title: Clopidogrel treatment may associate with worsening of endothelial function and development of new digital ulcers in patients with systemic sclerosis: results from an open label, proof of concept study.
abstract: Activated platelets release serotonin that binds 5-HT2B receptor on fibroblasts leading to fibroblast activation. Clopidogrel, an inhibitor of ADP-dependent platelet activation prevents fibrosis in animal models of systemic sclerosis (SSc). We aimed at assessing whether i) ADP-dependent platelet activation is increased in patients with SSc compared to healthy subjects and patients with rheumatoid arthritis (RA) and ii) whether clopidogrel can effectively suppress ADP-dependent activation, reduce circulating serotonin levels and hence, favorably affect fibrosis or vasculopathy in patients with systemic sclerosis.
  
  
  
  Thirteen patients with SSc were recruited. Platelet activation was assessed by aggregometry prior to and following 14 days of clopidogrel treatment. At the same time points serotonin and soluble vascular cell adhesion molecule 1 (s-VCAM1), a marker of endothelial dysfunction, were measured.
  
  
  
  ADP-dependent platelet activation was similar between patients with SSc (n = 13), patients with RA (n = 28) and healthy subjects (n = 22) (mean ± SEM AU*min: 392.1 ± 58.4, 535.5 ± 61.33 and 570.9 ± 42.9 in patients with SSc, patients with RA and healthy subjects respectively, p = 0.14). Clopidogrel treatment significantly reduced platelet activation in patients with SSc (mean ± SEM AU*min: 392.1 ± 58.4 vs 163.8 ± 51.7, p = 0.014). Clopidogrel treatment did not affect serotonin levels but led to a significant increase in s-VCAM1 (p = 0.03). Three patients developed new digital ulcers during the study. The potential association of the study drug with the development of new digital ulcers led to early termination of the study.
  
  
  
  Clopidogrel may worsen markers of endothelial function and associate with development of new digital ulcers in patients with SSc.
  
  
  
  ISRCTN63206606 . Registered 02/Dec/2014.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece. kosdelis@gmail.com.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Ntelis
authors.affiliation: Department of Cardiology, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.
authors.forename: Vasileios
authors.initials: V
authors.lastname: Gkizas
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Filippopoulou
authors.affiliation: Department of Cardiology, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.
authors.forename: Periclis
authors.initials: P
authors.lastname: Davlouros
authors.affiliation: Department of Cardiology, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Alexopoulos
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Andonopoulos
authors.affiliation: Division of Rheumatology, Department of Internal Medicine, Patras University Hospital, University of Patras Medical School, 26504, Rion, Patras, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Daoussis
mesh_terms: D000244:Adenosine Diphosphate / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000077144:Clopidogrel; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D005385:Fingers / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D015539:Platelet Activation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D000075082:Proof of Concept Study; D058921:Purinergic P2Y Receptor Antagonists / Q000009:adverse effects* / Q000627:therapeutic use; D012595:Scleroderma, Systemic / Q000097:blood / Q000188:drug therapy*; D012701:Serotonin / Q000097:blood; D012883:Skin Ulcer / Q000139:chemically induced*; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D019010:Vascular Cell Adhesion Molecule-1 / Q000097:blood
chemical_list: D010975:Platelet Aggregation Inhibitors; D058921:Purinergic P2Y Receptor Antagonists; D019010:Vascular Cell Adhesion Molecule-1; D012701:Serotonin; D000244:Adenosine Diphosphate; D000077144:Clopidogrel; D013988:Ticlopidine
keywords: Clopidogrel; Digital ulcers; Platelets; Scleroderma; Systemic sclerosis