Alterations in markers of coagulation and fibrinolysis in patients with Paroxysmal Nocturnal Hemoglobinuria before and during treatment with eculizumab. Issue 2 (August 2015)

• Record Type: Journal Article
• Authors: van Bijnen, S.T.A.; Østerud, B.; Barteling, W.; Verbeek-Knobbe, K.; Willemsen, M.; van Heerde, W.L.; Muus, P.
• Is Part Of: Thrombosis research. Volume 136:Issue 2(2015)
• Page Start: 274
• Page End: 281
• Publication Date: 2015-08
• Subjects: Thrombosis -- Periodicals; 616.135
• DOI: 10.1016/j.thromres.2015.06.008
• Languages: English
• ISSNs: 0049-3848

Abstract

<abstract abstract-type="author" id="ab0005"> <title id="st0005">Abstract</title> <sec> <title id="st0010">Background</title> <p id="sp0005">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.</p> </sec> <sec> <title id="st0015">Objectives</title> <p id="sp0010">A better understanding of the mechanism via which eculizumab reduces thrombotic risk by studying its pharmacodynamic effect on coagulation and fibrinolysis.</p> </sec> <sec> <title id="st0020">Methods</title> <p id="sp0015">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).</p> </sec> <sec> <title id="st0025">Results</title> <p id="sp0020">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.</p> </sec> <sec> <title id="st0030">Conclusions</title> <p id="sp0025">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.</p> </sec> </abstract>