9. Basic Haemostasis Flashcards
What are the functions of haemostasis?
Prevention of blood loss from intact vessels
Arrest of bleeding from injured vessels
What does the formation of an unstable platelet plug involve?
Platelet adhesion and platelet aggregation
What does the stabilisation of the platelet plug involve?
Activation of the blood coagulation and fibrin
What are the stages of haemostasis?
Primary and secondary
What happens in the initial response?
Platelets identify endothelial damage and forms a clump
What follows the initial response?
Coagulation takes place and is accelerated by the platelets
Define coagulation
The process by which blood is converted from a liquid to a solid state
What is Von Willebrand factor?
A plasma protein secreted by endothelial cells and platlets. It binds to collagen and attracts platelets
When the endothelial layer is damaged what is revealed?
The subendothelial layer which is rich in collagen
How is collagen recognised?
1) Von willebrand factor
2) Glycoprotein 1a Receptor on the platelets binds directly to the collagen
How do platelets bind to the von willebrand factor?
Via glycoprotein 1b receptor on the von willebrand factor
What method of recognising collagen is favoured in small blood vessels?
There could be high shear stress in small blood vessels, favouring the von willebrand mechanism
When do the platelets become active?
When the glycoprotein receptors on the platelets are engaged either to the Von Willebrand Factor or directly to the collagen
What is released when the platelets are active?
ADP and Prostaglandins (thromboxane)
What does fibrinogen bind to?
Activated platelets with available glycoproteins IIb and IIIa
What protease can also directly activate the platelets?
Thrombin
When platelets become activated how do they change?
They change their shape and hence their membrane composition.
There is a change in phospholipids and presentation of new proteins (GlpIIb + GlpIIIa)
Where are most clotting factors made?
Liver
Where is the Von Willebrand factor made?
Endothelial Cells
What are the precursors of platelets?
Megakaryocytes
What do megakaryocytes synthesise?
Factor V
Define Zymogen
an inactive substance (protease) which is converted into an enzyme when activated by another enzyme
What is the first zymogen in the clotting cascade?
Factor XII
What is factor XII converted to?
XIIa (active)
What does factor XIIa do?
It converts factor XI to XIa
What is factor XIa do?
It converts factor IX to IXa
What does the intrinsic pathway involve?
The activation of a zymogen and binding of coagulation factors to the activated platelet
What is factor IXa do?
It converts factor X to factor Xa with factor VIIIa on a platelet phospholipid membrane
What is factor X converted to?
Factor Xa
What converted factor X to factor Xa?
Factor, IXa, Factor VIIIa and the platelet phospholipid membrane
What is factor VIII
A Cofactor
What is tissue factor?
A membrane protein which isn’t normally found in the blood
What is the function of tissue factor?
It is a potent activator of the clotting cascade.
What does tissue factor bind to?
It binds to factor VII converting it to factor VIIa
What is the function of factor VIIa?
It converts factor X to factor Xa and factor IX to factor IXa
What does the extrinsic pathway involve?
Tissue factor and Factor VII
What is the function of factor Xa?
Converts prothrombin to thrombin (Factor V is required)
What does thrombin do to the platelet?
It further activates its forming a fibrin clot
What helps convert prothrombin to thrombin faster?
Factor Va
What converts Factor V to Factor Va?
Trace amounts of thrombin
What does thrombin do?
Converts fibrinogen (soluble) to fibrin forming a fibrin clot
What is the fibrin clot cross linked by?
Factor XIIIa
What is point of cross linking?
So the fibrin clot is stabilised and can’t be broken down by shear forces
What are the three pathways in the clotting cascade?
Intrinsic
Extrinsic
Common Pathway
What is the physiological initiator of coagulation?
Tissue factor hence the extrinsic pathway is the main driver of coagulation and heamostasis
What is factor XII mainly used for?
In vitro reactions
Where is tPA made?
Endothelial cells. It is usually quite low and made locally next to where the clot forms
What is tPA?
Tissue Plasminogen Activator
What is the role of tPA?
Converts plasminogen from an inactive zymogen to an active protease (plasmin)
Where does tPA catalyse its reaction?
On a fibrin clot that assembles the tPA and plasminogen on its surface
What is plasmin?
A powerful proteolytic enzyme that can break down the fibrin clot
What are the breakdown products of the fibrin clot?
Fibrin degradation products
What is measured during thrombolytic therapy?
FDP
What is used for the therapeutic thrombolysis for myocardial infarction?
tPA and Streptokinase
Why doesn’t blood clot completely whenever clotting is initiated?
Coagulation inhibitory mechanisms
What are the two coagulation inhibitory mechanisms?
Direct inhibition
Indirect inhibition
What is the mechanism of direct inhibition?
Direct inhibition of the activated coagulation factors
What is an example of a direct inhibitor?
Antithrombin
What can antithrombin inhibit?
XIa
IXa
Xa
thrombin
What is the mechanism of indirect inhibition?
Mechanism which slows down the amount of thrombin that is generated. Protein C must be activated in the protein C anticoagulant pathway
What does a reduction in antithrombin cause?
A higher risk of thrombosis
What accelerates the action of antithrombin?
Heparin
What is used for the immediate anticoagulation in venous thrombosis and pulmonary embolism?
Heparin
What is the mechanism of action for protein C?
It inactivates cofactors (factor VIII and V)
When coagulation inhibitory mechanisms fail there is an increased risk of…
Thrombosis
What failures of coagulation inhibitory mechanisms are there?
1) Antithrombin deficiency
2) Protein C deficiency
3) Protein S deficiency
4) Factor V Leiden
How many times do factor 8 and factor 5 accelerate thrombin formation?
10,000 fold
What protein can thrombin bind to on the surface of the endothelium?
Thrombomodulin
What happens to the thrombin when it binds to thrombomodulin?
It changes conformation and activates protein C and S
What is factor V Leiden
A common polymorphism resulting in an amino acid change in factor V meaning it cannot be inactivated.
What does thrombin normally do?
Form the clot, activate the platelets and activate factor VIII and V
