1
Q
What is anaemia?
A
Reduction in total circulating red blood cell mass
Reduction in oxygen carrying capacity of blood
2
Q
How is anaemia measured?
A
Haemoglobin concentration of blood
3
Q
How does anaemia arise?
A
Imbalance between rate of production of RBCs and rate of destruction
4
Q
What does the megakaryocyte/erythroid precursor (MEP) give rise to?
A
- Erythrocytes
2. Platelets
5
Q
What does the granulocyte/macrophage progenitor (GMP) give rise to?
A
- Macrophages
- Neutrophils
- Eosinohils
- Basophils
6
Q
What does the common myeloid progenitor give rise to?
A
- MEP
2. GMP
7
Q
What does the common lymphoid progenitor give rise to?
A
- B cells and plasma cells
- T cells
- Natural killer cells
8
Q
What are the erythroid progenitors?
A
- Erythroblasts (normoblasts)
2. Reticulocytes
9
Q
What is the diameter of a normal RBC?
A
6 - 9.5 µm (7µm average)
10
Q
What is the RBC life span?
A
120 days
11
Q
Where are RBCs destroyed?
A
Spleen
12
Q
What is the minor form of haemoglobin?
A
HbA2
α2 δ2 chains
13
Q
What are the signs and symptoms of anaemia?
A
- Thin skin and nails
- Pale mucous membranes
- Hypoxic damage in viscera
- Compensatory changes
14
Q
What are the results of hypoxic damage in viscera in anaemia?
A
- Weakness, malaise and easy fatiguability
- Angina pectoris
- Dimness of vision, headache, faintness
15
Q
What are the compensatory changes in anaemia?
A
- Hyperplasia of haematopoietic tissue in bone marrow
- Increased heart rate and cardiac output
- Increased breathing rate
16
Q
What causes anaemia?
A
- Dyserythropoiesis
- Increased destruction of RBCs
- Haemorrhage
17
Q
What is dyserythropoiesis?
A
Impaired generation of RBCs or their constituents
18
Q
What causes dyserythropoiesis?
A
- Stem cell abnormalities
2. Abnormalities of erythroblasts and red cell production
19
Q
What is aplastic anaemia?
A
Anaemia caused by stem cell abnormality
Little or no functional bone marrow
20
Q
What is megaloblastic anaemia?
A
Anaemia caused by defective DNA synthesis
21
Q
What is iron deficiency anaemia?
A
Anaemia caused by defective haem synthesis
22
Q
What is thalassaemia?
A
Anaemia caused by defective globin synthesis
23
Q
What causes haemolytic anaemias?
A
- Intrinsic abnormalities of the red blood cell (usually hereditary)
- Extrinsic abnormalities (usually acquired)
24
Q
What causes megaloblastic anaemia?
A
Deficiency of vitamin B12 or folic acid, which are coenzymes in the synthesis of thymidine
25
What are the features of megaloblastic anaemia?
1. Ineffective haemopoiesis leads to pancytopenia
2. Expansion of haematopoietic tissue
3. Megaloblasts - may appear in blood
4. Macrocytosis
5. Anisocytosis
6. Poikilocytosis
7. Iron deposition in organs
26
What are the effects of megaloblastic anaemia on other cells and tissues?
1. Neutrophils and megakaryocytes are large with hypersegmented nuclei
2. Enlarged nuclei in gut epithelial cells
27
What are megaloblasts?
Enlarged RBC precursors
28
What is macrocytosis?
Enlarged RBCs
29
What is anisocytosis?
RBCs are different sizes
30
What is poikilocytosis?
RBCs are different shapes
31
What is the role of vitamin B12?
Coenzyme required for conversion of transport form of folic acid to tetrahydrofolate (FH4)
32
What is the transport form of folic acid?
methyl-tetrahydrofolate
33
What is the role of tetrahydrofolate (FH4)?
Enables transfer of one-carbon units
Required for thymidine synthesis
34
Where does vitamin B12 come from?
Entirely diet
Animal sources
35
What is the minimum daily requirement of vitamin B12?
1µg
Average diet has hundreds of µg per day
36
Where is vitamin B12 absorbed?
