Mechanisms Of Aspirin Resistance Research Articles

Aspirin resistance: causes, clinical significance, correction

Aspirin is the most frequently prescribed antiplatelet agent today. It exerts its antiplatelet effect by irreversible inactivation of the platelet cyclooxygenase-1, resulting in an irreversible inhibition of thromboxane-A2 formation. The clinical benefit of antiplatelet therapy with acetylsalicylic acid (ASA) in high risk patients has been convincingly demonstrated through the results of multiple placebo-controlled trials. Nevertheless, a large number of patients treated with aspirin suffers an adverse cardiovascular event. This observation led to the concept of ”aspirin resistance“. The mechanisms of aspirin resistance remain to be determined, although different theories are being discussed. Several tests are used to assess resistance to ASA in vitro. Depending on which assay is used and which population is tested, the prevalence of aspirin resistance varies between 5% and 60%. So far, it was not possible to define a clear gold standard for detecting aspirin resistance, which considers both, biochemical data and clinical events, and correlates them in a reproducible way. The clinical implications of aspirin resistance are well-documented through a lot of studies, which conclude that resistance to aspirin in vitro is associated with a significant increased risk for adverse cardiovascular events in cardiovascular patients. Insufficient or excessive antiplatelet effect of acetylsalicylacid may be due not only to changes in the synthesized cyclooxygenase-1, but also to changes in its amount. Literature data on the association of various polymorphic markers of candidate genes with the effectiveness of antiplatelet therapy of ASA are few and contradictory. Therefore, it is currently impossible to identify genetic predictors of the effectiveness of ASA as well as any antiplatelet agent. Continuation of research in this area in the future will predict the patient’s response to a drug and, therefore, individualize the approach to the choice and dosage of antiplatelet drugs, which will reduce the incidence of adverse reactions.

Aspirin resistance mediated by oxidative stress-induced 8-Isoprostaglandin F2.

Aspirin resistance refers to a patient's poor response to aspirin. There are many factors that can contribute to aspirin resistance, including single-nucleotide polymorphisms, medication compliance, drug-drug interactions and inflammation. Recently, oxidative stress-induced 8-isoprostaglandin F2α has attracted considerable attention because it is considered as a mechanism of aspirin resistance in many diseases, including coronary artery disease, neurology system disease, metabolic syndrome, cancer, chronic obstructive pulmonary disease and chronic kidney disease. In these diseases, increased oxidative stress may promote platelet activation and reduce the efficacy of aspirin by producing excessive amounts of 8-isoprostaglandin F2α. Given the wide clinical use of aspirin, it is essential to understand why some patients do not response to it. This article reviews current research on aspirin resistance mediated by oxidative stress-induced 8-isoprostaglandin F2α.

Increased platelet expression of glycoprotein IIIa following aspirin treatment in aspirin-resistant but not aspirin-sensitive subjects.

Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects. Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2 , and blood was taken to measure arachidonic acid (AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting. In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance. In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker.

Aspirin and aspirin resistance in coronary artery disease

Aspirin is still the mainstay of antiplatelet therapy in the secondary prevention of coronary artery disease. However certain patients do not benefit from the antithrombotic effects of aspirin. The phenomenon of so-called aspirin resistance can be considered from the clinical and laboratory perspective. A variety of methods have emerged for the laboratory diagnosis of aspirin resistance. None of them is considered ideal as they provide conflicting information with significant inter-individual variability and weak correlation between them. With the mechanisms of aspirin resistance not fully understood and the phenomenon commonly observed in individuals with poor compliance, the existence of aspirin resistance has been challenged. The aim of this review is to present recent data on the impact of aspirin resistance in primary and secondary prevention of coronary artery disease.

Association of COX-2 rs20417 with aspirin resistance

Aspirin is the most commonly used antiplatelet drug for treatment of a serious vascular event, most notably stroke and myocardial infarction. However, despite the demonstrated benefit of aspirin, significant fraction of aspirin-treated patients may be resistant to the antiplatelet effects of the drug. The possible mechanisms of aspirin resistance (AR) are multifactorial. A genetic basis for AR has been suggested to exist. Therefore, the present study was taken up to investigate the role of -765G/C polymorphism (rs20417) in the cyclooxygenase-2 (COX-2) gene with AR in stroke patients. Four hundred and fifty stroke patients and four hundred and forty age and sex matched healthy controls were involved in the study. Baseline clinical data were collected and follow-up telephone interviews were conducted with patients at 3months post event to determine stroke outcome using Modified Rankin Scale. Blood samples were collected and genotypes determined by polymerase chain reaction-restriction digestion technique. The association between the genotypes and outcome was evaluated by stepwise multiple logistic regression analysis. The COX-2 CC and GC genotype showed a significant association with bad outcome. Therefore, the carriers of C allele of COX-2 -765G/C polymorphism are more prone to AR in comparison with non-carriers. These results support a potential role of -765G/C COX-2 gene polymorphism with AR in ischemic stroke patients.

