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Narrative Review: Paroxysmal Nocturnal Hemoglobinuria: The Physiology of Complement-Related Hemolytic Anemia

Robert A. Brodsky, MD
[+] Article, Author, and Disclosure Information

From Johns Hopkins Medical Institutions, Baltimore, Maryland.

Grant Support: From the National Institutes of Health (P01CA70970).

Potential Financial Conflicts of Interest:Consultancies: Alexion Pharmaceuticals. Honoraria: Alexion Pharmaceuticals. Grants received: National Institutes of Health. Patents received: U.S. patent number 6 393 095 B1 for detection of GPI-anchored proteins.

Requests for Single Reprints: Robert A. Brodsky, MD, Division of Hematology, Johns Hopkins Medicine, Ross Research Building Room 1025, 720 Rutland Avenue, Baltimore, MD 21205-2196; e-mail, brodsro@jhmi.edu.

Ann Intern Med. 2008;148(8):587-595. doi:10.7326/0003-4819-148-8-200804150-00003
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Dr. Paul Strübing provided one of the earliest descriptions of PNH (14). In 1882, he reported a 29-year-old cartwright who presented with fatigue, abdominal pain, and severe nocturnal paroxysms of hemoglobinuria. Later reports by Marchiafava and Micheli led to the eponym the Marchiafava–Micheli syndrome, but Enneking introduced the term paroxysmal nocturnal hemoglobinuria in 1925 (15).

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Figure 3.
Schematic representation of cell membrane showing transmembrane proteins and glycosylphosphatidylinositol (GPI)–anchored proteins.

The lipid portion of the GPI anchor inserts into the lipid bilayer; no peptide transmembrane portion or cytoplasmic tail is present.

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Figure 2.
Flow cytometric assay of normal and paroxysmal nocturnal hemoglobinuria granulocytes.

Top. Granulocytes from a normal control participant show bright fluorescein-labeled proaerolysin (FLAER) staining in all cells. Bottom. A patient with paroxysmal nocturnal hemoglobinuria who has a large population of paroxysmal nocturnal hemoglobinuria granulocytes (84% FLAER-negative) and 16% normal granulocytes.

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Figure 1.
Early morning urine sample in a patient with paroxysmal nocturnal hemoglobinuria.
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Grahic Jump Location
Figure 4.
Complement activation: classic, alternative, and lectin binding pathways converge at the point of C3 activation.

The alternative pathway is in a state of continuous activation. The formation of C5 convertase initiates the lytic pathway and leads to the assembly of the membrane attack complex from C5, C6, C7, C8, and multiple C9 proteins. Normally, CD55 inhibits C3 convertases and CD59 blocks incorporation of C9 into the C5b–8 complex. Eculizumab is a humanized monoclonal antibody that binds to C5, thereby preventing the formation of C5a and C5b (the initiating component of the membrane attack complex).

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