1
Q
Which component in the wall of the aorta is responsible for withstanding high blood pressures due to ejection of blood from the heart?
A
Elastic Fibres - Allow for stretch under high pressures and recoil under lower pressures
2
Q
Describe the ideas behind the Epidemiology of Allergies in the developed countries (3)
A
- Improved hygiene & less parasitic infections
- Vitamin D deficiency
- Dietary changes (later introduction of food items)
3
Q
Define Hypersensitivity
A
An inappropriate & excessive immunological reaction to an external antigen due to dysfunctional control of the immune system
4
Q
Distinguish between Allergy & Anaphylaxis
A
- Allergy - Local reaction e.g. mucous membranes, skin, lungs
- Anaphylaxis - Systemic reaction (including shock & death)
5
Q
Define Allergen
A
Antigen that induces a hypersensitivity reaction
6
Q
Define Antigen
A
A biological molecules that induces an immune response
7
Q
Describe the Classes of Hypersensitivity Reactions
A
- I - Immediate/IgE-Mediated - IgE binds to predominantly mast cells, eosinophils + basophils - e.g. Allergies, Anaphylaxis, Asthma, Atopy
- II - Anti-body dependent - IgM / IgG
- III - Immune Complex - IC
- IV - Delayed or Cell-Mediated - (Adaptive immune response - T-lymphocytes + macrophages
8
Q
Give examples of Class I Hypersensitivity reactions
A
- Allergies (most)
- Anaphylaxis
- Asthma
- Atopy
9
Q
Give examples of Class II Hypersensitivity reactions
A
- Autoimmune Haemolytic anaemia
- Goodpasture’s syndrome
- Myasthenia gravis
- Grave’s disease
10
Q
Give examples of Class III Hypersensitivity reactions
A
- Serum Sickness
- Extrinsic allergic alveolitis (EAA)
- Rheumatoid arthritis (RA)
- Systemic lupus erythematosus (SLE)
11
Q
Give examples of Class IV Hypersensitivity reactions
A
- Allergic contact dermatitis
- Chronic transplant rejection
- Multiple Sclerosis (MS)
- Tuberculin skin test (TST)
12
Q
Explain the Pathology of the Type I Hypersensitivity Response
A
- First exposure to allergen
- Antigen activation of TH2 cells and stimulation of IgE class switching B cells
- Production of IgE
- Binding of IgE to FCeRI on mast cells - No response seen in individual but Mast cell STIMULATED
- Second exposure to antigen
- Activation of STIMULATED Mast Cell –> DEGRANULATION: Release of inflammatory mediators including: Cytokines, Vasoactive amines, lipid mediators
- Results in immediate hypersensitivity within minutes and late phase reactions 6-24 hours later
13
Q
Outline the Pathology of the Type I Hypersensitivity Response
A
- B cell Stimulation
- IgE Production
- Mast cell Stimulation
- Mast cell Degranulation
14
Q
What does Degranulation of Mast cells in the Type I Hypersensitivity Response result in?
A
- Granules with preformed mediators - Degranulate and are released via exocytosis - Vasoactive enzymes + Proteases which cause vascular dilation and smooth muscle contraction and tissue damage
- Lipid Mediators released - Prostaglandins and Leukotrienes - Vascular dilation and smooth muscle constraction
- Cytokines - Inflammation (leukocyte recruitment
15
Q
Describe Clinical Features of Type I (Immediate/IgE-Mediated) Hypersensitivity Reactions including Allergies
A
- Sensitisation occurs first, thereafter exposure generates immediate response
- Airway + Eye mucous membranes - Pruritus (itchiness), sneezing, rhinorrhoea (Runny nose), Lacrimation (Runny eyes)
- Skin - Pruritus & urticaria (Also in Type IV reactions)
- Oral & Intestinal Mucous membranes - Pruritus + angioedema (swelling of tissues) - Can be serious
16
Q
Describe Clinical Features of Type IV (Delayed/Cell-Mediated) Reactions
A
- Usually T Cytotoxic response (slow+Specific) - Inappropriate + excessive
- Allergic contact dermatitis (best e.g. to learn): Allergens e.g. nickel, metals, latex - Slowly developing, pruritic, localised
- Will remain localised
17
Q
Outline investigations for Type I Hypersensitivity Reactions
A
- Type I (immediate/IgE-Mediated) hypersensitivity - Measure blood markers e.g. tryptase, IgE, Eosinophil - Done at time of reaction to determine if an allergic process
- To identify exact allergic in Type I - Skin prick testing (for a range of common allergens): Apply solutions of appropriate test allergens, negative & positive controls (saline & histamine) to skin, prick through solution into skin & read results after 15 mins, Positive result = Lesion >3mm larger than negative control
18
Q
Outline investigations for Type IV Hypersensitivity Reactions
A
- Type IV (Delayed/Cell-Mediated) Hypersensitivity - Skin patch testing, can test more than skin prick tests, no picking through skin, patches on back, can apply danders, pollens, medications, metals
- Left on for 2/3 days and then removed, tested against positive and negative controls to define allergens responded to
19
Q
Outline the Treatments of Hypersensitivity Reactions
A
- Avoidance: Pollen, house dust mites, animals, insects, foods/drugs, metals
- Mast cell stabilisers - Prevent mast cell deregulation, usually topical (e.g. eye drops, nasal sprays) directly to affected area
- Anti-histamines - Most common - Block histamine receptors & thus effects. Can be topical e.g. eye drops or systemic. Is the most vaso-active
- Steroids - More longer-term/severe, wide-ranging anti-inflammatory effects, Topical or systemic (e.g. hay fever/allergic rhinitis, often in conjunction with Anti-histamines)
- Leukotriene Receptor Antagonists - Block Leukotrine effects, systemic.
