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  • Title: Neutrophil activation and nucleosomes as markers of systemic inflammation in paroxysmal nocturnal hemoglobinuria: effects of eculizumab.
    Author: van Bijnen ST, Wouters D, van Mierlo GJ, Muus P, Zeerleder S.
    Journal: J Thromb Haemost; 2015 Nov; 13(11):2004-11. PubMed ID: 26333021.
    Abstract:
    BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by complement-mediated hemolysis and a high risk of life-threatening venous and arterial thrombosis. Uncontrolled complement activation and the release of cell-free heme may result in systemic inflammation, neutrophil activation, and the release of procoagulant neutrophilic proteases. Eculizumab, an antibody to complement factor C5, inhibits hemolysis and reduces thrombotic risk. OBJECTIVES: To study neutrophil activation and nucleosome levels in relation to thrombosis in PNH patients before and during treatment with eculizumab. PATIENTS/METHODS: In 51 untreated PNH patients, including 20 patients before and after commencing eculizumab treatment, we have assessed neutrophil activation by measuring elastase-α1 -antitrypsin (EA) complexes and circulating nucleosomes, as established markers for systemic inflammation and cell death. RESULTS: Nucleosomes (median; range; 95% confidence interval [CI]), but not EA complexes, were higher in PNH patients with a history of thrombosis (16; 7-264; 0.3-94 U mL(-1) , n = 12) than in those without (6; 6-35; 7-11 U mL(-1) , n = 39) or controls (8; 6-23; 7-12 U mL(-1) , n = 17). EA complexes, but not nucleosomes, decreased promptly and markedly upon eculizumab treatment. EA complexes (estimated marginal means; 95% CI) remained low at ≥ 12 weeks (50; 34-67) compared with baseline (12; -6 to 29). CONCLUSIONS: The increased nucleosome levels in PNH patients with a history of thrombosis suggest systemic inflammation and/or cell death. Neutrophil activation markers did not differ between patients with and without a history of thrombosis and healthy controls. Interestingly, basal neutrophil activation in PNH patients significantly decreases on treatment with eculizumab, indicating that neutrophil activation is C5a driven.
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