Correspondence

Hemolytic Anemia after Eculizumab in Paroxysmal Nocturnal Hemoglobinuria

N Engl J Med 2010; 363:993-994September 2, 2010

Article

To the Editor:

A 68-year-old man was referred to our hospital in 2008 because of a progressive onset of profound asthenia. Macrocytic anemia was evident with signs of hemolysis and recurrent hyperchromic urine. Inherited and immune-mediated mechanisms were ruled out, and paroxysmal nocturnal hemoglobinuria (PNH) was diagnosed on the basis of the absence of CD55 and CD59 expression on leukocytes. The patient was initially treated with supportive therapy, including blood transfusions, low-dose glucocorticoids (initial dose, 50 mg per day of prednisone, gradually tapered to a maintenance dose of 12.5 mg per day), erythropoietin (30,000 IU per week), iron, and folic acid. Nonetheless, after 18 months of this treatment, the hemoglobin level progressively decreased, accompanied by headache and abdominal pain. Treatment with eculizumab, a monoclonal antibody that binds to the C5 component of complement and inhibits terminal complement activation, was started, and prednisone was gradually discontinued. There was a rapid and clear improvement in hematologic values and quality of life. Two months later, signs of hemolysis reappeared, with a new finding of positive results on a direct antiglobulin test (DAT) (C3d fraction). Glucocorticoid therapy was reintroduced at an initial dose of 75 mg per day, in association with eculizumab, with satisfactory results. Clinical data for the patient are shown in Table 1Table 1Clinical Data from the Patient, According to the Timing of Therapy..

This report provides further evidence that extravascular hemolysis can develop in patients with PNH who are receiving eculizumab, despite initial good control of intravascular hemolysis.1 This relapse mimics the clinical and laboratory features of de novo autoimmune hemolytic anemia. However, the pathogenetic mechanism may instead depend on the accumulation of C3 fragments on red cells under the influence of eculizumab. To confirm this hypothesis, we documented by flow cytometry that C3 binding was confined to the PNH (i.e., CD55-negative) clone (Figure 1Figure 1Flow Cytometric Analysis of C3d Fraction Deposition on a Proportion of CD55-Negative Red Cells from a Patient with Paroxysmal Nocturnal Hemoglobinuria (PNH).). PNH red cells, which lack CD55 because of a somatic mutation in the X-linked gene encoding phosphatidylinositol glycan anchor biosynthesis class A (PIGA), are not protected from complement activation and subsequent intravascular hemolysis (Fig. 1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org). Eculizumab inhibits C5 cleavage, allowing the cells to survive long enough to accumulate C3. This determines DAT positivity and extravascular hemolysis.1,2

Alessandra Berzuini, M.D.
Fabio Montanelli, M.D.
Ospedale Alessandro Manzoni, Lecco, Italy
a.berzuini@ospedale.lecco.it

Daniele Prati, M.D.
IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

2 References

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   Hill A, Rother RP, Arnold L, et al. Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization. Haematologica 2010;95:567-573
   CrossRef | Web of Science | Medline

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   Luzzatto L, Risitano AM, Notaro R. Paroxysmal nocturnal hemoglobinuria and eculizumab. Haematologica 2010;95:523-526
   CrossRef | Web of Science | Medline

Citing Articles (6)

Citing Articles

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   B. Höchsmann, R. Leichtle, I. von Zabern, S. Kaiser, W. A. Flegel, H. Schrezenmeier. (2012) Paroxysmal nocturnal haemoglobinuria treatment with eculizumab is associated with a positive direct antiglobulin test. Vox Sanguinis 102:2, 159-166
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   C. J. Parker. (2011) Management of Paroxysmal Nocturnal Hemoglobinuria in the Era of Complement Inhibitory Therapy. Hematology 2011:1, 21-29
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   Akihiro Tomita, Yukari Shirasugi, Takahiko Ito, Hisashi Tsurumi, Tomoki Naoe. (2011) Extravascular hemolytic attack after eculizumab therapy for paroxysmal nocturnal hemoglobinuria. Annals of Hematology
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   Gareth Peter Gregory, Stephen Opat, Hang Quach, Jake Shortt, Huyen Tran. (2011) Failure of eculizumab to correct paroxysmal cold hemoglobinuria. Annals of Hematology 90:8, 989-990
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   Lucio Luzzatto, Giacomo Gianfaldoni, Rosario Notaro. (2011) Management of Paroxysmal Nocturnal Haemoglobinuria: a personal view. British Journal of Haematology 153:6, 709-720
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6. 6

   Risitano, Antonio M., , Notaro, Rosario, Luzzatto, Lucio, , Hill, Anita, Kelly, Richard, Hillmen, Peter, . (2010) Paroxysmal Nocturnal Hemoglobinuria — Hemolysis before and after Eculizumab. New England Journal of Medicine 363:23, 2270-2272
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