Review Series BONE MARROW FAILURE Paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disorder thatmanifests with hemolytic anemia, bone marrow failure, and thrombosis. One of the earliest descriptions of PNH was by Dr Paul Strübing, who in 1882 described a 29-year-old man who presented with fatigue, abdominal pain, and severe nocturnal paroxysms of hemoglobinuria. Strübing deduced that the hemolysiswas occurring intravascularly as the patient’s plasma turned red following severe attacks of hemoglobinuria. Later reports by Marchiafava and Micheli led to the eponym, Marchiafava-Micheli syndrome, but it was Enneking, in 1925, who introduced the term paroxysmal nocturnal hemoglobinuria. In 1937, Thomas Ham reported that PNH erythrocytes were hemolyzed when incubated with normal, acidified serum. This seminal discovery resulted in the first diagnostic test for PNH, the acidified serum (Ham) test. The cell lysis following acidified serum appeared to be complement dependent because heat inactivation abrogated the reaction; however, it was not until 1954,with the discovery of the alternative pathway of complement activation, that complementwas formally proven to cause the hemolysis of PNH red cells. In the 1980s, it was discovered that PNH cells display a global deficiency in a group of proteins affixed to the cell surface by a glycosylphosphatidylinositol (GPI) anchor. Two of the missing GPI anchored proteins (CD55 andCD59) regulate complement.A fewyears later, a genetic mutation (phosphatidylinositol glycan class A [PIGA]) responsible for the GPI anchor protein deficiency was discovered, and most recently, a humanized monoclonal antibody that inhibits terminal complement activation has been shown to ameliorate hemolysis and thrombosis and improve quality of life in PNH patients.