The Blood-Clotting Cascade

Question 1

How does being a cascade help the blood-clotting process?

Answer 1

A cascade allows the formation of a clot, and a relatively large response, from the activation of very small amounts of the initial factor

Question 2

What 2 pathways exist in the blood-clotting cascade?

Answer 2

The intrinsic and extrinsic pathways

Question 3

What triggers the intrinsic pathway?

Answer 3

A damaged endothelial lining of blood cells promotes binding of factor 12

Question 4

What triggers the extrinsic pathway?

Answer 4

Membrane damage/trauma exposes the extracellular domain of tissue, leading to the release of factor 3

Question 5

What are the next 2 factors activated after factor 3a in the extrinsic pathway? How are these factors activated?

Answer 5

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)

Question 6

What are the next 2 factors activated after factor 6a in the intrinsic pathway? How are these factors activated?

Answer 6

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)

Question 7

Why zymogen does factor 10a cleave? What does this produce?

Answer 7

Factor 10a cleaves prothrombin to produce thrombin

Question 8

How are factors 9 and 10 targeted to the membrane?

Answer 8

By Gla domains

Question 9

Describe the modular structure of prothrombin.

Answer 9

Prothrombin contains:

• 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)

Question 10

Describe and explain the role of the Gla (g-carboxyglutamate) residues.

Answer 10

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

Question 11

What zymogen does thrombin proteolytically cleave? What molecule does this produce?

Answer 11

Thrombin cleaves fibrinogen to produce fibrin

Question 12

What feedback mechanism does thrombin possess?

Answer 12

Thrombin exhibits positive feedback, allosterically activating previous clotting factors

Question 13

Describe the structure of fibrinogen?

Answer 13

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

Question 14

How is a fibrin clot further stabilised?

Answer 14

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

Question 15

What defects is present in classic haemophilia?

Answer 15

A defect in factor 8

Question 16

What condition is associated with an abnormal clotting factor 8? What pathway is this factor associated with? Is this X-linked dominant or recessive?

Answer 16

Haemophilia A - the intrinsic pathway - X-linked recessive - write more!!!