AA, arachidonic acid; COX-1, cyclooxygenase 1; MACE, major adverse clinical events; PFA-100, platelet function analyzer-100; RPFA, rapid platelet function analyzer.
Aspirin resistance: position paper of the Working Group on Aspirin Resistance
Article first published online: 9 MAY 2005
Journal of Thrombosis and Haemostasis
Volume 3, Issue 6, pages 1309–1311, June 2005
How to Cite
MICHELSON, A. D., CATTANEO, M., EIKELBOOM, J. W., GURBEL, P., KOTTKE-MARCHANT, K., KUNICKI, T. J., PULCINELLI, F. M., CERLETTI, C., RAO, A. K. and THE PLATELET PHYSIOLOGY SUBCOMMITTEE OF THE SCIENTIFIC AND STANDARDIZATION COMMITTEE OF THE INTERNATIONAL SOCIETY ON THROMBOSIS AND HAEMOSTASIS (2005), Aspirin resistance: position paper of the Working Group on Aspirin Resistance. Journal of Thrombosis and Haemostasis, 3: 1309–1311. doi: 10.1111/j.1538-7836.2005.01351.x
- Issue published online: 9 JUN 2005
- Article first published online: 9 MAY 2005
- Received 5 January 2005, accepted 10 February 2005
Aspirin irreversibly acetylates serine 529 of cyclooxygenase (COX)-1, resulting in inhibition of thromboxane A2 generation by platelets and prostacyclin by endothelial cells . Because platelets lack the synthetic machinery to generate significant amounts of new COX, aspirin-induced COX-1 inhibition lasts for the lifetime of the platelet. In contrast, endothelial cells retain their capacity to generate new COX and recover normal function shortly after exposure to aspirin.
Platelets have an increasingly well-defined, critical role in the acute thrombotic events associated with arterial diseases. Antiplatelet drugs have therefore assumed a major role in the therapy of these disorders . Aspirin reduces the odds of an arterial thrombotic event in high-risk patients by ∼25% . However, 10%–20% of patients with an arterial thrombotic event who are treated with aspirin have a recurrent arterial thrombotic event during long-term follow-up . In some studies, the occurrence of an arterial thrombotic event despite aspirin therapy has been termed ‘aspirin resistance’.
However, because arterial thrombosis is multifactorial, an arterial thrombotic event in a patient may reflect treatment failure rather than ‘resistance’ to aspirin. Furthermore, patient non-compliance with aspirin administration is a confounding problem. There is a well-documented variability between patients (and normal volunteers) with regard to laboratory test responses to aspirin [2–7]. This variability in laboratory test response has also been termed aspirin ‘resistance’ (Table 1). Possible mechanisms of aspirin ‘resistance’ are listed in Table 2.
|Basis of Test||Name of Test||Advantages||Disadvantages||Test reported to predict clinical aspirin ‘resistance’ (i.e. MACE)|
|In vivo cessation of blood flow by a platelet plug||Bleeding time||In vivo test Physiological||Insensitive High inter-operator coefficient of variation Can leave scar||No|
|In vitro cessation of high shear blood flow by a platelet plug||PFA-100®||Simple and rapid Low sample volume No sample preparation Whole blood assay High shear||Dependent on VWF and hematocrit No instrument adjustment||Yes |
|Shear-induced platelet adhesion||IMPACT® (cone and plate(let) analyzer)||Point-of-care Simple and rapid Low sample volume Whole blood assay High shear||Instrument not yet widely available.||No|
|Platelet-to-platelet aggregation||Aggregometry in response to AA and ADP (turbidometric)||Widely available||High sample volume Sample preparation Labor intensive||Yes |
|Aggregometry in response to ADP and collagen (impedance)||Whole blood assay||High sample volume Time-consuming||Yes |
|VerifyNow® (Ultegra RPFA) with AA or propyl gallate cartridge||Point-of-care Simple and rapid Low sample volume No sample preparation Whole blood assay||No instrument adjustment||Yes |
|Activation-dependent changes in platelet surface||Platelet surface P-selectin, platelet surface activated GPIIb-IIIa, leukocyte-platelet aggregates in response to AA (flow cytometry)||Low sample volume Whole blood assay||Sample preparation Requires flow cytometer and experienced operator||No|
|Activation-dependent release from platelets||Serum thromboxane B2||Directly dependent on aspirin's target: COX-1||Time consuming||No|
|AA- or collagen-induced platelet thromboxane A2 production, as measured by thromboxane B2||Directly dependent on aspirin's target: COX-1||Sample preparation Time consuming||No|
|Urinary 11-dehydro thromboxane B2||Directly dependent on aspirin's target: COX-1 Reflects in vivo thromboxane production||Dependent on renal function Potential contribution by cells other than platelets||Yes |
|Poor absorption (enteric coated aspirin)|
|Interference: NSAID coadministration|
|Incomplete suppression of thromboxane A2 generation|
|Accelerated platelet turnover, with introduction into bloodstream of newly formed, drug-unaffected platelets|
|Stress-induced COX-2 expression in platelets|
|Increased platelet sensitivity to ADP and collagen|
|Single nucleotide polymorphisms|
|Receptors: GPIIb-IIIa, collagen receptor, thromboxane receptor, etc.|
|Enzymes: COX-1, COX-2, thromboxane A2 synthase, etc.|
|Platelet interactions with other blood cells|
|Endothelial cells and monocytes provide PGH2 to platelets (bypassing COX-1) and also synthesize their own thromboxane A2|
|Smoking, hypercholesterolemia, exercise, stress, etc.|
|Rather than ‘resistance’, is it:|
|Aspirin response variability?|
|Platelet response variability?|
|Treatment failure (because arterial thrombosis is multifactorial)?|
There is evidence that major adverse clinical events (MACE) in the settings of acute coronary syndromes, stroke/transient ischemic attacks, and peripheral arterial disease can be predicted by some tests of aspirin ‘resistance’ (Table 1) [2–7]. However, in most of these studies [2–7] the number of MACE was low, and additional studies are therefore needed.
The correct treatment, if any, of aspirin ‘resistance’ is unknown. No published studies address the clinical effectiveness of altering therapy based on a laboratory finding of aspirin ‘resistance’. Therefore, other than in research trials, it is not currently appropriate to test for aspirin ‘resistance’ in patients or to change therapy based on such tests. A clinically meaningful definition of aspirin ‘resistance’ needs to be developed, based on data linking aspirin-dependent laboratory tests to clinical outcomes in patients.