Platelet biochemistry Flashcards
Why are platelets important in diseases?
Thrombosis:
- Formation of clot inside a vessel
- they have a central role in arterial thrombosis
Anti platelet medications can be life-saving
What is artherogenesis and artherothrombis?
It is a build up of plaque in the artery walls. When this plaque ruptures the platelets should help to fix this rupture but may not. This can lead to:
- Ischaemic stroke
- Cardiovascular death
- Myocardial Infarction (heart attack)
etc…
What does the platelet shape change lead to?
- When a platelet is activated it changes shape
- Goes from smooth discoid to spiculated and pseudopodia (arm-like projections)
- Increases the surface area
- Increases the possibility of cell-cell interactions and with other cells
What is the glycoprotein IIb/IIIA receptor?
-They are on the surface of platelet
- When a platelet is activated it will increase number of receptors and increase the affinity of the receptor to fibrinogen (which links receptors, binding platelets together: aggregation to form a mass)
Describe the platelet plug formation (long answer - 9 step)
- Damage to blood vessel leads to exposure of collagen
- Adhesion of platelets to collagen directly through glycoprotein 1a leads to exposure of glycoprotein IIb./IIIa
- Von Willebrand Factor binds to collagen through IIb/IIIa glycoproteins and increases platelet adhesion
- Platelet contains 2 types on granules: electron dense granules and alpha granules
- Electron dense granules release ADP/ATP, serotonin and calcium. ADP acts on P2Y1 and P2Y12 which lead to further activation and ATP binds to P2X1
- Thrombin binds to PAR1 and PAR4 – resulting in platelet activation
- Activation of platelets: change shape from discoid to spiculated/spikey shape with pseudopodia which increase surface area of platelet
- Activation of platelets leads to increase expression of Iib/IIIa and fibrinogen secreted from alpha granules bind it to which results in new platelets to adhere to old ones – platelet aggregation
9.Platelets produce thromboxane A2 which play a part in vasoconstriction – reduced blood flow which aids in forming the primary haemostatic plug
How are platelets activated?
- Platelet binds to collagen
- Releases Thromboxane A2
- Thrombin binds to PAR1 (releases ADP from dense granules) and PAR4
- free Thromboxane A2 binds to TP alpha
What does the production of Thrombonxane A2 rely on?
COX1
What is the effect of platelet activation?
- Change shape (Smooth to spiculated)
- Increased GPIIb/IIIa expression
- Form crosslinks with other platelets (aggregation)
What effect does aspirin have on platelet activation mechanisms?
It inhibits an amplification pathway.
- Specifically it inhibits COX-1 (small doses) and COX-2 (high doses). So no aggregation can occur and platelet function is altered
- If inhibits COX1, also means there is less thromboxane A2 so less aggregation
What happens when ADP binds to P2Y1?
- activation and amplification
- This creates protein Kinase C and Ca2+
- This is the initiation of aggregation and shape change
- Also results in GPIIb/IIIa fibrinogen cross-linking
What happens when ADP binds to P2Y12?
- inhibits cyclic AMP being made
- cAMP normally inhibits platelet activation
- so inhibiting this increases the activation of platelets
How is ADP regenerated?
- ADP causes platelet activation via P2Y receptors
- ADP comes from platelets, which when activated release dense granules
- Dense granules release ADP, which causes further activation
What does PAR-1 do?
- Activates platelets and ADP amplifies this activation
- Thrombin binds to PAR1 and PAR4 receptors - inducing platelet activation and further thrombin release - positive feedback
What does translocase do?
Keeps the aminophospholipids on the inner surface of the membrane lipid bilayer.
What happens to aminophospholipids when the platelet is activated?
- Platelet activation e.g. thrombin activating PAR-1
- Causes Ca2+ to be released from intracellular stores
- This inhibits translocase and activates scramblase which flips the aminophospholipids to the outer membrane leading to prothrombin to be converted to thrombin
What does Factor Xa do?
Factor Xa is the enzyme that converts prothrombin to thrombin - thrombin is the enzyme which then goes onto convert fibrinogen to fibrin for crosslinking
What is the Fibrinolytic system
FIBRINOLYTIC SYSTEM: a fibrin clot is not designed to last forever, it is a temporary fix until permanent repair of the vessel occurs:
- Plasmin then goes on to break fibrin down and thus the entire blood clot
What do platelet alpha granules do?
- Release inflammatory mediators
- This drives the healing process
What factors are activated in the coagulation cascade when there is damage to blood vessels?
Factors
9,10,11,12
What factor converts prothrombin into thrombin?
Factor 10 (with the help of 5)
What does thrombin convert in the coagulation cascade?
Fibrinogen into fibrin
How do other factors form clots in the coagulation cascade with fibrin?
Factor 13a and fibrin from a stable fibrin clot
How do intrinsic and extrinsic actions aid the fibrinolytic system?
Intrinsic action by factor 7a and extrinsic action of tissue plasminogen activator converts plasminogen into plasmin
Plasmin then leads to the degradation of fibrin
How does Factor 7/7a play a role as extrinsic and intrinsic factor?
Factor 7a is part of the extrinsic pathway in the coagulation cascade (tissue factor activating) and part of the intrinsic pathway in the fibrinolytic system
