The Clotting Cascade Flashcards
How is the clotting cascade activated?
Intrinsic pathway (more important as self-sustaining): - abnormal vessel wall - factors IX and X targeted to membrane by Gla domains.
Extrinsic pathway:
- membrane damage exposes extracellular domain of tissue factor III.
- autolytic activation of factor VII.
Where do the 2 pathways join?
- Activation of factor X.
- By factor IXa in intrinsic pathway and by factor VIIa in extrinsic pathway
What is the role of factor X?
Proteolytic cleavage of prothrombin to thrombin.
How is prothrombin maintained in the inactive form?
2 kringle domains form loops to keep prothrombin inactive.
What mediates the targeting of many clotting factors to their appropriate location?
- Post-translational modification of factors II, VII, IX and X in the liver.
- Addition of COOH groups to glutamate residues to form carboxyglutamate - super negatively charged.
- Allows binding of positive calcium ions - calcium bridges - for:
- interaction with sites of damage
- brings together clotting factors
What is the function of the C-terminal domain of prothrombin?
Is the thrombin part - contains a serine protease.
What is the function of thrombin?
- Converts fibrinogen into fibrin.
- By cleaving fibrinopeptides A and B from central globular domains of fibrinogen.
How do fibrin molecules form a blood clot?
Fibrin molecules polymerise: globular domains at C-terminal ends of beta and gamma chains interact with exposed sequences at N-termini of cleaved A and B chains to form mesh/clot.
How is the newly formed blood clot stabilised?
- By formation of amide bonds between side chains of lysine and glutamine residues in different monomers.
- Cross-linking reaction catalysed by transglutaminase (factor XIIIa) with is activated from protransglutaminase by thrombin.
What is the role of co-factor VIII?
Markedly stimulates the activity of factors IXa (serine protease).
Give an example of positive feedback regulation in the clotting cascade.
- Limited proteolysis by thrombin increases the activity of (co)factor VIII.
- Amplifies clotting signal and accelerates clot formation.
Which disease is associated with a defect in factor VIII? How is this treated?
- CLASSIC HAEMOPHILIA (X-linked recessive inheritance)
- Treatment with recombinant factor VIII.
How are clots localised to sites of damage?
- Prothrombin binds calcium ions via Gla residues.
- So only prothrombin next to site of damage will be activated.
How is the clotting process stopped?
- Dilution of clotting factors by blood flow, and removal by liver
- Digestion by proteases
- Specific inhibitors
Give an example of how protease digestion of clotting factors can stop the process.
- Factors Va and VIIIa are degraded by protein C.
- Protein C is activated by thrombin binding to endothelial receptor thrombomodulin.
- Defects in protein C can cause thrombotic disease.
