Aspirin resistance and diabetes mellitus

Published on Jan 16, 2008in Diabetologia7.518
· DOI :10.1007/S00125-007-0898-3
Ramzi Ajjan34
Estimated H-index: 34
(University of Leeds),
Robert F. Storey90
Estimated H-index: 90
(University of Sheffield),
Peter J. Grant87
Estimated H-index: 87
(University of Leeds)
Despite multiple interventions to reduce the risk of cardiovascular disease, the majority of people with diabetes develop macrovascular complications, and mortality following myocardial infarction remains unacceptably high [1]. Antiplatelet agents are used for both the primary and secondary prevention of cardiovascular disease, although current guidelines are not consistent in their recommendation for the use of aspirin in diabetes [2]. In fact, there is little direct evidence supporting its efficacy in this group of patients. Instead, there is convincing data in the literature to suggest inadequate cardiovascular protection by aspirin in diabetes. In a meta-analysis of 287 randomised trials, antiplatelet treatment (aspirin in most studies) reduced the risk of ischaemic events by 22%, but the risk reduction in the subgroup with diabetes was only 7%, which was not statistically significant [3]. This outcome was mirrored in the Primary Prevention Project trial, which reported that cardiovascular risk reduction with aspirin was marginal and non-significant in the presence of diabetes [4]. Despite this, there are no published studies specifically designed to evaluate the clinical efficacy of aspirin in individuals with diabetes, a surprising omission in the era of ‘evidencebased’ medicine. These findings from clinical trials raise the question as to why there should be a reduction in the clinical efficacy of aspirin in patients with diabetes compared with a nondiabetic population. Diabetes is intrinsically associated with particular biochemical abnormalities that may have the capacity to diminish the effects of aspirin on platelet function and cardiovascular risk—a possibility that has led to the hotly debated concept of aspirin resistance [5, 6]. Unfortunately, aspirin resistance suffers from a lack of a standardised definition, although now generally thought of as either (1) reflecting clinical aspirin resistance (or perhaps, more accurately, treatment failure), characterised by the occurrence of a thrombotic episode despite treatment with aspirin; or (2) biochemical aspirin resistance where platelet responses persist despite platelet exposure to aspirin. Controversy remains as to the cause of biochemical aspirin resistance, its relevance to clinical outcomes, and the place of aspirin treatment in the management of cardiovascular risk in diabetes patients. All of this highlights the urgent need to understand the mechanisms that underpin the interactions between diabetes and aspirin, to establish the role of aspirin in particular, and antiplatelet therapy in general, in the amelioration of cardiovascular events in individuals with diabetes. Diabetologia (2008) 51:385–390 DOI 10.1007/s00125-007-0898-3
📖 Papers frequently viewed together
5,767 Citations
26 Authors (Jill J. F. Belch, ..., Ron MacWalter)
735 Citations
9 Authors (Hisao Ogawa, ..., Yoshihiko Saito)
650 Citations
#1Antonio NicolucciH-Index: 65
#2Giorgia De BerardisH-Index: 23
Last. Gianni TognoniH-Index: 114
view all 4 authors...
Recently, major scientific societies in Europe and USA have issued guidelines on diabetes and cardiovascular (CV) disease. The conclusions of the two panels of experts regarding the use of aspirin for the primary prevention of CV disease in individuals with diabetes are totally divergent. The US statement recommends the use of aspirin for primary prevention in all individuals aged > 40 or with additional risk factors. In contrast, in the European guidelines there is no mention of aspirin for the...
68 CitationsSource
#1Shinichi Takahashi (Keio: Keio University)H-Index: 4
#2Miho Ushida (Keio: Keio University)H-Index: 1
Last. Mitsuru Murata (Keio: Keio University)H-Index: 42
view all 10 authors...
Abstract Introduction Aspirin is one of the most effective antiplatelet agents and is now commonly used to prevent vascular events. In some patients, however, recurrent vascular events have been demonstrated despite aspirin therapy. Our objective was to characterize individuals showing poor response to in vitro effect of aspirin, using PFA-100. Methods One hundred sixty-eight healthy male subjects were analyzed. We assessed platelet function tests, including PFA-100, whole blood aggregation, and...
37 CitationsSource
#1Richard M. CubbonH-Index: 27
Last. Alistair S. Hall (LGI: Leeds General Infirmary)H-Index: 87
view all 9 authors...
Aims Over the last decade, advances in treatment for patients sustaining an acute myocardial infarction (AMI) have reduced mortality rates. We aimed to assess whether patients with diabetes mellitus (DM) have derived similar benefits as patients without DM. Methods and results We compared characteristics, management, and survival of patients with and without DM who sustained an AMI in 1995 ( n = 1762) with a second group of patients who sustained an AMI in 2003 ( n = 1642). All patients were fol...
