Paroxysmal nocturnal hemoglobinuria

Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare bone marrow failure disorder that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias. The absence of two glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations. GPI anchor protein deficiency is almost always due to somatic mutations in phosphatidylinositol glycan class A (PIGA), a gene involved in the first step of GPI anchor biosynthesis; however, alternative mutations that cause PNH have recently been discovered. In addition, hypomorphic germ-line PIGA mutations that do not cause PNH have been shown to be responsible for a condition known as multiple congenital anomalies-hypotonia-seizures syndrome 2. Eculizumab, a first-in-class monoclonal antibody that inhibits terminal complement, is the treatment of choice for patients with severe manifestations of PNH. Bone marrow transplantation remains the only cure for PNH but should be reserved for patients with suboptimal response to eculizumab.

Figure 1

GPI anchor biosynthesis. (A) Core structure of the GPI anchor. The inositol-phospholipid (PI) is anchors into the lipid bilayer of the plasma membrane. The glycan core consists of a molecule of N-glucosamine, 3 manose molecules (Man), and a molecule of ethanolamine phosphate. The protein is covalently attached through an amide bond to an ethanolamine on the terminal mannose. (B) GPI anchor biosynthesis takes place in the endoplasmic reticulum. PIGA is 1 of 7 subunits involved in the first step of GPI anchor biosynthesis. There are ≥10 additional steps and >25 genes involved. After the protein is attached to the GPI anchor, the mature GPI-anchored protein goes to the Golgi, where fatty acid remodeling occurs and (C) eventually the GPI anchored protein is transported to the plasma membrane.

Figure 2

Complement regulation and eculizumab. The lectin, classical, and alternative pathways converge at the point of C3 activation. In PNH, hemolysis is usually chronic because the alternative pathway is always in a low-level activation state through a process known as tick-over. Terminal complement begins with cleavage of C5 to C5a and C5b. C5b oligomerizes with C6, C7, C8, and multiple C9 molecules to form the MAC. CD55 inhibits proximal complement activation by blocking the formation of C3 convertases; CD59 inhibits terminal complement activation by preventing the incorporation of C9 into the MAC. The absence of CD55 and CD59 on PNH cells leads to hemolysis, inflammation, platelet activation, and thrombosis. Eculizumab inhibits terminal complement activation by binding to C5 and preventing generation of C5a and C5b.