How Aspirin Works: From Vane's Prostaglandins to the Heart and Cancer Trials

When Felix Hoffmann wrote up his laboratory report on acetylsalicylic acid on 10 August 1897, nobody knew how the substance worked. It eased pain, brought down fever and calmed the swollen joints of rheumatic fever, as the older salicylates from willow bark and meadowsweet had done, and it was gentler on the stomach than sodium salicylate. For more than seventy years after it went on sale in 1899, aspirin was one of the most widely used medicines in the world while its mechanism remained a mystery.

This page follows aspirin through the twentieth century: how the name escaped its trademark, how the stomach-bleeding reports accumulated, how the English pharmacologist John Vane finally explained the drug in 1971, how the discovery of a single permanently altered platelet protein turned a painkiller into a heart medicine, and what the large randomised trials of the 1980s and later reported about heart attacks, Reye’s syndrome in children and deaths from cancer. It reports findings and history only; it gives no dosing guidance.

Table of Contents

  1. Aspirin Goes Around the World
  2. A Trademark Becomes a Common Word
  3. Early Reports of Stomach Irritation and Bleeding
  4. John Vane and the Prostaglandin Discovery of 1971
  5. Two Cyclooxygenases: COX-1 and COX-2
  6. Why One Dose Affects Platelets for Their Whole Life
  7. Lawrence Craven and the First Heart-Attack Observations
  8. ISIS-2 and the Antiplatelet Trials
  9. Reye’s Syndrome and Children
  10. Aspirin and Cancer Deaths in the Long-Term Trial Data
  11. Key Research Papers
  12. Connections
  13. Featured Videos

1. Aspirin Goes Around the World

The Neue Deutsche Biographie entry on Hoffmann records the outline of what happened next: the acetylsalicylic acid he had made in pure, stable form in 1897 proved superior to sodium salicylate because it caused fewer side effects, and it was put on the market under the name “Aspirin” in 1899. Heinrich Dreser’s pharmacology paper introducing the drug appeared in Pflügers Archiv the same year. The story of how the compound was made, and of the long dispute over who deserves the credit, is told on the companion page The 1897 Synthesis of Aspirin and the Eichengrün Question.

What followed was one of the great commercial and medical success stories of the age. Histories of the drug, such as Montinari, Minelli and De Caterina’s “first 3500 years of aspirin history” (2019) and Desborough and Keeling’s “from willow to wonder drug” (2017), trace how aspirin moved from a prescription product for rheumatism into a household remedy for headache, toothache, fever and everyday aches. It was cheap to make once salicylic acid itself could be produced industrially, it was stable on the shelf, and it could be taken as a tablet rather than as a bitter powder or solution.

The drug spread faster than the science that could explain it. Physicians used it empirically, the way Edward Stone had used willow bark in the 1760s: because it worked. Its three classic effects — relief of pain (analgesia), reduction of fever (antipyresis) and damping of inflammation — were well described long before anyone could say what linked them. That link would not be found until 1971, and when it was, it explained the drug’s side effects as well.

The plant behind the pill

Aspirin is a laboratory modification of a molecule that plants make for their own defence. Salicylic acid, the parent compound, is a plant hormone, and salicylates occur naturally in many fruits, herbs, spices and tea. That earlier history — willow bark in the ancient world, salicin, meadowsweet and the “spir” in the name — is on the companion page Willow Bark, Meadowsweet and the Natural Salicylates Behind Aspirin.

Back to Table of Contents

2. A Trademark Becomes a Common Word

“Aspirin” began life as a registered trademark. The name itself was a piece of chemistry and botany packed into seven letters: the “A” for the acetyl group that Hoffmann’s reaction added, and the “spir” recalling Spiraea, the old botanical name of meadowsweet, from which salicylic acid had once been obtained as “Spirsäure”. Hoffmann’s United States patent for acetylsalicylic acid, number 644,077, was granted on 27 February 1900; the German application had been refused because the compound, though not in a pure and stable form, had been made before.

Both Wood’s 2015 commentary in the Philosophical Transactions of the Royal Society and the Science History Institute’s profile of Hoffmann record what happened to the name after the First World War: the trademark was lost in several countries. In those countries “aspirin” became an ordinary word, written with a small “a”, that any manufacturer could use for acetylsalicylic acid. In others the trademark survived, which is why the same tablet can be “aspirin” in one country and “acetylsalicylic acid” or “ASA” in another.

The result is that aspirin is one of a small group of medicines whose brand name became the everyday name for the substance itself. It also meant that from the 1920s onward many companies made and sold the drug, which kept it cheap and spread it further still — part of the reason that, when the great trials of the 1980s were run, the medicine under test cost very little.

