3.9 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 to limit blood flow
Formation of an unstable platelet plug to limit blood loss
Formation of a stable fibrin clot to stop blood loss
Fibrinolysis to restore vessel integrity
Describe the vasoconstriction stage of haemostasis?
The blood vessel endothelium releases endothelin
Endothelin binds receptors on vascular smooth muscle, causing vasoconstriction
What two chemicals normally found in the blood are involved in ensuring the blood remains thin under normal conditions?
Nitric oxide and prostacyclin
How do platelets stick to damaged endothelium?
Direct – GP1a receptors bind to exposed collagen
Indirect – GP1b receptors bind VWF from damaged endothlium
How do activated platelets change shape?
From disc to round with spicules, promoting platelet-platelet interactions
What do activated platelets do?
a-granules release ADP
Dense granules release VWF and fibrinogen
Thromboxane A2 is released
Calcium is released for 2° haemostasis
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 via positive feedback
What does an exposed GP IIA / IIIb receptor lead to?
Conformational change in these receptors allow fibrinogen to bind
This stimulates further platelet activation and links the platelets together to form a platelet plug
What is prostacyclin?
A vasodilator which prevents platelet activation to prevent inappropriate platelet aggregation
How does aspirin work?
Binds cyclo-oxygenase which inhibits thromboxane A2 production, reducing platelet aggregation
What type of drug is clopidogrel and how does it work?
Antiplatelet drug
Binds to and blocks P2Y12 receptor, preventing ADP binding
How long do the effects of aspirin and clopidogrel last for?
7 days until all platelets are replaced
Which clotting factors are affected by vitamin K and how?
2, 7, 9 and 10
Vit K needed for carboxylation of glutamic acid residues
Describe the extrinsic coagulation cascade?
Tissue factor exposed by endothelial cells activates factor 7 to make factor 10 and 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 thrombomodulin on the surface of endothelial cells
This activates protein C which inactivates factors 5a and 8a in the presence of cofactor protein S
What does antithronbin inactivate?
Factor 10a and thrombin
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?
Potentiates the action of antithrombin when antithrombin binds endothelial cell associated heparins
Thus inactivates thrombin and factor Xa
How is heparin administered?
IV or subcutaneously
What are DOACs and how do they work?
Direct oral anticoagulants
Inhibit factor Xa and thrombin without antithrombin
How does Warfarin work?
Vitamin K antagonist
Decreases production of vitamin K dependent factors (factor 2, 7, 9, 10) in the liver
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 takes some time
How does the plasminogen/plasmin system work?
Plasmin circulates in inactive form plasminogen
Tissue plasmin activator and plasminogen bind lysine residues on fibrin
Plasmin breaks down fibrin into fibrin degradation products
What is tranexamic acid and how does it work?
Competitive inhibitor
Binds lysine residue on fibrin so that plasminogen cannot bind, reducing fibrinolysis
How does thrombolytic therapy work?
Recombinant t-PA is given which makes plasmin and lyses clots
For what conditions is thrombolytic therapy given?
Ischaemic 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?
1, 2, 5, 7, 10
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 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?
Haemophilia A (factor 8)
Haemophilia B (factor 9)
Factor 11 deficiency
Factor 12 deficiency (no severe bleeding)
What does an increased PT time indicate?
Reduction in factor 5, 7, 10, prothrombin and fibrinogen activity
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
Why does warfarin take sveral days to come into effect?
Warfarin is a vitamin K antagonist and affects protein carboxylation
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
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 bind to the phospholipid surface of the platelets
Calcium ions help binding
What are the three stages of the coagulation cascade?
- Initiation
- Amplification
- Propagation
Describe what happens in the initiation stage of the coagulation cascade?
Damaged tissue releases tissue factor
Tissue factor binds to factor 7 which activates factor 9 and 10
This produces a small amount of thrombin
Describe what happens in the amplification stage of the coagulation cascade?
Thrombin activates factors 5 and 8 and more platelets
Describe what happens in the propagation phase of the coagulation cascade?
Factor 11 activates factor 9 to 9a
Together with 8a this increases 5a production
This increases thrombin production, increasing fibrin production from fibrinogen to form the insoluble clot
How can heparin be used to block thrombin as well as antithrombin?
Inactivation of thrombin requires longer chains of heparin, which are able to wrap around both the antithrombin and thrombin
Which plasma protein inhibits plasmin?
Alpha-2 Macroglobulin
What type of drug is transexamic acid?
An anti-fibrinolytic drug
What might cause bleeding?
Reduction in platelet number or function
Reduction in coagulation factors
Increased fibrinolysis
What is meant by thrombosis?
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: contributes to both
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 fibrinolytic activity
Increased levels of clotting factors or platelets
In what circumstances is fibrinolytic activity reduced leading to venous thrombosis?
Pregnancy – where there is inhibition of plasminogen activation through the production of a specific inhibitor by the placenta (PAI-2)
What is FV leiden?
Mutation in FV gene makes it more resistant to inactivation by protein C, increasing coagulation
What can cause increased coagulation leading to venous thrombosis?
Pregnancy increasing factor 8
FV leiden
Myeloproliferative disorders
