Platelet Biochemistry Flashcards
What do platelets come together to form
A thrombus
What is atherogenesis
Build up of atherosclerotic plaque in the arterial wall
What happens in the blood vessels as age increases
As age increases the more common it becomes for atherosclerotic Plaque to build up and cause the vessel to erode or rupture
What is the first stage of atherosclerotic plaque build up
Fatty streaks
How does a breach in the vessel wall close
By platelets adhering and forming a clot
The first stages of atherosclerotic plaque build up are silent but what do they cause in the later stages
The build up can cause serious conditions such as
Myocardial infarction
Ischemia
Stoke
Sudden death
What are platelets
They are cell fragments which drive haemostasis
When platelets are activated due to a breach in the vessel what happens to the platelet
They undergo a shape change from smooth discoid to spiculated and pseudopodia with finger like projections
Why does the platelet need finger like projections when activated
They increase the surface area and the possibility to make cell-cell interactions with other platelets and also other cells such as those in the sub endothelial and white blood cells
What receptor is on the surface of platelets
Glycoprotein IIb/IIIa
What is glycoprotein IIb/IIIa also known as
Intergrin protein
Alpha IIb Beta 3
Approximately how many receptors are on the surface of a resting platelet
Between 50,000 and 100,000
What happens to the platelets once activated
The number of receptors increases on the platelet surface
The affinity for fibrinogen increases
What role does fibrinogen play in thrombosis
Fibrinogen is a plasma protein that links the platelets to each other via receptors on there surface which allows platelets to bind and aggregate
Aggregated platelets form….
Aggregated platelets bind via cross linking with fibrinogen to form a mass over the breach in the vessel
When the atherosclerotic plaque ruptures what becomes exposed
The sub endothelial tissue
Characteristics of the endothelial tissues which stops thrombus forming
Smooth
When the sub endothelial is exposed what does this trigger
It triggers the response of platelet activation
When the sub endothelial tissue is exposed what is exposed
Collagen
Von willebrand factors
Soluble agonists
What binds with collagen in the sub endothelial tissue
Platelets have a collagen receptor on there surface to allow for binding when exposed
What does Von willebrand factor bind with in the sub endothelial tissue
The glycoprotein IIb/IIIa receptor on the surface of the platelet binds to the Von willebrand factor in the sub endothelial tissue
What role do soluble agonists play in the sub endothelial tissue
They activate platelets
What does the endothelial mono layer do in the blood vessel
It keeps the blood flowing and separates the blood from touching the sub endothelial tissue
When a platelet is activated what does this cause
Shape change
Cross-linking of GPIIb/IIIa
Platelet aggregation
What does the glycoprotein VI receptor bind to
Binds to collegen to activate the platelet
When a platelet is activated what does it activate
The platelet activated the GPIIb/IIIa receptors
What happens when the GPIIb/IIIa receptor is activated
Allows binding of fibrinogen and allows cross linking which leads to platelet aggregation
When the platelets bind to the the collagen through GPVI what does this cause
This causes platelets to synthesise and release thromboxane A2
What is thormboxane A2
This is an amplification pathway to amplify the amount of platelets activated
What does Thromboxane A2 bind to and what does it result in
Binds to the TPalpha receptor on the platelet surface to further activate platelets and activation of new platelets just arriving at the breach
What is the target of aspirin
Aspirin inhibits the Amplification pathway of Thomboxane A2
What is aspirin
The oldest anti-platelet drug
What is Arachindonic Acid
This is what is converted by COX enzymes to Prostaglandin H2
In a platelet what is prostaglandin H2 converted into and what does it lead to
Thromboxane A2
This leads to platelet amplification and aggregation and vasoconstriction to limit blood flow through the vessel
In endothelial cells what is arachidonic acid converted by
COX-1
COX-2
What does the prostaglandins in endothelial cells lead to
In endothelial cells prostaglandin H2 is converted into prostacyclin
What does prostacyclin result in in endothelial cells
Prostacyclin inhibits platelet aggregation and vasoconstriction meaning it would be a vasodilator which would increase blood flow through the vessel
What does low dose aspirin act upon in platelets
Low dose aspirin would act upon the COX-1 enzyme which would inhibit the production of prostaglandin H2 which would inhibit the production of Thomboxane A2 and stop platelet amplification
Does low dose aspirin have an affect on endothelial cells
Limited effect as most of it would be used in the inhibition of COX-1 in the platelet that it wouldn’t reach endothelial cells and so the overall effect would be the inhibition of platelet aggregation
What affect would high dose aspirin have
High dose aspirin would inhibit both COX-1 and COX-2 in both platelets and endothelial cells meaning the production of prostaglandin H2 would stop nor only inhibiting platelet aggregation but also inflammatory pathways
What are platelet purinergic receptors
They are the P2Y receptors, which are G-protein coupled receptors which signals to intracellular pathways which are activated by adenine nucleotides mainly ADP
What P2Y receptors are found on the platelet surface and what glycoprotein is it linked to
P2Y 1 which is linked to the Gq protein
P2Y 12 which is linked to the Gi protein
What happens to ADP when released outside the cell in relation to P2Y 1 receptor
They become signalling molecules which binds to the P2Y 1 receptors on the platelet surface and activates it
When ADP binds to the P2Y 1 receptor what does this trigger
This activated the platelet through the pathway phospholipase C which triggers the release of Calcium from intra cellular stores and activates the protein kinase C pathway which all initiates the process of platelet aggregation and the shape change of the platelet.
