ASPIRIN

Mechanism of action

Here's a video (6m 41s) outlining how aspirin works as an antiplatelet and an explanation of why we give antiplatelet drugs in the first place.

Cyclo-oxygenase (COX)

What is cyclo-oxygenase?

Cyclo-oxygenase (COX) is an important enzyme that has 2 main variants: COX-1 and -2.

COX synthesises prostaglandins which are a family of chemical mediators and you may see specific prostaglandins denoted as 'PGE2' (which is prostaglandin E2). It also produces thromboxane A2 which is important in haemostasis.

COX-1 (the background enzyme)

COX-1 is involved in synthesising chemicals important in normal functions, such as:

Prostaglandins which are gastroprotective (by stimulating gastric mucus secretion) and renoprotective (by dilating the afferent arteriole and increasing renal blood flow).
Thromboxane A2 which promotes platelet aggregation (see below: 'Platelet plug formation and the role of thromboxane A2')

Cyclo-oxygenase-1

COX-2 (the inflammatory enzyme)

COX-2 is involved in synthesising chemicals important in inflammation and pain, such as:

Prostaglandins which pro-inflammatory and they sensitise peripheral nociceptors to painful stimuli.

Cyclo-oxygenase-2

Aspirin is a COX-inhibitor

Aspirin is ~10x more selective for COX-1 than COX-2

What does this mean?

Only low doses (75mg) are needed for COX-1 inhibition to produce anti-platelet effect (i.e. by reducing thromboxane A2 production, more below).
Higher doses (300mg) are needed for COX-2 inhibition to produce anti-inflammatory and analgesic effects.
However, with this higher dose comes the increased risk of gastro-toxicity (i.e. GI irritation, ulcers, bleeding) and reno-toxicity (i.e. renal impairment).

Aspirin irreversibly inhibits COX

What does this mean?

Platelets cannot regenerate COX, so anti-platelet effects last ~8-10 days (the lifespan of platelet).
Endothelial cells can regenerate COX, so anti-inflammatory effects only last ~2-4hours.

The arachidonic acid pathway and the inhibition of COX-1 and -2 by aspirin.

Platelet plug formation and the role of thromboxane A2

1. When the vascular endothelium is damaged, collagen and von Willebrand factor (vWF) are exposed to the blood plasma.

2. Platelets circulating in blood plasma bind to collagen and vWF and the platelets become activated.

3. These activated platelets are ones which have changed shape (or conformation) and release dense granular bodies containing thromboxane A2 and adenosine diphosphate (ADP).

4. The released thromboxane A2 facilities the activation of other platelets and enters these platelets to cause release of their dense bodies.

5. This results in a chain reaction where multiple platelets become activated leading to aggregatation of platelets - this forms the basis of a clot on the damaged endothelium.

In summary, thromboxane A2...

is synthesised inside platelets by COX-1 from phospholipids
is stored in platelets in dense bodies which are exocytosed following platelet activation
facilitates platelet activation and enables them to release their dense bodies. This chain reaction ultimately leads to platelet aggregation and clot formation.

TXA2 is released by activated platelets. It enters inactivated platelets and facilitates the release of their dense bodies.

TXA2 is synthesised in platelets by COX-1 from phospholipids. The TXA2 is stored in dense bodies with ADP and these are exocytosed upon activation of the platelet.

Aspirin inhibits platelet activation and aggregation

Aspirin irreversibly inhibits COX-1 meaning platelets cannot synthesise thromboxane A2.
This reduced release of TXA2 reduces platelet activation and aggregation.
Because aspirin irreversibly inhibits COX-1 and platelets are unable to make new COX-1, the anti-platelet effects last ~7-10 days (the lifespan of platelet), until new platelets are regenerated.

Aspirin inhibits COX-1 and so it is unable to synthesise TXA2. The reduction in TXA2 release from activated platelets leads to reduced platelet activation and aggregation.

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