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YEAR 2 - Principles of Pathology > 41. Cardiovascular Pathology (HT) > Flashcards

41. Cardiovascular Pathology (HT) Flashcards

1
Q

What is atherosclerosis?

A
  • A pathological process that damages the major arteries and leads to cardiovascular disease (CVD).
  • Atherosclerosis is a disease in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque.
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2
Q

What are some possible consequences of atherosclerosis?

A
  • Acute coronary syndromes:
    • Stable & unstable angina
    • Myocardial infarction
  • Cerebrovascular disease:
    • Strokes
    • Transient ischaemic attacks (TIAs)
  • Peripheral vascular disease:
    • Intermittent claudication
    • Renal failure
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3
Q

Give some statistics relating to the prevalence of atherosclerosis.

A
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4
Q

Where does atherosclerosis occur?

A
  • In large arteries, not veins
  • Particularly at bifurcations
  • Lesions in these arteries are particularly important:
    • Carotid arteries
    • Femoral arteries
    • Coronary arteries
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5
Q

What is this?

A

Carotid atherosclerosis, near the carotid bifurcation.

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6
Q

What is claudication?

A
  • Pain and/or cramping in the lower leg due to inadequate blood flow to the muscles.
  • It is caused by atherosclerosis in the peripheral vessels.
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7
Q

How common is claudication?

A

It affects around 5% of over 65s.

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8
Q

What is it important to remember about claudication?

A

Patients with claudication nearly always have disease in other parts of the circulation, especially the coronary arteries.

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9
Q

Describe and explain the different stages of an atherosclerotic lesion.

[IMPORTANT]

A
  • Fatty streak -> The initial accumulation of lipids in the tunica intima, which is taken up by macrophages that become foam cells. Most of the lipid is intracellular.
  • Fibro-fatty plaque (a.k.a. atheroma?) -> The progessed form of a fatty streak, with increased infiltration of macrophages, smooth muscle cells and T-cells. Contains a core of extracellular lipids and some connective tissue.
  • Complicated lesion -> When the atheroma ruptures, leading to surface events such as thrombosis.
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10
Q

Describe the progression of an atheroma.

A
  • In your 20s and 30s, fatty streaks develop in your arteries.
  • These develop and become early atheromas (a.k.a fibro-fatty plaques?)
  • As these atheromas grow, they can become vulnerable plaques
  • In these cases, the plaque is separated from the lumen by a thin fibrous cap
  • If the fibrous cap thickens, the plaque stabilises
  • If the fibrous cap ruptures, platelets are activated and a thrombus forms -> This is known as a complicated lesion
  • This can then heal, which leads to a very narrow lumen due to mass smooth muscle cell proliferation
  • It can also lead to myocardial infarction if it blocks the artery
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11
Q

In which layer of arteries does atherosclerosis happen?

A

Tunica intima

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12
Q

Summarise the main clinical manifestations of atherosclerosis that are mentioned in the spec.

[IMPORTANT]

A
  • Angina
  • Myocardial infarction
  • Claudication
  • Embolism
  • Aneurysm
  • Ischaemic stroke
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13
Q

What are the cell types involved in atherosclerotic plaques?

A
  • Endothelial cells
  • Smooth Muscle Cells
  • Platelets
  • Macrophages
  • CD4+ helper T cells
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14
Q

Draw the different layers of an artery, showing their relative thickness.

A
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15
Q

Do you need to know how atherosclerosis happens (in terms of cellular and molecular mechanisms)?

A

No, it is on the right hand side of the spec.

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16
Q

Describe the functions of endothelial cells that are relevant to atherosclerosis.

[EXTRA?]

A
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17
Q

Describe the factors released by endothelial cells that are relevant to atherosclerosis.

[EXTRA?]

A
  • Vasodilators
    • Nitric oxide (EDRF)
    • Prostaglandin I2 (PGI2)
  • Vasoconstrictors
    • Endothelin
    • Angiotensin II
  • Anti-thrombotic factors
    • Tissue Plasminogen Activator (tPA)
    • Prostaglandin I2 (PGI2)
  • Prothrombotic factors
    • Thromboxane A2
    • Plasminogen Activator Inhibitor-1(PAI-1)
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18
Q

How is NO implicated in atherosclerosis?

A
  • In normal individuals, NOS is used to synthesis NO in endothelial cells
  • In atherosclerosis, the NOS is uncoupled and instead synthesises superoxide radicals that further damage the endothelium

Thus, it is worth remembering that NOS has both positive and negative effects.

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19
Q

What are platelets and what is their function?

A
  • Small cytoplasmic fragments of megakaryocytes (2-5µM)
  • Play a key role in endothelial cell repair
  • Essential role in haemostasis
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20
Q

What is the lifespan of platelets in circulation?

A

8-10 days

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21
Q

How do platelets adhere to the sub-endothelium?

A

Via collagen receptors.

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22
Q

What do platelets secrete that is relevant to atherosclerosis?

