Initiation of Coagulation Flashcards
What is the domain structure of FVII/FVIIa?
Gla domain
2x EGF-like domains
Serine protease domain
What is the function of TFPI? How do its domains help it acheive its function?
TFPI blocks the active sites of SPs and inhibit
3 domains have different functions:
K2: binds xa and is slow - rate limiting - inhibits FXa (P1 Arg)
K1: binds TF/FVIIa - inhibits TF-FVIIa
K3: binds cofactor Protein S
Gla domain localises the TFPI to the membrane
What does the gla domain do?
binding to phospholipid surfaces
what does the egf domain do?
involved in protein-protein interactions
What is a serine protease and what is its function?
they contain a catalytic triad of his/asp/ser
once activated the serine protease is able to cleave and proteolyse the target substrate
What implications does TFPI hold for initiation of coagulation?
TFPI threshold must be breached before propogation can occur
suffieient FXa needs to be produced to generate thrombin and become independent of TF/FVIIa
What implications does TFPI hold for initiation of coagulation?
TFPI threshold must be breached before propagation can occur
sufficient FXa needs to be produced to generate thrombin and become independent of TF/FVIIa
How does Protein S enhance the rate of FXa inactivation?
It binds TFPI and brings it to the surface, bringing it in closer contact with the TF/FVIIa complex.
Where is TFPI made?
endothelium
What are the other forms of TFPI?
TFPI-ß
What is the function of TFPI-ß?
It binds covalently to the endothelial cell surface protein.
It is able to mediate the “fast” step of coagulation initiation as is already bound to the membrane
What are TF microparticles?
small cell-derived vesicles from monocytes and other TF expressing cells.
They express P-selectin as do activated platelets
they bear tissue factor in inactive forms
Absence of TF?
Lethal in-utero
Absence of TFPI?
Lethal in-utero
Absence of FVII and FX?
Fatal haemorrhage
