Paroxysmal nocturnal hemoglobinuria revisited: news on pathophysiology, clinical course and treatment

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare benign clonal disorder of hematopoiesis. Its etiologic basis is the clonal dominance of a PIGA-mutated hematopoietic progenitor that gives rise to GPI-deficient blood cells that are unable to express complement inhibitors like CD55 or CD59. These cells are prone to complement-induced hemolysis. In classic hemolytic PNH, granulocyte clone sizes can be up to 90% or more. Much progress has been made during the last years in understanding the interrelations of complement-dependent hemolysis; its consequences like thrombosis, renal failure or pulmonal hypertension; and possible treatment strategies. To gain clinical relevance, the PNH clone has to make a relevant contribution to blood cell generation; however, a minimal clone size as a threshold for the occurrence of symptoms such as thrombosis, dyspnea, chest or abdominal pain cannot be given. Such symptoms can be seen in a relevant proportion of patients with clone size smaller than 10%. The driver for the clonal dominance of the PIGA-mutated hematopoiesis is still not clear. Recently, data about coexisting mutations in cancer genes have been published and new mechanisms for autoimmunity have been presented. The success of eculizumab in the treatment of PNH patients has stimulated the development of a variety of new strategies for complement inhibition. This review will focus on the most important findings in pathophysiology, clinical course and treatments during the last years.