Resistance to aspirin is increased by ST-elevation myocardial infarction and correlates with adenosine diphosphate levels

Borna, Catharina; Lazarowski, Eduardo R.; Heusden, Catharina van; Öhlin, Hans; Erlinge, David

doi:10.1186/1477-9560-3-10

Cited by 76 publications

(12 citation statements)

References 29 publications

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“…Alternatively, aspirin resistance has been defined by incomplete suppression of urinary 11-dhTxB 2 excretion for which platelet response to ADP may be important [6, 8, 9]. In our study measurement of urinary 11-dhTxB 2 excretion, a marker for inhibition of thromboxane A 2 production, does not distinguish between those with complete or incomplete inhibition of platelet aggregation [1, 2].…”

Section: Discussionmentioning

confidence: 78%

“…Combination aspirin and clopidogrel is expected to cause inhibition of platelet aggregation through complementary mechanisms of inhibition of cyclooxygenase-dependent and adenosine-diphosphate (ADP)-dependent platelet aggregation [8,9,10]. Aspirin also inhibits platelet recruitment as measured ex vivo through the proaggregatory activity of cell-free releasates from activated platelets [7].…”

Section: Introductionmentioning

confidence: 99%

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Platelet Aggregation and Recruitment with Aspirin-Clopidogrel Therapy

Helgason

Grossi

Pandey³

et al. 2008

Cerebrovasc Dis

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Background: Aspirin-clopidogrel combination therapy inhibits platelet aggregation. The effect on platelet recruitment is unknown. Methods: Thirty chronic ischemic stroke patients taking aspirin alone followed by aspirin-clopidogrel combined therapy had platelet reactivity tests performed over 3 months: ex vivo platelet aggregation, platelet recruitment and urinary 11-dehydro-thromboxane B₂ (11-dhTxB₂)excretion. Statistical analysis of variance compared platelet aggregation and recruitment between aspirin alone and aspirin-clopidogrel, and longitudinal regression analysis estimated platelet recruitment over time. Nonlinear mapping defined variable connections in each patient. Results: Statistically significant differences were found between aspirin alone and aspirin-clopidogrel for (1) adenosine-diphosphate- and collagen-induced platelet aggregation and maximum inhibition of platelet recruitment and (2) increasing inhibition of platelet recruitment over time. Urinary 11-dhTxB₂ excretion did not predict platelet aggregation response. Nonlinear mapping showed patient-unique variable interconnections. Conclusions: Platelet inhibition with aspirin-clopidogrel may increase over time, and future studies should focus on this finding in the context of vascular complications.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Platelet Aggregation and Recruitment with Aspirin-Clopidogrel Therapy

Helgason

Grossi

Pandey³

et al. 2008

Cerebrovasc Dis

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“…Lipids were separated on a Zorbax Eclipse XDB-C8 column, 4. Measurement of Plasma Nucleotide Concentrations-Plasma levels of ATP, ADP, and adenosine were measured using minor adaptations of previously published procedures (35,36). In brief, plasma samples were collected directly into stop solution, deproteinated by extraction with perchloric acid, then neutralized by extraction with a mixture of tri-n-octylamine and Freon.…”

Section: Enpp2-tg and Enpp2mentioning

confidence: 99%

Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis

Pamuklar

Federico

Liu

et al. 2009

Journal of Biological Chemistry

133

132

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The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation. Transgenic overexpression of autotaxin/lysophospholipase D (Enpp2), the enzyme necessary for production of the bulk of biologically active LPA in plasma, elevated circulating LPA levels and induced a bleeding diathesis and attenuation of thrombosis in mice. Intravascular administration of exogenous LPA recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. Enpp2 ؉/؊ mice, which have ϳ50% normal plasma LPA levels, were more prone to thrombosis. Plasma autotaxin associated with platelets during aggregation and concentrated in arterial thrombus, and activated but not resting platelets bound recombinant autotaxin/ lysoPLD in an integrin-dependent manner. These results identify a novel pathway in which LPA production by autotaxin/lysoPLD regulates murine hemostasis and thrombosis and suggest that binding of autotaxin/lysoPLD to activated platelets may provide a mechanism to localize LPA production.

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“…High on-treatment platelet reactivity is linked to worse outcomes for both STEMI and NSTEMI patients undergoing procedures [17]. Platelet reactivity and anti-platelet resistance is suggested to be higher in STEMI patients than NSTEMI patients [18-20]. These differences in platelet reactivity and disease progression may result from gene expression differences between STEMI and NSTEMI cases.…”

Section: Introductionmentioning

confidence: 99%

Characterization of the platelet transcriptome by RNA sequencing in patients with acute myocardial infarction

et al. 2015

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Transcripts in platelets are largely produced in precursor megakaryocytes but remain physiologically-active as platelets translate RNAs and regulate protein/RNA levels. Recent studies using transcriptome sequencing (RNA-seq) characterized the platelet transcriptome in limited numbers of non-diseased individuals. Here, we expand upon these RNA-seq studies by completing RNA-seq in platelets from 32 patients with acute myocardial infarction (MI). Our goals were to characterize the platelet transcriptome using a population of patients with acute MI and relate gene expression to platelet aggregation measures and ST-segment elevation MI (STEMI) (n=16) versus non-STEMI (NSTEMI) (n=16) subtypes. Similar to other studies, we detected 9,565 expressed transcripts, including several known platelet-enriched markers (e.g., PPBP, OST4). Our RNA-seq data strongly correlated with independently ascertained platelet expression data and showed enrichment for platelet-related pathways (e.g., wound response, hemostasis, and platelet activation), as well as actin-related and post-transcriptional processes. Several transcripts displayed suggestively higher (FBXL4, ECHDC3, KCNE1, TAOK2, AURKB, ERG, and FKBP5) and lower (MIAT, PVRL3and PZP) expression in STEMI platelets compared to NSTEMI. We also identified transcripts correlated with platelet aggregation to TRAP (ATP6V1G2, SLC2A3), collagen (CEACAM1, ITGA2), and ADP (PDGFB, PDGFC, ST3GAL6). Our study adds to current platelet gene expression resources by providing transcriptome-wide analyses in platelets isolated from patients with acute MI. In concert with prior studies, we identify various genes for further study in regards to platelet function and acute MI. Future platelet RNA-seq studies examining more diverse sets of healthy and diseased samples will add to our understanding of platelet thrombotic and non-thrombotic functions.

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Resistance to aspirin is increased by ST-elevation myocardial infarction and correlates with adenosine diphosphate levels

Cited by 76 publications

References 29 publications

Platelet Aggregation and Recruitment with Aspirin-Clopidogrel Therapy

Platelet Aggregation and Recruitment with Aspirin-Clopidogrel Therapy

Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis

Characterization of the platelet transcriptome by RNA sequencing in patients with acute myocardial infarction

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