Terminal ileum
Requires intrinsic factor from gastric mucosa
37
Where is vitamin B12 stored?
Liver
5 year store
38
What causes vitamin B12 deficiency?
1. Inadequate intake, eg. vegans
2. Increased requirements
3. Malabsorption due to gastric causes
4. Malabsorption due to pancreatic insufficiency
5. Malabsorption due to ileal disease
39
What is pernicious anaemia?
Intrinsic factor deficiency due to autoimmune destruction of gastric mucosa
40
Where does folate come from?
Entirely diet
Vegetables and fruit
41
What is the minimum daily folate requirement?
50µg
42
Where is folate absorbed?
Jejunum
43
How long does folate storage provide for?
100 day reserve
44
What causes folate deficiency?
1. Inadequate intake, eg. elderly, alcoholics
2. Increased requirements
3. Inadequate absorption in small bowel disease
4. Impaired utilisation
45
What is methotrexate?
Folic acid antagonist
46
What is the commonest anaemia in the UK?
Iron deficiency anaemia
47
What are the features of RBCs in iron deficiency anaemia?
1. Microcytic
2. Poikilocytic
3. Hypochromic
48
What is the daily iron requirement?
7mg for male
| 15mg for female
49
What are dietary sources of iron?
1. Organic (haem) in animal produce (25% absorbed)
| 2. Inorganic (non-haem) in vegetables (5% absorbed)
50
What is ferritin?
Intracellular protein that binds iron and stores it
51
What is haemosiderin?
What ferritin is converted to in cases of iron overload
52
How is iron balance maintained?
Regulation of iron absorption in the duodenum
53
What is hepcidin?
Released by liver when hepatic iron levels rise
Prevents iron absorption
54
What are the causes of iron deficiency?
1. Impaired absorption
2. Increased demand
3. Chronic blood loss, eg. ulcer or malignancy
4. Low dietary intake
55
What are the effects of severe iron deficiency?
1. Loss of function of iron-containing enzymes
2. Malabsorption
3. Changes in nails, hair, tongue, etc.
56
Give two examples of iron-containing enzymes
1. Catalase
| 2. Cytochromes
57
What is extravascular haemolytic anaemia?
Removal of RBCs by macrophages, largely in spleen
Causes splenomegaly
58
What is intravascular haemolytic anaemia?
Lysis of RBCs within the circulation
59
What is the physiological response to haemolytic anaemia?
1. Increased erythropoiesis
2. Expansion of red marrow
3. Extramedullary haemopoiesis
60
What are some features of the blood in haemolytic anaemia?
1. Increased numbers of reticulocytes
| 2. May contain erythroblasts
61
What are the features of intrinsic haemolytic anaemia?
1. Hereditary
2. Deformed erythrocytes cannot travel through spleen sinusoids
3. Trapped RBCs are phagocytosed by macrophages
62
What are the intrinsic causes of haemolytic anaemia?
1. Structural defects
2. Enzyme defects
3. Haemoglobin abnormalities
63
What is hereditary spherocytosis?
Defects in RBC skeleton lead to abnormal spheroidal cells
64
What enzyme defects cause haemolytic anaemia?
Pyruvate kinase deficiency causes reduced ATP production from glycolysis
65
What are the extrinsic causes of haemolytic anaemia?
1. Immune
2. Physical
3. Chemical
4. Infection
66
What is haemolytic anaemia of the newborn?
Immune reaction between maternal antibodies and fetal red blood cells
67
What physical factors cause haemolytic anaemia?
Valve replacement
68
What chemical factors cause haemolytic anaemia?
Lead poisoning
69
What infectious factors cause haemolytic anaemia?
Malaria
70
What causes sickle cell disease?
Point mutation
Changes glutamic acid to valine
Changes polar amino acid on external surface of β globin protein
71
What are the effects of sickle cell disease in homozygotes?
HbS aggregates and polymerises due to infection, dehydration, decreased pO2, decreased pH
72
What are the consequences of sickle cell disease?
1. Haemolysis
2. Occlusion of small blood vessels
3. Tissue hypoxia/infarction
4. Chronic tissue hypoxia
73
Where does haemolysis mostly occur in sickle cell disease?
