Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance

Weber, Artur‐Aron; Zimmermann, Katja; Meyer-Kirchrath, Jutta; Schrör, Karsten

doi:10.1016/s0140-6736(99)00498-5

Cited by 173 publications

(116 citation statements)

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“…In HIV-1 infection, dysregulation of inflammatory responses points to the importance of studying critical molecules such as COX-2, which contributes to the pathogenesis of diseases with uncontrolled or chronic inflammation (50,51). We also observed higher constitutive levels of COX-2 in mDC from HIV-1 infected individuals.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cells from HIV-1 infected individuals are less responsive to toll-like receptor (TLR) ligands

Martinson

Román-Gonzaléz

Tenorio

et al. 2007

Cellular Immunology

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We compared TLR responsiveness in PBMC from HIV-1-infected and uninfected individuals using the TLR agonists: TLR7 (3M-001), TLR8 (3M-002) and TLR7/8 (3M-011). Activation and maturation of plasmacytoid dendritic cells (pDC)were measured by evaluating CD86, CD40 and CD83 expression and myeloid dendritic cell (mDC) activation was measured by evaluating CD40 expression. All agonists tested induced activation and maturation of pDC in PBMC cultures of cells from HIV+ and HIV− individuals. The TLR7 agonist induced significantly less pDC maturation in cells from HIV+ individuals. Quantitative assessment of secreted IFN-α and pro-inflammatory cytokines at the single cell level showed that pDC from HIV+ individuals stimulated with TLR7 and TLR7/8 induced IFN-α. TLR8 and TLR7/8 agonists induced IL-12 and COX-2 expression in mDC from HIV+ and HIV− individuals. Understanding pDC and mDC activation and maturation in HIV-1 infection could lead to more rational development of immunotherapeutic strategies to stimulate the adaptive immune response to HIV-1.

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Section: Discussionmentioning

confidence: 99%

Dendritic cells from HIV-1 infected individuals are less responsive to toll-like receptor (TLR) ligands

Martinson

Román-Gonzaléz

Tenorio

et al. 2007

Cellular Immunology

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“…The same effect can be progressively achieved with the chronic administration of daily doses of 30 to 50 mg. 1 COX has 2 isoforms with different tissue distribution and susceptibility to inhibition by NSAID. COX-2 in not inhibited by therapeutic doses of aspirin and, under physiological conditions, is present in a small fraction of platelets, [3][4][5] but the number of COX-2-expressing platelets may increase in conditions of high platelet regeneration. 5 Because aspirin acetylates COX-1 in all tissues, including endothelial cells, where the enzyme converts arachidonic acid into the vasodilator and natural platelet antagonist prostacyclin, for several years there has been the concern that the potential antithrombotic effect of aspirin could be blunted, or even overcome, by the theoretical prothrombotic effect associated with the parallel inhibition of prostacyclin.…”

Section: Aspirinmentioning

confidence: 99%

“…The following potential mechanisms could be considered responsible for "true" aspirin resistance: (1) decreased bioavalaibility of aspirin; (2) competition of aspirin with other NSAIDs (such as ibuprofen) preventing aspirin access at Ser530 of COX-1; 66 (3) accelerated platelet turnover, introducing newly formed, nonaspirinated platelets into blood stream; 39 (4) transcellular formation of TxA 2 by aspirinated platelets from PGH 2 released by other blood cells or vascular cells; 68,74 (5) TxA 2 production by the aspirin-insensitive COX-2 in newly formed platelets or other cells; 3,68 and (6) (theoretical) presence of variant COX-1 that is less responsive to aspirin inhibition. 68 In patients undergoing coronary artery bypass surgery, Zimmerman et al showed that aspirin inhibition of TxA 2 biosynthesis both in vitro and ex vivo is compromised within several days after surgery.…”

