Moderation of the platelet releasate response by aspirin

Coppinger, Judith A.; O'Connor, R.; Wynne, Kieran; Flanagan, Michelle; Sullivan, Matthew J.; Maguire, Patricia B.; Fitzgerald, Desmond J.; Cagney, Gerard

doi:10.1182/blood-2006-07-038539

Cited by 112 publications

(95 citation statements)

References 27 publications

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“…4 and 5). It is noteworthy that in multiple regression analysis circulating levels of angiogenin, an inducer of angiogenesis present in platelets and released in response to agonist stimulation (Coppinger et al, 2007), were inversely related to urinary PGI-M. There was also an inverse Spearman's correlation between urinary excretion of PGI-M and plasma levels of two mediators of angiogenesis and tumor progression, i.e., FGF-2 (Hanahan and Folkman, 1996) and HGF (Jiang et al, 1999) (Supplemental Fig.…”

Section: Discussionmentioning

confidence: 92%

Effects of Celecoxib on Prostanoid Biosynthesis and Circulating Angiogenesis Proteins in Familial Adenomatous Polyposis

Dovizio

Tacconelli

Ricciotti

et al. 2012

J Pharmacol Exp Ther

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Vascular cyclooxygenase (COX)-2-dependent prostacyclin (PGI 2 ) may affect angiogenesis by preventing endothelial activation and platelet release of angiogenic factors present in platelet ␣-granules. Thus, a profound inhibition of COX-2-dependent PGI 2 might be associated with changes in circulating markers of angiogenesis. We aimed to address this issue by performing a clinical study with celecoxib in familial adenomatous polyposis (FAP). In nine patients with FAP and healthy controls, pair-matched for gender and age, we compared systemic biosynthesis of PGI 2 , thromboxane (TX) A 2 , and prostaglandin (PG) E 2 , assessing their urinary enzymatic metabolites, 2,3-dinor-6-keto PGF 1␣ (PGI-M), 11-dehydro-TXB 2 (TX-M), and 11-␣-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), respectively. The impact of celecoxib (400 mg b.i.d. for 7 days) on prostanoid biosynthesis and 14 circulating biomarkers of angiogenesis was evaluated in FAP. Intestinal tumorigenesis was associated with enhanced urinary TX-M levels, but unaffected by celecoxib, suggesting the involvement of a COX-1-dependent pathway, presumably from platelets. This was supported by the finding that in cocultures of a human colon adenocarcinoma cell line (HT-29) and platelets enhanced TXA 2 generation was almost completely inhibited by pretreatment of platelets with aspirin, a preferential inhibitor of COX-1. In FAP, celecoxib profoundly suppressed PGE 2 and PGI 2 biosynthesis that was associated with a significant increase in circulating levels of most proangiogenesis proteins but also the antiangiogenic tissue inhibitor of metalloproteinase 2. Urinary PGI-M, but not PGE-M, was negatively correlated with circulating levels of fibroblast growth factor 2 and angiogenin. In conclusion, inhibition of tumor COX-2-dependent PGE 2 by celecoxib may reduce tumor progression. However, the coincident depression of vascular PGI 2 , in a context of enhanced TXA 2 biosynthesis, may modulate the attendant angiogenesis, contributing to variability in the chemopreventive efficacy of COX-2 inhibitors such as celecoxib.

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Section: Discussionmentioning

confidence: 92%

Effects of Celecoxib on Prostanoid Biosynthesis and Circulating Angiogenesis Proteins in Familial Adenomatous Polyposis

Dovizio

Tacconelli

Ricciotti

et al. 2012

J Pharmacol Exp Ther

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“…Platelets release multiple inflammatory molecules in response to various agonists in the clotting cascade (9). sCD40L (CD154) and RANTES (CCL5) are among the most abundant and commonly detected inflammatory mediators released by platelets.…”

Section: Resultsmentioning

confidence: 99%

“…We next measured the capacity of platelets to internalize the IgG-coated targets by fluorescence microscopy and flow cytometry, established techniques that can discriminate between bound and internalized targets and which are used to monitor leukocyte phagocytosis (41,42). Finally, since platelets secrete agents such as soluble CD40 ligand (sCD40L) (CD154) and RANTES (regulated upon activation, normal T cell expresses and secreted) in response to coagulation factors and IgG complexes, we investigated the relationship between platelet activation and cytokine secretion stimulated by IgG-coated targets (2,4,5,9,11,15,16,20,23,30,34). We report here that stimulation of platelets by IgG-coated targets results in substantial CD62P expression, internalization of the targets, and release of significant amounts of sCD40L and RANTES, further supporting a role for platelets in inflammatory and host defense responses.…”

mentioning

confidence: 99%

Internalization of IgG-Coated Targets Results in Activation and Secretion of Soluble CD40 Ligand and RANTES by Human Platelets

Antczak

Vieth

Singh

et al. 2011

Clin Vaccine Immunol

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Platelets are crucial elements for maintenance of hemostasis. Other functions attributable to platelets are now being appreciated, such as their role in inflammatory reactions and host defense. Platelets have been reported to bind immunological stimuli like IgG complexes, and for nearly 50 years it has been speculated that platelets may participate in immunological reactions. Platelets have been reported to bind and internalize various substances, similar to other leukocytes, such as macrophages and dendritic cells. In the present study, we tested the hypothesis that human platelets can bind and internalize IgG-coated particles, similar to leukocytes. To this end, we observed that interaction with IgG-coated beads resulted in platelet activation (as measured by CD62P expression), internalization of targets, and significant soluble CD40 ligand (sCD40L) and RANTES (regulated upon activation, normal T cell expresses and secreted) secretion. Blocking Fc␥RIIA with monoclonal antibody (MAb) IV.3 or inhibiting actin remodeling with cytochalasin D inhibited platelet activation, internalization, and cytokine production. These data suggest that platelets are capable of mediating internalization of IgG-coated particles, resulting in platelet activation and release of both sCD40L and RANTES.

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“…Therefore, future systematic studies are needed with both established and novel antiplatelet agents, to further understand the relationships between antiplatelet therapy and vascular inflammation and to improve the clinical outcome of patients at risk for recurrent cardiovascular events. Novel techniques like proteomics of platelet releasates (181) and platelet RNA-profiling (182) could help to better understand specific anti-inflammatory effects of antiplatelet therapies. Furthermore, testing of platelet function and inflammatory markers over time might help to identify patients at risk, who need a more pronounced and prolonged platelet inhibition beyond current guidelines as demonstrated by recent RCTs (191,192).…”

Section: Conclusion and Future Perspectivesmentioning

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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Moderation of the platelet releasate response by aspirin

Cited by 112 publications

References 27 publications

Effects of Celecoxib on Prostanoid Biosynthesis and Circulating Angiogenesis Proteins in Familial Adenomatous Polyposis

Effects of Celecoxib on Prostanoid Biosynthesis and Circulating Angiogenesis Proteins in Familial Adenomatous Polyposis

Internalization of IgG-Coated Targets Results in Activation and Secretion of Soluble CD40 Ligand and RANTES by Human Platelets

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

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