- De-sensitisation - ‘Allergen immunotherapy’
20
Q
Outline the Treatments of Hypersensitivity Reactions
A
- Avoidance: Pollen, house dust mites, animals, insects, foods/drugs, metals
- Mast cell stabilisers - Prevent mast cell deregulation, usually topical (e.g. eye drops, nasal sprays) directly to affected area
- Anti-histamines - Most common - Block histamine receptors & thus effects. Can be topical e.g. eye drops or systemic. Is the most vaso-active
- Steroids - More longer-term/severe, wide-ranging anti-inflammatory effects, Topical or systemic (e.g. hay fever/allergic rhinitis, often in conjunction with Anti-histamines)
- Leukotriene Receptor Antagonists - Block Leukotrine effects, systemic.
- De-sensitisation - ‘Allergen immunotherapy’
- Anaphylaxis treatment (severe Type I reaction)
21
Q
Describe De-Sensitisation Treatments for Hypersensitivity reactions
A
- ‘Allergen Immunotherapy’
- Relies on creating tolerance to allergens by exposure to gradually increasing doses delivered sublingually/subcutaneously
- Requires weekly/monthly treatment for ~3 years
- Risk of anaphylaxis during therapy
22
Q
Describe Treatment of Anaphylaxis (Severe Type I Reaction)
A
- Think Airway - Breathing - Circulation - ABC
- Lie patient down - Risk of fainting (due to vasodilator blood, circulating blood widely distributed + some leaking into tissues)
- High-flow oxygen - May have fluid in lungs, constriction of airways
- IV fluids - Vasodilated, fluid leakage, dropping BP –> Anaphylactic shock
- Adrenaline (epinephrine) 500mcg IM (o.5 ml of 1mg/ml) - Antidotes to smooth muscle contraction, vasodilation. IV would have too great effect on heart, Sub-cut would take too long
- IV Anti-histamine (chlorphenamine)
- IV Steroid (Hydrocortisone)
- Nebulised Bronchodilator (salbutamol) - bronchoconstriction
- Repeat Adrenaline IM if no improvement after 5 mins
23
Q
What generates the Electrical Impulse in the Heart?
A
- Sinoatrial Node - Where electrical signal originates (pacemaker of heart)
- Strip of specialised myocytes 20mm x 4mm long
- Located on posterior wall of RA close to SVC
- Has Intrinsic Automaticity (can spontaneously generate APs) which are propagated to surrounding atrial tissue and internodal pathways
- Discharge rate 70-80bpm
- Drives sinus rhythm
24
Q
What are the internodal pathways of conduction?
A
- Propagate electrical impulses from SAN to the AV nodes
25
What does intrinsic automaticity mean?
- Can spontaneously generate APs
| - Generally used to describe the SAN
26
What is the function of the AV node?
1. Only route by which electrical impulse can be propagated from atria to ventricles due to fibrous atrio-ventricular ring
2. AV node imposes a delay of 100ms in conduction
27
What is the Atrio-ventricular ring?
- Fibrous (cardiac skeleton) surrounding heart
- Electrical insulation
- Means that electrical impulse cannot pass directly from atria to ventricles. Is controlled and coordinated through AVN
28
What is the Bundle of His?
- Formed by AVN fibres penetrating the atrio-ventricular ring beginning Bundle of His
- Rapid-conducting fibres
- Extends into ventricular septum and bifurcates into left and right bundle branches projecting to apex
29
Describe the Conduction of the ventricles from the Bundle branch fibres
- Extend to apex and up base of heart
- Extensive branching into Purkinje fibres that penetrate into the ventricular myocardium and propagate signal to ventricular (contractile) myocytes
- Trying to excite ventricular wall as near simultaneously as possible
30
Identify the conduction velocities through the heart
- Atria - 1 m/s
- AV node - 0.01-0.06m/s
- His-Purkinje - 2-4 m/s (fast conducting fibres)
- Ventricle - 1 m/s
31
What are the Latent Pacemakers
- AV node - 40-50bpm
- Bundle of His - 40-50bpm
- Purkinje fibres - 20bpm
- Pacemaker with highest frequency usually dominant
- So damaged SAN, AV node becomes new pacemaker
32
What are Ectopic Pacemakers?