What happens when ADP binds to P2Y 12 receptor on the surface of the platelet
ADP binds to P2Y 12 and activates the Gi protein on the inside of the plate late with inhibits adenylate cyclase which inhibits the production of the signalling molecule cyclic AMP which leads to the signalling and activation of other pathways. The activation of the Gi pathway also activates the enzyme pathway PI3 kinase which together amplifies platelet activation, aggregation response and the release of granules
Describe ADP induced platelet aggregation
ADP binds to the P2Y1 receptor on the surface of the platelet causing platelet activation. When the platelet becomes activated the glycoprotein IIb/IIIa receptor is activated causing the fibrinogen to bind and the cross-linking of platelets so they stick together and are able to seal the breach in the vessel wall.
ADP then also binds with P2Y12 receptor on the surface of the platelet, this is an amplification pathway. This amplifies the whole response due to the activation of P2Y1 been relatively weak so adding in the activation of P2Y12 allows for a bigger and more sustained response to the breach.
Where does the ADP that binds to the P2Y receptors on the platelet surface come from
The ADP is actually released from inside the platelet.
The ADP come from the dense granules inside the platelet, which are released when the platelet is activated.
What is outside in signalling
This is a amplification pathway through Glycoprotein IIb/IIIa receptor.
What does thrombin bind to on the platelet surface
Thrombin binds to the PAR-1 receptor on the platelet surface
What does the binding of Thrombin with the PAR-1 receptor cause
This activates the platelet and aids the release of dense granules
How is thrombin created
Through the coagulation cascade
How do platelets aid the coagulation cascade and the release of thrombin
Platelets contribute to the coagulation cascade by creating a surface for the coagulation cascade proteins to attach to which is known as platelet procoagulant activity
Describe the resting state in platelet procoagulation activity
In the resting state there are aminophospholipids on the inner surface of the platelets so they aren’t expressed on the outer surface of the membrane, and this is kept the same through a process called translocase which is an enzyme in the lipid belayer which flips the aminophospholipids so that they are on the inner surface.
Describe what happens when the platelet coagulant activity is activated by the likes of thrombin on the PAR-1 receptor
When thrombin activates the PAR-1 receptor on the outside of the platelet, calcium is trigger to release from the intracelluar stores which is a signalling molecule within the cell. The calcium release is part of the activation process in platelets, the calcium inhibits the enzyme translocase and activates the enzyme scramblase. This enzyme breaks down the asymmetry in the phospholipid bilayer, which causes the flipping of the aminophospholipids to the external of the bilayer. This means they become expressed and allow them assembly of some of the coagulation cascade proteins so prothrombin and become thrombin through the prothrombinase complex (factor Va and factor Xa)
How does platelet procoagulant activity link to the increase in platelet activation
Thrombin activates the PAR-1 receptor which increases the release of intracellular calcium which causes the translocase enzyme to be inhibited and the scramblase enzyme to be activated flipping the aminophospholipids to the external of the bilayer where the prothrombase complex can bind and turn prothrombin into thrombin which is then released from the platelet and binds with the PAR-1 and PAR-4 receptors on the platelet surface to amplify the platelet aggregation
What is a platelet-fibrin clot, how does it form and why is it important
Due to the relationship between thrombin and the coagulation cascade, platelet-fibrin clots form. Platelets aggregate together along with red cells clumped together within a mesh o fibrin strands which formed due to thrombin cleaving fibrinogen into fibrin, which binds the clot together and stabilises the clot.
Why is it important that the clot contains the fibrin stands to stabilise it
This is important because when a fibrin Rich clot has formed it is really hard for the body to breakdown without activating the fibrinolytic system.
How does the fibrinolytic system work
Tissue plasminogen activator is release from the endothelium which converts the plasma protein plasminogen into plasmin. The plasmin is then used to break down the fibrin stands into degradation products
What inhibits tissue plasminogen activator
PAI-1/ plasminogen activator inhibitor-1
What inhibits plasmin
Anti plasmin complex inhibits plasmin
What are alpha granules in platelets
Play a role in Inflammation and healing.
When does the platelet release alpha granules
They begin to release alpha granules when the platelet becomes activated through any of the pathways.
What do alpha granules contain
Coagulation factors and inflammatory mediators
What is the role platelets have in inflammation
They do this through the expression of P-selectin which is bound to the inside surface of the alpha granules which then are released and fuse to the external membrane of the platelet. The counter receptor for P-selection is found on the surface of leukocytes and monocytes, which is PSGL-1. This allows the platelet to bind to the leukocyte or monocyte in question. Thus leads to cross talk between the cell and the platelet which can lead to a thrombotic response and increases the inflammatory response which can help with wound healing