A
  • Smooth muscle cell growth factors (esp. PDGF)
  • Vasoactive mediators (TxA2, 5HT)
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23
Q

How are smooth muscle cells involved in atherosclerosis?

[EXTRA?]

A
  • Secrete elastin and collagens in stable plaques
  • Macrophage-induced smooth muscle cell apoptosis is seen in vulnerable plaques
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24
Q

How are monocytes/macrophages recruited to the site of atherosclerosis?

A

Monocytes are recruited because atherosclerosis involves inflammation. These then turn into macrophages.

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25
Q

How are macrophages involved in atherosclerosis?

[EXTRA?]

A
  • Accumulate modified LDL via Scavenger Receptors (SRs) -> This forms foam cells, which are the main cell type in fatty streak lesions
  • Secrete inflammatory mediators and chemokines -> e.g. IL-1, TNF-a, LTB4
  • Secrete growth factors (M-CSF, PDGF, FGFs)
  • Involved in plaque rupture (via MMPs & TIMPs secretion)
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26
Q

Draw the life cycle of macrophages in atherosclerosis.

[EXTRA?]

A
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27
Q

What builds up the fibrous cap that holds the atherosclerotic plaque apart from the lumen of the artery?

A

Synthetic smooth muscle cells

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28
Q

What effect do macrophages have on the fibrous cap in atherosclerosis?

[EXTRA?]

A

They weaken it by:

  • Secreting proteases, such as matrix metalloproteinase (MMP), which break down the collagen, etc.
  • Secreting platelet derived growth factor (PDGF), which promotes smooth muscle cell proliferation (the SMC then die and damage the fibrous cap too) [CHECK THIS]
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29
Q

What is seen here?

A
  • On the left of each artery, there is the atherosclerotic plaque
  • The red bridge across the centre is the fibrous cap
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30
Q

Describe the different effects that different cell types have on the stability of atherosclerotic plaques.

A
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31
Q

What are some important plasma components involved in atherosclerosis?

[EXTRA]

A
  • Lipoproteins (LDL, mod.LDL, HDL)
  • Coagulation cascade components
  • C-Reactive Protein (CRP)
  • Complement components
  • Oxidants / anti-oxidants
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32
Q

Describe the structure of a lipoprotein particle.

A
  • The central core is filled with lipids, cholesterol and cholesterol esters
  • It is surrounded by a shell of phospholipids, cholesterol and apoproteins
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33
Q

How are lipoproteins classified and what are the different types?

A

They are classified based on density:

  • Chylomicrons
  • Very low density lipoprotein (VLDL)
  • Intermediate density lipoprotein (IDL)
  • Low density lipoprotein (LDL)
  • High density lipoprotein (HDL)
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34
Q

Which lipoproteins are pro and anti-atherogenic?

A
  • VLDL, IDL and LDL are pro-atherogenic
  • HDL is anti-atherogenic
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35
Q

Why is HDL anti-atherogenic?

A
  • Mediates reverse cholesterol transport
  • Has anti-oxidant properties
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36
Q

How can the effects of HDL be increased?

A
  • Medical intervention (e.g. niacin, fibrates)
  • Lifestyle changes (e.g. diet, exercise)
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37
Q

Is all HDL the same?

A
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38
Q

Give two examples of studies relating to atherosclerosis and CVD.

[EXTRA]

A
  • Framingham heart study
  • MRFIT (Multiple Risk Factor Intervention Trial)
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39
Q

Describe the Framingham heart study and its findings.

[EXTRA]

A
  • It was a prospective study of CHD in 5,209 men and women aged 30-62, started in 1948. Recruited 5,124 more adults and spouses in 1971.
  • Conducted physical examinations and lifestyle interviews then monitored every two years (BP, LDL-C, TGs, smoking etc)
  • Findings:
    • 1960 -> Cigarette smoking increases risk of CHD
    • 1961 -> Cholesterol level, hypertension and abnormal ECG increase risk of CHD
    • 1967 -> Obesity increases risk of heart disease
    • 1970 -> Hypertension increases risk of stroke
    • 1976 -> Menopause increases risk of heart disease
    • 1978 -> Psychosocial factors affect heart disease
    • 1988 -> High HDL reduces risk of death
    • 1996 -> Progression from hypertension to heart failure described
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40
Q

Describe the MRFIT study and its findings.

[EXTRA]

A
  • Prospective study of 361,662 middle aged men, recruiting from 1973-1975 at 22 centres in 18 US cities
  • 16 year follow up
  • Findings:
    • Showed a continuous graded relationship of mortality relative risk versus cholesterol levels -> JAMA (1999)
    • Reinforced the importance of muliple stimulatenous risk factors, such as smoking, cholesterol, blood pressure, etc.
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41
Q

Compare the meaning of relative risk and absolute risk in the context of CHD.

A
  • Relative Risk -> The ratio of the likelihood of CHD developing in persons with and without a given risk factor
  • Absolute Risk -> The probability of developing CHD in a finite period, e.g. within the next 10 years
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42
Q

Describe the absolute and relative risk of CVD in a young adult with a high plasma cholesterol level.

