Prasugrel Metabolites Inhibit Neutrophil Functions

Liverani, Elisabetta; Rico, Mario C.; Garcia, Analia; Kilpatrick, Laurie E.; Kunapuli, Satya P.

doi:10.1124/jpet.112.195883

Cited by 35 publications

(34 citation statements)

References 40 publications

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“…In an earlier study, we demonstrated that prasugrel metabolites inhibit neutrophil functions in vitro , even though neutrophils do not express the P2Y 12 receptor 36 . The data suggest a P2Y 12 independent effect for this class of drugs.…”

Section: Discussionmentioning

confidence: 88%

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P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation

Liverani

Rico

Tsygankov

et al. 2016

ATVB

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Objective Platelets modulate hemostasis and immune responses via interactions with immune cells, through secretion of immune-modulators and cell-cell interactions. The P2Y12 receptor mediates ADP-induced aggregation and secretion in platelets. Approach using a mouse model of intra-abdominal sepsis and acute lung injury, we investigated the role of the P2Y12 receptor in neutrophil migration and lung inflammation in P2Y12 null mice and in mice pre-treated with the P2Y12 antagonist clopidogrel. Results our data show a decrease in circulating white blood cells and a decrease in platelet activation and platelet-leukocyte interactions in treated mice compared to untreated. Additionally, lung injury and platelet sequestration were diminished in clopidogrel-treated mice compared to their untreated septic littermates. Similar results were observed in P2Y12 null mice: platelet activation and platelet-leukocyte aggregates were decreased in septic P2Y12 null mice compared to wild-type. P2Y12 null mice were refractory to lung injury compared to wild-type. Lastly, to evaluate P2Y12 independent effects of clopidogrel, we pre-treated P2Y12 null mice. Interestingly, the number of circulating neutrophils was reduced in treated septic P2Y12 null mice, suggesting neutrophils as a target for clopidogrel pleiotropic effects. No difference was observed in P2Y1 null mice during sepsis, indicating that the P2Y12 receptor is responsible for the effects. Conclusions P2Y12 null mice are refractory to sepsis-induced lung injury, suggesting a key role for activated platelets and the P2Y12 receptor during sepsis.

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Section: Discussionmentioning

confidence: 88%

“…Hence, clopidogrel may have P2Y 12 independent effects during sepsis, and neutrophils are the most likely target. Indeed, the P2Y 12 independent effects observed in vitro 36 may explain the altered neutrophil functions observed in vivo .…”

Section: Discussionmentioning

confidence: 99%

P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation

Liverani

Rico

Tsygankov

et al. 2016

ATVB

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“…Moreover, it was demonstrated that prasugrel might inhibit certain neutrophil functions [10]. Furthermore, platelets are involved in the formation of NETs (neutrophil extracellular traps), a recently discovered defensive mechanism against pathogens involving extracellular DNA, histones and neutrophil-derived antimicrobial proteins, such as elastase [11].…”

Section: Introductionmentioning

confidence: 99%

Potent irreversible P2Y12 inhibition does not reduce LPS-induced coagulation activation in a randomized, double-blind, placebo-controlled trial

et al. 2016

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Platelets play an important role in the activation of coagulation. P2Y12 receptor inhibition may be beneficial in inflammatory states. Prasugrel, a potent irreversible inhibitor of P2Y12 receptor-induced platelet activation may reduce activation of coagulation in a human LPS (lipopolysaccharide) model. A double-blind, randomized, crossover trial with a minimum washout period of 6 weeks was performed. Sixteen subjects were randomly assigned to a treatment group that received prasugrel or placebo 2 h before infusion of a bolus of LPS (2 ng/kg of body weight), whereas four subjects were assigned to a control group receiving prasugrel or placebo without LPS. hcDNA (histone-complexed DNA), coagulation and platelet-specific parameters were measured by enzyme immunoassay. Leucocyte aggregate formation was analysed by flow cytometry, and thromboelastometry was performed. LPS infusion markedly activated coagulation. However, prasugrel did not reduce changes in prothrombin fragments 1 and 2 (F1+2), thrombin-antithrombin complexes, microparticle-associated tissue factor, CD40 ligand, P-selectin, platelet-leucocyte aggregation, hcDNA levels or the coagulation profile measured by thromboelastometry. hcDNA plasma levels increased approximately 6-fold after LPS infusion in both treatment groups, but not in the control groups. Potent irreversible P2Y12 inhibition by prasugrel does not affect LPS-induced coagulation activation. The 6-fold increased hcDNA plasma levels after infusion of LPS indicates the formation of neutrophil extracellular traps during sterile inflammation.

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“…Furthermore, prasugrel also mediates non-platelet dependent effects. It has been shown that prasugrel metabolites inhibit neutrophil functions through neither the P2Y12 nor P2Y13 receptor in neutrophils (144).…”

Section: Prasugrelmentioning

confidence: 99%

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

Müller¹,

Chatterjee²,

Rath³

et al. 2015

Thromb Haemost

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SummaryPlatelets play a pivotal role in chronic inflammation leading to progression of atherosclerosis and acute coronary events. Recent discoveries on novel mechanisms and platelet-dependent inflammatory targets underpin the role of platelets to maintain a chronic inflammatory condition in cardiovascular disease. There is strong and clinically relevant crosslink between chronic inflammation and platelet activation. Antiplatelet therapy is a cornerstone in the prevention and treatment of acute cardiovascular events. The benefit of antiplatelet agents has mainly been attributed to their direct anti-aggregatory impact. Some anti-inflammatory off-target effects have also been described. However, it is unclear whether these effects are secondary due to inhibition of platelet activation or are caused by direct distinct mechanisms interfering with inflammatory pathways. This article will highlight novel platelet associated targets that contribute to inflammation in cardiovascular disease and elucidate mechanisms by which currently available antiplatelet agents evolve anti-inflammatory capacities, in particular by carving out the differential mechanisms directly or indirectly affecting platelet mediated inflammation. It will further illustrate the prognostic impact of antiplatelet therapies by reducing inflammatory marker release in recent cardiovascular trials.

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Prasugrel Metabolites Inhibit Neutrophil Functions

Cited by 35 publications

References 40 publications

P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation

P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation

Potent irreversible P2Y12 inhibition does not reduce LPS-induced coagulation activation in a randomized, double-blind, placebo-controlled trial

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

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Prasugrel Metabolites Inhibit Neutrophil Functions

Cited by 35 publications

References 40 publications

P2Y 12 Receptor Modulates Sepsis-Induced Inflammation

P2Y 12 Receptor Modulates Sepsis-Induced Inflammation

Potent irreversible P2Y12 inhibition does not reduce LPS-induced coagulation activation in a randomized, double-blind, placebo-controlled trial

Platelets, inflammation and anti-inflammatory effects of antiplatelet drugs in ACS and CAD

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Product

Resources

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P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation

P2Y ₁₂ Receptor Modulates Sepsis-Induced Inflammation