Background: Paroxysmal nocturnal hemoglobinuria is a rare, chronic condition in which patients experience breakdown of red blood cells (RBCs) which releases hemoglobin into the blood. This hemoglobin is then filtered into the kidneys and causes the patient to have dark-colored urine. Although patients can experience hemoglobinuria after a full nights sleep, this isn’t always the case, so the name is somewhat of a misnomer. The idea behind this process occurring mainly at night is that people have altered breathing patterns when sleeping which causes the blood to become more acidic. The acidic environment activates the complement system which goes on to cause hemolysis of RBCs. However, more recent studies have shown that hemolysis actually occurs anytime throughout the day and the urine just becomes more concentrated at night. Thus, it often appears darkest in the morning because of it being in a concentrated state.
Pathogenesis: I actually really like the image shown below for a visual explanation of the condition. Basically, patients with PNH lack the glycosyl-phosphotidylinositol (GPI) protein that functions as an anchor for CD55 (decay-accelerating factor or DAF) and CD59 (membrane inhibitor of reactive lysis or MIRL). This is due to an X-linked mutation on the PIGA gene. As a result, cells can’t “hold on” to the CD55 and CD59 proteins. Think of CD55 and CD59 as identification tags for the cells; without them, the cells can’t prove they belong! The complement system comes along and sees someone without proper identification, so it decides to do something about it. Thus, it attacks the “foreign” red blood cells which results in hemolysis and the release of hemoglobin. At first, a molecule called haptoglobin can go around and “sweep up” the hemoglobin. It’s like a specialized janitor for hemoglobin. Over time the janitors are all busy so the hemoglobin starts to accumulate in the blood and gets filtered into the urine for excretion.
Treatment: Also shown in the diagram, you can see that eculizumab blocks C5 which prevents formation of the membrane attack complex (MAC). As a result, there is decreased hemolysis of the RBCs. However, opsonization by C3b can still occur so that macrophages will eventually take care of business.
Additional Information: Hemolytic episodes can also be precipitated by drugs, trauma, infection etc. The most common cause of death in these patients is venous thrombosis. However, the thrombophilia present with PNH is not fully understood. Plasma hemoglobin can consume nitric oxide (NO) which is important for inhibiting platelet aggregation. Thus, one hypothesis is that the the reduction in NO causes increased clot formation. Patients are also at an increased risk of developing aplastic anemia.