A
  • A young adult with a high plasma cholesterol level carries a low absolute risk for CHD
  • But that young adult has a high relative risk compared with a young adult with a low serum cholesterol level
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43
Q

What are some non-modifiable risk factors for CHD?

A
  • A personal history of CHD
  • A family history of CHD
  • Advanced age
  • Gender
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44
Q

What are some modifiable risk factors for CHD?

A
  • High plasma LDL Cholesterol (>5.2mmol/L)
  • Hypertension (>140/90mm Hg)
  • Physical inactivity / Obesity (BMI > 30)
  • Smoking
  • Diabetes
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45
Q

What are the main risk factors for atherosclerosis that are mentioned in the spec?

[IMPORTANT]

A
  • Smoking
  • Diabetes
  • Genetic (LDL receptors)
  • Endocrine (sex)
  • Hypertension
  • Hyperlipidaemia (raised LDL as opposed to HDL)
  • Oxidised LDL
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46
Q

Describe the process of LDL receptor cycling and who discovered it.

A
  • LDL binds to its receptor, which is then internalised
  • The cholesterol joins the endogenously synthesised cholesterol
  • The receptor is then recycled

This was discovered by Michael Brown and Joseph Goldstein, who won the Nobel Prize for it in 1985.

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47
Q

What are some examples of genetic disorders that can increase or decrease the risk of atherosclerosis?

A
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48
Q

What genetic disorder may be caused by changes to LDL receptors?

[IMPORTANT]

A
  • Familial Hypercholesterolaemia
  • This is where there are mutations in the LDL receptors, so that there is reduced uptake into cells and therefore hypercholesterolaemia occurs
  • This increases the risk of atherosclerosis, etc.
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49
Q

What are some examples of genetic variation that contributes to CHD risk factors (i.e. not genetic disorders, just variations in enzymes, etc.)?

A
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50
Q

What are the main stages of atherogenesis?

A
  • Initiation
  • Progression
  • Complication
  • Clinical Sequelae (e.g. myocardial infarction)
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51
Q

Describe how initiation occurs in atherogenesis.

[EXTRA?]

A
  • LDL is transported to the sub-endothelial space of arteries (this is a primary iniating event)
  • The protein and lipids of LDL damaged (forming MM-LDL, oxLDL)
  • Endothelial damage leads to expression of ICAM-1, VCAM and MCP-1
  • This allows monocyte adhesion, diapedesis and chemotaxis
  • Monocytes differentiate into macrophages
  • Macrophage uptake modified LDL via scavenger receptors and become foam cells (found in fatty streak lesions)
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52
Q

Describe how progression occurs in atherogenesis.

[EXTRA?]

A
  • There is continued mononuclear cell recruitment
  • A lipid-rich necrotic core develops in atheromatous lesions
  • There is continued smooth muscle cell migration and proliferation -> These form a fibrous cap
  • Macrophage-smooth muscle cell interactions are important for plaque growth (see flashcards)
  • Microvessels develop within the plaque of intra plaque
  • Raised fibro-fatty plaques may cause arterial stenosis and are the sites of arterial thrombosis
  • It is worth noting the presence of T cells, which could be activated by dendritic cells and then contribute to further immune cell recruitment
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53
Q

How might T cells be involved in atherosclerosis?

A

(Hansson, 2011):

  • Dendritic cells patrol the atherosclerotic lesion
  • They can recognise epitopes on LDL and oxidised LDL, such as ApoB
  • In the lymph nodes, these dendritic cells activate naive T cells
  • These effector T cells then contribute to the recruitment of further cells to the atherosclerosis, etc.
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54
Q

Describe the complications that can occur in atherogenesis.

[EXTRA?]

A

Potential fates of fibro-fatty plaques:

  • Ulceration
  • Thrombosis
  • Vasospasm
  • Embolism
  • Plaque haemorrhage
  • Aneurysm (local dilatation)
  • Artery rupture (especially in cerebral arteries)
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55
Q

Is the mechanism of atherogenesis agree on?

A
  • No, there have been lots of hypotheses and these is still some uncertainty
  • For example, the “Response to Injury Hypothesis” (Russell Ross, 1976) argues that atherosclerosis can be viewed as an unusual form of inflammation which shows many features of wound repair
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56
Q

What are some experimental models of atherosclerosis?

A
  • Cholesterol-fed primates
  • Cholesterol-fed or Watanabe rabbits
  • Diabetic pigs on a high fat diet
  • Mouse models of atherosclerosis (LDLR knockout or ApoE knockout)
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57
Q

What two genes can be knocked out in mice to induce atherosclerosis?

[EXTRA]

A
  • LDL receptor
  • ApoE (this is an apoprotein that is part of VLDL, LDL, etc. that allows the molecule to bind to the LDL receptor)
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58
Q

How can the likelihood of LDL receptor / ApoE knockout mice developing atherosclerosis be increased?

