Aspirin is the first-choice antiplatelet agent in cardiocoronary prevention and an essential constituent of dual antiplatelet therapy. The reasons are its unique pharmacological mode of action; the long-lasting, more than 60 years, experience with its use as an antiplatelet agent; and the reliability of its pharmacological action in more than 95% of patients.

Mode of antiplatelet action

Aspirin, in contrast to most other antiplatelet drugs, is not a platelet-specific agent but exhibits a broad spectrum of biological activities on many cellular targets [1]. At low doses (≤300 mg), aspirin inhibits platelet-dependent prostaglandin-endoperoxide (PGEP) formation via irreversible acetylation of COX-1. This results in downstream inhibition of thromboxane A₂ (TXA₂) formation, the only significant PGEP end product in platelets. This COX-1-mediated inhibition of prostaglandin formation is the generally accepted mode of antiplatelet action of aspirin [2, 3].

Consequently, measurement of platelet-dependent thromboxane formation, for example, by determining thromboxane-forming capacity in serum ex vivo or in vitro, is a simple and specific means to determine the pharmacological potency of aspirin as an antiplatelet drug on an individual basis. Because of the nonlinearity between thromboxane levels and thromboxane-related platelet stimulation, this inhibition has to be apparently complete, that is, >95% in terms of serum capacity, to become effective. This degree of inhibition is obtained in the vast majority of patients, while only 1–2% remain pharmacologically “resistant” against aspirin. Thus, the much more variable clinical efficacy of aspirin in preventing atherothrombotic cardiovascular events is due to variable environmental conditions of circulating platelets including platelet stimuli, which might or might not require platelet-dependent thromboxane formation as an amplifying event.

Accordingly, the antiplatelet potency of aspirin in vivo is critically determined by the significance of thromboxane generation for platelet activation. This largely depends on the stimulus. Aspirin does not modify ADP-induced platelet aggregation and alpha-granule secretion in native blood. Nor does it prevent platelet aggregation induced by thrombin, shear stress, or other thromboxane-independent pathways of platelet activation.

The initial “explosion” of platelet-dependent thromboxane formation after appropriate stimuli starts platelet activation, secretion, and aggregate formation. However, the subcellular targets of thromboxane in platelets and their interactions are still not completely understood. At least theoretically, it is likely that thromboxane per se rather acts as a platelet-derived amplification factor for further platelet recruitment and activation than being a direct stimulus for platelet secretion [4, 5]. There is considerable clinical and experimental evidence for aspirin-sensitive, thromboxane-dependent thrombin formation, which occurs at the surface of activated platelets and connects platelet activation with the plasmatic clotting process [6, 7, 8, 9].