NDLI: Platelet P2Y$ _{12}$ Inhibitors Reduce Systemic Inflammation and Its Prothrombotic Effects in an Experimental Human Model

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Platelet P2Y$ _{12}$ Inhibitors Reduce Systemic Inflammation and Its Prothrombotic Effects in an Experimental Human Model

Content Provider	Scilit
Author	Thomas, Mark R. Outteridge, Samuel N. Ajjan, Ramzi A. Phoenix, Fladia Sangha, Gurpreet K. Faulkner, Rachael E. Ecob, Rosemary Judge, Heather M. Khan, Haroon West, Laura E. Dockrell, David H. Sabroe, Ian Storey, Robert F.
Copyright Year	2015
Description	Journal: Arteriosclerosis, thrombosis, and vascular biology Objective—: Clinical studies suggest that platelet P2Y$ _{12}$ inhibitors reduce mortality from sepsis, although the underlying mechanisms have not been clearly defined in vivo. We hypothesized that P2Y$ _{12}$ inhibitors may improve survival from sepsis by suppressing systemic inflammation and its prothrombotic effects. We therefore determined whether clopidogrel and the novel, more potent P2Y$ _{12}$ inhibitor, ticagrelor, modify these responses in an experimental human model. Approach and Results—: We randomized 30 healthy volunteers to ticagrelor (n=10), clopidogrel (n=10), or no antiplatelet medication (controls; n=10). We examined the effect of P2Y$ _{12}$ inhibition on systemic inflammation, which was induced by intravenous injection of Escherichia coli endotoxin. Both P2Y$ _{12}$ inhibitors significantly reduced platelet–monocyte aggregate formation and peak levels of major proinflammatory cytokines, including tumor necrosis factor α, interleukin-6, and chemokine (C–C motif) ligand 2. In contrast to clopidogrel, ticagrelor also significantly reduced peak levels of IL-8 and growth colony-stimulating factor and increased peak levels of the anti-inflammatory cytokine IL-10. In addition, ticagrelor altered leukocyte trafficking. Both P2Y$ _{12}$ inhibitors suppressed D-dimer generation and scanning electron microscopy revealed that ticagrelor also suppressed prothrombotic changes in fibrin clot ultrastructure. Conclusions—: Potent inhibition of multiple inflammatory and prothrombotic mechanisms by P2Y$ _{12}$ inhibitors demonstrates critical importance of platelets as central orchestrators of systemic inflammation induced by bacterial endotoxin. This provides novel mechanistic insight into the lower mortality associated with P2Y$ _{12}$ inhibitors in patients with sepsis in clinical studies.
Related Links	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663676/pdf https://www.ahajournals.org/doi/pdf/10.1161/ATVBAHA.115.306528
Ending Page	2570
Page Count	9
Starting Page	2562
ISSN	10795642
e-ISSN	15244636
DOI	10.1161/atvbaha.115.306528
Journal	Arteriosclerosis, thrombosis, and vascular biology
Issue Number	12
Volume Number	35
Language	English
Publisher	Ovid Technologies (Wolters Kluwer Health)
Publisher Date	2015-12-01
Access Restriction	Open
Subject Keyword	Journal: Arteriosclerosis, thrombosis, and vascular biology Peripheral Vascular Disease Antiplatelet Agents
Content Type	Text
Resource Type	Article
Subject	Cardiology and Cardiovascular Medicine

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