title: Human neutrophil α-defensins are associated with adenosine diphosphate-inducible neutrophil-platelet aggregate formation and response to clopidogrel in patients with atherosclerosis.
abstract: Human neutrophil α-defensins (HNPs) are antimicrobial peptides stored primarily in the azurophilic granules of polymorphonuclear leukocytes. Recently, it was shown that HNPs act as platelet agonists. We hypothesized that HNP levels are associated with the formation of neutrophil-platelet aggregates, and that they influence the response to clopidogrel therapy. HNP levels were determined by a commercially available enzyme-linked immunosorbent assay in 305 patients undergoing angioplasty and stenting for atherosclerotic cardiovascular disease. Neutrophil-platelet aggregates were measured by flow cytometry, and on-treatment platelet reactivity was determined using the VerifyNow P2Y12 and aspirin assays. HNP levels did not correlate with the formation of neutrophil-platelet aggregates in vivo (r = 0.05, P = 0.4). In contrast, HNP levels correlated significantly with adenosine diphosphate (ADP)-inducible neutrophil-platelet aggregate formation (r = 0.13, P = 0.04). On-treatment platelet reactivity by the VerifyNow P2Y12 assay was significantly more pronounced in patients with high HNP levels compared with patients with low HNP levels (211 P2Y12 reaction units [PRU; range, 143-293 PRU] vs 181 PRU [range, 129-237 PRU], P = 0.009). This association remained significant after adjusting for high-sensitivity C-reactive protein and interleukin 6 by multivariate regression analysis (P = 0.007). Moreover, high on-treatment residual platelet reactivity by the VerifyNow P2Y12 assay was more frequent in patients with high HNP levels than in patients with low HNP levels (40% vs 26.6%, P = 0.01). In conclusion, HNP levels are associated with ADP-inducible neutrophil-platelet aggregate formation and clopidogrel-mediated platelet inhibition. High levels of HNPs may, in part, be responsible for the observed response variability to clopidogrel.
authors.affiliation: Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria. Electronic address: thomas.gremmel@meduniwien.ac.at.
authors.forename: Thomas
authors.initials: T
authors.lastname: Gremmel
authors.affiliation: Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Durstberger
authors.affiliation: Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Beate
authors.initials: B
authors.lastname: Eichelberger
authors.affiliation: Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: Renate
authors.initials: R
authors.lastname: Koppensteiner
authors.affiliation: Division of Angiology, Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria.
authors.forename: Christoph W
authors.initials: CW
authors.lastname: Kopp
authors.affiliation: Department of Blood Group Serology and Transfusion Medicine, Medical University of Vienna, Vienna, Austria.
authors.forename: Simon
authors.initials: S
authors.lastname: Panzer
mesh_terms: D000244:Adenosine Diphosphate / Q000502:physiology*; D050197:Atherosclerosis / Q000097:blood / Q000188:drug therapy*; D002097:C-Reactive Protein / Q000378:metabolism; D000077144:Clopidogrel; D005434:Flow Cytometry; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D009504:Neutrophils / Q000378:metabolism*; D010974:Platelet Aggregation / Q000502:physiology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D013988:Ticlopidine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D023084:alpha-Defensins / Q000502:physiology*
chemical_list: D015850:Interleukin-6; D010975:Platelet Aggregation Inhibitors; D023084:alpha-Defensins; D000244:Adenosine Diphosphate; D002097:C-Reactive Protein; D000077144:Clopidogrel; D013988:Ticlopidine