The discovery of aspirin's antithrombotic effects

Abstract

Aspirin has long been established as a useful analgesic and antipyretic. Even in ancient times, salicylate-containing plants such as the willow were commonly used to relieve pain and fever. In the 20th century, scientists discovered many details of aspirin's anti-inflammatory and analgesic properties, including its molecular mechanism of action. In addition, the latter half of the century brought reports that daily, low doses of aspirin could prevent myocardial infarction and stroke. This finding was first reported by Lawrence Craven, a suburban general practitioner in Glendale, California. Unfortunately, Craven's work went largely unnoticed, and decades passed before his observations were verified by clinical trial. We present Craven's story, which demonstrates the value of a single physician's commitment to lifelong learning. In addition, we summarize the work of the physicians and scientists who discovered the molecular mechanisms by which aspirin exerts its antiplatelet effects. Collectively, these discoveries exemplify the complementary roles of basic science and clinical observation in advancing medicine.

Fig. 1 Acetylsalicylic acid (aspirin) retains the carboxyl group (COOH) of salicylic acid and makes a substitution in the hydroxyl group (OH). The drug was developed at Bayer by Felix Hoffmann. Acetylation made aspirin more tolerable to the gastrointestinal tract, which led to widespread use.

Fig. 2 Photograph of Dr. Lawrence L. Craven in 1914, at the age of 31, when he graduated from the University of Minnesota College of Medicine and Surgery. Photo courtesy of the University of Minnesota Archives.

Fig. 3 Inhibition of platelet thrombus formation by aspirin. Citrated blood was perfused over de-endothelialized rabbit aorta at arterial shear rates A) before ingesting aspirin, and B) 2.5 hr after ingesting 0.9 g of aspirin. The images were acquired by light microscopy. The black bar represents 10 μm. (Reprinted, with permission, from Weiss HJ, Tschopp TB, Baumgartner HR. Impaired interaction [adhesion-aggregation] of platelets with the subendothelium in storage-pool disease and after aspirin ingestion. A comparison with von Willebrand's disease. N Engl J Med 1975;293:619–23. Copyright © 1975, Massachusetts Medical Society. All rights reserved.)

Fig. 4 Synthetic pathway for prostaglandins and thromboxane A₂. Aspirin inhibits cyclooxygenase-1, which is necessary for the synthesis of thromboxane A₂ and prostaglandins. COX = cyclooxygenase; PGG₂ = prostaglandin G₂; PGH₂ = prostaglandin H₂