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Primary FRCA > Physiology 5 > Flashcards

Physiology 5 Flashcards

1
Q

What proportion of whole blood comprises plasma?

A

55%

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2
Q

What proportion of whole blood comprises platelets?

A

0.5%

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3
Q

What proportion of whole blood comprises erythrocytes?

A

45%

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4
Q

Describe the structure and activation of the vitamin K dependent coagulation factors

A

Active enzyme site and long tail of glutatamic acid molecules (prior to activation)
Vitamin K acts a cofactor in converting the glutamic acid to gamma-carboxyglutamic acid (which is negatively charged)
This charged tail binds to the platelet surface through electrostatic Ca2+ ion bridges and thus become haemostatically active.

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5
Q

Which are the Vit K-dependent coagulation factors?

A

FII, FVII, FIX, FX

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6
Q

Where is tissue factor found?

A

On the surface of smooth muscle cells and fibroblasts surrounding blood vessels

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7
Q

What is von Willebrand Factor? (vWF)

A

Long, string-like protein produced by endothelial cells and platelets.
Mostly bound to collagen in subendothelial layer but some released into plasma.
In low-shear conditions vWF is curled up and cannot bind to platelets.
In conditions of bleeding shear stress is increased and vWF stretches out, exposing binding sites which spontaneously bind to inactivated platelets

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8
Q

How does a breach in vessel walls lead to haemostasis?

A
  1. vWF unravels, attaching to subendothelial collagen and inactivated platelets loosely bind to the vWF through glycoprotein GP1b
  2. Factor VII in the plasma is activated by combining with tissue factor, initiating the coagulation cascade
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9
Q

How does FVII initiate the coagulation cascade?

A
  1. FVII binds to inactive FX, cleaving it to form FXa

2. FXa cleaves FII (prothrombin) to form FIIa (thrombin)

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10
Q

What follows initial activation of FIIa?

A
  • Platelet activation
  • FV ->FVa
  • FVIII -> FVIIIa
  • FXI -> FXIa (which then activates FIX -> FIXa)
  • FXIII -> FXIIIa
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11
Q

Describe the relevant features of inactive platelets

A
  • Neutral phospholipid membrane
  • Inactivated surface GPIIbIIIa
  • Alpha granules containing vWF, FV and fibrinogen
  • Dense bodies containing ADP and Ca2+
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12
Q

How do platelets become activated?

A

By the presence of:

  1. FIIa (thrombin)
  2. Collagen
  3. ADP release by other platelets
  4. GP1b binding to vWF
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13
Q

How do platelets change when activated?

A
  • Degranulation of alpha granules and dense bodies
  • Translocation of phospholipids to outside of platelet creating negatively charged membrane
  • Activation of GPIIbIIIa
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14
Q

How does platelet aggregation occur following activation?

A
  • Tight binding of platelets to vWF

- Binding of platelets to each other via GPIIbIIIa, vWF and fibrinogen crosslinking

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15
Q

How does the ‘second phase’ of the coagulation cascade occur?

A
  1. FXIa activates FIXa
  2. FVIIIa stabilises FIXa so that the active site can convert FX -> FXa in large quantities
  3. FV stabilises FXa so that active site can cleave FII -> FIIa in large quantities (‘thrombin burst’)
  4. FIIa cleaves fibrinogen to fibrin
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16
Q

What is the function of coagulation factor XIII?

A

FXIIIa cross-links fibrin strands, stabilising the clot and platelet plug

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17
Q

Define and outline the Type I hypersensitivity response

A

Type I: Immediate IgE-mediated hypersensitivity causing mast cell and basophil degranulation

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18
Q

What preformed mediators are released by mast cells?

A
  1. Chemoattractants: NCF, ECF-A
  2. Activators: Histamine (vasodilatation and vascular permeability), Tryptase (activates C3), Kininogenase (-> kinins -> vasodilatation)
  3. Spasmogens: Histamine (bronchial SM contraction, mucus secretion)
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19
Q

What newly formed mediators are released by mast cells?

A
  1. Chemoattractants: LTB4
  2. Activators: Platelet activating factor (PAF) -> microthrombi
  3. Spasmogens: PGD2, LTC4. LTD4
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20
Q

What are the clinical effects of Type I hypersensitivity reactions?