- Can arise from hyperexcitability of atrial or ventricular myocytes
33
Why is Coordinated Depolarisation of the Heart Contraction important?
- E-C Coupling
- Time for ventricular filling to ensure adequate stroke volume
- Atrioventricular concordance
- Contraction of ventricles from apex to base
- Refractory period for relaxation
34
Explain the Generation and Formation of Cardiac Action Potentials in the Sinoatrial node
- Slow response 'pacemaker potentials'
- Phases 0,3,4
- dependent on 3 Major membrane potentials
- Ca2+ current
- K+ current
- Pacemaker 'funny' current - What generates intrinsic automaticity - Unstable membrane potential
35
Explain the Generation and Formation of Cardiac Action Potentials in the Sinoatrial node
- Slow response 'pacemaker potentials'
- Phases 0,3,4
- dependent on 3 Major membrane potentials
- Ca2+ current
- K+ current
- Pacemaker 'funny' current - What generates intrinsic automaticity - Unstable membrane potential
36
Describe the Autonomic Nervous System Effects on Pacemakers
- Parasympathetic, Vagus nerve innervation, acetylcholine action on Muscarinic M2- Cholinergic receptors. Mostly innervates SAN and AVN to Slow heart rate
- Sympathetic, Noradrenaline on Beta-1 adrenoreceptors. Innervates conduction system and myocardium to Increase heart rate
37
How does the Parasympathetic System slow Heart rate?
- Vagal tone - dominant at rest
- Reduces inward ICa and If currents. Leading to less steep phase 4 and slower depolarisatoin
- Increased outward IK leading to hyperpolarisation and more negative diastolic potential
- Modulation of L-type Channels increasing threshold for activation of ICa
- So, Parasympathetic innervation causes SAN to decrease pacemaker firing = Negative Chronotopy
- Also, Causes AVN to decrease conduction velocity = Negative dromotopy
38
How does the Sympathetic System Raise Heart rate?
- Opposes vagal tone
- Increased inward ICa and If leading to steeper phase 4 and faster depolarisation
- Modulation of L-type channels decreasing threshold for activation of ICa
- Overall, Causes SAN to increase pacemaker firing - Positive Chronotrophy.
- Causes AVN to increase conduction velocity - Positive dromotropy
39
Where are Fast Response Cardiac Action Potentials found?
- Atrial Myocytes
- Purkinje fibres
- Ventricular myocytes
40
Describe the Fast Response Cardiac APs
- Non-pacemaker cells - Atrial myocytes, Purkinje fibres, Ventricular myocytes
- Phases 0-4
- Stable resting membrane potential
- Morphology made up of: Fast Na+ current (INa), Ca2+ current L-type (ICa), K+ current (Ik)
- Resting membrane potential Phase 4 (IKir)
- Rapid Phase 0 depolarisation (INa)
- Sustained plateau Phase 2 (ICa)
41
What is the Absolute / Effective refractory period?
- ARP / ERP
- From initial depolarisation for about 200ms
- No new AP can be generated
- Voltage-gated Na+ channels in inactive state
42
What is the Relative Refractory period?
- RRP
- Some voltage-gated Na+ channels in closed state
- Larger stimulus needed to elicit AP
43
What is the importance of the ERP
- Effective Refractory Period
- Ensures unidirectional propagation of the AP
- Ensures adequate time for ventricular filling prior to subsequent contraction
44
Describe the structure of cardiomyocytes
- Striated muscle cells - regular myofilament organisation (thick filaments: Myosin. Thin filaments: Actin, tropomyosin, troponin)
- Sarcolemma - Cell membrane
- T-tubules - Invaginations of sarcolemma to allow depolarisation of membrane to penetrate muscle fibre
- Sarcoplasmic reticulum - Intracellular store of Ca2+
45
Describe the functioning of the cardiomyocytes as a syncytium
- Cardiomyocytes branch and connect with other cells via intercalated discs
- Gap junctions (2x Connexons) - Between cells to form Channels for ion transfer --> Electrical coupling
- Desmosomes - Anchors cardiomyocytes together for coordinated linear contractions
- Contract as a unit: Functional Syncytium
46
Why are Gap junctions important between Cardiomyocytes
- Enable Electrical coupling - Rapid propagation of electrical impulse
- Due to Channels for ion transfer - Ca2+ and Na+
- Loss of which = loss of coordinated contraction = Can lead to arrhythmias
47
Explain the Propagation of cardiac action potentials at a cellular level
- Depolarisation in cardiac cell result in large increase in Na+ and Ca2+ entering cell
- Some will move through gap junction into resting cell B and depolarise the membrane to threshold
- Resulting in depolarisation of adjacent cell and action potential propagation in that cell
48
Describe the mechanism of excitation-contraction coupling in cardiac muscle
- Ca2+ enters cell via L-type Calcium channels during Phase 2 of action potential
- Stimulates further release of Ca2+ from Sarcoplasmic reticulum
- Binding of Ca2+ to Troponin C initiates contraction
- Ca2+ removed by sarcoplasmic reticulum Ca2+ - ATPase (SERCa) and Na+Ca2+-Exchanger
- Overall: Membrane potential depolarisation --> Calcium Transient --> Contraction
49
How is Contractility of the heart controlled?
