title: Potent irreversible P2Y12 inhibition does not reduce LPS-induced coagulation activation in a randomized, double-blind, placebo-controlled trial.
abstract: 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.
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Schoergenhofer
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Schwameis
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors.forename: Eva-Luise
authors.initials: EL
authors.lastname: Hobl
authors.affiliation: Department of Internal Medicine I, Clinical Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors.forename: Cihan
authors.initials: C
authors.lastname: Ay
authors.affiliation: Hemophilia and Thrombosis Center, Department of Medicine, UNC Chapel Hill, 170 Manning Drive, Chapel Hill, NC 27514, U.S.A.
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Key
authors.affiliation: Department of Emergency Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors.forename: Ulla
authors.initials: U
authors.lastname: Derhaschnig
authors.affiliation: Department of Clinical Pharmacology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria Bernd.jilma@meduniwien.ac.at.
authors.forename: Bernd
authors.initials: B
authors.lastname: Jilma
authors.affiliation: Department of Emergency Medicine, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
authors.forename: Alexander O
authors.initials: AO
authors.lastname: Spiel
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects*; D004247:DNA / Q000187:drug effects; D004311:Double-Blind Method; D064368:Healthy Volunteers; D006801:Humans; D008070:Lipopolysaccharides; D008297:Male; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D000068799:Prasugrel Hydrochloride / Q000494:pharmacology*; D058921:Purinergic P2Y Receptor Antagonists / Q000494:pharmacology*; D013916:Thrombelastography; D055815:Young Adult
chemical_list: D015415:Biomarkers; D008070:Lipopolysaccharides; D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D004247:DNA; D000068799:Prasugrel Hydrochloride
keywords: P2Y12 receptor; blood coagulation; histones; lipopolysaccharide; prasugrel; thromboelastometry