Haemostasis and fibrinolysis Flashcards
What are the steps in haemostasis?
- Injury exposes sub-endothelial matrix
- Primary haemostasis:
- Platelet adhesion
- Platelet aggregation
- Platelet activation (vasoconstriction + secondary haemostasis)
- Secondary haemostasis (coagulation cascade -> stable clot)
- Initiation
- Amplification
- Clot formation
What is the process of platelet adhesion?
- 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
What occurs in platelet aggregation?
- This results in irreversible platelet binding at the site of the injury
What is the process of platelet activation?
- 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
What is the role of thromboxane A2?
- It is a potent vasoconstrictor and mediates platelet aggregation
- It is synthesised from arachidonic acid by platelets
What is the purpose of secondary haemostasis?
This results in the formation of a stable clot
What is the initiation process of secondary haemostasis?
- The breach of endothelium exposes tissue factor (factor 3)
- This activates the extrinsic pathway
What is the amplification of secondary haemostasis?
- 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
How is a stable clot formed?
- When enough thrombin is present, fibrinogen will be converted into fibrin (factor 1)
- Fibrin spontaneously polymerises to form a clot
What is the intrinsic pathway of the coagulation cascade?
- Surface contact
- Factor 12 is activated
- Factor 11 is activated
- Factor 9 is activated
- Activated factor 8 then assists factor 9 in activating factor 10
- Then the common pathway occurs
What is the extrinsic pathway of the coagulation cascade?
- Tissue damage occurs
- Factor 7 is activated
- Trauma also exposes factor 3 which assists factor 7 in activating factor 10
- The common pathway then occurs
What is the common pathway of the coagulation cascade?
- Factor 10 is activated
- Factor 5, platelets and Ca2+ assist factor 10 in converting prothrombin to thrombin (factor 2)
- Factor 2 then converts fibrinogen to fibrin (factor 1)
- Then a stable clot is formed as a result
What does von Willebrand factor do?
- 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
Clotting factors
- Vitamin K are required for the synthesis of 2, 7, 9, 10
- They are made in the liver except for factors 3 and 8
What are co-factors?
- They are not catalyctically active molecules, but accelerate the catalytic activity of other factors
What is the role of calcium in haemostasis?
- Allows clotting factors to assemble on a charged membrane
- It is required by factors 1, 2, 7, 8, 10, 11
What are the negative regulators of haemostasis?
- 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
- Stimulates antithrombin III which inhibits:
NOTE: positive and negative mechanisms act simultaneously
What is fibrinolysis?
It is the mechanism of clot removal
What is the process of fibrinolysis?
- 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
What molecules inhibit fibrinolysis?
- Plasminogen activator inhibitors (PAI-1/2)
- Alpha-2-antiplasmin, alpha-2-macroglobulin
