title: Platelet P2Y12 Inhibitors Reduce Systemic Inflammation and Its Prothrombotic Effects in an Experimental Human Model.
abstract: OBJECTIVE
  Clinical studies suggest that platelet P2Y12 inhibitors reduce mortality from sepsis, although the underlying mechanisms have not been clearly defined in vivo. We hypothesized that P2Y12 inhibitors may improve survival from sepsis by suppressing systemic inflammation and its prothrombotic effects. We therefore determined whether clopidogrel and the novel, more potent P2Y12 inhibitor, ticagrelor, modify these responses in an experimental human model.
  
  
  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 P2Y12 inhibition on systemic inflammation, which was induced by intravenous injection of Escherichia coli endotoxin. Both P2Y12 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 P2Y12 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 P2Y12 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 P2Y12 inhibitors in patients with sepsis in clinical studies.
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: Mark R
authors.initials: MR
authors.lastname: Thomas
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Outteridge
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: Ramzi A
authors.initials: RA
authors.lastname: Ajjan
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: Fladia
authors.initials: F
authors.lastname: Phoenix
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: Gurpreet K
authors.initials: GK
authors.lastname: Sangha
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: Rachael E
authors.initials: RE
authors.lastname: Faulkner
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: Rosemary
authors.initials: R
authors.lastname: Ecob
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: Heather M
authors.initials: HM
authors.lastname: Judge
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: Haroon
authors.initials: H
authors.lastname: Khan
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: Laura E
authors.initials: LE
authors.lastname: West
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: David H
authors.initials: DH
authors.lastname: Dockrell
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.).
authors.forename: Ian
authors.initials: I
authors.lastname: Sabroe
authors.affiliation: From the Departments of Cardiovascular Science (M.R.T., S.N.O., G.K.S., R.E.F., R.E., H.M.J., H.K., L.E.W., R.F.S.) and Infection and Immunity (D.H.D., I.S.), University of Sheffield, Sheffield, United Kingdom; and Leeds Institute of Cardiovascular and Metabolic Medicine, University of Leeds, Leeds, United Kingdom (R.A.A., F.P.). r.f.storey@sheffield.ac.uk.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Storey
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002634:Chemotaxis, Leukocyte / Q000187:drug effects; D000077144:Clopidogrel; D016207:Cytokines / Q000097:blood; D004731:Endotoxins; D004739:England; D005260:Female; D005338:Fibrin Fibrinogen Degradation Products / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D018836:Inflammation Mediators / Q000097:blood; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D011446:Prospective Studies; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use*; D058925:Receptors, Purinergic P2Y12 / Q000097:blood*; D013927:Thrombosis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D000077486:Ticagrelor; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D016207:Cytokines; D004731:Endotoxins; D005338:Fibrin Fibrinogen Degradation Products; D018836:Inflammation Mediators; C548576:P2RY12 protein, human; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; C036309:fibrin fragment D; C044101:endotoxin, Escherichia coli; D000077144:Clopidogrel; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine
keywords: antiplatelet agents; clopidogrel; fibrin; infection; sepsis; thrombosis; ticagrelor