Spleen
74
Which microvascular beds are most likely to be occluded in sickle cell disease?
Where flow is slow
1. Spleen
2. Bone marrow
3. Sites of inflammation
75
How much Hb is HbS in heterozygotes?
40%
76
Why does HbS protect against malaria?
Only in heterozygotes
Increased clearance of parasitised red blood cells following sickling
77
What is thalassaemia?
Absent or reduced synthesis of globin chains of HbA
78
What RBC conditions protect against malaria?
1. Sickle cell trait
| 2. Thalassaemia
79
What are the two consequences of thalassaemia?
1. Reduced RBC production
| 2. Relative abundance of other globin chain
80
What are some features of RBCs in thalassaemia?
1. Hypochromic
2. Microcytic
3. Anisocytosis
81
What is the effect of relative abundance of other globin chain in thalassaemia?
1. Precipitates as inclusions
2. Damages cell membrane
3. Impaires DNA synthesis
4. Destruction of erythroblasts
5. Destruction of RBCs
82
Which chromosome codes for β chain?
Single gene on chromosome 11
83
What do mutations in β chain cause?
1. Loss of β chain (β0)
| 2. Inadequate synthesis of β chain (β+)
84
What processes might β chain mutations affect?
1. Gene transcription
2. RNA splicing
3. Translation
85
What is thalassaemia major?
Both β chain genes are mutated
β0/β0, β+/β+, β0/β+
Severe anaemia
86
What is thalassaemia minor?
Only one β chain gene is mutated
β0/β or β+/β
Mild anaemia
87
What are the physiological consequences of thalassaemia?
1. Bone marrow expansion with erosion of cortical bone
2. Extramedullary haemopoiesis
3. Excessive absorption of dietary iron
4. Iron overload
88
What are α chains encoded by?
Two duplicated genes on each chromosome 16
Each gene contributes 25% of α globin protein
89
What causes α thalassaemia?
Deletion of α chain genes
90
Which thalassaemia is more severe?
β thalassaemia
Free β and γ chains are more soluble than free α chains
91
What is HbH (β4) disease?
--/-α
Severe anaemia
92
What is Hb Barts (γ4) disease?
--/--
Lethal in utero
93
What is pancytopaenia?
Reduced numbers of RBCs, WBCs and platelets in blood
94
What is a reticulocyte?
Immature red blood cell that no longer contains a nucleus
95
What is an erythroblast?
Early nucleated red blood cell precursor
96
What is a normoblast?
Late nucleated red blood cell precursor
97
What is normal haemostasis?
Physiological response of blood vessels to injury, to prevent blood loss
98
What accomplishes haemostasis?
1. Platelets
2. Proteins of plasma-based coagulation cascade
3. Endothelial cells
99
What are platelets?
Discoid anuclear bodies
Produced by cytoplasmic fragmentation of megakaryocytes in bone marrow
100
What is the lifespan of a platelet?
7 days
101
How are platelets activated?
By extracellular matrix proteins
Especially collagens exposed when endothelial layer is monolayer damaged
102
How do platelets adhere to collagen?
Strongly
Via von Willebrand factor
103
What do platelets do once they adhere to collagen?
1. Change their shape
2. Shoot out long processes
3. Secrete chemical signals
104
What chemical signals do platelets secrete?
1. Thromboxane A2
2. Vasoactive amines, eg. 5HT
3. ADP
105
What do platelet signals promote?
1. Vasoconstriction
| 2. Platelet aggregation
106
What forms the primary haemostatic plug?
Aggregated platelets in damaged blood vessel
Platelet membranes drawn into close apposition with eventual fusion
107
What molecules mediate platelet contraction in the haemostatic plug?
1. Integrins, eg. aIIbβ3
2. Ig superfamily junctional adhesion molecules
3. Endothelial cell specific adhesion molecules
4. Kinase-ligand combination of eph and ephrin families
108
What are the effects of integrins and eph/ephrins?
1. Cytoskeletal alterations
2. Myosin-dependent contraction
3. Retraction of blood clot
109
What are the effects of haemostasis with reduced platelet number?
1. Purpura
| 2. Spontaneous haemorrhage
110
What is purpura?
Bleeding from skin capillaries
111
Where does tissue factor come from?