Back to Table of Contents

3. Early Reports of Stomach Irritation and Bleeding

Salicylates were never free of trouble. Hedner and Everts, in their 1998 history of salicylates in rheumatology and pain in Clinical Rheumatology, record that gastrointestinal intolerance and bleeding with salicylates were reported early — in the nineteenth-century era of salicin and sodium salicylate — but that these reports were largely neglected until the 1950s. Aspirin was introduced precisely because it was better tolerated than sodium salicylate, and for decades that comparison was enough to keep the problem in the background.

From the mid-twentieth century the picture sharpened. Physicians began to look more carefully at the stomach lining of people taking salicylates, and gastric irritation, ulceration and bleeding became recognised as the drug’s most important hazard. What nobody could yet explain was why a medicine swallowed for a headache would affect the stomach at all, or why aspirin also seemed to make people bleed more easily from small cuts and after operations.

The explanation, when it came, tied the benefits and the harms together. As section 5 describes, the same enzyme family that aspirin blocks to relieve pain also makes the protective substances that help the stomach lining defend itself, and the clotting signal made by platelets. The stomach bleeding and the anti-clotting effect turned out to be two faces of one mechanism. The site’s pages on aspirin side effects and peptic ulcer disease cover these findings in more detail.

Back to Table of Contents

4. John Vane and the Prostaglandin Discovery of 1971

The answer to aspirin’s seventy-year mystery came from a laboratory at the Royal College of Surgeons in London. John Vane, a pharmacologist who had spent years developing sensitive “bioassay” methods — using strips of living tissue that contract in response to tiny amounts of hormones and signalling molecules — turned those methods on a family of fatty-acid messengers called prostaglandins.

Prostaglandins are made in the body on demand from arachidonic acid, a fatty acid released from cell membranes when tissue is injured or inflamed. They sensitise nerve endings to pain, help raise body temperature in fever, dilate blood vessels and promote swelling. In 1971 Vane published in Nature New Biology a paper whose title states its finding: “Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs.” Aspirin and related drugs, he showed, stop cells from making prostaglandins.

The same issue of the journal carried two companion papers. J. Bryan Smith and Anthony Willis reported that aspirin selectively inhibits prostaglandin production in human platelets, and Ferreira, Moncada and Vane reported the same kind of effect in the spleen. Taken together, the work explained in one stroke why a single drug relieved pain, reduced fever and damped inflammation: all three depend in part on prostaglandins. In their 2003 review “The mechanism of action of aspirin”, Vane and Regina Botting summarise the finding as the inhibition of the enzyme cyclooxygenase (COX), which carries out the first committed step in turning arachidonic acid into prostaglandins.

Vane shared the 1982 Nobel Prize in Physiology or Medicine with the Swedish biochemists Sune Bergström and Bengt Samuelsson for discoveries concerning prostaglandins and related substances. His Nobel lecture, published in the Postgraduate Medical Journal in 1983 as “Adventures and excursions in bioassay — the stepping stones to prostacyclin”, tells the story of the work in his own words. His life and research are on the site’s John Vane page.

Back to Table of Contents

5. Two Cyclooxygenases: COX-1 and COX-2

Vane’s discovery raised a new puzzle. If prostaglandins cause pain and inflammation, they also do useful work — and aspirin blocks both. The resolution came with the finding, reviewed by Vane and Botting in 2003, that cyclooxygenase exists in two main forms.

COX-1: the housekeeping enzyme

COX-1 is present much of the time in many tissues. It makes the prostaglandins that help protect the stomach lining (by encouraging mucus and bicarbonate production and maintaining blood flow), that help regulate blood flow in the kidney, and, in platelets, the clotting signal thromboxane A2. Blocking COX-1 is therefore linked both to aspirin’s effect on blood clotting and to its effect on the stomach.

COX-2: the inducible enzyme

COX-2 was identified later as the inducible isoform: in most tissues it is switched on by injury, infection and inflammatory signals, and the prostaglandins it makes drive much of the pain, swelling and fever of inflammation. Vane and Botting describe how this two-enzyme picture explained why aspirin-like drugs have both their wanted anti-inflammatory effects (largely through COX-2) and their unwanted stomach effects (largely through COX-1).

Why aspirin is different from the other painkillers

Most non-steroidal anti-inflammatory drugs block cyclooxygenase reversibly: they sit in the enzyme’s active site for a while and then leave. Aspirin does something chemically distinctive. It transfers its acetyl group — the very group Hoffmann’s 1897 reaction had added to salicylic acid — onto the enzyme itself, disabling it permanently. The rest of the molecule, salicylic acid, goes on to act much as the older salicylates did. That permanent acetylation is the key to the next part of the story.

Back to Table of Contents

6. Why One Dose Affects Platelets for Their Whole Life

Platelets are tiny cell fragments that circulate in the blood and plug leaks when a vessel is damaged. When they are activated they make thromboxane A2, a signal that calls in more platelets and narrows the vessel; the site’s animation Platelets: The First Responders to a Cut shows the process.