Comparison of laboratory detection methods of aspirin resistance in coronary artery disease patients

Aspirin reduces the prevalence of nonfatal myocardial infarction, stroke, and death by 25.0% in high risk group of patients with cardiovascular disease. Previous studies have estimated that about 5.5-56.8% of the population are aspirin resistant. The mechanisms of aspirin resistance (AR) have not been fully understood. We compared the detection methods for AR using traditional platelet aggregometry and VerifyNow system. One hundred and seventy-two coronary artery disease patients who had taken aspirin only or combinations with aspirin and clopidogrel for over 7 days were included. Of the 55 patients with aspirin only, aggregometer detected six AR (10.9%) and VerifyNow identified 10 AR (18.2%) cases. Among 117 patients with combined therapy, none (0.0%) and 10 (8.5%) of AR were detected by aggregometer and VerifyNow, respectively. There were six (3.4%) patients of AR defined by both methods and they all received aspirin monotherapy. Although the correlation between the aggregometry and VerifyNow was low, with defined criteria both methods gave 91.9% agreement to find AR. VerifyNow showed a higher sensitivity to detect AR. Further studies are required to biologically define AR and to alter therapy based on platelet function tests.

Aspirin in coronary artery bypass surgery: new aspects of and alternatives for an old antithrombotic agent

The success of coronary artery bypass graft surgery (CABG) depends mainly on the patency of the graft vessels. Aortocoronary vein graft disease is comprised of three distinct but interrelated pathological processes: thrombosis, intimal hyperplasia and atherosclerosis. Early thrombosis is a major cause of vein graft attrition during the first month after CABG, while during the remainder of the first year, intimal hyperplasia forms a template for subsequent atherogenesis, which thereafter predominates. Platelets play a crucial role in the pathophysiology of graft thrombosis and aspirin is the primary antiplatelet drug that has been shown to improve vein graft patency within the first year after CABG. Nevertheless, a significant number of grafts still occlude in the early postoperative period despite 'appropriate' aspirin treatment. Moreover, laboratory investigations showed that the expected inhibition of platelet function is not always achieved. This has been called 'aspirin nonresponse' or 'aspirin resistance', although a uniform definition is lacking. The finding that a considerable number of patients show an impaired antiplatelet effect of aspirin after CABG brought new insight into the discussion concerning poor patency rates of bypass grafts: the early period after CABG shows a coincidence of an increased risk for bypass thrombosis (amongst others, due to platelet activation and endothelial cell disruption of the graft) and an increased prevalence of aspirin resistance. Hitherto, the underlying mechanisms of aspirin resistance are uncertain and largely hypothetical; amongst others, increased platelet turnover, enhanced platelet reactivity, systemic inflammation, and drug-drug interaction are discussed. Up to now available data concerning the clinical outcome of aspirin resistant CABG patients are limited, and there is evidence that platelets of patients with graft thrombosis are more likely to be resistant to aspirin compared with patients without thrombotic events. Many publications concerning aspirin resistance are available today, but reports addressing this topic in CABG patients are sparse. This review summarises recent insights into the antiplatelet treatment after CABG and describes the clinical benefit, but also the therapeutic failure of the well-established drug aspirin. Moreover, possible pharmacological approaches to improve antithrombotic therapy in aspirin nonresponders among CABG patients are discussed.

Clinical implications of aspirin resistance

Aspirin (acetylsalicylic acid) is one of the main therapeutic medications used in the prevention of thromboembolic vascular events. Aspirin exhibits its antiplatelet action by irreversibly inhibiting platelet cyclooxygenase-1 enzyme, thus preventing the production of thromboxane A2 (TXA2). Aspirin resistance, as measured in vitro, is the inability of aspirin to reduce platelet activation and aggregation by failure to suppress the platelet production of TXA2. Laboratory tests of platelet TXA2 production or platelet function dependent on TXA2can detect aspirin resistance in vitro. The clinical implication of this laboratory definition has not yet been elucidated via prospective trials that have controlled for confounders, such as hypertension, diabetes and dyslipidemia. Large meta-analyses have found low-dose aspirin to be as effective as high-dose aspirin in preventing vascular events, making a dose-dependent improvement in laboratory response clinically irrelevant. Possible causes of aspirin resistance include poor compliance, inadequate dose, drug interactions, genetic polymorphisms of cyclooxygenase-1, increased platelet turnover and upregulation of nonplatelet pathways of thromboxane production. However, there is currently no standardized approach to the diagnosis and no proven effective treatment for aspirin resistance. Further research exploring the mechanisms of aspirin resistance is needed in order to better define aspirin resistance, as well as to develop a standardized laboratory test that is specific and reliable, and can correlate with the clinical risk of vascular events. The intent of this paper is to review the literature discussing possible mechanisms, diagnostic testing and clinical trials of aspirin resistance and to discuss its clinical relevance as it pertains to cerebrovascular and cardiovascular disease.

