Haemostasis Flashcards
What does the balance of haemostasis depend on?
The balance between coagulation factors which cause a clot and fibrinolytic factors which break the clot down
What are the three stages of haemostasis?
Vasoconstriction
Formation of an unstable platelet plug
Formation of a stable fibrin clot
Then fibrinolysis - the breakdown of the cloth
Describe the vasoconstriction stage of haemostasis?
Endothilins are released from the endothelial lining of the blood vessels - they bind to specific receptors on the smooth muscle of the blood vessel, and cause it to contract, therefore leading to vasoconstriction. There is also reduced release of nitric oxide and prostaglandins
What two chemicals normally found in the blood are involved in ensuring the blood remains thin under normal conditions?
Nitric oxide and prostacyclin
Describe how a unstable platelet plug forms?
Platelets bind directly to exposed collagen
VwF is released - this binds to platelets using the GP1b receptor, causing the platelets to become activated and release alpha and beta granules after changing shape from disc to rounded with spicules to encourage aggregation. These granules contain ADP, Thromboxane A2 and Serotonin amongst other chemicals, which results in the platelets aggregating at the site of injury - positive feedback response.
What does ADP and Thromboxane A2 lead to?
They bind to P2Y12 receptors and Thromboxane A2 receptors and cause further platelet aggregation, activation and adhesion
What does an exposed GP IIA / IIIb receptor lead to?
Allows the platelets to bind to fibrinogen, linking the platelets together to form a platelet plug
What is prostacyclin?
A vasodilator which circulates in the blood to ensure that inappropriate platelet aggregation does not occur
How does aspirin work?
Binds to COX enzyme which inhibits Thromboxane A2 production therefore less platelet aggregation
What type of drug is clopidogrel and how does it work?
Antiplatelet drug - works by binding to and therefore blocking ADP’s P2Y12 receptor
How long do the effects of clopidogrel last for?
7 days
Describe the intrinsic coagulation cascade
12 to 12a 11 to 11a 9 to 9a 8 to 8a 10 to 10a 10 reacts with 5 and 4 (calcium ions) to form 2 2 to 2a (prothrombin to thrombin) 1 to 1a (fibrinogen to fibrin)
Which clotting factors are affected by vitamin K?
2, 7, 9 and 10
Describe the extrinsic coagulation cascade?
Tissue factor exposed by endothelial cells activated factor 7 to make factor 10, and also increase production of factor 9
What happens in the initiation stages?
The production of a small amount of thrombin via the extrinsic pathway allows the coagulation factors 5 and 8 of the intrinsic pathway to be activated
Describe how protein C and protein S affect coagulation
Thrombin binds to thrombomodulin on the surface of the endothelial cells, which causes Protein C to become activated = APC
APC causes the inactivation of factors 8a and 5a
What does antithronbin inactivate?
Factor 10a and thrombin
What protein is needed for protein C to become activated?
Protein S
What does factor 13 do in the coagulation cascade?
Cross links fibrin molecules so that the fibrin clot can become more stable
How does Heparin work?
Heparin works indirectly by potentiating the action of antithrombin leading to the inactivation of factors Xa and IIa (thrombin).
How is heparin administered?
By IV or subcutaneously
What are DOACs and how do they work?
Direct Oral Anti Coagulants - work by blocking factor 10a and 2a without involving antithrombin
How does Warfarin work?
It is a vitamin K antagonist, meaning it decreases the production of vitamin K dependent factors in the liver, so 2, 7, 9 and 10
What process does Vitamin K antagonists interfere with?
Gamma carboxylation - needed for the production of factors 2, 7, 9 and 10
What is the difference in the time taken for effect to come about between heparin and warfarin?
Heparin effect is immediate, warfarin we wait, effect takes some time
How does the plasminogen / plasmin system work?
Plasminogen and t-Pa binds to lysine residue on fibrin, which activates it to form plasmin. Plasmin breaks down fibrin into fibrin-degradation products
What is tranexamic acid and how does it work?
It is an anti-fibrinolytic - competitive inhibitor, binds to lysin residue on fibrin so that plasminogen cannot bind and therefor less plasmin produced, so clots are broken down less
What is thrombolytic therapy?
It is recombinant t-Pa which is IV administered
For what conditions is thrombolytic therapy given?
Stroke, pulmonary embolism
What is tranexamic acid used for?
Treat bleeding in trauma, surgery and bleeding disorders
Where does tissue factor come from?
The sub-endothelium
Which blood test is used to test the intrinsic pathway?
Activated Partial Thromboplastin Time - aPTT
Which blood test is used to test extrinsic pathways?
Prothrombin Time - PT
Which clotting factors does PT test the ability of?
10, 5, 2, 7, 1
Which clotting factors does aPTT test the ability of?