1. Damaged tissues
| 2. Surface of activated endothelial cells
112
What is the role of thrombin?
1. Catalyses conversion of fibrinogen into fibrin monomers, which then polymerise into fibrin strands
2. Activates platelets
3. Catalyses earlier steps in coagulation cascade
113
What accelerates reactions of activation of factor X?
If carried out on phospholipid-rich surface, eg. platelets or other microparticles
114
What are so-called 'microparticles'?
Fragments of monocyte or platelet plasma membrane
115
What forms the secondary haemostatic plug?
Meshwork of fibrin strands with fused platelets
116
What is the role of the fibrinolytic system?
To dissolve the fibrin plug
117
What is plasminogen?
The inactive precursor of the fibrinolytic system
Precipitated along with fibrin in interior of thrombus
118
What is the role of plasmin?
Activated form of plasminogen
Protease
Breaks down fibrin
119
What is the role of endothelial cells in normal blood vessels?
Inhibit haemostasis
Insulate tissues from blood
Produce enzymatic and chemical inhibitors
120
What enzymatic and chemical inhibitors are produced by endothelial cells in healthy blood vessels?
1. Nitric oxide
2. Prostacyclin
3. Antithrombin
4. Tissue factor pathway inhibitor
5. Thrombomodulin
6. Protein S
121
What do nitric oxide and prostacyclin do?
Potent inhibitors of platelet activation
122
What does antithrombin do?
Expressed on cell surface
Binds and inactivates thrombin
Complexes then released from endothelial cells and cleared in liver
123
What does tissue factor pathway inhibitor do?
Blocks activation of factor X by tissue factor
124
What does thrombomodulin do?
Expressed on cell surface
Changes conformation of thrombin so that it is less able to cleave fibrinogen during coagulation cascade
Enables thrombin to activate protein C
125
What is protein C?
Inhibits coagulation cascade
Inactivates factor V and factor VIII
126
What is protein S?
A co-factor for protein C
127
What is the role of damaged endothelial cells?
Promote haemostasis
Underlying tissue activates platelets and coagulation cascade when endothelial layer is breached
128
How do endothelial cells promote haemostasis?
1. Synthesis of necessary enzymes and chemical mediators
| 2. Express binding sites that increase activity of factors X and IX
129
What enzymes and chemical mediators are produced by damaged endothelial cells?
1. von Willebrand factor
| 2. Tissue factor (thromboplastin)
130
What is von Willebrand factor?
Promotes platelet adhesion to matrix proteins, such as collagen, following injury
131
What does tissue factor (thromboplastin) do?
Activates coagulation
132
What is thrombosis?
Inappropriate activation of haemostasis
133
What is a thrombus?
Mass formed from blood constituents in the circulation during life
134
What is a thrombus made of?
Fibrin and platelets, with entrapped red and white blood cells
135
Where might thrombi form?
1. Cardiac chamber
| 2. Blood vessel
136
How do thrombi cause damage?
1. Obstruct lumen of vessels in which they form
| 2. Break off and form emboli
137
What is a blood clot?
Formed in static blood
Involves coagulation system without interaction of platelets with vessel wall
138
What is the structure of a blood clot?
Soft, jelly-like and unstructured
Random mixture of blood cells suspended in serum proteins
139
What is Virchow's triad?
Factors predisposing to thrombosis
1. Changes in vessel wall
2. Changes in blood flow
3. Changes in constituents of blood
140
What causes changes in vessel wall?
1. Ischaemic hypoxia
2. Infection
3. Physical damage
4. Chemical damage
5. Immunological damage
141
What might cause physical damage to a vessel wall?
1. Rupture of atherosclerotic plaque
2. Crushing of veins
3. Haemodynamic stress in hypertension
142
What might cause chemical damage to a vessel wall?
1. Lipids
2. Bacterial LPS
3. Toxins from cigarette smoke
143
What is the effect of disruption of laminar flow?
1. Platelets come into contact with endothelium
2. Impaired removal of pro-coagulant factors
3. Impaired delivery of anti-coagulant factors
4. Direct injury or activation of endothelium
144
What causes a change in blood flow in the arteries or cardiac chambers?
