Potential mechanisms of aspirin resistance
| Reduced bioavailability of aspirin |
| Low compliance in aspirin-treated subjects85 |
| Underdosing or poor absorption, especially in case of the use of enteric-coated aspirin, or increased potential for aspirin hydrolysis by esterases during proton pump inhibitor administration79 |
| Simultaneous administration of other nonsteroidal anti-inflammatory drugs, especially ibuprofen, that interfere with aspirin-mediated COX-1 inhibition in platelets86–90 |
| Comorbid conditions, cigarette smoking,89 and hypercholesterolemia43 |
| Transient increase of platelet COX-1/COX-2 expression in new platelets: platelet turnover is accelerated in response to stress, eg, following coronary artery bypass grafting (CABG)90,91 |
| Alternative pathways of platelet activation |
| Augmented COX-2 expression in monocytes/macrophages leading to TXA2 synthesis92 |
| Increased sensitivity to collagen or adenosine diphosphate78,79 |
| Isoprostane formation, resulting from nonenzymatic lipid peroxidation, that may amplify the response to platelet agonists, eg, in diabetics, smokers, and hyperlipidemic patients79 |
| Expression of a new COX-2 isoform (COX-2a), demonstrated in patients after CABG93 |
| Common genetic polymorphisms affecting |
| COX-1 (eg, 50T), COX-2 (−765C), TXA2 synthase, or other enzymes involved in arachidonate metabolism94,95 ; the first 2 variants appear associated with changes in TXA2 production96 and recently, COX-1 haplotype has been reported to be related to platelet aggregation in the presence of aspirin97 |
| Platelet glycoproteins such as the β3 integrin (Pro33Leu), glycoprotein Ia/IIa (C807T), or Ib/V/IX34,94 |
| Proteins involved in blood coagulation, eg, FXIII (Val34Leu)33 |
| An ADP receptor P2Y198 |
| Tachyphylaxis99,100 |
| Other factors |
| Interference of aspirin- and nitric oxide-mediated antiplatelet effects |
| Elevated norepinephrine levels, especially following physical stress101 |
| Reduced bioavailability of aspirin |
| Low compliance in aspirin-treated subjects85 |
| Underdosing or poor absorption, especially in case of the use of enteric-coated aspirin, or increased potential for aspirin hydrolysis by esterases during proton pump inhibitor administration79 |
| Simultaneous administration of other nonsteroidal anti-inflammatory drugs, especially ibuprofen, that interfere with aspirin-mediated COX-1 inhibition in platelets86–90 |
| Comorbid conditions, cigarette smoking,89 and hypercholesterolemia43 |
| Transient increase of platelet COX-1/COX-2 expression in new platelets: platelet turnover is accelerated in response to stress, eg, following coronary artery bypass grafting (CABG)90,91 |
| Alternative pathways of platelet activation |
| Augmented COX-2 expression in monocytes/macrophages leading to TXA2 synthesis92 |
| Increased sensitivity to collagen or adenosine diphosphate78,79 |
| Isoprostane formation, resulting from nonenzymatic lipid peroxidation, that may amplify the response to platelet agonists, eg, in diabetics, smokers, and hyperlipidemic patients79 |
| Expression of a new COX-2 isoform (COX-2a), demonstrated in patients after CABG93 |
| Common genetic polymorphisms affecting |
| COX-1 (eg, 50T), COX-2 (−765C), TXA2 synthase, or other enzymes involved in arachidonate metabolism94,95 ; the first 2 variants appear associated with changes in TXA2 production96 and recently, COX-1 haplotype has been reported to be related to platelet aggregation in the presence of aspirin97 |
| Platelet glycoproteins such as the β3 integrin (Pro33Leu), glycoprotein Ia/IIa (C807T), or Ib/V/IX34,94 |
| Proteins involved in blood coagulation, eg, FXIII (Val34Leu)33 |
| An ADP receptor P2Y198 |
| Tachyphylaxis99,100 |
| Other factors |
| Interference of aspirin- and nitric oxide-mediated antiplatelet effects |
| Elevated norepinephrine levels, especially following physical stress101 |