[EXTRA]

A
  • Mice are highly resistant to atherosclerosis.
  • But it helps to feed them a very high cholesterol diet containing cholic acid (Paigen diet) or a Western diet
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59
Q

Describe the lipoprotein levels in normal mice and ApoE knockout mice.

[EXTRA]

A
  • LDL is generated from VLDL after its secretion.
  • But VLDL clearance is more efficient in mice than in humans, so LDL remains lower than in humans.
  • Part of this VLDL clearance is due to the content of apoE, which is better at binding to the LDL receptor than apoB.
  • Mice VLDL has comparatively more apoE, so it is cleared faster. A higher fraction is removed fast enough to avoid conversion to LDL.
  • However, in ApoE knockout mice, this does not happen and therefore the VLDL and LDL levels are increased, predisposing to atherosclerosis.
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60
Q

How can atherosclerosis in mice models be measured?

[EXTRA]

A
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61
Q

How can ApoE knockout mice be used to study the influence of different factors on atherosclerosis?

[EXTRA]

A
  • ApoE knockout mice can be bred with other knockout mice for a different factor, such as CCR2
  • The offspring that are knockouts for both genes are identified
  • The development of atherosclerosis (especially the number of macrophages) in these mice is compared with the mice with just ApE knockout
  • This tells us how important the CCR2 is in atherosclerosis and also helps us understand the pathogenesis of atherosclerosis (since it shows that CCR2 is involved in macrophage migration across the endothelium)

(Boring, 1998)

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62
Q

What causes an atherosclerotic plaque to progress to thrombosis?

A

The plaque gets large enough and ruptures through the endothelium, leading to the activation of platelets.

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63
Q

What is a common histological feature of arterial thrombus formation? What does it indicate?

A
  • Lines of Zhan
  • These are alternating layers of RBCs trapped in fibrin and platelets
  • This is characteristic of sites of rapid arterial blood flow
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64
Q

What are the different stages of haemostasis involving platelets?

A
  • Adhesion of platelets to vessel wall
  • Release of granule contents
  • Aggregation of plateles (plug formation)
  • Co-factors provided for clotting
65
Q

Describe how platelets adhese and aggregate at the site of an atherosclerotic rupture.

A

Adhesion:

  • Platelet GP Ia and VI bind Collagen
  • Platelet GP Ib binds Von Willebrand factor (vWf)

Aggregation:

  • Platelet GP IIb / GP IIIa heterodimers bind to fibrinogen -> This forms fibrinogen bridges

Note: GP = Glycoprotein

66
Q

What are the key mediators of platelet aggregation?

A
  • ADP and TxA2 (thromboxane A2)
  • Thrombin also activates platelets (but is not produced by them)
67
Q

What happens after platelets adhere to a damaged surface?

A

They change shape & release granule contents.

68
Q

What are the types of granules that platelets containand what is stored in each?

A
  • α-granules -> PDGF, thrombospondin, platelet factor 4, fibrinogen, fibronectin, vWf etc.
  • Dense bodies -> ATP, ADP, GDP, GTP, serotonin, calcium

Activated platelets also release TxA2, which is another mediator of platelet aggregation.

69
Q

How can platelet aggregation be studied?

A

Aggregometer:

  • Filled with platelet-rich plasma (PRP)
  • When the platelets aggregate, there is increased transmission of light through the solution, which is a measure of aggregation
70
Q

What is the effect of aspirinGive some exerimental evidence for this.

A
  • Aspirin is a thromboxane (TxA2) inhibitor
  • (Born, 2006) studied this by measuring the effect of adding aspiring to a solution in an aggregometer
71
Q

Are platelets involved in just haemostasis?

A

No, they have a wide range of functions.

72
Q

What are some different targets for drugs that block platelet action? What are these drugs?

[EXTRA?]

A
  • Thromboxane, ADP and thrombin can all be inhibited -> This prevents activation
  • Platelet glycoprotein adhesion receptors can be targeted -> This prevents adhesion
  • Integrins can be inhibited -> This prevent aggregation
73
Q

What are some types of drug that can be used to prevent arterial thrombosis?

[IMPORTANT]

A
  • Thrombolytic agents -> Dissolve existing thrombi
    • Streptokinase
    • Recombinant tissue plasminogen activator (tPA)
  • Antiplatelet agents -> Interfere with platelet activity
    • Aspirin
    • Clopidogrel
    • Abciximab
  • Anticoagulants -> Prevent clot formation and extension
    • Heparin (Warfarin)
74
Q

What is streptokinase and how is it useful?

[IMPORTANT]

A
  • It is an enzyme of beta-haemolytic Streptococci
  • It dissolves blood clots by converting plasminogen into plasmin, so it is good at treating thrombi
  • It is mostly used to treat acute myocardial infarction with aspirin
75
Q

How is streptokinase administered?

A

IV infusion or via catheter at site of arterial blockage

76
Q

What are the limitations of streptokinase use in treating thrombi?

