Summary.  Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease characterized by a clone of blood cells lacking glycosyl phosphatidylinositol (GPI)‐anchored proteins at the cell membrane. Deficiency of the GPI‐anchored complement inhibitors CD55 and CD59 on erythrocytes leads to intravascular hemolysis upon complement activation. Apart from hemolysis, another prominent feature is a highly increased risk of thrombosis. Thrombosis in PNH results in high morbidity and mortality. Often, thrombosis occurs at unusual locations, with the Budd–Chiari syndrome being the most frequent manifestation. Primary prophylaxis with vitamin K antagonists reduces the risk but does not completely prevent thrombosis. Eculizumab, a mAb against complement factor C5, effectively reduces intravascular hemolysis and also thrombotic risk. Therefore, eculizumab treatment has dramatically improved the prognosis of PNH. The mechanism of thrombosis in PNH is still unknown, but the highly beneficial effect of eculizumab on thrombotic risk suggests a major role for complement activation. Additionally, a deficiency of GPI‐anchored proteins involved in hemostasis may be implicated.

To cite this article: van Bijnen STA, Wouters D, van Mierlo GJ, Muus P, Zeerleder S. Neutrophil activation and nucleosomes as markers of systemic inflammation in paroxysmal nocturnal hemoglobinuria: effects of eculizumab. J Thromb Haemost 2015; 13:2004-11. Summary. 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-a 1 -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 À1 , n = 12) than in those without (6; 6-35; 7-11 U mL À1, n = 39) or controls (8; 6-23; 7-12 U mL À1, 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; À6 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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