Turbulence
145
What causes turbulence?
1. Narrowing
2. Aneurysms
3. Myocardial infarction
4. Abnormal cardiac rhythm
5. Valvular heart disease
146
What causes a change in blood flow in the veins?
Stasis
147
What causes stasis in veins?
1. Right-side heart failure
2. Immobilisation
3. Compressed veins
4. Varicose veins
5. Increased viscosity of blood
148
Which veins are most commonly affected by thrombosis?
1. Pelvic veins
2. Superficial leg veins
3. Deep leg veins
149
What genetic causes change the constituents of blood?
1. Antithrombin III deficiency
| 2. Protein C deficiency
150
What acquired causes change the constituents of blood?
1. Tissue damage
2. Post-operative state
3. Cigarette smoke
4. Oral contraceptives
5. Elevated blood lipid
6. Malignancy
151
What is the appearance of a thrombus in the arteries or cardiac chambers?
Compact mass
Granular and firm
Contains laminations
152
What are lines of Zahn?
Laminations in thrombus
Composed of pale branching layers of fibrin and platelets and darker layers with more erythrocytes
153
What is the appearance of a thrombus in the veins?
Pale head with long red tail
Tail is red due to enmeshed red cells
Few laminations
154
What is the fate of a thrombus?
1. Lysis
2. Propagation
3. Stenosis/occlusion
4. Organisation
5. Infection
6. Embolisation
155
How is a thrombus lysed?
Broken down by fibrinolytic system
May be accelerated by streptokinase therapy
156
What is thrombus propagation?
Occurs in relatively stagnant blood beyond an occluded vein
Propagates along tail toward heart
157
What is thrombus organisation?
Thrombus induces inflammatory reaction and subsequent organisation
1. Retraction of thrombus and partial digestion by leukocyte enzymes
2. Monocyte/macrophage phagocytosis of debris
3. Overgrowth and ingrowth of endothelium, forming new vascular channels
4. Migration of smooth muscle cells and fibroblasts
5. Synthesis of extracellular matrix
158
What is the fate of the organised thrombus?
1. Incorporated into vessel wall, narrowing lumen
| 2. New vascular channels may anastomose and dilate, leading to recanalisation
159
How may a thrombus be infected?
1. During a transient bacteraemia
| 2. From an infection in adjacent tissue
160
What is an embolus?
Intravascular mass carried by blood flow from its point of origin to a distant site
161
What are the different types of embolus?
1. Thrombus
2. Fat
3. Air
4. Atheromatous debris
5. Bone marrow
6. Amniotic fluid
162
What are the primary effects of thromboemboli?
1. Stenosis or occlusion of blood vessels
2. Ischaemia
3. Infarction
163
Where do emboli from systemic veins or right side of heart lodge?
Pulmonary artery
This is a pulmonary embolus
164
What are the effects of a pulmonary embolus?
1. Hypoxia
2. Reduced cardiac output
3. Shock
4. Death
5. Pulmonary infarction
6. Right sided heart failure
165
Where do emboli from arteries or left side of heart lodge?
Systemic arterial circulation
Brain, spleen, kidney, gut, legs, etc
166
What are the effects of arterial thrombi?
Infarction
Subsequent organ failure
167
What are the effects of infected emboli?
Pyaemia
Abscess formation where they lodge
168
What are the three layers of the arterial wall?
1. Tunica intima
2. Tunica media
3. Tunica adventitia
169
What does the tunica intima consist of?
Endothelial cells lying on a basement membrane
170
What functions do endothelial cells perform?
1. Containment of blood
2. Selective transport of ions, gases, fluids and proteins into tissues
3. Control of haemostasis
4. Control of blood pressure
171
Give three features of endothelial cells lining healthy adult blood vessels
1. Long lifespan (~5years)
2. Rarely divide
3. Resistant to apoptosis
4. Retain latent capacity to proliferate and remodel
172
What does the tunica media consist of?
Layers of perforated elastic laminae with smooth muscle cells in between
Internal elastic lamina on intimal side
External elastic lamina on adventitial side
173
What does the tunica adventitia consist of?
Connective tissue
Contains fibroblasts, leukocytes, nerves, lymphatics and arterial blood supply
174
What is the arterial wall blood supply?
