Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare, acquired blood disorder characterized by the destruction of red blood cells. This condition develops over a person’s lifetime, leading to hemolysis and various serious complications throughout the body.
The Underlying Genetic Defect
PNH originates from an acquired mutation in the PIGA gene within hematopoietic stem cells. These stem cells, located primarily in the bone marrow, produce all types of blood cells, including red blood cells, white blood cells, and platelets. The PIGA gene, situated on the X chromosome, plays a role in creating the glycosylphosphatidylinositol (GPI) anchor.
The GPI anchor acts as an attachment point, securing various protective proteins to the surface of blood cells. A mutation in the PIGA gene disrupts the biosynthesis of this anchor, resulting in a deficiency or complete absence of GPI-anchored proteins on affected blood cells. Among these are CD55 (Decay Accelerating Factor, DAF) and CD59 (Membrane Attack Complex Inhibitor).
Uncontrolled Complement Activation
The absence of protective GPI-anchored proteins renders blood cells vulnerable to the immune system. The complement system, a part of the innate immune response, identifies and eliminates foreign invaders. In PNH, without proper regulation, this system mistakenly targets and destroys the patient’s own red blood cells.
CD55 prevents early complement activation by accelerating C3 convertase breakdown, an enzyme complex initiating the complement cascade. CD59 inhibits the formation of the Membrane Attack Complex (MAC), the terminal component of the complement system. The MAC punches holes in cell membranes, leading to cell lysis. The lack of these two proteins allows for uncontrolled complement activation, leading to lysis of red blood cells primarily within the blood vessels, a process known as intravascular hemolysis.
How PNH Affects the Body
The chronic and uncontrolled destruction of red blood cells in PNH leads to various complications. Hemolysis results in anemia, causing symptoms such as fatigue, weakness, and shortness of breath due to reduced oxygen-carrying capacity. Another consequence is hemoglobinuria, where hemoglobin from destroyed red blood cells is released into the bloodstream and excreted in the urine, often leading to dark-colored urine, particularly noticeable in the morning.
PNH also increases the risk of blood clots (thrombosis), which can occur in unusual locations like the hepatic or cerebral veins. The mechanisms contributing to thrombosis are complex, involving complement activation, nitric oxide depletion, and platelet activation. Nitric oxide depletion, caused by free hemoglobin scavenging it, can also lead to smooth muscle dystonia, manifesting as abdominal pain, difficulty swallowing, or erectile dysfunction in men.
PNH often coexists with or can develop from other bone marrow disorders like aplastic anemia or myelodysplastic syndromes. This can result in impaired bone marrow function, leading to reduced production of other blood cell types, such as white blood cells and platelets. Chronic hemoglobinuria can also contribute to kidney damage over time, as the free hemoglobin can be toxic to kidney tissues.