Aspirin irreversibly acetylates serine 529 of cyclooxygenase (COX)-1, resulting in inhibition of thromboxane A2 generation by platelets and prostacyclin by endothelial cells [1]. 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 [1]. Aspirin reduces the odds of an arterial thrombotic event in high-risk patients by ∼25% [1]. 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 [1]. 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.

Table 1.  Laboratory tests of aspirin ‘resistance’
Basis of TestName of TestAdvantagesDisadvantagesTest reported to predict clinical aspirin ‘resistance’ (i.e. MACE)
  1. AA, arachidonic acid; COX-1, cyclooxygenase 1; MACE, major adverse clinical events; PFA-100, platelet function analyzer-100; RPFA, rapid platelet function analyzer.

In vivo cessation of blood flow by a platelet plugBleeding timeIn vivo test PhysiologicalInsensitive High inter-operator coefficient of variation Can leave scarNo
In vitro cessation of high shear blood flow by a platelet plugPFA-100®Simple and rapid Low sample volume No sample preparation Whole blood assay High shearDependent on VWF and hematocrit No instrument adjustmentYes [7]
Shear-induced platelet adhesionIMPACT® (cone and plate(let) analyzer)Point-of-care Simple and rapid Low sample volume Whole blood assay High shearInstrument not yet widely available.No
Platelet-to-platelet aggregationAggregometry in response to AA and ADP (turbidometric)Widely availableHigh sample volume Sample preparation Labor intensiveYes [5]
Aggregometry in response to ADP and collagen (impedance)Whole blood assayHigh sample volume Time-consumingYes [3]
VerifyNow® (Ultegra RPFA) with AA or propyl gallate cartridgePoint-of-care Simple and rapid Low sample volume No sample preparation Whole blood assayNo instrument adjustmentYes [6]
Activation-dependent changes in platelet surfacePlatelet surface P-selectin, platelet surface activated GPIIb-IIIa, leukocyte-platelet aggregates in response to AA (flow cytometry)Low sample volume Whole blood assaySample preparation Requires flow cytometer and experienced operatorNo
Activation-dependent release from plateletsSerum thromboxane B2Directly dependent on aspirin's target: COX-1Time consumingNo
AA- or collagen-induced platelet thromboxane A2 production, as measured by thromboxane B2Directly dependent on aspirin's target: COX-1Sample preparation Time consumingNo
Urinary 11-dehydro thromboxane B2Directly dependent on aspirin's target: COX-1  Reflects in vivo thromboxane productionDependent on renal function Potential contribution by cells other than plateletsYes [4]
Table 2.  Possible mechanisms of aspirin ‘resistance’
 Poor absorption (enteric coated aspirin)
 Interference: NSAID coadministration
Platelet function
 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
Other factors
 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.


  1. Top of page
  2. Conclusions
  3. References

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.


  1. Top of page
  2. Conclusions
  3. References
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