Section: True Aspirin Resistancementioning

confidence: 99%

Aspirin and Clopidogrel

Cattaneo

2004

ATVB

371

133

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Abstract-Aspirin and the thienopyridines ticlopidine and clopidogrel are antiplatelet agents that display good antithrombotic activity. In the past few years, the concept of aspirin resistance has been largely emphasized in the medical literature, although its definition is still uncertain. I suggest that "aspirin-resistant" should be considered as a description for those individuals in whom aspirin fails to inhibit thromboxane A 2 production, irrespective of the results of unspecific tests of platelet function, such as the bleeding time, platelet aggregation, or the PFA-100 system. Less well known than aspirin resistance, but certainly better characterized, is the issue of "clopidogrel resistance," which is probably mostly caused by inefficient metabolism of the prodrug clopidogrel to its active metabolite. At present, aspirin and clopidogrel resistance should not be looked for in the clinical setting, because there is no definite demonstration of an association with clinical events conditioning cost-effective changes in patient management. Key Words: aspirin resistance Ⅲ clopidogrel resistance Ⅲ antiplatelet agents Ⅲ cardiovascular diseases Ⅲ cerebrovascular diseases A spirin and the thienopyridines ticlopidine and clopidogrel are inhibitors of platelet aggregation that display good antithrombotic activity. They are used in the prophylaxis of patients undergoing vascular grafting or percutaneous angioplasty, in the medical management of acute coronary syndromes, and in long-term prevention of cardiovascular and cerebrovascular events.Both aspirin and the thienopyridines selectively inhibit a single pathway of platelet activation: aspirin affects the arachidonate-thromboxane A 2 (TxA 2 ) pathway by irreversibly inhibiting cyclo-oxygenase-1 (COX-1) (Figure 1). 1 The thienopyridines affect the adenosine diphosphate (ADP) pathway, by irreversibly blocking the ADP receptor P2Y 12 ( Figure 1). 2 Despite their selective mechanism of action, which does not counteract the many alternative pathways for platelet activation, aspirin and thienopyridines display a good antithrombotic activity. This is explained by the fact that both the arachidonate-TxA 2 pathway and the ADP pathway contribute to the amplification of platelet activation and are essential for the full aggregation and secretion response of platelets to agonists. 2

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“…4 The mechanism of aspirin resistance is unknown. Because platelets contain, besides cyclooxygenase (COX)-1, a variable amount of COX-2, 5,6 which is at least two orders of magnitude less sensitive to inhibition by aspirin than COX-1, 7,8 it has been speculated that an insufficient platelet response to aspirin may be caused by thromboxane formation via platelet COX-2. Nevertheless, the mechanism of aspirin resistance remains unclear, probably because appropriate experimental models are not available.…”

mentioning

confidence: 99%

Functional and Biochemical Evaluation of Platelet Aspirin Resistance After Coronary Artery Bypass Surgery

et al. 2003

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Background-Aspirin inhibits platelet activation and reduces atherothrombotic complications in patients at risk of myocardial infarction and stroke. However, a sufficient inhibition of platelet function by aspirin is not always achieved. The causes of this aspirin resistance are unknown. Methods and Results-Patients undergoing coronary artery bypass grafting (CABG) have a high incidence of aspirin resistance. To evaluate functional and biochemical responses to aspirin, platelet-rich plasma was obtained before and at days 1, 5, and 10 after CABG. Thromboxane formation, aggregation, and ␣-granule secretion were effectively inhibited by 30 or 100 mol/L aspirin in vitro before CABG, but this inhibition was prevented or attenuated after CABG. Whereas the inhibition of thromboxane formation and aggregation by aspirin in vitro partly recovered at day 10 after CABG, oral aspirin (100 mg/d) remained ineffective. The inducible isoform of cyclooxygenase in platelets, COX-2, has been suggested to confer aspirin resistance. In fact, immunoreactive COX-2 was increased 16-fold in platelets at day 5 after CABG, but the COX-2 selective inhibitor celecoxib did not alter aspirin-resistant thromboxane formation. By contrast, the combined inhibitor of thromboxane synthase and thromboxane receptor antagonist terbogrel equally prevented thromboxane formation of platelets obtained before (control) and after CABG. Conclusions-Platelet aspirin resistance involves an impairment of both in vivo and in vitro inhibition of platelet functions and is probably due to a disturbed inhibition of platelet COX-1 by aspirin. (Circulation. 2003;108:542-547.)

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Cyclooxygenase-2 in human platelets as a possible factor in aspirin resistance

Cited by 173 publications

References 4 publications

Dendritic cells from HIV-1 infected individuals are less responsive to toll-like receptor (TLR) ligands

Dendritic cells from HIV-1 infected individuals are less responsive to toll-like receptor (TLR) ligands

Aspirin and Clopidogrel

Functional and Biochemical Evaluation of Platelet Aspirin Resistance After Coronary Artery Bypass Surgery

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