title: A phase 1 study of prasugrel in patients with sickle cell disease: effects on biomarkers of platelet activation and coagulation.
abstract: BACKGROUND
  Prasugrel, a P2Y₁₂ adenosine diphosphate (ADP) receptor antagonist effectively inhibits ADP-mediated platelet activation and aggregation, and may be useful in reducing vaso-occlusive crises in sickle cell disease (SCD). In this study, we assess the effect of prasugrel on biomarkers of platelet activation and coagulation in patients with SCD.
  
  
  METHODS
  Twelve adult patients with SCD and 13 healthy subjects were examined before and after 12 ± 2 days of 5.0 or 7.5 mg/day oral prasugrel. Assessed cellular biomarkers included monocyte- and neutrophil-platelet aggregates, activated glycoprotein IIb-IIIa (GPIIbIIIa), P-selectin, CD40 ligand (CD40L), tissue factor (TF) expression on circulating platelets and on monocyte-platelet aggregates, and platelet-erythrocyte aggregates. Soluble biomarkers included CD40L, prothrombin fragment 1.2 (F1.2), thromboxane B₂ (TXB₂), P-selectin, and TF.
  
  
  RESULTS
  Patients with SCD had increased platelet baseline activation compared to healthy subjects, as measured by percentages of monocyte-platelet aggregates, neutrophil-platelet aggregates, and platelets expressing CD40L. Likewise, baseline levels of soluble F1.2 and TXB₂ were elevated in patients with SCD compared to healthy subjects. After 12 days of prasugrel, patients with SCD had a significant reduction in platelet-monocyte aggregates that was not observed in healthy subjects. Following prasugrel administration, those with SCD maintained higher levels of monocyte-platelet aggregates and soluble F1.2, but had lower levels of platelet-erythrocyte aggregates and soluble TF compared to healthy subjects.
  
  
  CONCLUSIONS
  These results provide evidence for chronic platelet activation in the SCD steady state, activation that was in part attenuated by prasugrel, thereby suggesting that ADP may mediate platelet activation in SCD.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN USA. Electronic address: joseph@lilly.com.
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Jakubowski
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN USA.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Zhou
authors.affiliation: King's College, London UK.
authors.forename: Stipo
authors.initials: S
authors.lastname: Jurcevic
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Winters
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, UK.
authors.forename: D Richard
authors.initials: DR
authors.lastname: Lachno
authors.affiliation: Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, MA USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Frelinger
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN USA.
authors.forename: Neehar
authors.initials: N
authors.lastname: Gupta
authors.affiliation: Guy's and St. Thomas' Hospital, London UK.
authors.forename: Jo
authors.initials: J
authors.lastname: Howard
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Windlesham, Surrey, UK.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Payne
authors.affiliation: Quintiles Drug Research Unit at Guy's Hospital, London UK.
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Mant
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000328:Adult; D000755:Anemia, Sickle Cell / Q000188:drug therapy* / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001777:Blood Coagulation / Q000187:drug effects*; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use*; D015539:Platelet Activation / Q000187:drug effects*; D000068799:Prasugrel Hydrochloride; D058921:Purinergic P2Y Receptor Antagonists / Q000627:therapeutic use*; D013876:Thiophenes / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D015415:Biomarkers; D010879:Piperazines; D058921:Purinergic P2Y Receptor Antagonists; D013876:Thiophenes; D000244:Adenosine Diphosphate; D000068799:Prasugrel Hydrochloride
keywords: ADP; Biomarkers; CD40 ligand; CD40L; EDTA; GPIIbIIIa; P2Y(12) receptor antagonist; PD; PK; Platelets; Prasugrel; RBCs; SCD; SD; Sickle cell disease; TF; TXB(2); VOC; adenosine diphosphate; ethylenediaminetetraacetic acid; glycoprotein IIb-IIIa; pharmacodynamics; pharmacokinetics; red blood cells; sickle cell disease; standard deviation; thromboxane B(2); tissue factor; vaso-occlusive crisis