- Greater the increase in cytosolic Ca2+, the greater the strength of contraction
50
What is meant by contractility of the heart
- The force generated by cardiac muscle for a given fibre length
51
Define Haemostasis
- Series of regulated processes that culminate in the formation of a blood clot that limits bleeding from an injured vessel
- 1. Vascular wall (Endothelium and Sub-endothelial structures) 2. Platelets 3. Coagulation Cascade
52
What is the function of Haemostasis
- Allows blood in fluid state in normal vessels
- Formation of a localised Haemostatic clot at sites of vascular injury
- prevents haemorrhage
53
What is the role of endothelium in haemostasis
- Antiplatelet
- Anticoagulant
- Fibrinolytic
- Express factors which prevent thrombosis in undamaged vessels and limit clot formation to site of vascular injury
- Barrier between thrombogenic subendothelium + coagulation factors in blood
- Damage to endothelial cells cause release of factors which promote clot formation and exposes subendothelium
54
What is the role of platelets in Haemostasis
- Form Primary Haemostatic Plug
- Provide a surface for recruitment and concentration of coagulation factors
- Acts as a catalytic membrane (negatively charged when activated)
55
What is the role of Vascular Stroma in Haemostasis
- Smooth muscle supporting blood vessels
| - Vasoconstriction at area of injury to limit blood to area transiently until clotting occurs.???
56
List the sequence of events initiated at a site of vascular injury to maintain normal Haemostasis
- Vasoconstriction
- Primary Haemostasis
- Secondary Haemostasis
- Clot stabilisation + Reabsorption
57
Describe the sequence of events initiated at a site of vascular injury to maintain normal Haemostasis
- Vasoconstriction - Mediated by reflex neurogenic mechanisms and release of endothelin (potent vasoconstrictor) from endothelial cells. Minimises blood loss. Maximises time for interactions between platelets, clotting factors and vessel wall
- Primary Haemostatic plug - Platelets, provide surface for recruitment and concentration of Coagulation Factors. Stages: Adhesion, Activation, Aggregation
- Secondary Haemostatic Plug - Damage to vessel wall exposes Tissue Factor (TF) on subendothelial cells. Binds and activates Factor VII --> Coagulation cascade --> Thrombin generated and cleaves fibrinogen to fibrin --> Consolidates primary platelet plug. Fibrin makes it insoluble
58
Describe the role of platelets in Primary Haemostasis
- Platelet Adhesion: Damage to vessel wall --> Exposure of subendothelial matrix
- Von Willebrand factor (circulating and released by endothelial cells) binds to exposed subendothelial collagen
- Transient tethering - Platelets bind to collagen - Bound vWF
- Platelet adhesion - Platelets bind directly to subendothelial collagen
- Platelet Activation: Platelets change shape to promote platelet-platelet interactions. Conformational change in GPIIb/IIIa Receptors. Platelet release reaction. ADP and Thromboxane A2 released by platelets --> Activates additional platelets
- Platelet aggregation - Platelets bind via GP IIb/IIa Receptors with fibrinogen as cross-bridge
- Forms primary platelet (haemostatic) plug
59
What is the Platelet release reaction?
- During formation of Primary Haemostatic Plug
- Degranulation of secretory granules to release substances outside platelets
- ADP and Thromboxane A2 (TXA2)
- Promote vasoconstriction
- Activate and recruit further platelets
60
Which platelet receptor undergoes a conformational change during platelet activation, allowing platelets to bind to each other?
- GP IIb IIa
61
What is the purpose of the platelet release reaction?
- Enable more platelet aggregation + Activation to site of injury
62
What substance is used as a cross-bridge to enable binding between activated platelets?
- In primary Haemostatic Plug - Fibrinogen
63
What is the end result of primary haemostasis?
