Alterations in markers of coagulation and fibrinolysis in patients with Paroxysmal Nocturnal Hemoglobinuria before and during treatment with eculizumab. Issue 2 (August 2015) - van Bijnen, S.T.A.
Abstract: 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. Highlights: Eculizumab treatment induces a rapid and sustained decrease of D-dimer levels. PNH patients have lower thrombin peak height and thrombin potential. No evidence for TF activity or abnormalities in fibrinolysis in PNH patients. PNH patients with a history of thrombosis have elevated D-dimer and F1 + 2 levels.