Vasa vasorum
175
What are elastic arteries?
Large arteries
Prominent elastic laminae in their media
Exposed to high pulsatile pressures
Elastic recoil assists maintenance of continuous flow
176
What are muscular arteries
Medium and small arteries
Media composed largely of smooth muscle cells with fewer elastic fibres
177
What is atherosclerosis?
Disease of the intima of large and medium sized arteries
The lesions are focal thickenings of intima called plaques
178
What are atherosclerotic plaques?
Deposits of fibrous tissues and lipids
179
What is arteriosclerosis?
Loss of elasticity and physical hardening of arterial wall of any cause
Often accompanied by calcification of wall
180
Give the four MAJOR positive risk factors for atherosclerosis
1. Hyperlipidaemia
2. Cigarette smoking
3. Hypertension
4. Diabetes mellitus
181
Give some of the minor positive risk factors for atherosclerosis
1. Obesity
2. Excess alcohol consumption
3. Advancing age
4. Family history
5. Male gender
6. Stressful/sedentary lifestyle
7. Low birth weight
8. Socioeconomic status
9. Infection, eg. chlamydia
182
Give four negative risk factors for atherosclerosis
1. Moderate alcohol consumption
2. Female gender
3. High circulating HDL levels
4. Cardiovascular fitness
183
What do lipoproteins consist of?
Lipid core surrounded by apolipoproteins
184
What is found in the lipid core of a lipoprotein?
1. Triglycerides
2. Cholesterol
3. Cholesterol
4. Phospholipids
185
What are the two pathways by which lipoproteins transfer the proteins they carry into cells?
1. LDL receptor pathway
| 2. Scavenger receptor pathway
186
What is the LDL receptor pathway?
Most active in hepatocytes
Responsible for cholesterol breakdown
187
What does underactivity of the LDL receptor pathway lead to?
Hypercholesterolaemia
188
What is the scavenger receptor pathway?
Used by macrophages to take up lipoproteins that have been modified
Leads to uncontrolled accumulation of cholesterol
189
What are foam cells?
Macrophages containing lost of cholesterol due to the scavenger receptor pathway
190
What is dyslipoproteinaemia?
Abnormality in the constitution/concentration of lipoproteins in the blood
191
What causes dyslipoproteinaemia?
1. Genes - familial hypercholesterolaemia
| 2. Secondary to other diseases - diabetes, hypothyroidism
192
What kind of blood lipid profile increases the risk of atherosclerosis?
Increased cholesterol, triglycerides, LDL and lipoprotein A
Decreased HDL
193
What have mice models shown about atherosclerosis?
Mice deficient for ApoE or LDL receptors develop advanced atherosclerotic lesions
Mice deficient for scavenger receptors SR-A or CD36 show a modest reduction in lesions
Mice that cannot store cholesterol due to a deficiency in ACAT have a reduction in lesions
194
What initiates atherosclerosis?
Endothelial cell injury or dysfunction
195
What does endothelial injury result in?
1. Altered permeability
2. Adhesion of leukocytes
3. Activation of thrombosis
196
Which adhesion molecules are expressed in response to endothelial injury?
1. P and E selectin
2. VCAM-1
3. ICAM-1
197
Which chemokines are expressed in response to endothelial injury?
1. MCP-1
2. IL-1 and IL-8
3. M-CSF
198
Which chemokine receptors do macrophages express inside lesions?
1. CCR2
| 2. CXCR2
199
What are the roles of macrophages when they migrate to intima lesions?
1. Present antigens to T cells
2. Activate endothelial cells
3. Oxidise/take up lipids via scavenger receptors
4. Modify matrix
5. Activate smooth muscle cells
6. Promote coagulation
200
How are smooth muscle cells activated in atherosclerosis?
Macrophages, platelets and endothelial cells produce growth factors and ROS
201
What happens to smooth muscle cells activated in atherosclerosis?
1. Migrate to intima
2. Change phenotype from contractile to synthetic
3. Secrete ECM
4. Release enzymes that assist in matrix remodelling
202
What does collagenase do?
1. Breaks down collagen
| 2. Assists in matrix remodelling
203
What causes lipoprotein oxidation?
