Principles of the coagulation cascade Flashcards
Define coagulation?
Series of protein conversions that lead to fibrin formation
What does fibrin form?
Network of fibres that trap blood cells & proteins to prevent bleeding
What are the protein conversions mediated by?
Proteases cleave peptide bonds in proteins at specific sites eg. thrombin
What is fibrin’s signal?
Exposure of tissue factor
What is the structure of thrombin?
Catalytic triad containing the AAS histidine, asparagine & serine
What are exosites I and II required for?
specific recognition of the correct substrates
What aas of fibrinogen are key for binding to proteases?
Phe
Val
Arg (especially Arg - involved in all targets of thrombin)
What peptide bond is the site of catalytic cleavage?
Bond between Arg and Gly
What are the 3 steps of catalytic cutting between thrombin & fibrinogen?
Fibrinopeptide A -> Fibrin monomer -> fibrin network
What do EGF and Kringle domains mediate?
Protein/protein interactions & are involved in substrate binding
What do Gla domains mediate?
Membrane binding & serve as cofactors and/or substrate binding sites
What type of bond links the protease to the rest of the protein?
A disulphide bond
What happens if you remove calcium?
Clotting stops
What structure on cell membranes do clotting factors need to assemble into functional complexes?
-vely charged phospholipids found on activated platelets
Where do all Gla-domain clotting factors get carboxylated?
On glutamate residues
What do Gla domains bind?
Ca2+ ions
What does carboxylation result in?
additional -ve charges which are required for membrane bind
What is carboxylase?
Liver enzyme that depends on cofactor vit. K
What absorbs vitamin K from our diet?
Bile salts from the liver
What enzyme regenerates used, oxidized vitamin K?
Vitamin K epoxide reductase (VKOR)
What can VKOR be blocked?
By vitamin K antagonists (warfarin)
What happens if vitamin K is depleted?
Reduced Gla residues -> loss of coagulation factor function -> reduced clotting
What is the result of thrombin cleaving off small peptides from fibrinogen?
Generates the fibrin monomer by uncovering polymerization sites (knobs A & B)
What does fibrin polymerization involve?
Knob-hole interactions (knob A binds hole a, know B binds hole b)
What are Ca2+ used for in the fibrin polymer?
Stability
What are 4 properties of fibrin clots?
Elastic
highly extensible
viscous
stiffens in response to shear, tension or compression
What are 5 factors that affect fibrin formation?
Thrombin conc.
blood flow
clot retraction by platelets
incorporation of other plasma proteins
degree of crosslinking by factor FXIII
Which factor stabilizes the fibrin netwrok?
Factor XIII (plasma transglutamase) -> links side chains
