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BSc module 3 > Von Willebrand Factor > Flashcards

Von Willebrand Factor Flashcards

1
Q

Functions of VWF

A
  1. Forms a bridge between damaged vessel wall (collagen) and platelets (primary haemostasis)
  2. Stabilise and protect Factor VIII
  3. Regulate vascular inflammation (?)
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2
Q

VWF domains

A
  1. Pro-peptide cleaved off (can later be found in blood, but does not appear to have a function)
  2. Dimerization and multimerisastion structures important for platelets to bind to each other
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3
Q

Sequence of events in VWF pathway

A
  1. Two C terminals join to create a dimer
  2. These dimers form together
    This large structure essential for platelet to fulfil its functions
    Initial multimers are ‘ultra-large’ and highly reactive
  3. Moves out to the plasma, when molecules get into the circulation their size and activity is regulated by ADAMTS13
    → this circulating enzyme can chop up the large multimers to make them smaller and regulate clotting
    • TTP occurs when a pt does not have ADAMTS13
    • With too much ADAMTS13 → bleeding disorder
    (rare)
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4
Q

What is ADAMTS13

A

Cleaves VWF once in plasma

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5
Q

NO ADAMTS13

A

TTP

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6
Q

Too much ADAMTS13

A

Bleeding disorder

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7
Q

Property of VWF when initially released into plasm

A

Ultra large multimer

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8
Q

What regulates functional activity and size of VWF

A

ADAMTS13

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9
Q

When is VWF most reactive

A

When is a large multimer

  • greatest binding
  • greatest clotting activity
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10
Q

What is the only thing not affects by size of VWF multimer

A

FVIII

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11
Q

Size of circulating VWF

A

extremely large multimers: up to 20MD

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12
Q

Structure of circulating VWF and why

A

Globular structures most of the time - so most of binding sites not available

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13
Q

When does VWF structure extend

A

Shear - if platelet captured by collage, the molecule can unravel to expose all binding sites

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14
Q

Where is vWF synthesised

A

Endothelial cells

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15
Q

What clotting factors are synthesised in endothelial cells

A

vWF and FVIII

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16
Q

Where are most clotting factors made?

A

Liver

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17
Q

Where is vWF stored

A
  1. Weibel Palade bodies in endothelial cells
  2. Platelet alpha granules in megakaryocytes
    MOST ENDOTHELIAL
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18
Q

What are weibel-palade bodies

A

Cigar shaped organelles found only in endothelial cells

- store vWF

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19
Q

Structure of weibel-palade bodies

A
  • cigar shaped but unravels when vWF released
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20
Q

What is needed for formation of weibel-palade bodies

A

vWF

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21
Q

What do weibel-palade bodies contain?

A 
HMW VWF
Also contain
• P-selectin and CD63
• Angiopoietin 2
• Endothelin
• IL-8
• Osteoprotegerin
• And others
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22
Q

vWF synthesis in megakaryocytes

A

All platelet VWF is stored in alpha granules
Does not contribute to plasma VWF (BMT effect) → Don’t constitutively secrete this into the plasma
VWF released on platelet activation
ABO antigens are not added
Not subject to degradation in plasma

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23
Q

vWF plasma level

A

VWF plasma levels vary over a six fold range 40 – 240%

One of the greatest ranges of any molecule

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24
Q

Circumstances where vWF is elevated

A
  • Birth
  • Ill
  • Rises slowly with age (~10% per decade)
25
Q

Blood group with less vWF

A

O

26
Q

Blood group with most vWF

A

AB

27
Q

Why does blood group affect vWF

A

Blood groups expressed on endothelial cells -
where vWF is made (not true for other factors made in the liver)
ABO blood group sugars put on vWF
This appears to affect rate of clearing of vWF from the circulation

28
Q

Clearance of vWF in blood group O sugars vs AB

A

More rapid in O - hence lower vWF

29
Q

Implication of less vWF in blood group O

A

Less likely to have thrombosis but more likely to have bleeding disorder

30
Q

When vessel damage occurs what is blood now exposed to?

A
  1. Collagen (contributes to formation of primary platelet plug)
  2. Tissue factor (triggers coagulation cascade)
31
Q

vWF sequence of events after vessel damage

and what is this called?

