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
