Flashcards in The Blood-Clotting Cascade Deck (16)
How does being a cascade help the blood-clotting process?
A cascade allows the formation of a clot, and a relatively large response, from the activation of very small amounts of the initial factor
What 2 pathways exist in the blood-clotting cascade?
The intrinsic and extrinsic pathways
What triggers the intrinsic pathway?
A damaged endothelial lining of blood cells promotes binding of factor 12
What triggers the extrinsic pathway?
Membrane damage/trauma exposes the extracellular domain of tissue, leading to the release of factor 3
What are the next 2 factors activated after factor 3a in the extrinsic pathway? How are these factors activated?
Factor 3a activates factor 8a (via proteolytic cleavage of its zymogen, factor 8) - factor 8a then activates factor 10a (via proteolytic cleavage of its zymogen, factor 10)
What are the next 2 factors activated after factor 6a in the intrinsic pathway? How are these factors activated?
Factor 6a activates factor 9a (via proteolytic cleavage of its zymogen, factor 9) - factor 9a then activates factor 10a (via proteolytic cleavage of its zymogen, factor 10)
Why zymogen does factor 10a cleave? What does this produce?
Factor 10a cleaves prothrombin to produce thrombin
How are factors 9 and 10 targeted to the membrane?
By Gla domains
Describe the modular structure of prothrombin.
- a Gla domain at its N-terminus targets the zymogen to the appropriate activation site
- 2 Kringle domains which help keep the prothrombin in its inactive form (due to their shape)
- a serine protease, at the C-terminus that contains the protease function (the thrombin part)
Describe and explain the role of the Gla (g-carboxyglutamate) residues.
Glutamate residues are negatively charged - addition of carboxyl groups on glutamate residues makes them 'super' negatively charged - Ca2+ can then bind and form bridges between to molecules, holding the clot closer together
What zymogen does thrombin proteolytically cleave? What molecule does this produce?
Thrombin cleaves fibrinogen to produce fibrin
What feedback mechanism does thrombin possess?
Thrombin exhibits positive feedback, allosterically activating previous clotting factors
Describe the structure of fibrinogen?
Contains 2 sets of tripeptides (alpha, beta, and gamma) joined at the N-terminus by disulphide bonds - it also comprises 3 globular domains linked by rods
How is a fibrin clot further stabilised?
The clot is further stabilised by the formation of amide bonds between the side chains of lysine and glutamine residues in different monomers, forming a cross-link
What defects is present in classic haemophilia?
A defect in factor 8