title: Platelet tissue factor activity and membrane cholesterol are increased in hypercholesterolemia and normalized by rosuvastatin, but not by atorvastatin.
abstract: High plasma LDL-cholesterol (LDL-C) and platelet responses have major pathogenic roles in atherothrombosis. Thus, statins and anti-platelet drugs constitute mainstays in cardiovascular prevention/treatment. However, the role of platelet tissue factor-dependent procoagulant activity (TF-PCA) has remained unexplored in hypercholesterolemia. We aimed to study platelet TF-PCA and its relationship with membrane cholesterol in vitro and in 45 hypercholesterolemic patients (HC-patients) (LDL-C >3.37 mmol/L, 130 mg/dL) and 37 control subjects (LDL-C <3.37 mmol/L). The effect of 1-month administration of 80 mg/day atorvastatin (n = 21) and 20 mg/day rosuvastatin (n = 24) was compared.
  
  
  
  Platelet TF-PCA was induced by GPIbα activation with VWF-ristocetin.
  
  
  
  Cholesterol-enriched platelets in vitro had augmented aggregation/secretion and platelet FXa generation (1.65-fold increase, p = 0.01). HC-patients had 1.5-, 2.3- and 2.5-fold increases in platelet cholesterol, TF protein and activity, respectively; their platelets had neither hyper-aggregation nor endogenous thrombin generation (ETP). Rosuvastatin, but not atorvastatin, normalized platelet cholesterol, TF protein and FXa generation. It also increased slightly the plasma HDL-C levels, which correlated negatively with TF-PCA.
  
  
  
  Platelets from HC-patients were not hyper-responsive to low concentrations of classical agonists and had normal PRP-ETP, before and after statin administration. However, washed platelets from HC-patients had increased membrane cholesterol, TF protein and TF-PCA. The platelet TF-dependent PCA was specifically expressed after VWF-induced GPIbα activation. Rosuvastatin, but not atorvastatin treatment, normalized the membrane cholesterol, TF protein and TF-PCA in HC-patients, possibly unveiling a new pleiotropic effect of rosuvastatin. Modulation of platelet TF-PCA may become a novel target to prevent/treat atherothrombosis without increasing bleeding risks.
authors.affiliation: Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Olga
authors.initials: O
authors.lastname: Panes
authors.affiliation: Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: César
authors.initials: C
authors.lastname: González
authors.affiliation: Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Patricia
authors.initials: P
authors.lastname: Hidalgo
authors.affiliation: Faculty of Medicine and Odontology, University of Antofagasta, Chile.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Valderas
authors.affiliation: Department of Cardiology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Mónica
authors.initials: M
authors.lastname: Acevedo
authors.affiliation: Department of Nutrition and Metabolic Diseases, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Susana
authors.initials: S
authors.lastname: Contreras
authors.affiliation: Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Ximena
authors.initials: X
authors.lastname: Sánchez
authors.affiliation: Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Jaime
authors.initials: J
authors.lastname: Pereira
authors.affiliation: Department of Nutrition and Metabolic Diseases, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Attilio
authors.initials: A
authors.lastname: Rigotti
authors.affiliation: Department of Hematology-Oncology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile. Electronic address: dmezzano@med.puc.cl.
authors.forename: Diego
authors.initials: D
authors.lastname: Mezzano
mesh_terms: D000328:Adult; D000368:Aged; D000069059:Atorvastatin / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects* / Q000235:genetics; D002677:Chile; D002784:Cholesterol / Q000097:blood*; D008076:Cholesterol, HDL / Q000097:blood; D015951:Factor Xa / Q000378:metabolism; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D000068718:Rosuvastatin Calcium / Q000627:therapeutic use*; D013925:Thromboplastin / Q000378:metabolism*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D008076:Cholesterol, HDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor; D000068718:Rosuvastatin Calcium; D013925:Thromboplastin; D002784:Cholesterol; D000069059:Atorvastatin; D015951:Factor Xa
keywords: Coagulation; Hypercholesterolemia; Platelets; Statins; Thrombosis; Tissue factor