In 1975 Gerald Roth and Philip Majerus at Washington University reported in the Journal of Clinical Investigation the experiment that explained aspirin’s lasting effect on platelets. Using aspirin carrying a radioactive label on its acetyl group, they showed that aspirin permanently acetylates a single protein in human platelets, of about 85,000 daltons, which they identified as most likely the cyclo-oxygenase, and that the acetylation lasts for the lifetime of the platelet.

The reason this matters is that platelets have no nucleus. An ordinary cell whose enzyme has been disabled can make a fresh supply; a platelet cannot. Once its cyclooxygenase has been acetylated, that platelet makes little thromboxane for the rest of its life in the circulation — about a week to ten days — and the effect wears off only as the bone marrow releases new, untouched platelets. This is why the antiplatelet effect of aspirin long outlasts the drug itself in the bloodstream, and why it can be produced by amounts far smaller than those used for pain or inflammation.

Roth and Majerus’s finding connects directly to Hoffmann’s chemistry: the acetyl group that made aspirin a new compound in 1897 is the part of the molecule that makes it an antiplatelet drug. It also gave a molecular explanation for the observations a Californian general practitioner had been publishing two decades earlier.

Back to Table of Contents

7. Lawrence Craven and the First Heart-Attack Observations

Lawrence Craven was a general practitioner in Glendale, California. In 1950 he published a short note in the Annals of Western Medicine and Surgery titled “Acetylsalicylic acid, possible preventive of coronary thrombosis”. Over the following years, as Miner and Hoffhines describe in their 2007 history of the discovery of aspirin’s antithrombotic effects in the Texas Heart Institute Journal, Craven reported that men to whom he gave daily aspirin seemed to escape heart attacks and strokes.

His observations came from his own practice, without a comparison group or randomisation, and they were published in regional journals. Miner and Hoffhines record that his work went largely unnoticed for decades. Only after the molecular discoveries of the 1970s — Vane’s prostaglandin work, Smith and Willis’s platelet findings and Roth and Majerus’s permanent acetylation — did his idea gain a mechanism that physicians and trialists could test.

Craven’s story is often told as an example of a clinical observation running ahead of the science. It also shows the limits of observation alone: uncontrolled reports could not show whether the men who took aspirin would have fared just as well without it. That question needed randomised trials, and in the 1980s it got them.

Back to Table of Contents

8. ISIS-2 and the Antiplatelet Trials

ISIS-2, 1988

The Second International Study of Infarct Survival (ISIS-2), published in the Lancet in 1988, enrolled 17,187 people admitted to hospital with a suspected heart attack. In a factorial design, patients were randomly assigned to an intravenous clot-dissolving drug (streptokinase), to oral aspirin given at 160 mg a day for one month, to both, or to neither. The trial reported that aspirin alone reduced deaths from vascular causes over five weeks from 11.8% to 9.4% — an odds reduction of 23% — and that the combination with streptokinase did better than either alone.

ISIS-2 was large enough to settle a question that small trials had left open, and it turned a cheap, century-old painkiller into a standard part of emergency care for heart attack. The site’s pages on heart attack and aspirin and heart attack prevention cover the clinical picture.

The Antithrombotic Trialists’ Collaboration, 2002

In 2002 the Antithrombotic Trialists’ Collaboration published in the BMJ a meta-analysis of 287 randomised studies of antiplatelet therapy in people at high risk of vascular events — those who had already had a heart attack, a stroke or a transient ischaemic attack, or who had other high-risk conditions. The collaboration reported that antiplatelet therapy reduced the combined outcome of serious vascular events (non-fatal heart attack, non-fatal stroke or vascular death) by about a quarter. It also reported that daily aspirin in the range of 75–150 mg was at least as effective as higher doses in those trials.

Benefit and bleeding

The same platelet effect that prevents clots also increases bleeding, including bleeding from the stomach and, more rarely, within the skull. The antiplatelet trials therefore measure a balance between vascular events prevented and bleeds caused, and that balance differs between people who have already had a heart attack or stroke and people who have not. These are findings from the trial literature, summarised here as history.

Back to Table of Contents

9. Reye’s Syndrome and Children

Reye’s syndrome is a rare but serious illness, seen mainly in children and teenagers, in which acute brain swelling occurs together with fatty damage to the liver, typically during or just after a viral infection such as influenza or chickenpox. From the late 1970s, studies in the United States reported an association between the syndrome and the use of salicylates during these infections, and from 1980 warnings about salicylate use in children with influenza or chickenpox were issued.

Belay and colleagues at the US Centers for Disease Control and Prevention analysed national surveillance data in the New England Journal of Medicine in 1999. They reported that the number of reported cases in the United States fell from a peak of 555 in 1980 to no more than 36 a year from 1987 onward, a decline that followed the public warnings about salicylates and the resulting fall in aspirin use in children.

