title: Evaluation of hemostasis and endothelial function in patients with paroxysmal nocturnal hemoglobinuria receiving eculizumab.
abstract: BACKGROUND
  Paroxysmal nocturnal hemoglobinuria (PNH) is associated with an increased risk of thrombosis through unknown mechanisms.
  
  
  METHODS
  We studied 23 patients with PNH, before and after five and 11 weeks of treatment with eculizumab. We examined markers of thrombin generation and reactional fibrinolysis (prothrombin fragment 1+2 (F1+2), D-dimers, and plasmin antiplasmin complexes (P-AP), and endothelial dysfunction tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), soluble thrombomodulin (sTM), intercellular adhesion molecule 1 (sICAM-1), vascular cell adhesion molecule (sVCAM-1), endothelial microparticles (EMPs), and tissue factor pathway inhibitor (TFPI).
  
  
  RESULTS
  At baseline, vWF, sVCAM-1, the EMP count, and F1+2 and D-dimer levels were significantly elevated in the patients, including those with no history of clinical thrombosis. Treatment with eculizumab was associated with significant decreases in plasma markers of coagulation activation (F1+2, P=0.012, and D-dimers, P=0.01), and reactional fibrinolysis (P-AP, P=0.0002). Eculizumab treatment also significantly reduced plasma markers of endothelial cell activation (t-PA, P=0.0005, sVCAM-1, P<0.0001, and vWF, P=0.0047) and total (P=0.0008) and free (P=0.0013) TFPI plasma levels.
  
  
  CONCLUSIONS
  Our results suggest a new understanding of the contribution of endothelial cell activation to the pathogenesis of thrombosis in PNH. The terminal complement inhibitor, eculizumab, induced a significant and sustained decrease in the activation of both the plasma hemostatic system and the vascular endothelium, likely contributing to the protective effect of eculizumab on thrombosis in this setting.
authors.affiliation: Service d'Hématologie Biologique, Hôpital Européen Georges Pompidou, 20-40 Rue Leblanc, 75908 Paris cedex 15, France. dominique.helley@egp.aphp.fr
authors.forename: Dominique
authors.initials: D
authors.lastname: Helley
authors.forename: Régis Peffault
authors.initials: RP
authors.lastname: de Latour
authors.forename: Raphaël
authors.initials: R
authors.lastname: Porcher
authors.forename: Celso Arrais
authors.initials: CA
authors.lastname: Rodrigues
authors.forename: Isabelle
authors.initials: I
authors.lastname: Galy-Fauroux
authors.forename: Jeanne
authors.initials: J
authors.lastname: Matheron
authors.forename: Arnaud
authors.initials: A
authors.lastname: Duval
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Schved
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Fischer
authors.forename: Gérard
authors.initials: G
authors.lastname: Socié
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000378:metabolism; D003182:Complement C5 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D006457:Hemoglobinuria, Paroxysmal / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006487:Hemostasis / Q000187:drug effects*; D006801:Humans; D007167:Immunotherapy; D008875:Middle Aged; D011956:Receptors, Cell Surface / Q000378:metabolism; D013927:Thrombosis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D003182:Complement C5; D011956:Receptors, Cell Surface; C481642:eculizumab