Aspirin Resistance: An Evaluation of Current Evidence and Measurement Methods

Christopher P. Martin, Pharm.D.; Robert L. Talbert, Pharm.D., FCCP


Pharmacotherapy. 2005;25(7):942-953. 

In This Article

Aspirin Pharmacology

Aspirin, or acetylsalicylic acid, exerts its anti-platelet action through the irreversible acetylation of platelet cyclooxygenase (COX)-1 at serine residue 530 (Figure 1). This enzyme is responsible for conversion of arachadonic acid to the various eicosanoids, such as leukotrienes, prostaglandins, thromboxane A2 (TXA2) and prostacyclin, or prostaglandin I2 (PGI2) (Figure 1). Thromboxane A2 is a potent vasoconstrictor and platelet agonist found in the α-granules of the platelet, which are released during platelet activation. Production of TXA2 has been completely inhibited by doses of aspirin as low as 100 mg.[6]

Aspirin's mechanism of action. COX = cyclooxygenase; ASA = acetylsalicylic acid (aspirin); PGG2 = prostaglandin G2; PGH2 = prostaglandin H2; PGI2 = prostacyclin; TXA2 = thromboxane A2.

Prostaglandin I2 is a vasodilator and platelet inhibitor produced both by platelets and vascular endothelium. Once acetylated by aspirin, COX-1 is permanently deactivated and, as anucleate cells, platelets cannot replace the defective enzyme. This effectively halts platelet TXA2 production for the entire 10-day life span of the platelet. In contrast, inhibited COX-1 in vascular endothelial cells is replaced with functional enzymes, and the synthesis of prostacyclin continues. In addition, PGI2 is produced by the enzymatic activity of COX-2, which is 50-100 times less affected by binding with aspirin than COX-1.[7] Therefore, aspirin imparts a platelet inhibitory effect not only by reducing the amount of available TXA2 agonist, but also by increasing the amount of PGI2 relative to TXA2. However, this later effect becomes less significant with higher doses of aspirin.