Week 2- Haemostasis Flashcards
What is haemostasis the balance between?
Coagulating factors and platelets vs anticoagulating proteins and fibrinolytic factors
What are the aims of haemostasis?
- To allow stimulation of blood clotting (coagulation)
- To prevent excessive blood clotting (thrombosis)
- To allow the fibrin clot to break down (fibrinolysis)
What are the 3 stages of haemostasis?
- Construction of blood vessels
- Primary haemostasis: Formation of a temporary platelet plug (platelet aggregation and adhesion)
- Secondary haemostasis: Formation of a fibrin clot (coagulation)
Which cells do platelets come from?
Myeloid stem cells
What is the lifespan of an average platelet?
10 days
How are platelets made?
Via megakaryocyte fragmentation
Describe the structure of platelets
They are discoid, non nucleated, have glycoproteins on their cell surface, contain granules
How do platelets attach to endothelium cells?
Directly: to collagen via GP1a receptor
Indirectly: via Von Willebrand factor (VWF) and GP1b receptor
What granules do platelets contain and describe how granular contents are released from platelets
They contain alpha and dense granules, contents are released via cannicular system that is formed from invaginated surface
What do granules in platelets contain?
ADP, fibrinogen and VWF
How is thromboxane A2 synthesized?
From arachadonic acid that comes from the cell membrane
What is the function of thromboxane A2?
To help with platelet aggregation and vasoconstriction
Describe the process of platelet aggregation
- Granular release of ADP and thromboxane A2
- Conformational change in GPIIb/IIIa receptor
- Fibrinogen binds to receptor
- Fibrin clot can form
What is prostacyclin and where is it used?
It is a chemical vasodilator that is released during platelet aggregation to prevent excessive aggregation
Name the anti-platelet drugs and their mechanism of action
Aspirin- blocks thromboxane A2 synthesis
Clopidrogel- blocks ADP receptors on cell membrane
When may anti-platelet drugs be prescribed?
In cardiovascular/cerebrovascular disease to prevent strokes/heart attacks
What is VonWillebrand factor?
It mediates adhesion of platelets to the sight of injury and promotes platelet to platelet aggregation. It is also a carrier of factor VIII
What chemical do coagulating pathways rely on and what is its function?
Thrombin- it cleaves fibrinogen to allow fibrin clots to form
Where are the main clotting factors produced? What are the exceptions?
Nearly all are produced in the liver apart from factor V which is produced in megakaryocytes and VWF which is produced in endothelial cells or megakaryocytes
Which clotting factors need Vit K and why?
Factors II, VII, IX & X need vit K to cleave their glutamic acid residues
What characterizes the steps in the blood coagulation pathway?
The conversion of an inactive zymogen (proenzyme) into an active clotting factor by breaking peptide bonds to expose the active site
NOTE: often occurs on phospholipid surface of platelets to accelerate activity and Ca2+ plays a role in allowing binding of active clotting factors to phospholipid surfaces of platelets
Describe the coagulation pathway
INITIATION PHASE:
Blood encounters tissue factor (TF) at sites of vascular injury only
TF binds to factor VIIa causing conversion of factors IX to IXa and X to Xa
Leads to activation of prothrombin to generate a small amount of thrombin
AMPLIFICATION PHASE:
Small amount of thrombin mediates activation of factors V and VIII, zymogen factor XI and platelets
PROPAGATION PHASE:
Factor XI converts more IX to IXa and along with VIIa this amplifies conversion of X to Xa. This causes a burst of thrombin to be produced which cleaves fibrinogen to form an insoluble fibrin clot
What are the anticoagulant drugs and their mechanisms of action?
Heparin- administered orally or by subcut injection, prevents the conversion of IX to IXa or X to Xa
Warfarin- administered orally, requires regular blood tests, prevents vit K cleaving glutamic acid residues so no factors II, VII, IX, X made
DOACs- administered orally, no need for observation, inhibits thrombin (factor X)
What proteins are involved in natural anticoagulant pathways
Protein C,S and antithrombin
Describe the anticoagulant pathway
Thrombin binds to thrombomodulin
Protein C (APC) is activated
It inactivates factor Va and VIIIa in the presence of co factor protein S
Antithrombin binds to thrombin and factor Xa inactivating them (it’s actions are amplified by heparin)
What is the enzyme involved with fibrinolysis
Plasmin (present as plasminogen- an inactive zymogen)
Describe the fibrinolytic pathway
In presence of t-pa (tissue plasminogen activator) plasminogen is activated to plasmid when they come together on lysine on the fibrin clot. This allows the breakdown of fibrin to occur, releasing fibrin degradation produces
How is thrombolytic therapy administered and how does it work?
Recombinant t-pa is given intravenously and it breaks down clots in the event of stroke etc. Has to be administered very quickly for it to be effective
What is the main antifibrinolytic drug and how does it work?
Tranexamic acid competitively binds to lysine on fibrin clots, preventing plasminogen activation as it and t-pa can’t come together
What are the 2 main tests for coagulation?
Prothrombin time and activated partial thromboplastin time
How is the prothrombin test for coagulation carried out?
Blood is mixed with sodium citrate
It is spun and phospholipid, tissue factor and calcium are added
A longer time for coagulation can indicate a lack of prothrombin ie factors II, V, VII or X
How is the activated partial thromboplastin time test for coagulation carried out?
A contact activation test for factor XII is done by spreading blood onto a silica plate
Prolonged time can indicate hemophilia A/B or factor XI deficiency
What is Von Willebrand’s disease?
When there is a lack of WVF, autosomally inherited, treated by replacing clotting factors w recombinant ones, both males and females affected with males having mainly haemophilia A and sometimes B
What are acquired causes of decreased coagulation factors?
Liver disease, anticoagulant drugs and dessimated intravascular coagulation (DIC)
What is dessimated intravascular coagulation?
Widespread excessive thrombosis due to over expression of tissue factor, leads to small thrombi in blood vessels (known as micro circulation)
What are the contributory factors to thrombosis?
Virchow’s triad:
Blood (more for venous thrombosis)
Vessel wall (more for arterial thrombosis)
Blood flow (for both)
What changes in blood contribute to increased risk of venous thrombosis?
Reduction in anticoagulation proteins, pregnancy (increased factor VIII) and factor V Leiden (when factor V fails to be inactivated by vit C)
