Von Willebrand Factor Flashcards
(58 cards)
1
Q
Functions of VWF
A
- Forms a bridge between damaged vessel wall (collagen) and platelets (primary haemostasis)
- Stabilise and protect Factor VIII
- Regulate vascular inflammation (?)
2
Q
VWF domains
A
- Pro-peptide cleaved off (can later be found in blood, but does not appear to have a function)
- Dimerization and multimerisastion structures important for platelets to bind to each other
3
Q
Sequence of events in VWF pathway
A
- Two C terminals join to create a dimer
- These dimers form together
This large structure essential for platelet to fulfil its functions
Initial multimers are ‘ultra-large’ and highly reactive - 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)
4
Q
What is ADAMTS13
A
Cleaves VWF once in plasma
5
Q
NO ADAMTS13
A
TTP
6
Q
Too much ADAMTS13
A
Bleeding disorder
7
Q
Property of VWF when initially released into plasm
A
Ultra large multimer
8
Q
What regulates functional activity and size of VWF
A
ADAMTS13
9
Q
When is VWF most reactive
A
When is a large multimer
- greatest binding
- greatest clotting activity
10
Q
What is the only thing not affects by size of VWF multimer
A
FVIII
11
Q
Size of circulating VWF
A
extremely large multimers: up to 20MD
12
Q
Structure of circulating VWF and why
A
Globular structures most of the time - so most of binding sites not available
13
Q
When does VWF structure extend
A
Shear - if platelet captured by collage, the molecule can unravel to expose all binding sites
14
Q
Where is vWF synthesised
A
Endothelial cells
15
Q
What clotting factors are synthesised in endothelial cells
A
vWF and FVIII
16
Q
Where are most clotting factors made?
A
Liver
17
Q
Where is vWF stored
A
- Weibel Palade bodies in endothelial cells
- Platelet alpha granules in megakaryocytes
MOST ENDOTHELIAL
18
Q
What are weibel-palade bodies
A
Cigar shaped organelles found only in endothelial cells
- store vWF
19
Q
Structure of weibel-palade bodies
A
- cigar shaped but unravels when vWF released
20
Q
What is needed for formation of weibel-palade bodies
A
vWF
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
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
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
24
Q
Circumstances where vWF is elevated
A
- Birth
- Ill
- Rises slowly with age (~10% per decade)
25
Blood group with less vWF
O
26
Blood group with most vWF
AB
27
Why does blood group affect vWF
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
Clearance of vWF in blood group O sugars vs AB
More rapid in O - hence lower vWF
29
Implication of less vWF in blood group O
Less likely to have thrombosis but more likely to have bleeding disorder
30
When vessel damage occurs what is blood now exposed to?
1. Collagen (contributes to formation of primary platelet plug)
2. Tissue factor (triggers coagulation cascade)
31
vWF sequence of events after vessel damage
| and what is this called?
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
Size of platelets
2-5 um diameter
33
Lifespan of platelets
7-10 days
34
Normal platelet number in blood
150-450 x109 /L
35
Where are platelets produced
Megakaryocytes
36
Key interaction for activation of platelets
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
Under high shear, what is binding of platelets
Only to vWF, then they slow down and can bind to collagen as well
38
Steps in primary haemostasis
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
What does vWF binding to FVIII do?
Stabilises and protects FVIII from degradation
| - Prevents premature association with FX, phospholipids
40
How does FVIII circulate in the blood
As a complex with vWF
41
If no vWF, what happens to FVIII levels?
Half life of free FVIII = 2hrs
| vWF bound FVIII half life = 12 hrs
42
What is impact of no vWF
1. No adhesive function - can't capture platelets on collagen surfaces
2. End up with v low FVIII
Type 3 VWD
43
What is type 2n VW disease?
Mutation in VWF around FVIII binding site
44
What is Type 3 VWD
Problem with primary haemostasis and secondary haemostasis
45
Features of VWD
• Defect of primary haemostasis → Prolonged
bleeding time
• Reduced level of Factor VIII → Coagulation defect
– deep bleeding
46
Treatment of VWD
```
Infusions of vWF
- recombinant vWF
OR
Utilise stores in endothelial cells
- Despmopressin
```
47
What is desmopressin
DDAVP
| Vasopressin derivative
48
Action of desmopressin
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
When is desmopressin used
Minor surgery/dental work
50
When may excess vWF activity occur
1. ADAMTS 13 deficiency
| 2. Excess VWF concentration
51
What is TTP
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
Clinical features of TTP
* Microangiopathic haemolytic anaemia (MAHA)
* Thrombocytopenia
* Neurological abnormalities
* Renal impairment
* Fever
53
Pathophysiology of TTP
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
Plasma vWF risk for IHD
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
vWF knockout and atherogenic prone
VWF -/- have fewer atheromatous lesions
| Localised reduction in atheroma in VWF deficient mice
56
If vWF really involved in human atheroma formation?
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
ADAMTS13 level relationship with vWF level
↘ 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
Pts with ↑ADAMTS13 levels have risk of...
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
