are less likely to die of malaria and have reduced parasite density, compared with A/A children.
The protection is probably due to increased clearance of parasitized red cells following sickling
195
What types of haemoglobin do people normally have
what happens in sickle cell
Normally, humans have haemoglobin A, which consists of two alpha and two beta chains, haemoglobin A2, which consists of two alpha and two delta chains, and haemoglobin F, consisting of two alpha and two gamma chains in their bodies. Of these three types, haemoglobin F dominates until about 6 weeks of age. Afterwards, haemoglobin A dominates throughout life
at least one of the β-globin subunits in haemoglobin A is replaced with what is known as haemoglobin S.
196
What is thalassemia
how common is it
Absent or reduced synthesis of globin chains of HbA (alpha2 beta2)
Endemic in many parts of the world
197
Are people with Thalassaemias protected against malaria
how consistent is the phenotype
yes
| Wide variations in genotype and phenotype
198
What are 2 consequences of thalassaemias
□ Reduced production ofRBCs
o Low globin levels
o Red cells hypochromic, microcytic. May be anisocytosis.
□ Relative excess of other chain (e.g. alpha4, beta4), which precipitate as inclusions.
o Causes damage to cell membrane and impaired DNA synthesis. There is destruction of erythroblasts (ineffective haemopoiesis) and RBCs (haemolysis in spleen).
199
why does haemolysis occur in the spleen in sickle cell
oddly shaped RBCs cannot transverse the capillaries and sinusoids in the spleen
200
What are the β chains of Hb coded by
what do mutations here cause
a single gene on each Chr 11 (2 alleles: b1 and b2. Both contribute 50%)
either a loss of chains ( β0) or inadequate synthesis ( β+) - can lead to β thalassaemias
201
What do mutations in β genes for Hb affect on a genetic expression level
gene transcription (promoter mutations)
RNA splicing (splice sites destroyed or new ones created)
translation (nonsense or frameshift mutations)
202
How does the body compensate for β thalassaemias
Compensatory increase in HbF and sometimes HbA2
203
Which genotypes can lead to thalassaemia major
what is this seen as clinically
β0/β0
β+/β+
β0/β+
where loss of chains = β0 and inadequate synthesis = β+
severe anaemia
204
Which genotypes lead to thalassaemia minor
how is this seen clinically
β0/β
β/β+
where normal= β; loss of chains = β0; and inadequate synthesis = β+
mild anaemia
205
what does ineffective erythropoiesis lead to (3)
bone marrow expansion with erosion of cortical bone (e.g. skull);
extra-medullary haemopoiesis (e.g. liver and spleen);
excessive absorption of dietary iron, producing iron overload (e.g. heart).
206
What encodes the α chain in Hb
What is α thalassaemia usually caused by
2 duplicated genes on each Chr 16
(Each contributes 25% of α globin protein)
Deletion of these genes - levels of α chain synthesis depends on how many genes are deleted
207
How does haemopoiesis and haemolysis compare between α and β thalassaemia
Free β and γ are more soluble than free α chains so haemopoiesis and haemolysis is less severe in α thalassaemia compared to β
208
Can α thalassaemia be silent
Yes if the genotype is:
| -α/αα (only one deletion)
209
What is the genotype of mild anaemia from α thalassaemia
2 deletions:
—/αα or -α/-α
This gives α thalassaemia trait
210
What causes severe anaemia from α thalassaemia
—/-α (3 deletions)
HbH (β4) disease
211
When is α thalassaemia lethal in utero
```
—/— (4 deletions)
Hb Barts (γ4) disease
```
212
What are the 4 types of alpha thalassaemia
Silent: αα/-α (1 deletion)
α thalassaemia trait: -α/-α (2 deletions leading to mild anaemia)
HbH (β4) disease: —/-α (3 deletions leading to severe anaemia)
Hb Barts (γ4) disease: —/— (4 deletions leading to death in utero)
213
define Anisocytosis
abnormal variation in cell size
214
define aplastic anaemia
anaemia due to little or no functional marrow
215
define erythroblast
early nucleated red cell precursor
216
define:
Hypochromia
Hypoplastic anaemia
Macrocyte/Macrocytosis
Hypochromia: pale staining
Hypoplastic anaemia: anaemia due to reduced cellularity of marrow
Macrocyte/Macrocytosis: red cells abnormally large
217
# Define:
Megaloblast:
Microcyte/Microcytosis:
Normoblast:
Megaloblast: abnormally large red cell precursor
Microcyte/Microcytosis: red cells abnormally small
Normoblast: late nucleated red cell precursor
218
What is pancytopaenia
RBC, WBC and platelets in reduced numbers in blood
219
# Define:
Poikilocytosis
Reticulocyte
Spherocyte
Poikilocytosis: abnormal variation in cell shape
Reticulocyte: immature red cell which no longer contains a nucleus
Spherocyte: small spherical red cell
