10. Haemostasis Flashcards
What does primary and secondary haemostasis involve?
- Primary - identification of endothelial damage, formation of an unstable platelet plug (platelet adhesion, platelet aggregation)
- Secondary - stabilisation of the plug with fibrin (blood coagulation - liquid => solid)
What is fibrinolysis?
Dissolution of a platelet plug and vessel repair
What is Von Willebrand factor?
A clotting plasma protein secreted by endothelial cells and platelets
Describe the platelet adhesion
• Damage - subendothelial layer (rich in collagen) is exposed
• Collagen recognised in 2 ways (as circumstances can be different):
- Von Willebrand factor binds to collagen and attracts platelets (to Glycoprotein 1b Receptor on VWf)
- Glycoprotein 1a Receptor on the platelets directly binds to the collagen in the subendothelial layer
• Small blood vessel - high shear stress - favours Von Willebrand mechanism
• When glycoprotein receptors on the platelets are engaged - platelet activation
Describe the platelet aggregation
- Activated platelets release ADP and prostaglandins (thromboxane in particular)
- Prostaglandins activate other platelets so they can aggregate - the glycoproteins IIb/IIIa receptors become available, which the fibrinogen can bind to
- Thromboxane acts on the surface of the receptor
- A protease called thrombin is generated in the blood coagulation cascade
- Thrombin can also directly activate the platelets - aggregation
How do platelets change as they activate?
- Change shape
- Change membrane composition
- Certain phospholipids move from the inside to the outside
- These phospholipids bind to the coagulation factors
What is the lifespan of platelets?
8 days
What are the sites of synthesis of clotting factors, fibrinolytic factors and inhibitors?
- Liver - most made here
- Endothelial cells - Von Willebrand factor made in high concentration here
- Megakaryocytes (bone marrow cell) - synthesis of Factor V, for production of platelets
Outline the intrinsic pathway of the clotting cascade
- XII => XIIa, which converts:
- XI => XIa, which converts:
- IX => IXa
- VIIIa is a cofactor that speed up IXa converting: X => Xa on platelet membrane phospholipid
(Factor XII is zymogen, a precursor of a protease)
Outline the extrinsic pathway of the clotting cascade
- Vessel damage
- Blood comes into contact with tissue factor [membrane protein in smooth muscle (subendothelial) cells, but not in normally in blood]
- Tissue factor is a potent initiator of the clotting cascade
• Tissue factor binds to Factor VII converting it to VIIa
• VIIa converts X => Xa
(• It can also convert IX => IXa in the intrinsic pathway
• This is slower but produces more)
Outline the common pathway of the clotting cascade (from Xa)
- Xa converts prothrombin => thrombin (IIa)
- Thrombin can activate the platelet - forms a fibrin clot
- Thrombin helps V => Va (on Pl), which helps Xa convert prothrombin => thrombin
- Thrombin converts fibrinogen (soluble) => fibrin (insoluble), forming a fibrin clot
- The clot can be cross-linked by XIIIa (from XIII)
What is coagulation initiated by?
- Tissue factor is the physiological initiator of coagulation
- Not initiated by Factor XII (this is mainly an in vitro reaction that is useful for some diagnostic tests)
What is Tissue Plasminogen Activator (tPA) and how does it work?
- Protein made by the endothelial cells
- Fibrin clots assemble the tPA and plasminogen together on their surfaces
- This brings them close together and triggers a cleave reaction:
- tPA converts plasminogen (inactive zymogen) into plasmin (active protease)
- Plasmin is a powerful proteolytic enzyme that can break down the fibrin clot
What is tPA and streptokinase used for?
- Streptokinase is a bacterial activator
- tPA and streptokinase are used in therapeutic thrombolysis for myocardial infarction
- Essentially a clot busting drug
- Used as circulating tPA is usually quite low
What is the clotting cascade?
An amplification system where a small amount of Factor VIIa produces a large amount of thrombin (incomplete due to coagulation inhibitory mechanisms)
What is direct inhibition (of coagulation)?
- Antithrombin, circulates in the blood in fairly high concentrations
- Broad scale inhibitor of most coagulation proteinases (done so directly)
- Sometimes known as antithrombin III
What is indirect inhibition (of coagulation)?
- Mechanism that slows down the amount of thrombin that is generated
- Doesn’t inhibit thrombin itself
- Involves the activation of Protein C in the Protein C Anticoagulant Pathway
Which activated clotting factors are not coagulation proteinases?
XIIIa
What is heparin?
- Anticoagulant
- Accelerates the action of antithrombin
- Immediate anticoagulation in venous thrombosis and pulmonary embolism
What happens when there is an excess of coagulation factors?
- Antithrombin inhibits them by forming an inactive complex with the coagulation factor
- Complexes cleared from circulation
- If there is a reduction in antithrombin, there is a higher risk of thrombosis
Which coagulation factors are activated by trace amounts of thrombin?
- VIII and V
- The activate forms are cofactors
- They bind to the surface of platelets to speed up thrombin formation (10,000 fold)
What does Protein C do?
- Inactivates the cofactors (V and VIII)
* This is the second anticoagulant mechanism
What is thrombomodulin and what happens when thrombin binds to it?
- Thrombomodulin is a protein on the surface of the endothelium
- When thrombin binds to it, thrombin changes its specification
- This then activates Protein C (+ Protein S)
- These proteins inactivate factor Va and VIIIa
What is Factor V Leiden?
- Common polymorphism in the population (4%)
- Involves an amino acid change in Factor V
- Cannot be inactivated as well as wild type (normal) Factor V
- Protein C anticoagulant pathway can’t inactivate Factor V Leiden well
- More thrombin generated - higher risk of thrombosis