1. ROS intermediates
| 2. Enzymes released by platelets, macrophages and endothelial cells
204
What do oxidised lipoproteins do?
1. Chemoattractant for monocytes
2. Phagocytosed by macrophages
3. Stimulate various cells in plaque to release cytokines and growth factors
4. Induce dysfunction in smooth muscle, macrophages, endothelium
5. May be immunogenic
6. Inhibit plasminogen activation
205
What do anti-oxidants do?
1. Inhibit formation of oxidised lipids
| 2. Reduce risk of myocardial infarction
206
Give two examples of anti-oxidant
1. Vitamin E
| 2. Nitric oxide
207
What is the role of T lymphocytes in atherosclerotic plaque formation?
Activate immune responses and cytotoxic killing in plaque
208
What do platelets do in early atherosclerotic lesions?
1. Adhere to injured endothelium
| 2. Release PDGF
209
What is PDGF?
Platelet-derived growth factor
Activates smooth muscle cells
210
What do platelets do in advanced atherosclerotic lesions?
Involved in thrombosis in rupture of plaque occurs
211
What are the four types of intimal lesions?
1. Isolated monocytes/macrophages
2. Fatty dots or fatty streaks
3. Fibro-fatty atherosclerotic plaques
4. Complicated plaques
212
Where are fatty streaks found?
Throughout vascular tree but particularly at branch points
By second decade of life
213
What are fatty streaks?
Clusters of lipid-laden smooth muscle cells and foam cells
214
Where are fibro-fatty atherosclerotic plaques found?
Principally in abdominal aorta, coronary arteries, carotid arteries, circle of Willis, arterial branch points
Appear by third/fourth decade in men, later in women
215
What are fibro-fatty atherosclerotic plaques?
Raised white-yellow plaques that may coalesce
Atrophic media
Fibrous cap, lipid core and shoulder
216
What is the fibrous cap?
On extreme intimal surface of plaque
Composed of collagen, smooth muscle cells, macrophages and T cells
217
What is the lipid core?
In plaque
Contains foam cells
May contain necrotic debris and extracellular lipid, esp. cholesterol
218
What is the shoulder of the cap?
Contains foam cells, smooth muscle cells, T cells and new blood vessels
219
What are the features of complicated plaques?
May be calcified
May expand due to haemorrhage
May rupture/ulcerate
May form aneurysms due to thinning media
220
What is diffuse intimal thickening?
Due to build up of smooth muscle cells, collagen and elastin in intima
Associated with ageing, hypertension and chronic inflammation
221
What are the most important clinical sequels of atherosclerosis?
1. Ischaemic heart disease
2. Peripheral vascular disease
3. Cerebrovascular disease
4. Aneurysms
5. Renal failure
222
What causes intermittent claudication?
Peripheral vascular disease
223
What is ischaemia?
Insufficient local blood supply to an organ
Insufficient quantity
224
What is infarction?
Necrosis due to ischaemia
225
What are the five causes of ischaemia?
1. External occlusion of blood vessels
2. Internal occlusion
3. Spasm of vessel
4. Capillary blockage
5. Shock
226
What is shock?
Circulatory failure with low arterial blood pressure
Causes impaired perfusion of tissues
227
What are the four types of shock?
1. Cardiogenic
2. Hypovolaemic
3. Anaphylactic
4. Septic
228
What causes cardiogenic shock?
Heart cannot pump blood due to MI, arrhythmia, outflow obstruction, external compression
229
What causes hypovolaemic shock?
1. Haemorrhage
| 2. Severe burns
230
What causes septic shock?
Gram positive and Gram negative bacterial infection
231
What causes anaphylactic shock?
Generalised type 1 hypersensitivity
232
What are the metabolic consequences of ischaemia?
1. Hypoxia
2. Poor nutrient supply
3. Failure to remove waste products
233
What are the cellular consequences of ischaemia?
1. Reduced aerobic respiration
2. Decreased ATP production
3. Reduced protein synthesis
4. Damage to DNA, membrane and cytoskeleton
5. Cell swelling due to failure of sodium pump
234
Which cells are most susceptible to ischaemia?
