Below is a short summary and detailed review of this video written by FutureFactual:
Aspirin and COX Inhibition: Mechanism, Lipoxins, and Safety in NSAIDs
Aspirin, a member of the salicylic acid class of NSAIDs, uniquely inhibits COX enzymes irreversibly by transferring an acetyl group to the active site. This action prevents pro-clotting prostaglandins in platelets while vessels can still produce anti-clotting prostaglandins, contributing to aspirin’s low-dose blood-thinning effect. The talk also covers aspirin-triggered lipoxins, the potential anti-inflammatory benefits of these ATLs, and safety considerations such as aspirin sensitivity in asthma and the risk of Reye's syndrome in viral illnesses, with acetaminophen often preferred for fever in children.
Background: Aspirin within the NSAID family
Non-steroidal anti-inflammatory drugs (NSAIDs) broadly reduce fever, pain, and inflammation by inhibiting cyclooxygenase (COX) enzymes. Aspirin is unique in its historical and pharmacological profile: it was synthesized by Felix Hoffmann at Bayer in 1899 by acetylating salicylic acid, creating acetyl salicylic acid. Unlike other NSAIDs that compete for active-site substrates, aspirin binds covalently to COX enzymes, creating an irreversible inactivation that persists in enzymes that have already inhibited, with new enzymes needing to be synthesized to restore activity. The presentation also touches on aspirin’s clinical roles in anti-platelet therapy and heart disease prevention, contrasting it with other fever-reducing options.
Mechanism: Irreversible COX inhibition by acetylation
Aspirin’s defining action is acetylation of specific COX serine residues—serine 529 in COX-1 and serine 516 in COX-2—resulting in permanent enzyme inactivation. This irreversible modification distinguishes aspirin from other NSAIDs, which inhibit COX temporarily by competitive binding. Once acetylated, COX enzymes cannot perform their prostaglandin-synthesis function, and new enzyme synthesis is required for activity to return. The low-dose regimen that targets platelets leverages this irreversible inhibition to tilt the prostaglandin balance toward anti-clotting activity in the vasculature, contributing to aspirin’s cardioprotective effects.
"Aspirin acetylates serine 529 in COX 1 and serine 516 in COX2." - Professor Dave
Physiological consequences: Platelets versus vessel cells
In blood, COX enzymes in platelets generate TXA2, a pro-clotting prostaglandin, while endothelial cells line blood vessels generate PGI2, an anti-clotting prostaglandin. Platelets lack a nucleus and cannot synthesize new proteins, so acetylation of COX in platelets endures for the platelet’s lifetime (about 8–9 days), producing a lasting anti-thrombotic effect. Vessel cells, however, continually synthesize new COX enzymes, so their prostaglandin production remains dynamic. This shift in the pro- versus anti-clotting balance underlies aspirin’s cardiovascular benefits, especially with chronic low-dose use. The talk also notes metabolic aspects, including how aspirin is absorbed in the gut, carried via the portal vein to the liver, and rapidly metabolized to salicylic acid.
"Platelets lack a nucleus and therefore have no capacity to generate new RNA transcripts for protein production." - Professor Dave
Aspirin-triggered lipoxins and anti-inflammatory activity
Acetylation of COX-2 by aspirin leaves certain enzyme functions intact, enabling the production of aspirin-triggered lipoxins (ATLs). These ATLs, such as 15-epi-lipoxin A4, are epimers that may enhance aspirin’s anti-inflammatory effects by generating novel anti-inflammatory mediators beyond its classic prostaglandin modulation. This adds a layer to aspirin’s pharmacology, potentially contributing to its broader anti-inflammatory actions beyond fever and pain relief.
"This epimer has been found to have potent anti-inflammatory effects, and it is thought that this actually increases aspirin's anti-inflammatory activity." - Professor Dave
Safety considerations and clinical use
Despite its wide utility, aspirin can cause hypersensitivity in some individuals, particularly 10–25% of asthma patients, and is associated with Reye's syndrome, a rare but serious condition affecting the liver and brain in viruses-infected children and young adults. Because of this, aspirin is avoided for viral-fever treatment in younger populations, with acetaminophen (paracetamol) commonly used as a fever reducer in children due to its lower risk of Reye's syndrome and gastric side effects. The video emphasizes aspirin’s role in cardiovascular prevention while acknowledging the need for caution in patients with asthma and in pediatric viral illnesses.
Conclusion
The narrative highlights aspirin’s unique irreversible mechanism, the resulting platelet-specific effects that support cardiovascular protection, and the complex biology including ATLs that may broaden its anti-inflammatory profile. It also underscores safety considerations that influence its use across populations and symptoms, balancing benefits with potential risks.