8, 9, 11, 12
What happens to the PT for people with Haemophillia A and B
Normal
What happens to the aPTT for people with Haemophillia A (VIII) and B (IX)?
Longer clotting time
What is a normal aPTT time?
25-29 seconds
What is a normal PT time?
12 seconds
What causes bleeding?
Increase in fibrinolytic factors
What is thrombosis?
Clotting
Margherita knows that there is a certain blood clotting disease in her family and goes into the clinic to find out more information. Tests reveal that she has an increased prothrombin time (PT), but her activated partial thromboplastin time (APTT) is unaffected. Given these results, what could the family disease be?
factor 7 defiiency
What does an increased aPTT indicate?
an ‘intrinsic’ pathway deficiency, such as Haemophilia A or B.
What does an increased PT time indicate?
If PT is increased, this may indicate an ‘extrinsic’ pathway deficiency, such as factor VII deficiency.
How do platelets form?
From the fragmentation of megakaryocytic cells
What receptor do platelets use to bind directly to the exposed collagen following damage to the endothelium?
GPIa receptor
When platelets adhere to the damaged vessel, what changes occur in the platelets?
Changes their shape from a disc to more rounded with spicules
Why does warfarin take sveral days to come into effect?
Because warfarin is a vitamin K antagonist, therefore interfering with protein carboxylation
hence, since its effects are mediated through the inhibition of synthesis rather than the inhibition of existing factors, it takes more time for the effects to come into play
Describe the formation of the platelet plug?
- Following injury, platelets adhere to the vessel wall using GP1a receptor directly or using VWF which binds platelets using GP1b receptor
- This causes the platelets to change shape from disc to rounded with spicules
- The adhesion of the platelets cause them to release the contents of their storage granules - they have alpha and beta granules = ADP, Fibrinogen, VWF, Thromboxane A2
- ADP and Thromboxane A2 promote further platelet aggregate by binding to P2Y12 and thromboxane A2 Receptors
- Fibrinogen binds to GPIIb/IIIa receptors which helps the platelets bind together more
- How are clotting factors activated?
The peptide bonds of the zymogen (inactive form) are broken and the active enzyme site is exposed
How to clotting factors work and why do calcium ions help?
They work by binding to the phospholipid surface of the platelets and therefore enhancing the reaction, hence calcium ions help as they help the clotting factors bind to the phospholipid surface- -
what are the three stages of the coagulation cascade?
- Initiation
- Amplification
- Propagation
Describe what happens in the initiation stage of the coagulation cascade?
- damage tissue releases tissue factor
- Tissue factor binds to factor 7, which causes a small amount of thrombin to be produced through the activation of factor 9 and 10
Describe what happens in the amplification stage of the clotting cascade?
- This small amount of thrombin, mediates the activation of factors 5 and 8, and more platelets
Describe what happens in the propagation phase of the coagulation cascade?
- Factor 11 activates 9->9a
- This in concert with 8a causes more 5a to be produced
- This leads to a rapid burst in thrombin production, which therefore means fibrin can be cleaved from fibrinogen, producing the insoluble clot
How can heparin be used to block thrombin as well as antithrombin?
Inactivation of thrombin requires longer chains of heparin chains, which are able to wrap around both the antithrombin and thrombin
Which plasma protein inhibits plasmin?
Alpha-2 Macroglobulin
How does thrombolytic therapy work?
Thrombolytic agents such as recombinant t-PA work by generating plasmin to lyse clots and are administered intravenously to selected patients presenting with ischaemic stroke.
What conditions might patients present with which would result in the prescription of thrombolytic therapy?
Ischaemic stroke
What type of drug is transexamic acid?
An anti-fibrinolytic drug
What might cause bleeding?
Reduction in platelet number or function (primary haemostasis –platelet plug)
Reduction in coagulation factor(s) (secondary haemostasis – fibrin clot)
Increased fibrinolysis
What is meant by thrombosis
Thrombosis is the term used to describe the formation of a blood clot within an intact blood vessel.
What are the three contributory factors for thrombosis? And what is this triad called?
‘Virchow’s triad’:
Blood: dominant in venous thrombosis
Vessel wall: dominant in arterial thrombosis
Blood flow: complex, contributes to both arterial and venous thrombosis
When we consider venous thrombosis, changes in what is more important?
blood constituents
Changes in blood that increase the risk of venous thrombosis include:
Reduced levels of anticoagulant proteins
reduced levels of fibrinolytic activity
Increased levels of clotting factors or platelets
In what circumstances is fibrinolytic activity reduced
pregnancy - where there is inhibition of plasminogen activation through the production of a specific inhibitor by the placenta (PAI-2)
What happens to levels of factor 8 in pregnancy?
Increases
