Q1

Describe the vascular changes in acute inflammation.

  • Vasodilatation: opening of arterioles and capillary beds mediated by histamine and Nitric Oxide leading to increased blood flow
  • Increased vascular permeability
  • Stasis: due to PP permeability and increased viscosity

Pass criteria:

  • All 3

What are the mechanisms of increased vascular permeability?

  • Endothelial contraction / retraction: gaps in venules due to histamine and leukotrienes < 30mins, immediate transient response eg.ultraviolet radiation and kinins and leukotrienes 2-12hrs, delayed prolonged leakage eg. late appearing sunburn
  • Direct vascular endothelial injury eg. in severe burns, microbial toxin injury, amplified by neutrophil activation, rapid onset but may last days
  • Leukocyte mediated leakage, in venules and pulm capillaries, long lasting for hours
  • Trancytosis increased Tx of fluid and protein thru endothelial cell, VEGF

Pass Criteria:

  • 2 out of 4

 


Q2

Describe the vascular changes in acute inflammation.

  • Vasodilatation: opening of arterioles and capillary beds mediated by histamine and Nitric Oxide leading to increased blood flow
  • Increased vascular permeability
  • Stasis: due to PP permeability and increased viscosity

Pass criteria:

  • All 3

What are the mechanisms of increased vascular permeability?

  • Endothelial contraction / retraction: gaps in venules due to histamine and leukotrienes < 30mins, immediate transient response eg.ultraviolet radiation and kinins and leukotrienes 2-12hrs, delayed prolonged leakage eg. late appearing sunburn
  • Direct vascular endothelial injury eg. in severe burns, microbial toxin injury, amplified by neutrophil activation, rapid onset but may last days
  • Leukocyte mediated leakage, in venules and pulm capillaries, long lasting for hours
  • Trancytosis increased Tx of fluid and protein thru endothelial cell, VEGF

Pass Criteria:

  • 2 out of 4

Q3

Describe the pathogenesis of thrombosis.
Prompt: What factors predispose to thrombus formation? Give examples where each of these factors operate?

  • (Virchows triad) endothelial injury – most important, may alone result in thrombosis eg heart and arterial circulation where flow is high
  • Blood flow stasis / turbulence eg turbulence over atheromatous plaques, aneurysms, AMI with poor contractility, left atrial dilatation
  • Blood hypercoaguability eg primary hypercoaguability (factor V mutation, protein C/S resistance, hyperhomocysteinemia) / secondary hypercoaguability (CCF, trauma, OCP, pregnancy, Ca)

Pass criteria:

  • 3/3

What are the potential fates of a thrombus?

  • Propagation – accumulate more platelets / fibrin and lead to vessel obstruction
  • Embolisation – eg pulmonary or systemic (arterial)
  • Dissolution – by fibrinolytic activity
  • Organisation and recanalisation –  inflammation, fibrosis then recanalised

Pass Criteria:

  • 3 out of 4 bold

 


Q4

What are the 2 main roles of platelets in haemostasis?

  • Primary Haemostatic Plug
  • Provides surface to recruit and concentrate activated coagulation factors

Pass criteria:

  • Bold points

How is the primary haemostatic plug formed?

After vascular injury, platelets contact exposed ECM eg. collagen, adhesive glycoprotein, vWF

  • Adhesion – via glycoprotein 1b (GpIb) receptor to vWF forming bridge between plat and ECM collagen
    • necessary to overcome high shear force of blood flow, deficient in vW disease or Bernard-Soulier syndrome
  • Activation resulting in shape change and secretion – granule release (ADP,TxA2).
  • Aggregation – ADP potent activator of platelet aggregation and +ve feedback for more ADP release. Agonist binding causes intracellular protein phosphorylation cascade => degranulation, including dense body content release of Ca++, required for coagulation cascade.  Platelet activation causes appearance of negatively charged phospholipids on surface => bind Ca, critical nucleation sites for assembly of coagulation factor complexes.
  • TxA2 amplifies platelet aggregation => leads to formation of primary haemostatic plug.
  • Aggregation reversible at this stage but not after next stage of stabilization via coagulation cascade with formation of thrombin

Pass criteria:

  • 4 out of 7 bold

 


Q5

What is angiogenesis?

  • The process of blood vessel formation in the adult. 2 methods:
    • Branching and extension of existing vessels
    • Recruitment of endothelial progenitor cells (EPCs)

Pass criteria:

  • Bold and 1 other

Please give some examples.

  • Wound healing
  • Chronic inflammation
  • Proliferating endometrium
  • Tumours

Pass criteria:

  • Any 2

What steps are involved in angiogenesis from pre-existing vessels?

  • Steps in angiogenesis
    • Vasodilation
    • Proteolytic degradation of basement membrane
    • Endothelial cells migrate to angiogenic stimuli
    • Maturation
    • Capillary formation
    • Recruitment of periendothelial cells for support structure formation
  • Inhibitors such as endostatin are released by proteinases (This is a small fragment of collagen that inhibits endothelial proliferation and also angiogenesis)

Pass criteria:

  • Any 3

 

 


Q6

What factors govern the movement of fluid between the vascular and interstitial spaces?