- Formation of primary Haemostatic Plug which stops bleeding temporarily
64
Explain Fibrin Generation in Secondary Haemostasis
- Damage to vessel wall --> Exposure of Tissue Factor (TF) on Subendothelial cells
- TF binds + activates Factor VII --> Coagulation cascade
- End result is Thrombin generated which cleaves fibrinogen to fibrin
- Fibrin is insoluble and reinforces network between platelet plug + polymerises to form chain like network around plus + trap additional blood + platelet cells within it
- Forms Secondary Haemostatic Plug
65
What is Tissue Factor
- Glycoprotein on Smooth Muscle cells + fibroblasts in Subendothelium
66
What is a PT assay of clotting
- Used to evaluate coagulation factor function in a lab
- Clinically measured - Prothrombin Time
- Measures Extrinsic pathway of Coagulation Cascade
- Initiated by Tissue Factor + Phospholipids + Calcium added to plasma sample
67
What is aPTT assay of clotting
- Used to evaluate coagulation factor function in a lab
- Clinically measured: activated Partial Thromboplastin Time
- Measures Intrinsic pathway of Coagulation cascade in lab - Not same as in vivo
- Initiated when FXII comes into contact with negatively charged surface --> FXIIa
- In lab add Negatively charged particle 'ground glass' + Phospholipids + Calcium to plasma sample
- Measure time for fibrin clot to be generated
68
Explain the role of the coagulation cascade in Haemostasis
- A cascade involving proteolytic cleavage of proenzymes to active enzymes
- Amplification system: Allows formation of clot from activation of v. small amount of activation factor
- Involves Coagulation factors (proteins)
- Goal: To produce Thrombin which converts fibrinogen to fibrin, stabilising the clot (secondary haemostasis)
69
What are the components required for the Coagulation cascade?
- Coagulation factors
- Cofactors (reaction accelerators) - Factors V + VII
- Negatively charged phospholipid surface - Activated platelets (catalytic membrane for cascade reactions)
- Calcium ions (Ca2+)
- Vitamin K - Factors VII, IX, X and Prothrombin dependent on vitamin K for correct production
70
What can occur with vitamin K deficiency?
- Excessive bleeding
71
Describe the Clinical Extrinsic Pathway
- Measured clinical Prothrombin time (PT)
- Tissue Factor: FVII --> FVIIa
- Complex: TF + FVIIa + Ca2+
- Activates FIX in intrinsic pathway
- And Activates FX --> Common pathway
72
Describe the Clinical Intrinsic pathway
- Clinically measured: activated Partial Thromboplastin time (aPTT)
- Factor XIIa: FIX --> FIXa
- Tenase Complex: FXIIIa + FIXa + Ca2+
- More powerful activator of FX - more FXa produced than extrinsic pathway
73
Describe the Common pathway of the Coagulation Cascade
- Factor Xa forms complex w/FVa + Ca2+ = Prothrombinase Complex
- Cleaves prothrombin --> Thrombin
74
Describe the Actions of Thrombin
- Conversion of fibrinogen to fibrin
- Amplifies coagulation process by further activating: FXI, FVIII, FV - Generation of thrombin further activates more thrombin production
- Activated FXIII - Covalently cross-linking fibrinogen polymers - Stabilises Secondary Haemostatic plug!
- Further platelet activation
- Pro-inflammatory effects - Contributes tissue repair and angiogenesis
- Anticoagulant effects - When interacting with normal endothelium, Helps limit clots to site of injury
75
How is Coagulation different in vivo?
- Different to PT + aPTT assays - more closely linked
- 2 phases: Initiation + Amplification + All occurs on surface of activated platelets
- Initiation - Exposure of TF in subendothelium activates and binds FVII --> Complex w/Ca2+. Activates FIX and Activates small amount FX. Surface of activated platelet acts as catalyst prothrombin->thrombin by FXa alone.
- Thrombin activates FV, FVIII, FXI
- FVIII complex with FIXa + Ca2+ ions = Tenase complex. Large amounts FXa produced
- Amplification process: FXa complex with FVa + Ca2+ = Prothrombinase complex
- x300,000 more powerful in converting prothrombin -> thrombin
- Fibrinogen -> Fibrin
76
What Factors limit Coagulation
- Dilution (blood flow washes away activated Coagulation factors to remove by liver)
- Need for negatively charged surface provided by activated platelets
- Factors expressed by adjacent intact endothelium: Platelet inhibitory effects, Anticoagulant, Fibrinolytic
- Circulating inhibitors - Antithrombin III
- Fibrinolytic cascade - limits size and contributes to their breakdown
77
Why is limiting coagulation important?
- To restrict coagulation to site of injury only
| - To prevent spontaneous activation of coagulation in the absence of injury
78
What is proenzyme and what role do proenzymes play in the coagulation cascade?