A 
Eyes: conjunctivitis
Nasopharynx: Rhinorrhoea, rhinitis
Lungs: Bronchospasm
CV: Vasodilatation/shock
Skin: Urticaria/eczema
GI: Gastroenteritis
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21
Q

Define and outline the Type II hypersensitivity response

A

Type II: Cytotoxic hypersensitivity reactions mediated by IgG and IgM Abs activating three possible mechanisms of cytotoxic response:

  1. Complement activation via classical pathway
  2. Phagocytosis
  3. Antibody-dependent cell-mediated cytotoxicity (ADCC) via NK cells and cytotoxic T lymphocytes
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22
Q

What are the possible clinical manifestations of the Type II hypersensitivity reaction?

A 
CV: Heart valvular damage (rheumatic)
Joints: Rheumatic inflammation
Lungs: Goodpasture's Syndrome
Muscles: Myasthenia gravis
Blood: Haemolytic reactions, ITP
23
Q

Define and outline the Type III hypersensitivity response

A

Type III: Immune-complex hypersensitivity mediated by IgG and IgM Abs forming Ab-Ag complexes.

Complexes may become trapped in vessels, activating complement and promoting neutrophil degranulation, causing tissue damage eg. vasculitis

24
Q

What are the possible clinical manifestations of the Type III hypersensitivity reaction?

A 
Skin: SLE, Arthus reaction (localized vasculitis usually following antigen injection)
Lungs: Aspergillosis
Heart: Subacute bacterial endocarditis
Joints: RhA
Blood: Serum sickness
Renal: Lupus nephritis
25
Q

Define and outline the Type IV hypersensitivity reaction

A

Type IV: Delayed-type or cell-mediated hypersensitivity which is independent of antibodies and mediated by the T-cell response to APC-presented antigen and promotes a T-cell and macrophage response.

26
Q

What are the possible clinical manifestations of the Type IV hypersensitivity reaction?

A

Thyroid: Thyroiditis
Lungs: TB, hypersensitivity pneumonitis, Granulomatosis with Polyangiitis (GPA)
Skin: Atopic dermatitis
Pancreas: T1DM

27
Q

What are the main features of an acute inflammatory response?

A
  1. Release of chemical mediators
  2. Activation of plasma enzymes
  3. Vascular changes
  4. Leucocyte migration
28
Q

What are the important mediator systems activated by the acute inflammatory response?

A 
Cytokines
Fibrin
Kinin system
Coagulation system
Complement system
Arachidonic acid system
29
Q

How do leucocytes migrate to inflamed tissues?

A

Three phases:

  1. Margination - adherence to vessel walls due to selectins and then integrins and inter-cellular adhesion molecules (ICAMs)
  2. Diapedesis - transendothelial migration through endothelial junctions
  3. Chemotaxis - Leucocytes bind to EC matrix proteins and move up a chemotactic gradient towards inflammation.
30
Q

What are the possible pathological sequelae of acute inflammation?

A
  1. Abscess formation
  2. Scar formation
  3. Chronic inflammation
31
Q

What type of neurones innervate skeletal muscle?

A

Myelinated Aα neurones

32
Q

How many muscle fibres may be supplied by one motor neurone?

A

10-150 fibres

33
Q

Outline the anatomy of the motor endplate

A

The axonal terminal is surrounded by a synaptic cleft in the muscle which comprises multiple folds.
ACh receptors are concentrated at the shoulders of the postjunctional folds and AChE is found in high concentrations at the bottom of the folds.

34
Q

How and where is ACh formed?

A

ACh is formed in the terminal part of the motor neurone by the combination of Acetyl-CoA and Choline by Choline acetyltransferase (ChAT)

35
Q

How is ACh stored?

A

Stored in vesicles concentrated in the terminal neurone.
Vesicles are acidified by an H+ pump and then ACh is exchanged for H+ ions.
Each vesicle contains between 10000-12000 molecules of ACh
-19% stored as a stationary store not usually involved in transmission
-80% stored in a reserve pool (called VP1) ready for use in repetitive stimulation. Tethered to cytoskeleton by actin, synapsin and synaptotagmin
-1% stored in immediately available pool (VP2) located adjacent to release sites on presynaptic membrane.

36
Q

Explain how an action potential triggers release of ACh into the synaptic cleft

A
  1. AP causes voltage-gated Calcium channels to open, causing an influx.
  2. Ca2+ influx activates SNARE proteins on the vesicular and presynaptic membranes which control docking and exocytosis of vesicles.
  3. Ca2+ influx also causes phosphorylation of synapsin molecules holding vesicles in the VP1 and making them immediately available in the VP2
37
Q

How does botulinum toxin cause flaccid paralysis?

A

BoTox inactivates SNARE proteins, making release of ACh impossible.

38
Q

How many vesicles can be released with one action potential?

