S T A van Bijnen1, B Østerud2, W Barteling3, K Verbeek-Knobbe3, M Willemsen3, W L van Heerde3, P Muus4. 1. Department of Hematology, Radboudumc, Nijmegen, The Netherlands. 2. Department of Laboratory Medicine, Laboratory of Hematology, Radboudumc, Nijmegen, The Netherlands. 3. Department of Medical Biology, Faculty of Health Sciences, University of Tromsø, Norway. 4. Department of Hematology, Radboudumc, Nijmegen, The Netherlands. Electronic address: petra.muus@radboudumc.nl.
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 2hours, 1, 4 and≥12weeks 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 1hour (p=0.008) and remained decreased at≥12weeks (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.
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 2hours, 1, 4 and≥12weeks 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 1hour (p=0.008) and remained decreased at≥12weeks (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.
Authors: Adam Miszta; Dana Huskens; Demy Donkervoort; Molly J M Roberts; Alisa S Wolberg; Bas de Laat Journal: Int J Mol Sci Date: 2021-03-09 Impact factor: 5.923