The authors also noted that, because the syndrome had become so rare, some children with inherited metabolic disorders that can mimic it may be misdiagnosed. The Reye’s syndrome findings are one of the main reasons the aspirin story in children differs from the story in adults. The site’s aspirin side effects page reports the hazard alongside the drug’s other risks.

Back to Table of Contents

10. Aspirin and Cancer Deaths in the Long-Term Trial Data

The heart trials had an unexpected afterlife. Many of them had randomly assigned thousands of people to daily aspirin or to no aspirin for several years, and the participants could be followed long after the trials ended. That made it possible to ask a question none of the trials had been designed to answer: did aspirin change the risk of dying from cancer?

In 2011 Peter Rothwell and colleagues at Oxford published in the Lancet an analysis of individual patient data from eight randomised trials of daily aspirin, covering 25,570 patients. They reported that allocation to daily aspirin reduced deaths from cancer during the trials, with a pooled odds ratio of 0.79, and that the benefit became apparent only after about five years of follow-up. In the long-term follow-up the reduction was most evident for cancers of the digestive tract, including colorectal cancer.

The finding drew wide attention because it suggested a second, slower-acting effect of the drug beyond the platelet. Montinari and colleagues’ 2019 history places the anticancer research in the long arc that began with willow bark, and the mechanism is still debated: proposed explanations include the platelet effect itself, since activated platelets release growth signals, as well as effects on COX-2, which is often switched on in tumours of the bowel. The site’s pages on aspirin and cancer prevention and colorectal cancer report the later trials in more detail.

Back to the plants

The cancer and heart findings have prompted a further research question that brings the story back to its origins: whether the natural salicylates in fruit, vegetables, herbs, spices and tea contribute anything to the lower rates of some diseases seen in people who eat plenty of plant foods. That question, and what is known about salicylic acid in the blood of people who do not take aspirin, is covered on Willow Bark, Meadowsweet and the Natural Salicylates Behind Aspirin.

Back to Table of Contents

Key Research Papers

  1. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol. 1971;231(25):232-5. PubMed PMID: 5284360
  2. Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nat New Biol. 1971;231(25):235-7. PubMed PMID: 5284361
  3. Vane JR, Botting RM. The mechanism of action of aspirin. Thromb Res. 2003;110(5-6):255-8. PubMed PMID: 14592543
  4. Vane JR. Nobel lecture. Adventures and excursions in bioassay--the stepping stones to prostacyclin. Postgrad Med J. 1983;59(698):743-58. PubMed PMID: 6361717
  5. Roth GJ, Majerus PW. The mechanism of the effect of aspirin on human platelets. I. Acetylation of a particulate fraction protein. J Clin Invest. 1975;56(3):624-32. PubMed PMID: 1159076
  6. Craven LL. Acetylsalicylic acid, possible preventive of coronary thrombosis. Ann West Med Surg. 1950;4(2):95. PubMed PMID: 15403207
  7. Miner J, Hoffhines A. The discovery of aspirin's antithrombotic effects. Tex Heart Inst J. 2007;34(2):179-86. PubMed PMID: 17622365
  8. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet. 1988;2(8607):349-60. PubMed PMID: 2899772
  9. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71-86. PubMed PMID: 11786451
  10. Belay ED, Bresee JS, Holman RC, Khan AS, Shahriari A, Schonberger LB. Reye's syndrome in the United States from 1981 through 1997. N Engl J Med. 1999;340(18):1377-82. PubMed PMID: 10228187
  11. Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011;377(9759):31-41. PubMed PMID: 21144578
  12. Hedner T, Everts B. The early clinical history of salicylates in rheumatology and pain. Clin Rheumatol. 1998;17(1):17-25. PubMed PMID: 9586674
  13. Montinari MR, Minelli S, De Caterina R. The first 3500 years of aspirin history from its roots - A concise summary. Vascul Pharmacol. 2019;113:1-8. PubMed PMID: 30391545
  14. Desborough MJR, Keeling DM. The aspirin story - from willow to wonder drug. Br J Haematol. 2017;177(5):674-683. PubMed PMID: 28106908
  15. Wood JN. From plant extract to molecular panacea: a commentary on Stone (1763) 'An account of the success of the bark of the willow in the cure of the agues'. Philos Trans R Soc Lond B Biol Sci. 2015;370(1666):20140317. PubMed PMID: 25750237

PubMed Topic Searches

  1. PubMed: aspirin, cyclooxygenase and mechanism
  2. PubMed: aspirin and platelet acetylation
  3. PubMed: aspirin history
  4. PubMed: aspirin, cancer mortality and randomised trials
  5. PubMed: Reye syndrome and salicylates

Further Reading

Back to Table of Contents

Connections