Journal
THROMBOSIS RESEARCH
Volume 136, Issue 2, Pages 274-281Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.thromres.2015.06.008
Keywords
Paroxysmal Nocturnal Hemoglobinuria; Thrombosis; Eculizumab; Complement C5; Hemostasis
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Funding
- Alexion Pharmaceuticals
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Background: Paroxysmal Nocturnal Hemoglobinuria is characterized by complement-mediated hemolysis and an increased thrombosis risk. Eculizumab, an antibody to complement factor C5, reduces thrombotic risk via unknown mechanisms. Clinical observations suggest that eculizumab has an immediate effect. Objectives: A better understanding of the mechanism via which eculizumab reduces thrombotic risk by studying its pharmacodynamic effect on coagulation and fibrinolysis. Methods: We measured microparticles (MP), tissue factor (TF) activity, prothrombin fragment 1 + 2 (F1 + 2), D-dimer and simultaneously thrombin and plasmin generation in 55 PNH patients. In 20 patients, parameters were compared before and during eculizumab treatment (at 1 and 2 hours, 1, 4 and >= 12 weeks after commencement). Results: Patients with a history of thrombosis had elevated D-dimers (p = 0.02) but not MP. Among patients on anticoagulants, those with thrombosis had higher F1 + 2 concentrations (p = 0.003). TF activity was undetectable in plasma MP. Unexpectedly, thrombin peak height and thrombin potential were significantly lower in PNH patients than in healthy controls. Fibrinolysis parameters were normal. During eculizumab treatment D-dimer levels significantly decreased after 1 hour (p = 0.008) and remained decreased at >= 12 weeks (p = 0.03). F1 + 2 (p = 0.03) and thrombin peak height (p = 0.02) in patients not on anticoagulants significantly decreased at >= week 12. MP remained unchanged. Conclusions: Eculizumab induces an immediate decrease of D-dimer levels but not of other markers. The decrease in thrombin peak height and F1 + 2 suggests that eculizumab reduces thrombin generation. Elevated D-dimer levels in untreated PNH patients with a history of thrombosis suggest possible value in predicting thrombotic risk. (C) 2015 Elsevier Ltd. All rights reserved.
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