A
  • Most individuals have anti streptokinase antibodies
  • Contraindications include recent Strep infection, stroke, pregnancy
77
Q

What is recmobinant tPA and how is it useful?

[IMPORTANT]

A
  • Recombinant tissue plasminogen activator
  • This works by speeding up the conversion of plasminogen to plasmin
  • It is mostly used to treat acute myocardial infarction with aspirin and heparin
78
Q

How is recombinant tPA administered?

A

IV infusion or via catheter at site of arterial blockage.

79
Q

Give an example of a recombinant tPA.

A

Alteplase

80
Q

What is aspirin used for in arterial thrombosis? How does it work?

[IMPORTANT]

A
  • Non-competitive inhibitor of COX-1 and COX-2
  • Low dose aspirin blocks platelet TxA2 production
  • This prevents platelet activation and aggregation
  • It is used mostly after myocardial infarction, ischaemic stroke or in TIA Unstable angina. It can also be used prophylactically.
81
Q

What are some potential problems in aspiring use (in treating thrombi)?

A
  • Liver or kidney disease
  • Uncontrolled bleeding
  • GI tract problems
  • Aspirin and allergy (AAAS)
  • Alcohol use
82
Q

What is clopidogrel and how is it used?

[EXTRA?]

A
  • It is an inhibitor of the platelet ADP receptor
  • This prevents platelet activation and aggregation
  • It is sometimes used in the treatment and prevention of thrombosis-related conditions instead of aspirin, since it avoids many of the side effects of aspirin
83
Q

What is abciximab and how is it used?

[IMPORTANT]

A
  • It is a type of GPIIb / IIIa inhibitor
  • It is a monoclonal antibody that blocks via steric hinderance
  • This prevents the aggregation of platelets
84
Q

Give some experimental evidence for the effectiveness of abciximab in preventing/treating thrombosis-related conditions.

[EXTRA]

A
  • EPIC trial -> Addition of abciximab to heparin reduced incidence of death, MI, and need for urgent revascularization from 12.8% to 8.3% at 30d
  • EPISTENT -> Endpoint = death, MI, urgent revascularisation in patients within 30d:
    • Stenting plus abciximab-heparin (5.3%)
    • Stenting plus placebo-heparin (10.8%)
85
Q

What are the two types of prevention in cardiovascular disease?

A
86
Q

What surgical treatments for cardiovascular disease are mentioned in the spec?

[IMPORTANT]

A
  • Balloon angioplasty
  • Stenting
  • Coronary bypass
87
Q

What is balloon angioplasty?

A

Using a balloon to stretch open a narrowed or blocked artery with atherosclerotic lesions.

88
Q

What is the problem with balloon angioplasty?

A

The artery can re-narrow quite quickly, so a stent may be placed on top of the balloon to permanently hold the artery open.

89
Q

What is coronary artery bypass and what is it used for?

A
  • A vein from elsewhere in the body is harvested (or the mammary/radial artery can be used)
  • It is used to bypass a blockage in the heart
90
Q

What lifestyle choices can be made to prevent the development of cardiovascular disease?

A
  • Smoking
  • Obesity
  • Physical activity
  • Blood pressure
  • Diet
91
Q

What are some strategies used to lower cholesterol levels?

[Mostly EXTRA]

A
  • Diet and exercise -> Less saturated fat, More aerobic exercise
  • Statins
  • Bile acid sequestrants -> Bind up the bile acid and prevent absorption of cholesterol
  • Nicotinic acid
  • Fibrates -> Decrease triglycerides, but have little effect on total cholesterol
  • Plant stanols (e.g. Flora Pro-Activ) -> Compete with bile acids for uptake
  • Exetimide -> Cholesterol uptake inhibitor
  • Anti PCSK9 antibodies
92
Q

What are statins and how do they work?

[IMPORTANT]

A
  • They are drugs used to lower blood LDL
  • They inhibit HMG-CoA reductase, which means that cholesterol production is reduced
  • They also increases hepatic LDL receptor expression
  • This leads to decreased plasma LDL and plasma triglycerides, as well as slightly increased plasma HDL
93
Q

What are the annual worldwide sales of statins?

A

>$4 billion

94
Q

Give an example of a statin.

[IMPORTANT]

A

Simvastatin

95
Q

Give some experimental evidence for the cost-effectiveness of statins.

[EXTRA]

A

4S study (Scandinavian Simvastatin Survival Study):

  • 4444 patients with angina pectoris or previous myocardial infarction and serum cholesterol 5.5-8.0 mmol/L on a lipid-lowering diet were randomised to double-blind treatment with simvastatin or placebo.
  • At follow-up, the incidence of cardiovascular events was decreased in the treatment group. The requirement for coronary procedures was also decreased.
  • This shows that statins are very cost effective drugs.
96
Q

Is the only effect of statins to decrease plasma LDL?

