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Aspirin Resistance

Aspirin Resistance

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Published by: Ika Lismayani on Apr 20, 2011
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ASPIRIN RESISTANCE: A REVIEW OFDIAGNOSTIC METHODOLOGY, MECHANISMS,AND CLINICAL UTILITY
Kenneth A. Schwartz
Department of Medicine, Michigan State University, Michigan
1. Abstract. . . . .. . . . .. . . .. . . .. . . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . 812. Introduction . . . . . .. . . .. . . .. . . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . 822.1. Aspirin Resistance: Definition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 833. Aspirin: Mechanism of Action. . . . . . .. . . . .. . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . 834. Methods to Detect Aspirin Resistance. . . . .. . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . 844.1. Aspirin Pharmacodynamics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 854.2. Prostaglandin Metabolites. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874.3. Aggregometry. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 874.4. Template
Bleeding Time. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 924.5. Point
of 
Care Assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 934.6. Ideal Aspirin
Resistant Assay. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 955. Aspirin Resistance Associated with Adverse Outcomes. . . . . . .. . . .. . . . .. . . .. . . 956. Mechanisms of Aspirin Resistance . . . . . . . .. . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . 976.1. Proven and Clinically Relevant Mechanisms. . . . . . . . . . . . . . . . . . . . . . . . . . . 986.2. Ibuprofen’s Interference with Antiplatelet Effect of Aspirin . . . . . . . . . . . . . 996.3. Other Mechanisms of Resistance to Aspirin . . . . . . . . . . . . . . . . . . . . . . . . . . . 1007. Aspirin Resistance Associated with Cardiovascular andCerebrovascular Disease . . . . . . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . 1037.1. Cardiovascular Correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1047.2. Cerebral Vascular Correlates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1058. Summary and Recommendations . . . .. . . . .. . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . 106References. . . . . . . .. . . .. . . .. . . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . .. . . . .. . . .. . . 107
1. Abstract
Ingestion of a daily aspirin in patients with coronary artery diseasedecreases the rate of occlusive atherosclerotic events by about 25 percent [1].Some patients whose platelets are minimally inhibited by aspirin are categor-ized as aspirin resistant. Three reports document an increased risk for future
81
0065-2423/06 $35.00 Copyright 2006, Elsevier Inc.DOI: 10.1016/S0065-2423(06)42003-5 All rights reserved.ADVANCES IN CLINICAL CHEMISTRY, VOL.
42
 
vascular events in aspirin resistant patients [2–4]. Aspirin’s platelet inhibitorye
ect is measured using a variety of techniques. The demarcation betweenminimal and expected aspirin inhibition of platelets is arbitrarily determinedby each investigator which leads to confusion in translating these reports topatient care. The focus of this report is the relative merits of the di
erenttechniques and their utility for defining patients with minimal aspirin inducedplatelet inhibition. The clinically useful mechanisms underlying decreasedaspirin induced platelet inhibition include failure of a patient to take theirdaily aspirin, poor compliance, and nonsteroidal anti
inflammatory drugs(NSAIDs) interference with aspirin’s ability to get to its binding site on thecyclooxygenase enzyme
1 (COX
1) [5, 6]. Compliance is best assessedby comparing the results obtained with arachidonic acid (AA) stimulatedlight aggregation at two time points. The first time point is while the patientis supposedly taking their usual daily aspirin and the second time point is2 hours after the patient is observed to ingest 325 mg of aspirin. Afterobserved ingestion of aspirin, those patients with minimal aspirin inhibitionof platelets are best detected using light aggregation stimulated by a newplatelet agonist platelet prostaglandin agonist (PPA) [7]. In order for theresults of a particular technique to be clinically meaningful it must beshown that those patients with minimal aspirin inhibition of platelets havean increased risk for a future vascular event that is independent from knownmajor cardiovascular risk factors.
2. Introduction
A daily aspirin retards the progression of occlusive atherosclerotic vascu-lar disease [2–4]. Because aspirin is inexpensive,readilyavailable, and has few side e
ects, it has become a mainstay of treatment for both cardiac andcerebral vascular disease. As demonstrated with a large meta
analysis of patients with a history of myocardial infarction who are taking aspirinhave a 25 percent decrease in adverse events that included nonfatal myocar-dial infarction, nonfatal stroke or vascular death [1]. Similarly, patients withan increase in angina symptoms have a 50 percent decrease in vasoocclusiveevents with aspirin therapy [8, 9]. Aspirin is even recommended for patients who have as yet not developed symptoms from vascular occlusive disease,but have a high probability of doing so, like diabetics [10]. Since aspirin has an important role in treating atherosclerotic vascular disease, the rapidprogression of symptomatic occlusion in some patients has lead to thenotion that some patients may be resistant to aspirin. Indeed, multiplestudies, using di
erent methodologies to measure the antiplatelet e
ects of aspirin, have shown that patients who are supposed to be taking aspirin may82
KENNETH A. SCHWARTZ
 
not demonstrate an antiplatelet e
ect and are judged to be ‘‘aspirin resis-tant.’’ Patients who do not demonstrate an aspirin e
ect have a more rapidprogression of their atheroscleroticdisease[11–13]. Hence, assessing aspirin resistance is important from a clinical perspective. In reality it is the di
erentmethods that are used to measure some aspect of aspirin’s antiplatelet e
ectthat define aspirin resistance. Although multiple mechanisms leading toaspirin resistance have been proposed, only poor compliance and interactionwith non
aspirin nonsteroidal anti
inflammatory drugs (NANSAIDs) can becurrently evaluated clinically. This review will focus on the merits of thedi
erent techniques used to identify aspirin resistant patients, the proposedmechanisms underlying aspirin resistance, clinical conditions associatedwith aspirin resistance, and suggest a rational approach for the laboratoryevaluation of a patient suspected of being resistant to aspirin.2.1. A
SPIRIN
R
ESISTANCE
: D
EFINITION
Aspirin resistance is best defined as suboptimum aspirin
induced inhibi-tion of platelet function that has been proven to be an independent factor foran increased risk of a future vasoocclusive event. In the literature, aspirinresistance is defined using particular technique to delineate a subgroup of patients whose platelets are weakly inhibited by aspirin.
3. Aspirin: Mechanism of Action
The main mechanism of aspirin inhibition of platelet aggregation is viainhibition of COX
1. Aspirin covalently acetylates serine at position 530resulting in permanent enzyme inhibition (Fig. 1) [14]. In platelets, inhibition of COX
1 blocks the metabolism of AA to thromboxane A
2
(TXA
2
)—apotent platelet agonist and vasoconstrictor. Aspirin produces a relativelymild inhibition of platelet function believed to reduce the rate of occlusiveatherogenic events. Aspirin has other potentially antithrombotic e
ects thatmay contribute to its utility as an agent that decreases the rate of atherogen-esis (Table 1)[15]. Aspirin acetylates fibrinogen which is less e
ective insupporting adenosine diphosphate (ADP)
stimulated platelet aggregationas measured by light aggregometer [16]. In addition, acetylated fibrinogenis more easily lysed by tissue plasminogen activator [16]. Inflammatoryendothelial dysfunction produced in healthy volunteers by
Salmonella typhi 
vaccination is prevented by aspirin [17]. The anti
inflammatory propertiesof aspirin may also contribute to its antithrombotic e
ects [18]. The greatestpreventative benefit for aspirin vs placebo was observed in patients whowere stratified to the highest quartile of C
reactive protein. Although other
REVIEW OF ASPIRIN RESISTANCE
83

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