- A proenzyme is an inactive precursor of an enyzme
- Converted into active enzyme often by cleavage of peptide bonds by another enzyme
- Coagulation factors circulate as proenzymes, when coagulation pathway initiated by tissue injury, activated in sequential way
79
Which coagulation assays measure the intrinsic and extrinsic coagulation pathways respectively?
- Prothrombin Time (PT)
| - activated Partial Thromboplastin Time (aPTT)
80
How is the in vivo coagulation pathway initiated?
- Exposure of TF in subendothelium, which then binds and activates FVII and forms the TF-FVIIa-Ca2+ Complex
81
What is the tenase complex and what is its role in the in vivo coagulation pathway?
- Complex of FIXa + FVIIIa + Ca2+
- Formed during amplification process
- Potent Activator of FX to FXa
- Results in large amounts of FXa being produced
82
What complex does Fxa form at the end of the amplification phase of the in vivo pathway and what is its role?
- Prothrombinase Complex
- FVa + FXa + Ca2+
- Role to convert Prothrombin --> Thrombin
- Which will convert fibrinogen -> Fibrin amongst other roles in Secondary haemostasis
83
Describe the basic pharmacology of unfractionated heparin in the context of the coagulation cascade
- Binds reversibly to antithrombin III and enhances its inactivation of thrombin and FXa
- Unfractionated heparin inactivates both FXa and thrombin
- Sometimes used less favourably in prophylaxis and treatment of venous thromboembolism
- Low dose: inhibits thrombosis
- Higher dose: Prevents progression of existing clots
- Heparin binds Antithrombin III and activate - Inducing conformational change that opens up active site to coagulation factors
84
Describe the basic pharmacology of low molecular weight heparin in the context of the coagulation cascade
- Binds reversibly to antithrombin III and enhances its inactivation of thrombin and FXa
- E.g. Dalteparin and Tinzaparin
- Primarily inactivates FXa
- Favourable in prophylaxis and treatment of venous thromboembolism
- Low dose: inhibits thrombosis
- Higher dose: Prevents progression of existing clots
- Heparin binds Antithrombin III and activate - Inducing conformational change that opens up active site to coagulation factors
85
List the sequence of events initiated at the site of vascular injury to maintain normal haemostasis
- FXIIIa mediates formation of covalent cross-links between fibrin polymers
- Fibrin and platelet aggregates undergo contraction to form a permanent plug
- Counter-regulatory mechanisms limit coagulation to site of injury
- Clot reabsorption and tissue repair - Involves fibrinolytic system
86
Describe the Fibrinolytic System
- Inactivate circulating plasminogen converted to plasmin
- Converted by FXII-dependent pathway/Plasminogen activators (tissue plasminogen activator (t-PA)
- Plasma breaks down fibrin polymers
- Antifibrinolytic factors oppose fibrinolysis (so depends on balance of these factors)
- Formation of Fibrin degradation products - D-Dimers - Circulate in blood but not sensitive to just blood clotting
87
What is Thrombosis?
- Pathological Process
- Formation of solid mass of blood products in vessel lumen (thrombus)
- Can lead to vascular occlusion, ischaemia, and infarction
88
Compare Haemostasis vs Thrombosis
- Haemostasis allows blood to be in fluid state in normal vessels, formation of LOCALISED clots at sites of vascular injury
- Failure leads to haemorrhage
- Thrombosis is a pathological process, formation of solid mass of blood products in vessel lumen (thrombus).
- Can lead to vascular occlusion, ischaemia and infarction
89
Define Haemorrhage
- Extravasation of blood into extravascular space
- E.g. Tissues, Body cavities, Out of the body
- Purpora - general term for haemorrhage
- Petechiae - V. small specks
- Ecchymoses - Larger >1cm. 'bruises'
90
Explain the Mechanisms of haemorrhage
- Damage to blood vessel e.g. Trauma, Atherosclerosis, Inflammatory or neoplastic erosion, Chronically congested tissues
- Defective Haemostasis - Haemorrhagic Disorders - Inherited (Haemophilia A, FVIII deficiency), Acquired - (Disseminated intravascular coagulation (DIC)
91
Explain the factors affecting the clinical significance of Haemorrhage
- Volume of blood loss
- Rate of blood loss
- Medical fitness pre blood loss
- Site of bleeding
- Chronic or recurrent external blood loss (e.g. heavy periods/ peptic ulcer)
92
What is the role of Protein C in limiting coagulation? What may the result of protein C deficiency be?
- Protein C forms a complex with protein S and inactivates FVa and FVIIa
- Deficiency in protein C/protein S can increase the risk of blood clots forming in blood vessels (thrombosis)
93
How does unfractionated heparin limit coagulation?
