Von Willebrand Factor Flashcards
What is the role of vWF in haemostasis? What is its mechanism?
vwf binds to exposed collagen secreted from EC
Shear stress elongates vwf and exposes the multiple binding sites
Platelets roll along vwf via GP1b and then activate to activate GPIIB/IIIa
The platelet is then fixed to VWF via the IIbIIIa leading to degranulation and release of more VWF
More platelets catch leading to formation of platelet plug
How is vWF structured? What are the binding sites?
What does the affinity depend on?
it is a large multimeric plasma glycoprotein
2 collagen binding sites:
A1 - binds collagen type I, IV and VI - initial platelet capture and tethering
A3 - binds collagen type I and III - mediates recruitment to injured vessel wall
A2bB3 - stable tethering of activated platelets
Affinity depends on the size of the multimeric structure
How is vWF produced?
In the ER:
There are vwf monomers which dimerise via disulphide bonds on c-terminus
they are then glycosylated . and ABO blood group sugars are added
there is then n-terminal multimerisation
Propeptides are then removed by furin
How is vWF regulated? What is its inactive form?
In the circulation it exists in a globular conformation shielding most of its domains to avoid constant activity
How is vWF regulated?
In the circulation it exists in a globular conformation shielding most of its domains to avoid constant activity
A major regulator is ADAMTS13 which causes VWF proteolysis
What is the haemostatic defect in vWD?
What are the types of VWD?
VWD can have increased tendency to bleed due to defect of primary haemostasis and reduced level of FVIII
T1: low levels
T2: Have normal levels but dysfunctional
T3: No vwf
What is the relationship between FVIII and vWF?
Factor VIII and vWF circulate in complex which protects FVIII from degradation in the unbound form. When unbound FVIII has a half life of 2 hours and when bound a half like of 12 hours.
Activation of FVIII releases it from VWF
On vwf, what does the A1 binding site do? Why is this binding exhibited?
It binds the GP1B site on platelets, it is a “rapid on rapid off” binding which means it binds and then immediately releases
This binding allows the platelets to slow down and activates them, slowed plaelets are captured permanently by GpIIb/IIIa
What does the C4 domain on vwf bind?
The C4 domain contains RGDS, which binds the GpIIb/IIIa receptor on platelets, it is a much stronger bond and leads to platelet adhesion
This requires “inside out” activation
Under what conditions is VWF proteolysis increased?
Elevated shear stree
VWD type 2a
Denaturants
Under what conditions is VWF proteolysis increased?
Elevated shear stress
VWD type 2a
Denaturants
What is the structure of vwf?
D3, A1, A2, A3, D4, C1, C2, C3, C4, C5, C6, CK
D1-D2 propeptide is removed by furin
