FV and FVIII

Question 1

Describe the physiology of FV

Answer 1

synthesised in hepatocytes and is stored in a partially active form.
FV circulates as a full length single chain molecule and is taken up by megakaryocytes in humans, glycosylated and partially activated.
FV binds to and stimulates TFPI

Question 2

Describe the physiology of FVIII

Answer 2

synthesised in endothelial cells, NOT hepatocytes and possibly the lymphoid tissue.
FVIII is stored as a complex bound with VWF in Weibel-Palade bodies in endothelial cells.

Question 3

How is FVIII’s t 1/2 prolonged in circulation?

Answer 3

Half life of FVIII prolonged when bound to VWF; from <2 hours to 12 to 20 hours

Question 4

Describe the structure of FV and FVIII in terms of their domain

Answer 4

In FV: A1 A2 B A3 C1 C2
In FVIII: A1 a1 A2 a2 B a3 A3 C1 C2
FVIII contains 3 acidic peptides; a3 contains VWF binding site
A domains involved in protein-protein interaction
B domains between the two factors have very low sequence similarity. Both are heavily N-glycosylated
C domains for phospholipid binding

Question 5

Briefly explain the role of B domain in FV

Answer 5

Important role in coagulation
Essential for regulation of cofactor function by blocking interaction with FXa
Thrombin activates FV by cleaving B domain

Question 6

Briefly explain the role of B domain in FVIII

Answer 6

Important role in intracellular trafficking (not in coagulation).
B domain allows FVIII to bind to chaperone proteins within ER, such as LMAN1/ LMAN2, CNX/ CRT chaperone proteins.
These proteins facilitate protein folding and regulate quality control.
FVIII exists in plasma as a mixture of heterodimers with B domains of varying lengths.
Thrombin activates FVIII by cleaving the B domain.