Binds to Antithrombin III, opens up active site via conformational change allows action of Antithrombin III to Inactivate FXa and Thrombin
94
How is FXIII activated and what is its role in coagulation?
- Activated by Thrombin.
| - FXIIIa mediates formation of covalent cross-links between fibrin polymers which further stabilises the clot
95
what role does thrombin play in formation of secondary haemostatic plug?
- Fibrin - Insoluble, reinforces primary platelet plug + Polymerises to form long fibres forming mesh-like network around plus - More stable Secondary Haemostatic plug
96
what is the role of tissue plasminogen activator (t-PA) and plasmin in the fibrinolytic system?
- Produced by intact endothelial cells + interacts with plasminogen bound to fibrin
- Converts to plasmin - Breaks down the fibrin network by breaking bonds within fibrin polymers
- Destroys architecture and stability of clot/plug
97
State the layers of blood vessels
- Tunica Intima (innermost)
- Tunica Media
- Tunica Adventitia (externa)
98
Describe the Layers of Blood vessels from innermost to outer most
- Tunica intima - Endothelium --> Basement membrane --> Subendothelium --> Internal Elastic Lamina
- Tunica media - Smooth muscle fibres (concentrically arranged) --> External elastic lamina
- Tunica Adventitia - Connective tissue (collagen + elastic fibres) --> Vasa Vasorum (small blood vessels provide O2 to outer wall of vessel)
99
What are the two types of artery?
- Elastic and Muscular
- Distension of large, elastic arteries during systole provides the driving force to maintain blood flow in the circulation during diastole
- Smaller muscular arteries vary their resistances to provide appropriate blood supply to organs they supply
100
What are the two types of artery?
- Elastic and Muscular
- Distension of large, elastic arteries during systole provides the driving force to maintain blood flow in the circulation during diastole
- Smaller muscular arteries vary their resistances to provide appropriate blood supply to organs they supply
101
Describe Elastic Arteries
- 10-30mm size
- Tunica media is thickest layer: Sheets of elastic tissue separated by smooth muscle cells + thin layers of collagen fibres
- Largest of these (ascending aorta etc), too thick to obtain oxygen and nutrients from their lumen by diffusion so have their own small arteries (vasa vasorum) in tunica adventitia
- Also postganglionic sympathetic nerves, nervi vasorum
102
Which arteries are elastic arteries
- aorta, the branches originating from the aortic arch (the brachiocephalic trunk, common carotid arteries, and the subclavian arteries), the common iliac arteries, and the pulmonary trunk.
103
What arteries maintain arterial blood supply during diastole?
Elastic arteries
104
Which component in the medium artery wall allows the artery to control the diameter of the lumen via vasoconstriction and vasodilation?
Smooth muscle cells - Contracts and relaxes, diameter of artery changes
105
What is the purpose of anastomoses?
- Protect against the loss of blood supply that would result from blockage of an artery
- If an artery that supplies blood to the area is blocked or narrowed, blood flow from the other blood vessels can perfuse and preserve the area
106
Outline the characteristic of An elastic artery
- Thick tunica intima - With developed subendothelial layer. Internal elastic lamina present but may blend in with elastic fibres of tunica media
- Thick tunica media - Composed of smooth muscle cells and many elastic fibres; external elastic lamina may be present but may blend
- Relatively thin tunica adventitia - vasa vasorum present
107
Outline the characteristic of a muscular artery
- Thin Tunica intima - Distinct internal elastic lamina
- Thick tunica media - many layers of smooth muscle arranged concentrically, distinct external elastic lamina
- Thick Tunica adventitia - mostly composed of collagen and elastin, in large muscular arteries layer may contain prominent vasa vasorum
108
What happens when the arterioles vasoconstrict slightly?
- There is a large increase in vascular resistance
- As arterioles constrict, radius is reduced which increases vascular resistance
- Even small change in radius has a great effect since resistance varies as 1/r4
- Reduce radius of vessel by 15%, this would double the resistance to blood flow, and reducing radius by 50% would increase the resistance by 16-fold
109
Describe the characteristics of arterioles
- Arise from muscular arteries
- 5-100micrometres in diameter
- Tunica media layer of arterioles contain smooth muscle, tunica adventitia and intima layers contain elastic fibres - Allows arterioles to contract and relax - regulate blood flow to capillaries
- Smallest may lack internal elastic membrane
- Some arterioles drain into metarterioles that can either allow blood flow to bypass the capillaries and drain directly into venules or open into capillaries
110
What is the nerve supply to arterioles
- Only nerve supply is sympathetic postsynaptic axons
- Release norepinephrine at their synaptic terminals
- Resting tone reflects strength of nervous stimulation. Increasing this results in vasoconstriction, reducing it results in vasodilation
- Active vasodilatation possible in some vessels since smooth muscle cells have beta-adrenergic receptors respond to low levels of circulating adrenaline
111
Which type of capillary is most permeable?