Decreasing order of sensitivity:
1. Neurons
2. Renal proximal tubule epithelium
3. Myocardium
4. Skeletal muscle
235
Which cells are least susceptible to ischaemia?
Macrophages and fibroblasts are insensitive
236
How long does it take for neurons to suffer irreversible damage following anoxia?
3 minutes
237
How long does it take for myocardium to suffer irreversible damage following anoxia?
20 minutes
Functional impairment after one minute
238
What determines the susceptibility of organs to ischaemia?
Anatomy of blood supply to the organ
239
What is the dual blood supply of the lungs?
Pulmonary and bronchial arteries
240
What is the dual blood supply of the brain?
Circle of Willis
241
What is the dual blood supply of the liver?
Hepatic artery and portal vein
242
Which organs are most susceptible to ischaemia?
Organs supplied from a single vessel
Kidney and spleen
243
Give eight factors that affect outcome of ischaemia
1. Anatomy of blood supply to organ
2. Size of block
3. Degree of block
4. Speed of onset
5. Persistence of block
6. Vulnerability of tissue
7. Demand of tissue
8. General adequacy of circulation
244
What causes transient ischaemia?
Unstable thrombi that break down
245
What are the outcomes of ischaemia?
1. No effect
2. Functional defects
3. Reversible cell damage
4. Infarction
5. Ischaemic reperfusion injury
246
What are the microscopic features of infarction?
1. Ischaemic coagulative necrosis
2. Acute inflammation around the edges after 24 hours
3. Organisation of infarct
4. Non-functional fibrous scar after 6 - 8 weeks
247
What are the features of coagulative necrosis?
1. Cytoplasm shows eosinophilia
2. Nuclei may be pale, shrunken or fragmented
3. Tissue architecture preserved for several days
248
What is karyolysis?
Pale nucleus
249
What is pyknosis?
Shrunken nucleus
250
What is karyorhexis?
Fragmented nucleus
251
When do macrophages appear in the infarct?
3 - 5 days
Granulation tissue starts to develop
252
How does the infarct appear in the early stages?
Red due to capillary dilatation and haemorrhage
Poorly defined
253
What is a pale infarct?
Infarct in solid tissue
After 24 hours
Well demarcated
254
What is a red infarct?
Infarct remains red due to haemorrhage
Result of artery occlusion or venous occlusion
255
What is the shape of an infarct?
Determined by blood supply to tissue
Usually cone-shaped
Apex at point of occlusion
Base at organ surface
256
What is on the surface of the infarcted organ in the early stages?
Acute inflammation and granulation tissue at margin of infarct
Fibrinous exudate on surface of organ
257
What is the infarct eventually replaced by?
Grey scar tissue
258
What is a septic infarct?
Secondary infection of infarct that may lead to abscess formation
259
What occurs after an infarct in the brain?
Liquefactive necrosis
Necrotic cells digested quickly
Forms cyst containing liquid
Surrounding by reactive glial cells
260
What is ischaemic reperfusion injury?
Reversible injury that becomes irreversible due to restoring blood flow to ischaemic tissue
Due to generation of fresh mediators of cell injury
Initiation of acute inflammation by delivery of neutrophils and complement
261
What causes myocardial infarction?
Usually coronary artery atherosclerosis
Predominantly affects left ventricle
262
What are the effects of myocardial infarction?
1. Dysrhythmia
2. Sudden death
3. Cardiogenic shock
4. Rupture of infarct
5. Mural thrombosis
6. Scarring leading to cardiac aneurysm
7. Adaptation to inadequate cardiac output
8. Cardiac failure
263
What causes pulmonary infarction?
Thromboembolism from pelvic or leg veins
264
What are the effects of pulmonary infarction?
1. Silent
2. Impaired lung function
3. Pressure overload on right heart
4. Right sided heart failure
5. Infection
265
What are the causes of cerebral infarction?
1. Cerebral artery thrombosis
2. Embolism
3. Shock
266
Where does embolism to brain usually come from?
Heart or atheroma
Usually in common carotid arteries
Thrombus or plaque
267
What are the outcomes of cerebral infarction?
1. Liquefactive necrosis and cyst formation
| 2. Sudden onset of inadequate cerebral function (stroke)
BOD
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