A

No, they also lead to:

  • Decreased lipoprotein oxidation
  • Improved endothelial function
  • Suppression of inflammation
  • Improved platelet function
  • Increased plaque stability

However, we don’t know if this is due to the direct effects of statins, or if it is just secondary to the lowered LDL.

97
Q

What is a thrombus?

A

A blood clot that forms in situ within a blood vessel that impedes blood flow.

98
Q

What is an embolus?

A

An abnormal mass transported in the bloodstream.

99
Q

What is deep vein thrombosis (DVT)?

A

The formation of a thrombus in a deep vein, most commonly in the legs or pelvis.

100
Q

What is venous thromboembolism (VTE)?

A
  • It is a term for the combination of deep vein thrombosis and pulmonary embolism.
  • It is where a thrombus forms in the deep veins and then dislodges and travels to the lungs, where it causes an embolism
101
Q

What is thrombophlebitis?

A
  • Inflammation of superficial veins due to a blood clot.
  • It is less serious than deep vein thrombosis (DVT).
102
Q

Compare how arterial and venous thrombi form.

[IMPORTANT]

A
  • Arterial thrombi
    • Initiated by platelet activation
    • “White” thrombus
  • Venous thrombi
    • Initiated by venous stasis and hypercoagulability
    • “Red” thrombus

Both may contain the same things, but arterial thrombi have more platelets since they are triggered by endothelial ruptute, while venous thrombi rely more on the clumping of RBCs.

103
Q

Are all emboli derived from thrombi?

A

About 95% are.

104
Q

What does pulmonary embolism lead to?

A
  • Massive pulmonary embolism -> Leads to death
  • Intermediate pulmonary embolism -> Leads to infarction
105
Q

How many pulmonary emboli happen each year in the USA? How many are fatal?

A
  • 600,000 per annum
  • 20,000 are fatal
106
Q

What is systemic embolism, where does it typically originate and what are the causes?

[IMPORTANT]

A
  • An embolism that lodges in a systemic artery (rather than the lungs) [CHECK]
  • Typically originates in LHS of the heart
  • Causes: Atrial fibrillation, Myocardial infarction, Infective endocarditis
107
Q

How does the spec define embolism?

A

Haemostasis in wrong place.

108
Q

Aside from thrombi, what other things can be emboli be made of?

[IMPORTANT]

A
  • Air
  • Fat
  • Pus
  • Athero plaque

And others.

109
Q

Is blood clotting the same as platelet accumulation?

A
  • Haemostasis is the process of preventing excess blood loss
  • Platelet accumulation at the site of injury is considered the first wave of hemostasis and the second wave of haemostasis is mediated by the blood coagulation pathway.
  • The blood clot forms on top of the primary plug.
110
Q

Describe the principle of blood clotting.

A
  • It is a enzyme-controlled pathway that converts fibrinogen to fibrin strands, leading to the formation of a clot.
  • It involves a series of proteases that, when activated, act on one another sequentially to ultimately produce insoluble fibrin.
111
Q

What monomers and enzyme are involved in blood clotting?

A
  • Fibrinogen is converted into fibrin strands
  • This is mediated by thrombin
112
Q

What enzyme is responsible for converting fibrinogen to fibrin?

A

Thrombin

113
Q

What is the inactive form of thrombin?

A

Prothrombin

114
Q

What are the 3 parts of the blood clotting pathway?

A
  • There is the common pathway
  • This is fed into by either the intrinsic or extrinsic pathway
115
Q

What are the two types of fibrin clot and how can they be interconverted?

A

Fibrin loose clot can be converted to a tight clot by factor VIIIa.

116
Q

How are different blood coagulation factors symbolised?

A
  • They are given Roman numerals
  • e.g. Prothrombin is II
117
Q

What are the 4 major blood coagulation factors mentioned in the spec and what is the active form of each?

A
  • Tissue factor (active)
  • Factor VIII
    • Factor VIIIa when active
  • Prothrombin (II)
    • Thrombin (IIa) when active
  • Fibrinogen (I)
    • Fibrin (Ia) when active
118
Q

What activates the intrinsic and extrinsic pathway of blood clotting?

A
  • Intrinsic -> Negatively charged surface
  • Extrinsic -> Tissue and vessel damage
119
Q

Draw a summary of how the 3 pathways of blood clotting are connected.

A
120
Q

Draw out the whole blood clotting pathway in detail.

A
121
Q

Draw out a simplified full pathway of blood clotting.

A
122
Q

Summarise the common pathway of blood clotting.

A
  • Factor X is converted to Factor Xa by either:
    • Factors VIIIa and IXa, Platelet phospholipid and Ca2+ (Intrinsic pathway)
    • Tissue factor XIIa and Ca2+ (Extrinsic pathway)
  • Factor Xa now, along with factor Va and Ca2+ converts prothrombin (II) to thrombin (IIa)
  • Thrombin converts fibrinogen into fibrin, which is in a loose clot
  • The loose clot is turned into a tight clot by factor XIIIa
123
Q

Show how positive feedback occurs in the common pathway of blood clotting.