100 CitationsSource
Summary This review examines ulcers and gastrointestinal bleeding with low-dose aspirin, focusing on randomized placebo-controlled trials. The single endoscopic trial assessing ulcers showed no significant difference in 12-week ulcer incidence: 6% of 381 given placebo vs. 7% of 387 given 81 mg enteric-coated aspirin. The relative risk of major gastrointestinal bleeding with low-dose aspirin in a meta-analysis of placebo-controlled trials of vascular protection was 2.07 (95% CI: 1.61–2.66). The a...
116 CitationsSource
#1Tsukasa OhmoriH-Index: 27
#2Yutaka Yatomi (UTokyo: University of Tokyo)H-Index: 73
Last. Yoichi SakataH-Index: 25
view all 8 authors...
Summary. Objectives: Although the concept of aspirin resistance is extensively reported in medical literature, its precise mechanisms and clinical outcomes are largely unknown. In this study, we examined individual thromboxane biosynthesis and platelet aggregation in aspirin-treated patients, and whether the results of a platelet aggregation test influenced clinical outcomes. Results: Subjects taking 81 mg of aspirin (n = 50) and controls (n = 38) were evaluated for platelet aggregation and plat...
106 CitationsSource
#1Ramzi Ajjan (University of Leeds)H-Index: 34
#2Peter J. Grant (University of Leeds)H-Index: 87
Atherothrombotic disease arises secondary to a complex gene-environment interaction. In the initial stages, the condition is clinically silent but with more advanced disease, an occlusive thrombus is formed resulting in the classical clinical manifestations. Both environmental factors and genetic variations in elements of the clotting cascade influence thrombosis risk by inducing quantitative and qualitative changes in the mature protein, which may affect the final structure of the clot and dete...
90 CitationsSource
Summary. Background: Some data suggest that biological ‘resistance’ to aspirin or clopidogrel may influence clinical outcome. Objective: The aim of this study was to evaluate the relationship between aspirin and clopidogrel responsiveness in healthy subjects. Methods: Ninety-six healthy subjects were randomly assigned to receive a 1-week course of aspirin 100 mg day−1 followed by a 1-week course of clopidogrel (300 mg on day 1, then 75 mg day−1), or the reverse sequence, separated by a 2-week wa...
87 CitationsSource
Platelets possess two receptors for ADP, P2Y 1 and P2Y 12 . ADP is released from platelet dense granules upon platelet activation by numerous agonists and thereby amplifies platelet responses regardless of the initial stimulus. The P2Y 1 receptor is one of many platelet receptors coupled to Gq and initiates ADP-induced activation. The P2Y 12 receptor on the other hand is linked to Gi and plays a special role in the amplification of platelet activation initiated by numerous other pathways. Platel...
143 CitationsSource
#1Emma J. Dunn (University of Leeds)H-Index: 5
#2Helen Philippou (University of Leeds)H-Index: 30
Last. Peter J. Grant (University of Leeds)H-Index: 87
view all 4 authors...
Aims/hypothesis The aim of this study was to determine the influence of type 2 diabetes on fibrinolysis by assessing interactions between the regulatory components of fibrinolysis and the fibrin clot, using fibrinogen purified from 150 patients with type 2 diabetes and 50 matched controls.
144 CitationsSource
#1Cezary WatalaH-Index: 27
#2Olga UlicnaH-Index: 10
Last. Józef DrzewoskiH-Index: 30
view all 7 authors...
The effect of chronic hyperglycaemia on blood platelet response to acetylsalicylic acid was studied in rats with experimental diabetes. Platelet aggregation was determined in non-diabetic and streptozotocin-diabetic rats treated orally with 4 or 40 mg aspirin (ASA)/kg per day (for 8 weeks from the eighth day of diabetes) using whole blood impedance aggregometry with arachidonic acid or ADP as platelet agonists. The dose-dependent effect of ASA 'therapy' on ADP-agonized platelets was significant ...
24 CitationsSource
Cited By66
#1Agata Hanna Bryk (Jagiellonian University Medical College)H-Index: 7
#2Katharina Zettl (MPG: Max Planck Society)H-Index: 3
Last. Anetta Undas (Jagiellonian University Medical College)H-Index: 33
view all 4 authors...
Abstract Acetylsalicylic acid (ASA) and type 2 diabetes mellitus (T2DM) affect fibrin clot properties through fibrinogen acetylation or glycation. We aimed to identify glycation and acetylation sites on fibrinogen in plasma fibrin clot of T2DM patients with respect to effects of ASA and fibrin clot properties. In fibrin clots generated from plasma of 9 T2DM patients, we performed mass-spectrometric analysis of Ne-fructosyl-(FL), Ne-carboxyethyl-(CEL) and Ne-carboxymethyl-lysine (CML), and acetyl...
3 CitationsSource
#1Kazumitsu AmariH-Index: 4
#2Eriko SugawaraH-Index: 4
Last. Ken JohkuraH-Index: 13
view all 6 authors...
