Haemostasis Flashcards
What are the main anti-coagulation substances/factors that are found in the blood?
Heparans
TFPI*
Thrombomudulin
Nitric oxide (NO)
Prostacyclin
*Tissue factor pathway inhibitor
When you cut yourself - your blood should solidify at the site of trauma and stop the bleeding
What substances/systems are responsible for:
a) making the clot
b) confining the clot to the site of injury
c) removing the clot after healing
a) Making the clot:
- platelets
- vWF (von Willebrand factor)
- coagulation factors
b) confining the clot to the site of injury:
- natural anticoagulants
c) removal of the clot
- fibrinolytic system
What stops all the various coagulation factors and platelets etc from clumping together normally?
They exist in the blood in an unactivated form
They are only activated under certain conditions that arise through trauma - by signals
What signals cause the activation of platelets and coagulation factors?
There are 2 main signals that do this…
1) Damage to the endothelium exposes collagen which activates platelets
2) Damage causes local release of physiological factors which activate the coagulation factors
What receptors and glycoproteins are present on the surface of platelets?
Give an overview of what these moelcules are responsible for?
Platelet surface has cell surface receptors and platelet glycoproteins
Cell surface receptors:
- respond to chemicals released at site of injury
- ADP, Epinephrine, thrombin
Platelet glycoproteins:
- allow platelets to adhere by binding to ligands
- binding sites for:
- fibrinogen
- vWF
- collagen
On this diagram of a platelet - identify the different bits
What is the function of the open cannalicular system that is found in platelets
Allows the contents of the alpha and dense granules and the lysosomes to be released onto the surface of the platelets
In platelets, what is released by:
a) aplha granules
b) dense granules
a) alpha granules:
- vWF
- thrombin
b) dense granules:
- ADP/ATP
- calcium
- serotonin
Platelets have a number of glycoproteins on their surface that allow them to attach to certain ligands
How does the platelet attach to the exposed collagen?
Attaches directly to the exposed collagen using two different glycoproteins
But also attaches indirectly to collagen by attaching to vWF which itself attaches to collagen
FOllowing the adherance of platelets to the exposed collagen following an injury - how is the definitive fibrin clot formed?
Once platelet is activated and has adhered to the injury sit - one of the glycoproteins undergoes a confirmational change and allows binding to fibrinogen
This allows the A&B peptides on fibrinogen to be cleaved which paves the way towards the final fibrin clot
What drugs target the ADP (P2Y12) pathway to stop platelets from working properly?
(antiplatelets)
Prasugrel
Clopidogrel
Ticagrelor
What drug works by inhibiting the COX (cyclooxygenase) pathway, thus reduces platelet activity?
Aspirin
What is dual antiplatelet therapy?
Combination of:
1) ADP pathway inhibitors (clopidogrel, ticagrelor etc)
2) COX pathway inhibitors (aspirin)
What is the function of the scramblase enzyme in platelets?
Scramblase causes some phospholipid molecules which are normally contained on the internal surface of platelets to be expressed on the external surface
This is important as this external expression of phospholipids is key in activating coagulation factors
vWF basically exists to help stuff stick together in clots. What are the different molecules that vWF binds to?
Factor VIII
GP 1b (platelet glycoprotein)
Collagen
GP 2b/3a
As we know, the primary haemostatic plug (platelet plug) is the first and rapidly forming plug that plugs over a cut, plug
It is made up of adhered platelets, vWF and fibrinogen
What is the next step in the haemostatic process?
Fibrinogen is cleaved by thrombin to form fibrin
once this plug is formed - bleeding stops
fibrin is produced through the coagulation cascade
Go and look at the coagulation cascade if you fancy
All you really need to know is that every factor (factor VIII etc) is needed for it to work effectively
Natural anticoagulants act to confine a clot to the area of injury.
What are the 3 most important natural anticoagulant systems?
TFPI - tissue factor pathway inhibitor
Protein C and S
AT - antithrombin
How does TFPI act?
TFPI binds to and inhibits:
- Factor VIIa
- Factor Xa
the ‘a’ after the factor means its activated form so TFPI binds to and inhibits the activated form
this prevents the conversion of prothrombin to thrombin and thus the conversion of fibrinogen to fibrin
How do protein C and protein S prevent coagulation once activated?
Inhibit Factor VIIIa and Va
How does the AT system prevent coagulation?
Most powerful of the natural anticoagulants
Binds to and inactivates:
- a fair dinkum of factors (esp Factor Xa)
- thrombin
The fibrinolytic system is what breaks down clots after stuffs healed
How does it work?
The clot induces local endothelial cells to release chemicals called plasminogen activators:
t-PA (tissue plasminogen activator)
u-PA (urokinas plasminogen activator)
These molecules convert plasminogen (a zymogen) into plasmin
Plasmin is what breaks down fibrin into fibrin degredation products
What is the most clinically significant FDP (fibrin deg product) that we can measure?
D-dimer
d-dimer blood tests are used to detect thromboses
Like with all of these pathways, the fibrinolytic system has a number of inhibitors
What are the main ones?
Inhibitors of plasminogen:
PA1-1
PA1-2
Inhibitors of plasmin:
a2 anti-plasmin
a2 macroglobulin
