Basic Haemostasis Flashcards
What are the functions of haemostasis?
- Prevention of blood loss from intact vessels
- Stop bleeding from injured vessels
Outline the main steps of haemostasis in reponse to injury
- vessel constriction
- formation of unstable platelet plug (platelet adhesion and aggregation)
- stabilisation of plug with fibrin (coagulation)
- dissolution of clot and vessel repair
What are the two main stages of haemostasis and describe them?
primary- formation of unstable plug
secondary - stabilisation
Define coagulation
process by which blood is converted from liquid to solid
Outline the formation of the platelet plug
- endothelial damage exposes the collagen in the subendothelial layer
- collagen is recognised by Von Willebrand factor or glycoprotein 1a receptor
- when the glycoprotein receptors on the platelets are engaged either to the Von Willebrand Factor or directly to the collagen, the platelets become activated
- the platelets will release ADP and prostaglandins (thromboxane)
- thromboxane acts on the surface of the receptor
- prostaglandins activate other platelets so the platelets aggregate - the glycoproteins IIa and IIIb receptors become available which the fibrinogen can bind to
- protease called thrombin gets generated which can also directly activate the platelets so that they aggregate
What is Von willenbrand factor?
A plasma protein made by endothelial cells and platelets. It binds to collagen and attracts platelets. The platelets bind to glycoprotein 1b receptor on the VWF
Where is glycoprotein 1a receptor found?
platelets and directly binds to collagen
What determines which mechanism is used to identify collagen?
- Because the circumstances within the vasculature will vary - the stressors in the blood can be different
- In a small blood vessel there could be very high shear stress which favours the Von Willebrand mechanism
What is the clinical significance of thrombin?
specific receptors for thrombin on the platelets which are therapeutic targets
What happens to the platelet when it gets activated?
- When platelets are activated they change shape and hence its membrane composition
- Certain phospholipids which are usually inside the platelet come to the outside (they bind to the coagulation factors)
- The platelet presents new or activated proteins on their surface (e.g. GlpIIb and IIIa - this becomes an active conformation so it can react with the fibrinogen)
Where are clotting factors, fibrinolytic factors and inhibitors made?
- most made in liver
- VWF made in the endothelium
- factor 5 is made in the megakaryocyte
Describe the intrinsic pathway
- factor 12 (precursor protease called zymogen) is converted to factor 12a
- this converts factor 11 to factor 11a
- this converts factor 9 into factor 9a
- this converts factor 10 into 10a
- factor 8a accelerates conversion of 10 to 10a
is factor 8 a zymogen?
no it is a cofactor
What is a zymogen?
inactive enzyme precursor
Describe the extrinsic pathway of blood coagulation
- vessel damage means blood comes into contact with tissue factor
- tissue factor is a smooth membrane protein not normally in blood
- it initiates the clotting cascade
- it binds to factor 7 and converts it into 7a
- 7a converts 10 into 10a
- 10a converts prothrombin into thrombin
- 5a helps convert prothrombin to thrombin faster
- factor 5a is generated from factor 5 by trace amounts of thrombin
- thrombin converts finbrinogen into fibrin making an insoluble clot
- the clot can be crosslinked by factor 13a so it is stabilised
- tissue factor can also activate factor 9 to 9a when it binds to factor 7
What are the three main pathways in the coagulation cascade?
- Intrinsic (involves factor 12)
- Extrinsic (involves tissue factor and factor 7)
- Common Pathway (where the intrinsic and extrinsic pathways converge - from factor 10a onwards)
What is the main initiator/driver for physiological coagulation?
tissue factor
(Factor 12 can be activated to Factor 12a, this is mainly an in vitro reaction that is useful for some diagnostic tests
What is the importance of the coagulation surface?
The surface is made of activated phospholipids which localise and accelerate the reactions
Plasminogen and tPA
- Tissue Plasminogen Activator (tPA) is a protein made by the endothelial cells
- It converts plasminogen from an inactive zymogen to an active protease called plasmin
- Normally, there is no interaction that takes place between these two proteins
Describe how fibrinolysis occurs
- The fibrin clot assembles the tPA and the plasminogen on its surface, bringing them close together and triggers the cleavage reaction where the tPA can convert plasminogen to plasmin
- Plasmin is a powerful protease that can break down the fibrin clot
What are the breakdown products of the fibrin clot?
Fibrin Degradation Products
What can FDP be used for?
measured when giving thrombolytic therapy
What can tPA and streptokinase be used for?
Therapeutic thrombolysis for myocardial infarction
What is the clotting cascade actually?
An amplification system where a small amount of Factor 7a produces a large amount of thrombin
Why doesn’t all the blood clot during clotting?
coagulation inhibitory mechansims
direct and indirect
What is the direct inhibition mechanism?
- Direct inhibition of the activated coagulation factors
- This takes place by an inhibitor that circulates in the blood in quite high concentrations called antithrombin
- It is a broad scale inhibitor of most of the coagulation proteinases
- Antithrombin is sometimes known as antithrombin III
What is the indirect inhibition mechanism?
- Mechanism that slows down the amount of thrombin that is generated
- This involves the activation of Protein C in the Protein C Anticoagulant Pathway
How does antithrombin work?
When there is an excess of the coagulation factors, antithrombin will inhibit them by forming a complex with them and then the complexes are cleared from the circulation
Reduction in antithrombin —-> Higher risk of thrombosis
What does herparin do?
it accelerates the action of antithrombin so used in immediate anticoagulation of venous and pulmonary thrombosis
What is the importance of cofactor 5 and 8 and how are they activated?
activated by trace amounts of thrombin and they make coagulation faster
Second anticoagulation mechanism
- Protein C inactivates the cofactors (Factor 8/5)
- The thrombin generated can bind to a protein on the surface of the endothelium called thrombomodulin which changes the conformation of thrombin
- Thrombin is normally involved in forming the clot, activating the platelets and activating Factor 8 and Factor 5
- When the thrombin binds to thrombomodulin, it changes its specification
- It activates Protein C which is an inactive zymogen to activated protein C (along with Protein S)
- Activated Protein C and Protein S inactivates Factor 5a and Factor 8a
- This is the second anticoagulant mechanism
What happens if you have a deficiency of one of the inhibitory proteins (S/C) ?
You can’t control the amount of coagulation via the indirect inhibitory pathway
Factor 5 Leiden
- It is a common polymorphism in the population
- There is an amino acid change in Factor 5 called Factor 5 Leiden which cannot be inactivated as well as wild type Factor 5
- If you have this polymorphism then the protein C anticoagulant pathway can’t inactivate Factor 5 Leiden as well and so there is higher risk of thrombosis
- More thrombin is generated if you have this
Which mechanism failures can lead to increased thrombosis risk?
- Antithrombin Deficiency
- Protein C Deficiency
- Protein S Deficiency
- Factor V Leiden
What is the lifespan of a platelet?
8 days