Review: Aspirin and diabetes

Type 2 diabetes accounts for a large proportion of cardiovascular disease within the UK. Inflammation is increasingly seen as a core process (even touted as a causative factor) connecting the metabolic syndrome and cardiovascular disease. Inflammatory markers, adhesion molecules, transcription regulators such as PPAR-gamma and NF-kappa B are being recognised as key elements of the underlying pathological process. In particular the links between oxidative stress, metabolic syndrome components and a pro-inflammatory milieu are becoming increasingly recognised.Salicylates have been used extensively for more than a hundred years but remain the subject of much research and scientific debate. Mechanisms of aspirin action, such as effects on endothelial function, oxidative stress, hyperglycaemia, inflammation, and mechanisms of aspirin resistance are being elucidated. With the advent of COX-2 selective inhibitors, the importance of the cyclo-oxygenase (COX-1 & COX-2 enzymes) pathways and the implications of more selective COX manipulation are being re-evaluated. There is no universal consensus on the use and dose of aspirin in diabetes. This review focuses upon the impact that aspirin may have to ameliorate the pathophysiology of diabetes and CVD.

Aspirin Resistance: An Evaluation of Current Evidence and Measurement Methods

Aspirin resistance is a poorly characterized phenomenon, whereby certain patients do not benefit from the antithrombotic effect of aspirin. The frequency of aspirin resistance is unknown, but estimates range from 5-60%. The mechanism of aspirin resistance also is unknown; proposed mechanisms are poor patient compliance, poor aspirin absorption, increased isoprostane activity, platelet hypersensitivity to agonists, increased cyclooxygenase-2 activity, a cyclooxygenase-1 polymorphism, and the platelet alloantigen 2 polymorphism of platelet glycoprotein IIIa. Aspirin resistance appears to be dose related in some patients and therefore may be overcome with high doses. Evidence indicates that aspirin resistance is a dynamic state, with significant intrapatient variability in aspirin sensitivity with time. To date, a sensitive and specific assay of aspirin effect that reliably predicts treatment failure has not emerged. However, several commercially available products are being marketed for this purpose without convincing clinical data. Despite a wealth of literature on the topic, aspirin resistance remains an enigma. Further investigation is needed regarding strategies to identify and treat patients resistant to aspirin.

The role of platelet glycoprotein IIIa polymorphism in the high prevalence of in vitro aspirin resistance in patients with intracoronary stent restenosis

The aim of our study was to determine the relation between platelet glycoprotein IIIa (Pl A ) polymorphism and aspirin resistance in patients with intracoronary stent restenosis. Clinically, aspirin resistance is defined as having thrombotic and embolic cardiovascular events despite regular aspirin therapy. Platelet glycoprotein IIIa polymorphism is said to be a possible mechanism of aspirin resistance. We studied the prevalence of aspirin resistance in 204 previously intracoronary stent-implanted patients with stable coronary artery disease. In 102 of these patients, intracoronary stent restenosis was present. Platelet functions were analyzed in a platelet function analyzer (PFA-100, Dade Behring, Germany) with collagen and/or epinephrine (Col/Epi) and collagen and/or adenosine diphosphate cartridges. Closure time <186 seconds was defined as aspirin resistance with Col/Epi cartridges of PFA-100. The Pl A polymorphisms of 43 aspirin-resistant and 51 aspirin-sensitive subjects were determined with polymerase chain reaction and restriction fragments length polymorphism. A total of 31.3% (n = 32) of patients with intracoronary stent restenosis and 10.7% (n = 11) of patients with patent intracoronary stents were resistant to aspirin by PFA-100. The Pl A1,A1 allele of glycoprotein IIIa was present in 36 subjects (83.7.%) and the Pl A1,A2 allele was present in 7 subjects (16.2.%) in the aspirin-resistant patients group. The Pl A1,A1 allele of glycoprotein IIIa was present in 37 subjects (72.5%) and the Pl A1,A2 allele was present in 14 subjects (27.5%) in the aspirin-sensitive patients group ( P = .195). Our results suggest that platelets of patients with intracoronary stent restenosis with or without Pl A2 heterozygosity of glycoprotein IIIa are more likely to be resistant to low-dose aspirin therapy.

2P-0596 Mechanisms of aspirin resistance in atherosclerosis

2P-0596 Mechanisms of aspirin resistance in atherosclerosis

Possible mechanisms of aspirin resistance.

Data regarding possible mechanisms of aspirin (ASA) resistance in patients with recurrent myocardial infarction (MI) or vascular ischemia are limited. Five major possible mechanisms of ASA resistance are documented in the primary literature and are discussed in this paper. These mechanisms include: (1) inadequate blockade of erythrocyte-induced platelet activation; (2) biosynthesis of F2-isoprostane 8-iso-prostaglandin (PGF2alpha), a bioactive product of arachidonic acid peroxidation; (3) stimulation of platelet aggregation by cigarette smoking; (4) ASA resistant platelet aggregability by increased levels of norepinephrine, as seen during excessive exercise or periods of mental stress; and (5) increased platelet sensitivity to collagen. Recognizing mechanisms of platelet activation and identifying reversible risk factors such as smoking and mental stress may help decrease the occurrence of ASA resistance and possibly improve patient outcomes. Until more definitive data become available, when prescribing and dosing ASA for the prevention of MI or vascular ischemia, clinicians should identify possible risk factors for ASA resistance. Whether or not patients at risk for ASA resistance are candidates for additive antiplatelet therapy remains to be determined.