These may develop in common sites (deep vein thrombosis of the leg and resultant pulmonary embolism when these clots break off and enter the lungs), but in PNH blood clots may also form in more unusual sites: the hepatic vein (causing Budd-Chiari syndrome), the portal vein of the liver (causing portal vein thrombosis), the superior or inferior mesenteric vein (causing mesenteric ischemia) and veins of the skin. Cerebral venous thrombosis, an uncommon form of stroke, is more common in those with PNH. Pathophysiology
All cells have proteins attached to their membranes, often serving as a mode of communication or signaling between the cell and the surrounding environment. These signaling proteins are physically attached to the cell membrane in various ways, commonly anchored by glycolipids such as glycosyl phosphatidylinositols (GPI). PNH occurs as a result of a defect in the assembling of these glycolipid-protein structures on the surface of blood cells.The most common defective enzyme in PNH is phosphatidylinositol glycan A (PIGA), one of several enzymes needed to make GPI. 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). A mutation in the PIGA gene can lead to the absence of GPI anchors expressed on the cell membrane.
Eculizumab
In 2007, the drug eculizumab was approved for the treatment of PNH. Prior to eculizumab, the median life expectancy of an individual with PNH was approximately 10 years. Since that time, short and mid-term studies of patients on eculizumab demonstrate that the drug returns the patient to a normal life expectancy, improves quality of life, and decreases the need for blood transfusions.Eculizumab is controversial due to its high cost, as it is among the most expensive pharmaceuticals in the world, with a price of US$440,000 per person per year. Eculizumab is a humanized monoclonal antibody that acts as a terminal complement inhibitor. The drug interferes with the formation of the membrane attack complex in erythrocytes by binding to C5, compensating for the loss of protective function that results from CD59 deficiency. This alleviates the primary source of intravascular hemolysis, but it does not reduce the opsonization of erythrocytes caused by CD55 deficiency, so patients who receive this medication often still experience mild to moderate hemolysis. The U.S. Food and Drug Administration (FDA) has issued a black-box warning as those who take the medication have a 1,000 to 2,000-fold greater risk of invasive meningococcal disease. People on eculizumab are strongly advised to receive meningococcal vaccination at least two weeks prior to starting therapy and to consider preventative antibiotics for the duration of treatment. Pegcetacoplan
Pegcetacoplan was approved for medical use in the United States in May 2021. Epidemiology
PNH is rare, with an annual rate of 1-2 cases per million. The prognosis without disease-modifying treatment is 10–20 years.