Colorectal cancer 0.4–0.7 Acute renal failure 0.02–0.08 separate the participation of COX-1 in physiological processes and COX-2 in pathological processes (4), it is not yet clear how COX-1–dependent propagation of platelet activation can carry out its physiological role (primary hemostasis) without permitting the uncontrolled progression that would cause arterial thrombosis. The factors responsible for the localization and termination of the process or its unrestricted propagation most likely include the nature and duration of the pathophysiologic stimuli to platelet activation and the adequacy of the counterregulatory mechanisms evoked by platelet COX-1 activity. COX-2 induction in adjacent vascular endothelial cells may represent one such counterregulatory mechanism, one that may help amplify and prolong the antiplatelet signal initially evoked by COX-1–dependent PGI2 release at sites of platelet–vessel wall interaction. A very large database of randomized clinical trials now offers the most compelling evidence that prevention of myocardial infarction and ischemic stroke by aspirin is largely due to permanent inactivation of platelet COX-1. These studies, which tested the efficacy and safety of the drug when given at daily doses ranging from as low as 30 mg to as high as 1,500 mg (6), have established two important facts. First, the antithrombotic effect of aspirin is saturable at doses in the range of 75–100 mg, as expected from ex vivo studies of the dose requirement for platelet COX-1 inactivation (1). Second, despite a half-life of approximately 20 minutes in the human circulation, the antithrombotic effect of aspirin is observed with dosing intervals of 24–48 hours, reflecting the permanent nature of platelet COX-1 inactivation and the duration of TXA2 suppression following oral dosing in humans (1). Other mechanisms of action that have been suggested to contribute to the antithrombotic effect of aspirin, such as an anti-inflammatory effect of the drug, are simply incompatible with these requirements. Although the search for the lowest effective dose of aspirin for platelet inhibition was largely driven by the explicit concern of concomitant inhibition of vascular PGI2 production (7), it is still uncertain whether dosedependent suppression of the latter attenuates the antithrombotic effect of aspirin in clinical syndromes of vascular occlusion. The biochemical selectivity of low-dose aspirin arises from both pharmacokinetic determinants, such as the acetylation of platelet COX-1 that occurs in portal blood (prior to first-pass metabolism), and pharmacodynamic determinants, such as the limited sensitivity of endothelial COX-2 to the drug (6). Aspirin is an effective antithrombotic agent in a wide range of daily doses. However, both indirect comparisons of trials using different doses of aspirin in a variety of vascular disorders (8) and a recent randomized comparison of doses ranging from 81 to 1,300 mg in patients undergoing carotid endarterectomy (9) suggest an inverse relationship between the aspirin daily dose and the relative risk reduction in vascular events. This effect is consistent with dose-dependent inhibition by aspirin of a mediator of thromboresistance. Aspirin’s unique features in inhibiting platelet COX-1—its ability to inactivate the enzyme permanently through a short-lived active moiety (10)—are ideally suited to its role as an antiplatelet drug, because they severely limit the extent and duration of extraplatelet effects of the drug, including the inhibition of PGI2. Moreover, the cumulative nature of platelet COX-1 acetylation by repeated low doses of aspirin (11) explains the clinical efficacy of doses as low as 30–50 mg daily, the predictable, high-grade inhibition of …