Haemostasis Flashcards
what different things are involved in normal blood flow and what is responsible for making sure blood maintains its liquid form?
Green cells responsible for making sure blood maintains liquid form
What happens when you cut yourself? :
- You bleed at the site of the injury
- For how long?
- Stops – you form a clot (what causes this?)
- The clot remains confined to the site of injury (how?)
- 1 week later the clot has vanished (how?)
Platelets, vWF, Coagulation Factors
Natural Anticoagulants
Fibrinolytic System
what is vWF?
von Willebrand factor (VWF) is a blood glycoprotein involved in hemostasis
VWF is an adhesive plasma glycoprotein which performs its haemostatic functions through binding to FVIII, to platelets surface glycoproteins, and to constituents of connective tissue. VWF acts as a stabilizer of FVIII in the circulation.
Big sticky molecule that you want when there is a clot
Binds to factor 8 which is needed for a clot
Different types of vWF disease
resting in blood vessles are:
- Platelets
- Coagulation factors
when do they become activated?
they become activated when the vessel wall is damaged
Platelets see an abnormal surface, has a receptor for the collagen, and binds to it
Also when you damage a blood vessel you release a small amount of physiological activator
when there is vessel damage, what happens to the platelets?
Platelets in the area of the damage have become activated and sticks
platelet adhesion
collagen indictaes abnormal surface
we release a small amount of tissue factor when there is damage and htis is the normal physiological activator which starts the coagulation casade so you can form a definitive clot
what is the surfcae of a platelet like?
Platelet has receptor for these things
The Glycoprotein bind to important ligands
Series of receptors for things that are released during trauma
what forms the primary and then definitive fibrin clot?
Platelet has stuck to the collagen holding the platelet in place
Also stuck to vWF
Binds fibrinogen on the top
Binds to collagen, bind to vWF, platelets bind to each other - forms primary clot
ONce the fibrinopeptides A and B are cleaved off, Fibrinogen forms the definitive fibrin clot
what is the role of platelets in haemostasis?
- Adhere (to abnormal surface)
- Activation (through variery of pathways)
- Aggregation
- Provide phospholipid surface for coagulation
when actiavted hwat do platelets adhere to?
collagen
vWF
how are platelets activated?
through multiple pathways
what causes the platelets to aggregate?
thromboxane
a hormone of the prostacyclin type released from blood platelets, which induces platelet aggregation and arterial constriction
what needs ot happen in a platelet to allow coagulation to happen?
Scramlase allows phospholipid to be expressed on the outside surface of the platelet
Phospholipid helps coagulation as some of the reactions are phospholipid dependent
Phospholipid normally on the internal membrane of the platelet so this allows it to be expressed on the external surface
how is the Primary Haemostatic (Platelet) Plug formed?
30 seconds – 1 minute after a cut
Platelets become activated, stuck to collagen, stuck to vWF, changed conformation and now bound fibrinogen
If you have a platelet plug you need a fibrin plug otherwise you will bleed
Need to cleave the fibrinogen
what clots is the one htat stops the bleeding?
Definitive Haemostasis: Fibrin formation
what is haemophilia?
Haemophilia is a mostly inherited genetic disorder that impairs the body’s ability to make blood clots, a process needed to stop bleeding. This results in people bleeding for a longer time after an injury, easy bruising, and an increased risk of bleeding inside joints or the brain.
what does the normal clotting sequence look like?
what happens if there is a defective clotting sequence?
what is the process involved in fibrinogen eventually being cleaved into fibrin to form the definitive clot?
End point is manage to cleave fibrinogen into fibrin
Thrombin cleaves fibrinogen onto of the clot into fibrin to form the plug
Intrinsic pathway fed by thrombin to form more thrombin to form a stable fibrin clot
All factors need to be there but if the clotting factors not there (congenital is haemophilla or aquired is liver disease) then you wont form adequate thrombin and wont form stable clots
Why does clot stay In the area you cut yourself?
Natural Anticoagulants (3 min ones in yellow)
All these are responsible for making sure your clot is refined to the area it is meant to be
If problem in any of these things then you can get DVT and pulmonary embolism
what does Natural Anticoagulants TFPI do?
If inhibit 7 and 10 then you don’t make much thrombin and stop making clot – switch things back off when you have made the clot
what does Natural Anticoagulants Protein C and S do?
Activated protein C binds to its cofactor protein S and these molecules switch of activated factor 8 and 5 and stopping thrombin production and reducing the clot formation
what does Natural Anticoagulants Antithrombin do?
Binds to and inactivates lots of coagulation factors
Specifically factor 10 and thrombin
probably hte most powerful of the natural anticoagulants
what happens to this after a couple weeks?
If you look at hand a couple weeks after your hand is normal so a lot of remodelling has to happen
Need to get rid of the clot
Clot _________ to the area of tissue damage
confined
what is fibrinolysis?
the enzymatic breakdown of the fibrin in blood clots
what causes fibrinolysis?
When you form a clot your endothelial cells secrete activators of plasminogen
Plasmin is a zymogen and just needs to be converted into its activated form, it attacks the clot and breaks it down and when you beak down the clot you get FDP, most common one is the d-dimer - direct result of cleavage of cross linked fibrin
Plasminogen is the inactive precursor of plasmin, a potent serine protease involved in the dissolution of fibrin blood clots
can fibrinolysis be stopped?
Numerous inhibitors
PAI 1 preventing plasmin activator
When you prevent cleave of plasminogen then you don’t get plasmin which breaks the clot down
Obesity can lead to increased PAI-1
what are some different Mechanisms of antithrombotic drugs
Aspirin – prevents production of thromboxane
Gp 2/3 receptor – prevent binding fibrinogen to GP 2/3 – people continuing thrombosis of their stent
how does warfarin work?
Anticoagulant
Vitamin K antagonist
Vitamin K is required for posttranslational modification of these things
Reduced functional levels of 2, 7, 9 and 10 – all need to be gammacarboxylated
Factor 2 is prothrombin
how do heparins work?
Most common Parental anticoagulant
LMWH is same thing but side chains cleaved off it
Heparins bind to antithrombin allows cleavage more quickly
what does Rivaroxaban, Edoxaban, Apixaban do?
Small molecules
Prevent cleavage of prothrombin to thrombin therefore no fibrin formation
Preventing clot formation
prevent serum proteases
sit on the active sit of activated factor 10
what does Dabigatran and Bivalirudin/Argatroban do?
Direct thrombin inhibitors
directly stick to thrombin and stopping it doing its functioning which is to cleave fibrionogen to fibrin e.g. preventing clot formation
Summary:
- Localised development of an appropriate clot - what is involved?
- Limited by - what?
- Cleared up by - what?
•Localised development of an appropriate clot:
- Platelets
- Von Willebrand Factor
- Coagulation factors
•Limited by:
- Natural Anticoagulants (step in once enough clot and switch clot forming process off)
•Cleared up by:
- Fibrinolytic system
