Haemostasis and fibrinolysis

Question 1

What are the steps in haemostasis?

Answer 1

1. Injury exposes sub-endothelial matrix
2. Primary haemostasis:
   
   1. Platelet adhesion
   2. Platelet aggregation
   3. Platelet activation (vasoconstriction + secondary haemostasis)
3. Secondary haemostasis (coagulation cascade -> stable clot)
   
   1. Initiation
   2. Amplification
   3. Clot formation

Question 2

What is the process of platelet adhesion?

Answer 2

• Injury to endothelium exposes the endothelial matrix - endothelial matrix has a high affinity for von Willebrand factor (vWF)
• vWF bings to matrix and platelets
• Platelets then bind to other platelets

Question 3

What occurs in platelet aggregation?

Answer 3

• This results in irreversible platelet binding at the site of the injury

Question 4

What is the process of platelet activation?

Answer 4

• Release of thromboxane A2 causes vasoconstriction and more platelet aggregation
• ADP is released
• Activated platelets have a negative charge whcih is required for assembly of coagulation factors
• This then leads into secondary haemostasis

Question 5

What is the role of thromboxane A2?

Answer 5

• It is a potent vasoconstrictor and mediates platelet aggregation
• It is synthesised from arachidonic acid by platelets

Question 6

What is the purpose of secondary haemostasis?

Answer 6

This results in the formation of a stable clot

Question 7

What is the initiation process of secondary haemostasis?

Answer 7

• The breach of endothelium exposes tissue factor (factor 3)
• This activates the extrinsic pathway

Question 8

What is the amplification of secondary haemostasis?

Answer 8

• Small quantities of thrombin (factor 2) activate other clotting factors/co-factors
• This produces more thrombin via positive feedback and subsequently, more clotting factors/co-factors, etc

Question 9

How is a stable clot formed?

Answer 9

• When enough thrombin is present, fibrinogen will be converted into fibrin (factor 1)
• Fibrin spontaneously polymerises to form a clot

Question 10

What is the intrinsic pathway of the coagulation cascade?

Answer 10

1. Surface contact
2. Factor 12 is activated
3. Factor 11 is activated
4. Factor 9 is activated
5. Activated factor 8 then assists factor 9 in activating factor 10
6. Then the common pathway occurs

Question 11

What is the extrinsic pathway of the coagulation cascade?

Answer 11

1. Tissue damage occurs
2. Factor 7 is activated
3. Trauma also exposes factor 3 which assists factor 7 in activating factor 10
4. The common pathway then occurs

Question 12

What is the common pathway of the coagulation cascade?

Answer 12

1. Factor 10 is activated
2. Factor 5, platelets and Ca2+ assist factor 10 in converting prothrombin to thrombin (factor 2)
3. Factor 2 then converts fibrinogen to fibrin (factor 1)
4. Then a stable clot is formed as a result

Question 13

What does von Willebrand factor do?

Answer 13

• It has binding sites for collagen - once it binds to collagen it is activated and can then bind to platelets
• It is also a carrier for factor 8

Question 14

Clotting factors

Answer 14

• Vitamin K are required for the synthesis of 2, 7, 9, 10
• They are made in the liver except for factors 3 and 8

Question 15

What are co-factors?

Answer 15

• They are not catalyctically active molecules, but accelerate the catalytic activity of other factors

Question 16

What is the role of calcium in haemostasis?

Answer 16

• Allows clotting factors to assemble on a charged membrane
• It is required by factors 1, 2, 7, 8, 10, 11

Question 17

What are the negative regulators of haemostasis?

Answer 17

• Thrombin:
  
  • Activates protein C with cofactor protein S
  • These proteolyse factors 5 and 8
    
    • 5 required in the common pathway
    • 8 required in the intrinsic pathway
• Heparin:
  
  • Stimulates antithrombin III which inhibits:
    
    • Thrombin
    • Factor 10
    • Coagulation serum proteases

NOTE: positive and negative mechanisms act simultaneously

Question 18

What is fibrinolysis?

Answer 18

It is the mechanism of clot removal

Question 19

What is the process of fibrinolysis?

Answer 19

• Tissue plasmin activator (tPA) and urokinase plasmin activator (uPA) convert plasminogen to plasmin
• Plasmin then proteolyses fibrin into fibrinogen degradation products (FgDPs) and fibrin degradation products (FDPs)
  
  • Some D-dimers are released here as well

Question 20

What molecules inhibit fibrinolysis?

Answer 20

• Plasminogen activator inhibitors (PAI-1/2)
• Alpha-2-antiplasmin, alpha-2-macroglobulin