Paroxysmal Nocturnal Hemoglobinuria - Pathophysiology

Pathophysiology

All cells have proteins attached to their membranes that are responsible for performing a vast array of functions. There are several ways for proteins to be attached to a cell membrane. PNH occurs as a result of a defect in one of these mechanisms.

The enzyme phosphatidylinositol glycan A (PIGA) is needed to make glycosylphosphatidylinositol (GPI), a molecule that anchors proteins to the cell membrane. The gene that codes for PIGA is located on the X chromosome, which means that only one active copy of the gene for PIGA is present in each cell (initially, females have two copies, but one is silenced through X-inactivation). If a mutation occurs in this gene then PIGA may be defective, which leads to a defect in the GPI anchor. When this mutation occurs in a bone marrow stem cell (which are used to make red blood cells as well as white blood cells and platelets), all of the cells it produces will also have the defect. Several of the proteins that anchor to GPI on the cell membrane are used to protect the cell from destruction by the complement system, and, without these anchors, the cells are more easily targeted by the complement proteins. The complement system is part of the immune system and helps to destroy invading microorganisms. Without the proteins that protect them from complement, red blood cells are destroyed. The main proteins that carry out this function are the decay-accelerating factor (DAF) (CD55), which disrupts formation of C3 convertase, and protectin (CD59), which binds the membrane attack complex and prevents C9 from binding to the cell.

The increased destruction of red blood cells results in anemia. The increased rate of thrombosis is due to dysfunction of platelets due to binding by complement, or possibly due to low nitric oxide levels.

The symptoms of esophageal spasm, erectile dysfunction, and abdominal pain are attributed to the fact that hemoglobin released during hemolysis binds with circulating nitric oxide, a substance that is needed to relax smooth muscle. This theory is supported by the fact that these symptoms improve on administration of nitrates or sildenafil (Viagra), which improves the effect of nitric oxide on muscle cells. There is a suspicion that chronic hemolysis causing chronically depleted nitric oxide may lead to the development of pulmonary hypertension (increased pressure in the blood vessels supplying the lung), which in turn puts strain on the heart and causes heart failure.