A
  1. VWF binds to collagen causing it to unfold and elongate
  2. GpIb binding sites of vWF now exposed
    3 Platelets are captured by binding GpIb (and subsequently GpIIb/IIIa) and become activated Change in shape → Release of α granules
    4.Hence more vWF
    Then more platelet binding

Primary platelet plug forms
Can also bind fibrinogen

32
Q

Size of platelets

A

2-5 um diameter

33
Q

Lifespan of platelets

A

7-10 days

34
Q

Normal platelet number in blood

A

150-450 x109 /L

35
Q

Where are platelets produced

A

Megakaryocytes

36
Q

Key interaction for activation of platelets

A

Under shear Gp1b alpha complex that sets into action 2 things
1. Slows down platelets, which can then bind to collagen via GP1a/IIa and GPVI which activates the platelets

37
Q

Under high shear, what is binding of platelets

A

Only to vWF, then they slow down and can bind to collagen as well

38
Q

Steps in primary haemostasis

A
  1. VWF binds to exposed collagen
  2. Shear stress elongates VWF exposing multiple binding
    sites
  3. Shear stress opens GpIb – catches on VWF
  4. Platelets roll along VWF via GpIb
  5. GpIIb/IIIa adopts active configuration
  6. Platelets ‘fixed’ to VWF via IIbIIIa
  7. Platelets degranulate, releasing more VWF
  8. Platelet feedback completes activation
  9. Fibrinogen links platelets via IIbIIIa
  10. Further platelets captured forming platelet plug
39
Q

What does vWF binding to FVIII do?

A

Stabilises and protects FVIII from degradation

- Prevents premature association with FX, phospholipids

40
Q

How does FVIII circulate in the blood

A

As a complex with vWF

41
Q

If no vWF, what happens to FVIII levels?

A

Half life of free FVIII = 2hrs

vWF bound FVIII half life = 12 hrs

42
Q

What is impact of no vWF

A
  1. No adhesive function - can’t capture platelets on collagen surfaces
  2. End up with v low FVIII
    Type 3 VWD
43
Q

What is type 2n VW disease?

A

Mutation in VWF around FVIII binding site

44
Q

What is Type 3 VWD

A

Problem with primary haemostasis and secondary haemostasis

45
Q

Features of VWD

A

• Defect of primary haemostasis → Prolonged
bleeding time
• Reduced level of Factor VIII → Coagulation defect
– deep bleeding

46
Q

Treatment of VWD

A 
Infusions of vWF
- recombinant vWF
OR
Utilise stores in endothelial cells 
- Despmopressin
47
Q

What is desmopressin

A

DDAVP

Vasopressin derivative

48
Q

Action of desmopressin

A

Acts via V2 receptors
Releases VWF from WPB
→ Triggers endothelial cells to degranulate
And release all stored vWF and FVIII from Weibel-Palade bodies
Same release is triggered by adrenaline, stress, etc.
2-5 fold rise in vWF-VIII (VIII>vWF) As an acute phase reactant

49
Q

When is desmopressin used

A

Minor surgery/dental work

50
Q

When may excess vWF activity occur

A
  1. ADAMTS 13 deficiency

2. Excess VWF concentration

51
Q

What is TTP

A

Thrombotic thrombocytopenic purpura
- Disorder of excess vWF activity
Either congenital defect or development of an autoantibody so they don’t have any ADAMTS13 activity - means large multimers

52
Q

Clinical features of TTP

A
  • Microangiopathic haemolytic anaemia (MAHA)
  • Thrombocytopenia
  • Neurological abnormalities
  • Renal impairment
  • Fever
53
Q

Pathophysiology of TTP

A

Loss of ADAMTS 13 activity
→ Congenital (rare)
→ Acquired (more frequent: due to development of autoantibody against ADAMTS13)
Ultra large VWF multimers
Platelet captured and deposition in arterioles Thrombocytopenia
Microangiopathy and Haemolytic anaemia Organ dysfunction (esp. brain and kidney)
In heart - kills you

54
Q

Plasma vWF risk for IHD

A

Appears to be a weak risk
BUT
Elevated VWF is associated with acute occlusions Platelet VWF may be the source of VWF in arterial occlusions
Expression of VWF may mediate inflammation and atheroma formation

55
Q

vWF knockout and atherogenic prone

A

VWF -/- have fewer atheromatous lesions

Localised reduction in atheroma in VWF deficient mice

56
Q

If vWF really involved in human atheroma formation?

A

Confounded in humans
Type 3 VWF do get more atheroma - however they are not purely knockout individual (often other problems with their VWF)
Moot point: animal data says important, suggest vWF involved in atheroma
Human data is inconclusive and much less clear

57
Q

ADAMTS13 level relationship with vWF level

A

↘ There is NO relationship between vWF levels and ADAMTS13
High ADAMSTS13 don’t have lover vWF levels It is shredded more → but levels are the same
↘ However relationship between ADAMTS13 and vWF size/activity
↘ Results in ability to affect IHD and stroke risk

58
Q

Pts with ↑ADAMTS13 levels have risk of…

A

Stroke and MI
• ↓ADAMST13 and ↑vWF
Gives a significantly higher risk of IHD and stroke
• Inability to regulate function of ↑VWF does put you at higher risk

BSc module 3 (10 decks)

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