A

100-300

39
Q

Describe the ACh receptor

A

It is a ligand-gated ion channel comprising five polypeptide subunits and a molecular weight of approximately 250,000 Da.
Each glycoprotein subunit contains four membrane-spanning α-helices.
Adult receptors are made up of 2xα, 1xβ, 1xδ and 1xε subunit.
Foetal receptors have the ε subunit replaced by a γ subunit.

40
Q

Describe the genetic variation in ACh receptors

A 
α subunit: 10 types
β subunit: 4 types
γ subunit: 1 type
δ subunit: 1 type
ε subunit: 1 type
41
Q

Outline the function of the AChR

A

When both α subunits of the AChR are bound to ACh, the channel opens, allowing free movement of Na+, K+ and Ca2+ ions. A negative charge at the mouth of the channel repels negative ions.
The predominant direction of ionic movement is influx of Na+ ions down the electrochemical gradient.
ACh is bound to AChR for 1-2 ms then returns to the synaptic cleft

42
Q

Where are AChRs found?

A

Most highly concentrated on crests of the post-junctional folds.
Also small numbers found on muscular membrane outside of NMJ (extrajunctional receptors). These have γ subunits replacing ε, like foetal receptors.
AChRs are also found on the presynaptic motor nerve terminal, providing a positive feedback mechanism on ACh release during repetitive stimulation.

43
Q

Explain the relationship between muscle relaxants and burns and denervating conditions

A

In burns or denervating conditions, extrajunctional receptors proliferate, increasing sensitivity to depolarising muscle relaxants.

44
Q

Explain ‘fade’ found on neuromuscular assessment

A

AChRs on the presynaptic motor nerve terminal are blocked by non-depolarising muscle relaxants and thus the positive feedback required during repetitive stimulation is lost.

45
Q

Outline the role of AChE in at the NMJ

A

AChE is found in large quantities bound to collagen-Q at the bottom of the synaptic cleft.
It has two binding sites, the anionic binding site and the esteratic site, 0.5 nm apart which are involved in cleaving ACh to form Choline and Acetic acid

46
Q

How does AChE cleave ACh?

A

The quaternary amide group in ACh binds to the anionic site (which is composed of a negatively charged glutamate group).
The esteratic site contains serine residues which hydrolyses the ACh molecule into acetic acid and choline.

47
Q

Describe the arrangement of muscle cells

A

Each collection of sarcomeres (contractile units) are arranged into myofibrils (~1um diameter) which are bundled together into muscle fibres (myocytes) of ~10-100um diameter. Myocytes are further collected together into bundles.

48
Q

Describe the function of the T-tubule in muscle contraction.

A

T-tubules are internal extensions of the sarcolemma which facilitate rapid spreading of the action potential throughout the muscle fibre.

49
Q

Outline the role of the sarcoplasmic reticulum

A

The sarcoplasmic reticulum acts as a storage for intracellular calcium.

50
Q

Explain excitation-contraction coupling in the myocyte

A

An action potential travels down the t-tubules initiating release of calcium from the sarcoplasmic reticulum, which brings about muscular contraction.

This happens due to the membrane action potential stimulating the dihydropyridine receptor in the membrane of the T-tubule which lies immediately adjacent to the ryanidine receptors of the cisternae of the sarcoplasmic reticulum.

Ryanidine receptor is a Ca2+ channel which releases calcium into the sarcoplasm, triggering contraction.

51
Q

Describe the steps of actin-myosin interaction in muscular contraction

A
  1. Relaxed state: Troponin-tropomyosin complex covers active sites for myosin binding on actin filaments. Myosin bound to ADP in ‘cocked’ position.
  2. Calcium binds to troponin C in the troponin complex, inducing conformational change which results in the uncovering of the myosin binding sites on the actin filament, allowing interaction,
  3. Following actin-myosin binding, ADP is released from the myosin head, causing a rotational movement and a tractional shortening of the muscle fibre.
  4. ATP binds to the myosin head following the ‘powerstroke’. This causes release of the myosin head from the actin binding site.
  5. ATP is cleaved into ADP + PO4, which ‘cocks’ the myosin head back into position.

If calcium is still present in the myofibril and binding sites are still available, the above steps will repeat until maximum possible contraction is reached or binding sites are re-covered due to a drop in calcium concentration.

52
Q

By how much does each ‘powerstroke’ shorten a sarcomere?

A

Approx 10nm

53
Q

How fast can a myosin head repeatedly ‘ratchet’ actin?

A

Approx 5 times per second.

54
Q

How does a muscular contraction end?

A

Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (SERCA) pumps calcium into the sarcoplasmic reticulum and the muscle relaxes as calcium concentrations drop.

Primary FRCA (34 decks)

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