  • Hydrostatic Pressure –
  • Osmotic Pressure- protein/ Na
  • Normal capillary walls- most protein retained
  • Small fluid out art end
  • Most back venous end
  • Small amount back via lymphatics

Pass criteria:

  • 3 concepts mentioned
  • A > c >V
  • May know some Pressures, may mention gravity/ leg v head. Capillaries are fluid leak vessels. Normal tissue flow important. Thoracic duct  return of lymphatics

What are the major mechanisms of oedema formation (with examples)?

  • >Increased Hydrostatic Pressure (local- DVT/ systemic- CCF)/venous obstruction
  • < Oncotic P ( mainly prot loss e.g. Nephrotic syndrome or poor production eg cirrhosis/ malnutrition or loss via gut)
  • Capillary leak– ( inflammatory  injury/ systemic / infection)
  • Obstructive lymphatics– e.g. lymphodema/ tumour/ op etc
  • Na retention with H2O ( renal insuff/ renin angio)- mainly dilutional

Pass Criteria:

  • 3 key features + a couple of examples

 


Q7

In the normal coagulation cascade, what happens after factor X is activated?
Prompt: tell candidate factor X is where the intrinsic and extrinsic pathways join.

  1. Conversion of Prothrombin ( II ) to Thrombin ( IIa ) requiring Calcium ( Ca ) and activated factor V ( Va ) as cofactors. Occurs on surface of damaged endothelium or activated platelets
  2. IIa catalyses fibrinogen ( I ) to fibrin ( Ia ) in presence of Ca
  3. IIa catalyses factor XIII to XIIIa in presence of Ca leading to cross-linking of fibrin

Pass criteria:

  • Bold to pass

Describe the process of normal fibrinolysis.

  1. Plasmin is produced from circulating plasma protein plasminogen, either by factor XIIa – dependent pathway, or by plasminogen activators. ( PA, see 2. below )
  2. Plasmin breaks down fibrin to FSPs, (eg D-dimerand disrupts polymerisation
  3. a) t-PA from endothelial cells most important PA, and most active when attached to fibrin
    b) Urokinase – like TPA ( u-TPA ) circulating protein
  4. Free plasmin inactivated by alpha 2 plasmin inhibitor

Pass Criteria:

  • Bold to pass

 


Q8

Describe how angiogenesis occurs.

  • Mobilisation of Endothelial precursor cells (EPC) from the bone marrow & from pre-existing vessels.
  • EPC migrate to a site of injury or tumour growth.
  • EPC differentiate & form a mature network by linking with existing vessels.
  • Stabilisation: Endothelial cells from pre-existing vessels become motile & proliferate to form capillary sprouts.
  • Vessels mature involving pericytes & smooth muscle cells to form periendothelial layer.

Pass criteria:

  • Bold to pass

What are the factors involved at a cellular level?

  • Haemangioblast generates haemopoietic stem cells and angioblasts.
    • Angioblasts like EPC are stored in adult bone marrow initiate antiogenesis.
    • Participate in replacing lost endothelial cells, in vascular impant endothelization and in neovascularising ischaemic organs, cutaneous wounds and tumours.
  • Vasodilatation of pre-existing vessels
    • Increased permeability, degradation of basement membrane, disruption of endothelial cell to cell contact, proliferation and migration towards angiogenic stimulus, and endothelial cell maturation/growth inhibition/remodelling capillary beds.
  • Factors:
    • VEFG
    • Angioproteins 1 and 2
    • PDGF
    • TGFB
  • Receptors:
    • VEGFR-2
    • FGF-2
    • EC receptor Tie 2

 


Q9

What clinical conditions may cause fat embolism?

  • (Microscopic) fat globules travelling in the circulation.
  • Long bone #
  • Soft tissue trauma/burns –rare
  • Very common with severe skeletal injury but rarely (<10%)  of clinical significance

Pass criteria:

  • 2 to pass

What is the pathogenesis of fat embolism syndrome?

  • Mechanical obstruction of microvasculature (lungs & brain): fat globules/aggregated platelet and RBCs.
  • Biochemical injury: FFAs from fat globules > endothelial injury, platelet activation & mediator release.

Pass Criteria:

  • 2 to pass

What are the potential clinical sequelae of fat embolism?

  • Asymptomatic (Majority)
  • Neurological: altered LOC.
  • Pulmonary: Inc RR, SOB, hypoxia.
  • Haem: thrombocytopenia & anaemia.

Pass criteria:

  • 2 out of 4

 


Q10

Describe the causes of oedema formation.

  • Hydrostatic pressure;
  • Decreased plasma oncotic pressure;
  • Lymphatic obstruction;
  • Sodium and water retention;
  • Inflammation

Pass criteria:

  • Bold PLUS 1 other point

How does increased hydrostatic pressure causes oedema?

  • Local:
    • Impaired venous outflow
    • Thrombosis
    • External pressure
    • Prolonged dependency with inactivity
  • Generalised impaired venous return – CCF, Constrictive pericarditis, Ascites
  • Arteriolar dilatation – Heat, Neurohumeral dysregulation

Pass Criteria:

  • 2 out of 3 categories
  • At least 4 examples

What is the pathogenesis of cardiac oedema?

  • Decreased cardiac output
  • Decreased renal perfusion
  • Secondary aldosteronism
  • Increased blood volume
  • Increased venous pressure

Pass criteria:

  • 3 to pass

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