A
124
Q

How are platelets involved in the common pathway of blood clotting?

A
  • The conversion of prothrombin to thrombin, using factors Xa and Va, as well as Ca2+ occurs on the phospholipid membrane of a platelet
  • The conversion of factor X to Xa using Ca2+ and factors VIIIa and IXa from the extrinsic pathway occurs on the phopholipid membrane of a platelet
125
Q

Which blood coagulation factor is fibrinogen?

A

Factor I

126
Q

Where is fibrinogen made?

A

Liver

127
Q

Which coagulation factor is prothrombin?

A

Factor II

128
Q

What does prothrombin require for activation to thrombin?

A
  • Prothrombin binds calcium binds platelet phospholipid
  • Colocalisation with Factors Xa & Va on platelet membrane
  • Colocalisation -> 10, 000x increase in rate of cleavage
129
Q

What are serine proteases?

A
  • Active forms of Factors II, VII, IX, X, XI & XII are serine proteases
  • (i.e. IIa, VIIa, etc.)
  • The previous serine protease cleaves the next one to activate it
130
Q

How does positive feedback happen in the intrinsic pathway of blood clotting?

A

Thrombin increases the conversion of VIII -> VIIIa

131
Q

What is the crucial modifier that speeds up the intrinsic pathway of blood clotting?

A

Factor VIIIa increases the rate of the conversion of factor X to Xa 200, 000-fold.

132
Q

Draw a diagram showing the different point in the blood clotting pathway that can be targeted pharmacologically (to prevent thrombi, etc.).

A

Note: Heparin and warfarin are mentioned on the spec.

133
Q

What are some natural inhibitors of blood clotting?

[EXTRA?]

A
  • Anti thrombin III (ATIII)
  • Thrombomodulin (TM)
  • Activated protein C (APC)
  • Heparin Cofactor II
  • EPI a.k.a. TFPI
134
Q

What is anti-thrombin III and how is it relevant to cardiovascular disease?

A
  • It is a serpin (serine proteinase inhibitor) produced by endothelial cells and the liver
  • ATIII deficiency can be acquired (eg liver damage) or genetic
  • ATIII-thrombin interaction is stabilised ~2000-4000x by heparin due to allosteric activation, explaining how heparin works
135
Q

What is thrombomodulin and what is its function?

[EXTRA?]

A
  • It is a protein that is activated by thrombin.
  • Therefore, it is activated whenever there is blood clotting, helping to prevent it form becoming excessive.
  • It activates protein C into activated protein C (APC) which has anticoagulant activity and induces fibrinolysis.
136
Q

What is activated protein C (APC) and what it its clinical importance?

[EXTRA?]

A
  • Protein C is activated by thrombin to become Activated Protein C (APC)
  • It cleaves Activated Factor V and Factor VIII
  • Clinical importance:
    • Individuals with genetically inherited resistance to APC are at increased risk of thrombosis
    • Recombinant human APC was shown to protect baboons from lethal coagulopathy caused by E. coli sepsis but clinical trials of recombinant APC in human sepsis have shown no benefit
137
Q

Describe the pathogenesis of pulmonary embolism.

A

An embolism travels to the pulmonary arteries, blocking them and thus cutting off perfusion of the lungs.

138
Q

What are some risk factors for venous thrombosis?

[IMPORTANT]

A
  • Age
  • Venous stasis (esp. in the elderly)
  • Any surgery (esp. orthopaedic and prostate)
  • Pregnancy
  • Infection
  • Malignancy (esp. adenocarcinomas)
  • Genetic
    • AT-III deficiency
    • Protein C Resistance (incl. Factor V Leiden)
    • Others?
139
Q

What is factor V Leiden and why is it relevant?

A
  • It is a mutated allele for clotting factor V.
  • The mutation increases your risk of developing thrombosis.
140
Q

How is cancer related to thromboembolism?

[EXTRA?]

A
  • Cancer patients have a high incidence of thromboembolism, especially those with solid tumours
  • This may be due to:
    • Treatments -> Tamoxifen doubles the risk of VTE and many patients have central venous catheters which are a risk factor for VTE.
    • Decreased liver production of anti-coagulants
    • Direct Factor X activation (involved in conversion of prothrombin)
    • Autoantibodies to phospholipids
    • Cancer cells often express Tissue Factor (TF) or induce TF expression in neighbouring stromal cells -> Tissue factor is part of the blood clotting cascade
    • Local and systemic inflammation induces a pro-thrombotic state
    • Cancer cells shed microparticles
141
Q

Give some experimental evidence for a RCT that studied the prevention of thromboembolism.

[EXTRA]

A

CLOT investigators study (2003):

  • 676 patients with cancer treatment with subcutaneous (sc) heparin monotherapy (dalteparin) was compared with sc heparin switching to oral warfarin.
  • In the 6-month follow up period 8% of the dalteparin group patients had recurrent VTE compared to 15.8% of patients (Hazard ratio 0.48, p = 0.002).
  • No significant difference in bleeding episodes between the two treatment groups.
142
Q

What are the different types of stroke? How common is each? How are they related to thrombi?