Sinusoidal capillary
112
Where are Continuous Capillaries found?
- Brain
- Hand
- Lower limb
- Urinary bladder
113
Where are Fenestrated capillaries found?
- Renal glomerulus
| - Small intestine
114
Where are Sinusoidal Capillaries found?
- Lymphoid tissue
- Bone marrow
- Spleen
- Liver
115
Describe the characteristic of Capillaries
- Anastomosing forms capillary beds
- Specialised to allow rapid exchange between blood and tissues
- Consist of a layer of endothelial cells, BM, supporting cells pericytes
- Pericytes also help repair capillaries after injury
- Blood flow controlled by arterioles and muscular sphincters at the arteriolar-capillary junctions = Precapillary sphincters
116
Describe the characteristics of venules
- Have thin tunica intima without elastic fibres
- Thin tunica media with 1 or 2 layers smooth muscle
- Little to no tunica adventitia
- 10micrometres - 1mm
- Vascular resistance and BP within venules low
117
Describe Venules
- Little resistance to flow and can increase their volume with little increase in pressure to accommodate additional blood
- 70-80% total blood volume found in systemic venous circulation
- Postcapillary venules < Collecting venules < Small muscular venules
- Function
- Collect blood from capillary beds, starting return of blood to heart
- Exchange of large and fluid occurs in postcapillary venules
- Regulation of capillary hydrostatic pressure - Dilation of venules decreases capillary pressure
- Leukocytes extravasation occurs. Pass from bloodstream to reach interstitial tissues
118
Describe Venules
- Little resistance to flow and can increase their volume with little increase in pressure to accommodate additional blood
- 70-80% total blood volume found in systemic venous circulation
- Postcapillary venules < Collecting venules < Small muscular venules
- Function
- Collect blood from capillary beds, starting return of blood to heart
- Exchange of large and fluid occurs in postcapillary venules
- Regulation of capillary hydrostatic pressure - Dilation of venules decreases capillary pressure
- Leukocytes extravasation occurs. Pass from bloodstream to reach interstitial tissues
119
What is the main function of medium veins?
- Return blood toward the heart without backflow
| - Valves present in medium veins help prevent backflow of blood returning to the heart
120
Describe the characteristics of Medium veins
- Tunica intima - Relatively thin and indistinct internal elastic lamina
- Tunica media - 3-5 layers of loosely organised smooth muscle cells, interwoven with collagen fibres and fibroblasts, indistinct external elastic lamina
- Tunica adventitia - Very thick, twice as thick as tunica media. Collagen, elastic fibres, few scattered smooth muscle cells
121
Why are vasa vasorum so widespread in veins?
- By the time blood returns to veins. PO2 decreased from arterial value ~`100mmHg to ~40mmHg
- So, although veins thinner walled and less smooth muscle, lower driving force for O2 diffusion limits the diffusional delivery of O2 to the full thickness of the vessel wall from the lumen
- Just as in the arteries. vasa vasorum supply O2, at a PO2 of ~100mmHg to outer layers of vessel wall
122
Why are valves present in veins but not arteries?
- Blood pressure in veins much lower compared to arteries, therefore needs valves to prevent backflow of blood as it flows toward heart
- Valves also help blood to flow against gravity
- Arteries do not need valves because pressure from heart pumping blood out into the arteries is strong enough that backflow cant occur
123
Compare Veins and Venules
- Venules - Thin layers of tunica adventitia, blood flow is slow
- Veins - May contain valves, Thick layers of tunica adventitia
- Both - Thin layers of tunica intima, 70-80% of total systemic blood volume at rest, low pressure vessels
124
A patient develops a erythematous, pruritic, circumferential rash on their distal forearm. The rash started under their new watch.
What is the most appropriate treatment?
- The patient is having a localised allergic reaction (Type 4 hypersensitivity reaction). If the patient can simply avoid the stimulus, prescribing any medication (which could expose the patient to potential side effects) is to be avoided.
- Change watch strap
125
Contraction of a cardiac myocyte relies on the generation of a calcium transient by an action potential by the process of excitation-contraction coupling.
After contraction, what membrane protein is largely responsible for removing the calcium ions from the cytoplasm to allow the myocyte to relax?
- Calcium is taken up from the cell cytoplasm by sarcoendoplasmic reticulum calcium- ATPase (SERCA) into the sarcoplasmic reticulum. Some calcium is also removed by sodium-calcium exchanged into the extracellular space.
- Sarcoplasmic reticulum calcium ATP-ase (SERCA)
126
Which of the ECG limb leads is facing away from the mean vector and produces the largest negatively deflected QRS complex?
aVR - Facing down right atrium
Block 2
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