The multiple roles of thrombin Flashcards
What are the procoagulant actions of thrombin?
Fibrin formation FV and FVII activation FXIII activation FXI activation Platelet activation via PARs Cleaves GpV
What are the anticoagulant actions of thrombin?
Inactivated by AT to form thrombin-antithrombin complex
Activation of protein C via TM
TAFI release via TM
What happens when thrombin is cleaved?
The whole serine protease domain is removed exposing the active site and cryptic exosites which are essential for interactions with other substrates or cofactors
How is thrombin able to be specific for many different substrates?
There are specificity pockets and exosites for different substrates and the exosites help bring the substrate into the active site cleft
How does thrombin interact with fibrinogen?
It binds via exosite 1 and cleaves FPA and FPB
Which are the independent roles of thrombin (ie no cofactors necessary)?
FIbrinogen and factor V and VIII
What is required to form the AT-T complex?
Initially inefficient
When heparan sulphate binds in exosite 2 there is 1000x efficiency in binding
What is required to form the thrombin protein c complex?
Thrombomodulin binding first increases efficiency by 10,000 times
What is required for the actvation of FXIII by thrombin?
Fibrin acts as a cofactor
Fibrin and TM compete for the exosite 1
TM has a higher affinity for exosite 1 so has priority
Why is fibrin as a cofactor unique for thrombin?
Thrombin generates fibrin by cleaving fibrinogen to fibrin so essentially creates its own cofactor
In platelet activation how does thrombin help?
Glp1Ba acts as a cofactor for Thrombin-PAR binding, it competes with heparan sulphate for binding
Which roles of thrombin require cofactors and which are independent?
The initial procoagulant function are direct substrate interactions
Additional roles require cofactors for acting via exosites
Draw/describe the full story of thrombin roles
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