A
  • 90% of strokes are ischaemic, 10% are haemorrhagic
  • Of ischaemic strokes 20% are cardioembolic, almost all from patients with atrial fibrillation (AF)
143
Q

What cardiac event may lead to embolism?

A
  • Atrial fibrillation can lead to the pooling of blood in the fibrillating left atrium.
  • This leads to clot formation, which can detach and cause strokes.
144
Q

How can cardioembolic strokes (ischaemic strokes that result from an embolism that forms in the heart) be prevented?

A
  • Traditionally the drug used was warfarin or aspirin
  • But warfarin action is labile -> Thus it is costly and problematic to monitor
  • Newer drugs include NOACs (novel oral anticoagulants), which antagonise the coagulation cascade:
    • Antagonism of Factor Xa (e.g. rivaroxaban)
    • Antagonism of Thrombin (e.g. dabigatran)
  • These produce better results than warfarin, but have side effects, so it is often patient choice
145
Q

What are some examples of anticoagulant drugs for treatment and prevention of venous thromboembolism?

A
  • Heparin [IMPORTANT]
  • Warfarin [IMPORTANT]
  • Apixaban
  • Rivaroxaban
  • Dabigatran
146
Q

Describe the structure of heparin.

A

A long, unbranched polysaccharide chain composed of repeating disaccharide units.

147
Q

How does heparin work?

A
  • ATIII (anti-thrombin III) is an endogenous inhibitor of coagulation factors, especially Factor Xa and Thrombin (IIa)
  • Heparin stabilises these interactions, slowing the clotting cascade
  • Therefore, it is useful for prevention and treatment of thrombosis
148
Q

What conditions is heparin effective against?

A
  • Venous thrombosis (esp. Hip replacement)
  • Pulmonary Embolism
149
Q

How is heparin administered and how quickly does it act?

A
  • Given as IV bolus then subcutaneous
  • Active in minutes
150
Q

What are some problems with heparin use?

A
  • Uncontrolled bleeding
  • Heparin-induced thrombocytopenia (low levels of platelets)
151
Q

How does warfarin work?

A
  • In coagulation factors, the glutamic acid residues must be gamma carboxylated into order to bind calcium, which is necessary for formation of complexes with platelet surfaces.
  • This gamma carboxylation is dependent on vitamin K.
  • Warfarin inhibits this conversion, thus making certain clotting factors ineffective -> Including factors II, VII, IX and X
152
Q

What conditions is warfarin effective against?

A
  • Deep Vein Thrombosis (DVT)
  • Pulmonary Embolism (PE)
  • Thrombosis after heart valve replacement
  • After myocardial infarction / atrial fibrillation -> For prevention of systemic embolisation
153
Q

What are some problems with warfarin use?

A
  • Narrow window of therapeutic effectiveness
  • Major adverse effect is haemorrhage -> Factors affecting bleeding risk include:
    • Intensity of anticoagulation
    • Use of other medications
    • Quality of management
    • Diet
    • Age
  • Contraindications: Pregnancy, alcoholism
154
Q

What are some alternative drugs to warfarin/heparin? Give some experimental evidence for why these are better.

A
  • Newer oral anticoagulant drugs (NOACs)
  • They often target other parts of the coagulation cascade
  • ARISTOTLE trial:
    • 18,201 subjects with atrial fibrillation and one additional risk factor for stroke assigned to either direct factor Xa inhibitor apixaban (5mg twice a day) or oral warfarin (INR 2.0-3.0)
    • Apixaban group had a 21% reduction in stroke risk and a 31% decreased risk of major bleeds. Also showed a 11% decrease in all cause mortality.
155
Q

What is Virchow’s triad?

A

3 main factors that promote thrombosis:

  • Changes in the intimal surface of the vessel
    • Atherosclerosis
    • Trauma
    • Inflammation
    • Neoplasia
  • Changes in the pattern of blood flow
    • Changes in speed -> Systemic (e.g. heart failure) or local (e.g. immobilisation)
    • Turbulent blood flow -> Atrial aneurysm, atrial fibrillation, myocardial infarction
  • Changes in blood constituents
    • Increased procoagulant factors
    • Decreased anticoagulant factors
    • Increased blood viscosity
    • Increased platelet numbers and adhesion/aggregation
    • Presence of anticardiolipin antibodies (eg in SLE)
    • Release of procoagulant factors by tumours

These apply to arterial and venous thrombosis, and atrial fibrillation.

156
Q

Draw a diagram to compare thrombosis in arteries and veins.

A
157
Q

Give a summary of different drug types that can be used to treat clotting disorders.

A
158
Q

What are the different effects of thrombosis that are mentioned in the spec?

[IMPORTANT]

A
  • Stenosis
  • Ischaemia
  • Infarction
  • Embolism
  • Venous leg ulcers
159
Q
A

YEAR 2 - Principles of Pathology (18 decks)

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