When would haemostasis promotion be required?
Haemostasis promotion is promoting blood clotting. This is rarely necessary except when there are defects in the blood clotting system. This is normally in response to diseases such as:
- Haemophilia
- Extensive anticoagulation therapy
- Haemorrhage after surgery
- Menorrhagia
Why are platelets essential?
- To maintain the integrity of circulation.
- Essential for haemostasis, healing of vessels and inflammation
- They’re also essential for the formation of thrombi and they’re the very first step of the clotting cascade.
What properties do platelets have?
- Adhere to following vascular damage
- Shape change
- Secretion of granule contents
- Biosynthesis of PAF and prostaglandins
- Aggregation (forming cluster)
- Exposure of acidic phospholipid on surface (promotes aggregation)
What are the mechanisms of platelet activation?
- Usually platelets are not active
- However when they are exposed to damage, they will become activated.
- There are many different pathways that can activate them.
- In the atherosclerotic development, the first that happens is that you have endothelial damage and endothelial cell death and this will lead to exposure of the basement membrane to the blood. The 2 components that can activate platelets of the extracellular matrix are the Von Willebrand factor and collagen and there are receptors for both of these on the platelets. When exposed to these extracellular matrix components, they can bind and start to activate platelet activation.
- There are also soluble factors that are involved. There are lots of different receptors on platelets and they bind to different things. So things like Thromboxane-A2, ADP etc, they bind to the ligands of these receptors and will stimulate platelet activation.
- Another mechanism is platelet aggregation will lead to further platelet activation and this is where there are receptors that will bind to fibrin and fibrin will then form links between the platelets causing aggregation and further stimulating the activation of the platelets.
- The change in shape is driven by the cytoskeleton of the platelet.
What factors prevent/limit the activation of platelets?
Nitric oxide and Prostacyclin
- These are both made by endothelial cells and are released into the blood and these both inhibit activation and aggregation.
- There are also enzymes on the endothelial cell which will remove ADP. ADP will be cleaved to AMP. Hence the endothelial cells will reduce the levels of ADP as well.
How can we influence platelet aggregation?
- If we want to inhibit platelet activation and aggregation, then we can target the factors that promote it. Hence we can target factors that will inhibit Thromboxane A2 production or activity and same for ADP, we can either remove ADP or we can inhibit it from binding to receptors on the platelets itself, and we can also stop the cells from aggregating as well and have blockers that will block the binding to Von Willebrand factor or Collagen which both lead to platelet activation.
- We can also stimulate the production of the inhibitors of platelet activation as well. We can stimulate nitric oxide production although this strategy doesn’t work so well because it very short lived. We can also increase the level of Prostacyclin formation, hence inhibiting platelet activation. Or we can increase the removal of ADP as well. So by removing ADP, it’ll lead to less activation of platelets.
What are anti platelet drugs?
They decrease platelet aggregation and inhibit thrombus (thrombi) formation in arterial circulation.
Name some examples of anti platelet drugs.
- Aspirin
- Thienopyridines - Clopidogrel (Prasugrel, ticlopidine)
-Ticagrelor - Glycoprotein IIb/IIIa inhibitors (Eptifibatide, Tirofiban, Abciximab)
- Dipyridamole
What is the goal of anti platelet drugs?
Overall aim is to inhibit the pathways that activate the platelet activation or lead to platelet aggregation.
We can target:
- Thromboxane synthesis
- Thromboxane binding to receptors
- We can target ADP pathways
- We can target the glycoproteins responsible for aggregation of platelets
- We can target the aggregation step by Nitric Oxide although it’s very short lived so it’s not really a therapeutic option.
What is the pharmacology of Aspirin?
- Aspirin will irreversibly inactivate cyclooxygenase (COX). Both COX 1 and COX 2
- COX 1 is found in the platelets themselves and is important for the platelet aggregation step.
- COX 2 is found in the endothelial cells and is also important for platelet aggregation and regulation of aggregation.
- These two enzymes are important because they are responsible for the synthesis of Thromboxane A2 in the platelets. So when the platelet becomes activated, COX 1 is essential for the production of Thromboxane A2 which will further stimulate the activation of other platelets. In the endothelial cells COX 2 is essential for the formation of Prostacyclin, the inhibitor of platelet activation.
- Aspirin is now inhibiting both an inhibitor and an activator of platelet activation. So in the case of platelet activity, it will inhibit thromboxane A2 = promotion of platelet aggregation and also inhibit prostacyclin formation = inhibition of platelet aggregation.
- Aspirin irreversibly inactivates COX 1:
1. Reduces thromboxane A2 formation
2. REDUCES platelet aggregation - Aspirin irreversibly inactivated COX 2:
1. Reduces prostacyclin formation
2. INCREASES platelet aggregation
SO THE NET EFFECT IS ZERO.
So why does Aspirin work?
- We know that the endothelial cells can synthesise new COX 2.
- But platelets can’t because endothelial cells have a nucleus whereas platelets don’t.
- So endothelial cells can make fresh RNA and fresh protein for the COX 2 whereas the platelets can’t.
- This means that overtime the endothelial cells will start to make more COX 2 and start to make more prostacyclin whereas the platelets now can’t make COX 1 so they don’t make any thromboxane. So overtime you start to recover the prostacyclin levels but thromboxane A2 levels will remain low.
- We also know that the inhibition are dose dependant. So at lower doses you will just inhibit platelets so COX 1 activity. At higher doses you can inhibit both.
What is the pharmacology of Clopidrogel & Prasugrel?
- These are Thienopyridines, and they are inhibitors of the ADP-induced aggregation (ADP receptor antagonists)
- These serve as an additive effects to aspirin because they work on separate pathways (so can take both drugs at the same time).
- They work by antagonising the platelet P2Y12 receptor (purinergic receptor) that will bind ADP and trigger platelet activation. Hence blocking the ability to block ADP binding to the receptor and inhibit the activation of the pathway.
What is the pharmacology of Ticagrelor?
- Ticagrelor is a nucleoside analogue - it looks like adenosine
- It works by blocking P2Y12 ADP receptors on platelets
- It acts on a different binding site than ADP so its an allosteric inhibitor and blockage reversible and therefore acts faster and for shorter period.
- PLATO trial- Ticagrelor less mortality from all CV causes than clopidogrel
Side effects:
- More non-lethal bleeding
- However effects can be quickly reversible though
What is the pharmacology of Glycoprotein IIB/IIIA receptor antagonists?
They inhibit all pathways of platelet activation because they bind to glycoprotein IIB/IIIA receptors, blocking fibrinogen binding so inhibiting aggregation
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Cardiac physiology20
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Cardiac Electrical activity and ECG26
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Cardiovascular risk assessment25
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Use of Statins17
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Stroke6
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Coronary Heart Disease2
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Lipid Transport20
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Dyslipidemia13
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Atherosclerosis5
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Antiplatelets13
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Coagulation4
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Anticoagulation pharmacology17
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Fibrinolytics9
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Antianginal pharmacology14
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Anti-arrhythmic drug pharmacology9
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Coronary heart disease44
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Heart failure58
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Cardiac arrhythmias38