#5Samreen Ahsan (University of Engineering and Technology, Lahore)H-Index: 3
#6Tariq Mehmood (University of Engineering and Technology, Lahore)H-Index: 4
#1Agata Hanna BrykH-Index: 7
#2Dorota Satala (Jagiellonian University)H-Index: 5
Last. Anetta UndasH-Index: 33
view all 5 authors...
: In type 2 diabetes mellitus (T2DM), increased α2-antiplasmin incorporation in fibrin and impaired fibrinolysis have been reported. Acetylsalicylic acid (ASA), used in cardiovascular prevention, modulates fibrinolysis and exerts weaker therapeutic effect in this disease. We investigated how glycation and acetylation of α2-antiplasmin affects its interaction with fibrin. Using surface plasmon resonance, we analyzed fibrin binding by α2-antiplasmin incubated with no β-D-glucose or ASA (control); ...
2 CitationsSource
#1Jing Wang (Nanjing Medical University)H-Index: 4
#2Samee Abdus (Nanjing Medical University)H-Index: 1
Last. Chunjian Li (Nanjing Medical University)H-Index: 7
view all 9 authors...
Abstract Background and aims It has been reported that elevated serum uric acid (SUA) is related to inflammation and potentially to platelet hyper-reactivity. However, the relationship between elevated SUA and residual platelet reactivity is uncertain in patients on dual antiplatelet treatment (DAPT) with aspirin and clopidogrel. Methods and results A cross-sectional cohort study was conducted on 2569 patients undergoing DAPT with aspirin and clopidogrel. Patients’ SUA levels, residual platelet ...
1 CitationsSource
Platelet hyperactivation is involved in the established prothrombotic condition of metabolic diseases such as Type 2 Diabetes Mellitus (T2DM) and familial hypercholesterolemia (HC), justifying the therapy with aspirin, a suppressor of thromboxane synthesis through the irreversible inhibition of cyclooxygenase-1 (COX-1), to prevent cardiovascular diseases. However, some patients on aspirin show a higher than expected platelet reactivity due, at least in part, to a pro-oxidant milieu. The aim of t...
5 CitationsSource
#1Judith J. de Vries (EUR: Erasmus University Rotterdam)H-Index: 3
#2Charlotte J. M. Snoek (EUR: Erasmus University Rotterdam)H-Index: 2
Last. Moniek P.M. de Maat (EUR: Erasmus University Rotterdam)H-Index: 51
view all 4 authors...
OBJECTIVE: Post-translational modifications of fibrinogen influence the occurrence and progression of thrombotic diseases. In this systematic review, we assessed the current literature on post-translational modifications of fibrinogen and their effects on fibrin formation and clot characteristics. Approach and Results: A systematic search of Medline, Embase, Cochrane Library, and Web of Science was performed to find studies reporting post-translational modifications of fibrinogen and the effects...
14 CitationsSource
#1Agata Hanna Bryk (Jagiellonian University Medical College)H-Index: 7
#2Dominik Cysewski (PAN: Polish Academy of Sciences)H-Index: 12
Last. Anetta Undas (Jagiellonian University Medical College)H-Index: 33
view all 4 authors...
Abstract Background The post-translational protein modification via lysine residues can significantly alter its function. α2-antiplasmin, a key inhibitor of fibrinolysis, contains 19 lysine residues. Aim We sought to identify sites of glycation and acetylation in human α2-antiplasmin and test whether the competition might occur on the lysine residues of α2-antiplasmin. Methods We analyzed human α2-antiplasmin (1) untreated; (2) incubated with increasing concentrations of β- d -glucose (0, 5, 10,...
3 CitationsSource
#1Paul Harrison (University of Birmingham)H-Index: 162
#2M. Angelyn Bethel (University of Oxford)H-Index: 17
Last. Rury R. Holman (University of Oxford)H-Index: 116
view all 6 authors...
AbstractThe antiplatelet efficacy of aspirin (ASA) is reduced in type 2 diabetes (T2D). As the best ex vivo method of measuring ASA efficacy remains uncertain, we compared nine platelet function tests to assess responsiveness to three ASA dosing regimens in 24 T2D patients randomized in a three-treatment crossover design to ASA 100 mg/day, 200 mg/day, or 100 mg twice daily for 2-week treatment periods. Platelet function tests compared were as follows: light transmission aggregometry (LTA)–0.5 mg...
11 CitationsSource
#1Aldo Bonaventura (UniGe: University of Genoa)H-Index: 27
#2Luca Liberale (UZH: University of Zurich)H-Index: 19
Last. Fabrizio Montecucco (UniGe: University of Genoa)H-Index: 59
view all 3 authors...
BACKGROUND: Patients with diabetes are at high cardiovascular (CV) risk due to an exaggerated platelet activation and aggregation. In the first 2000s low-dose aspirin was first recommended for primary prevention, but then re-discussed. METHODS: This short narrative review, based on the material searched for and obtained via PubMed up to February 2018, aims at clarifying this controversial topic. RESULTS: The JPAD2 study has been designed to evaluate the occurrence of any CV event in a cohort of ...
8 CitationsSource