Authors: Michael Graf, Vincent S. Gallicchio.
Paroxysmal nocturnal hemoglobinuria is an acquired, rare, nonmalignant hematological disease that is characterized by uncontrolled complement activation and thus intravascular hemolysis. It is caused by somatic mutations in the PIG-A gene that leads to a deficiency in necessary GPI-anchored proteins, which leads to uncontrolled complement activation and thus the clinical manifestations that PNH is often associated with. It is generally accepted that Dr. Paul Strübing first described the disease in 1882, albeit it was Thomas Hale Ham who designed the first diagnostic test (Ham test or acidified serum test) to diagnose the rare disease. Since then, Ham’s test has become obsolete and PNH is detected via flow cytometry. PNH is divided into 3 categories: classical, presence of another bone marrow failure syndrome, and subclinical. Classic PNH is often associated with bone marrow failure, intravascular hemolysis, and/or thrombophilia. A thromboembolic event is the most common cause of mortality for patients with PNH. Before the introduction of anti-complement drugs, allogeneic hematopoietic stem cell transplantation was a common therapy for patients with PNH, although it carried significant risk and has declined drastically as the preferred treatment option of patients. Presently, there are 3 FDA-approved drugs, two terminal complement inhibitors (eculizumab and ravulizumab) and one proximal complement inhibitor (pegcetacoplan). Eculizumab remains the mainstay of treatment as it has since 2007. There is ongoing research and clinical trials in other proximal complement inhibitors to relieve patients of extravascular hemolysis and other common side effects.
View/Download pdf