Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, disease that is caused by a mutation in bone marrow stem cells. The disease is characterized by destruction of red blood cells (hemolytic anemia), blood clots (thrombosis), impaired bone marrow function, and a 3% to 5% lifetime risk of developing leukemia. PNH affects only one or two people per million of the population and is a disease of young adults; the average age of diagnosis is 35 to 40 years of age, with occasional cases diagnosed in childhood or adolescence. PNH is closely related to aplastic anemia. In fact, up to 30 percent of newly diagnosed cases of PNH evolve from aplastic anemia. Similarly, the risk for developing PNH after treatment for aplastic anemia with immunosuppressive therapy (anti-thymocyte globulin and cyclosporine) is approximately 20% to 30%. The median survival after diagnosis is 10 years; however, now that effective therapy exists, most PNH patients should be able to live a normal life expectancy.
PNH is caused when mutations of the PIG-A gene occur in a bone marrow stem cell. Stem cells give rise to all the mature blood elements including red blood cells (RBC), which carry oxygen to our tissues; white blood cells (WBC), which fight infection; and platelets (PLT), which are involved in forming blood clots. The affected stem cell passes the PIG-A mutation to all cells derived from the abnormal stem cell. Cells harboring PIG-A mutations are deficient in a class of proteins called GPI-anchored proteins. Certain GPI-anchored proteins (such as CD55 and CD59) protect red blood cells from destruction. The majority of the disease manifestations like hemolytic anemia, thrombosis and infection result from a deficiency of these GPI-anchored proteins.
If your doctor suspects PNH he/she may order a variety of blood tests to confirm the diagnosis. Flow cytometry has become the gold standard for making the diagnosis. This test can determine the percentage of red cells and white blood cells that carry the PIG-A mutation.
Due to the wide spectrum of symptoms associated with PNH, it is not unusual for months or years to pass before the correct diagnosis is established. Some of the prominent symptoms of PNH include severe abdominal pain crises, severe headaches, back pain, excessive weakness, fatigue and recurrent infections. The classic symptom of bright red blood in the urine (hemoglobinuria) occurs in less than 30 percent of patients. Frequently patients notice their urine is a dark tea-color, sometimes cola-colored or even bright red. Typically, hemoglobinuria will be most noticeable in the morning and clear as the day progresses. Attacks of hemoglobinuria may be precipitated by infections, alcohol, exercise, stress or certain medications. Many patients note a feeling of fatigue that may be disabling during periods of hemoglobinuria. The excessive fatigue does not appear to be related to the degree of anemia, as it improves when the hemoglobinuria abates. Blood clots (thrombosis) occur almost exclusively in veins, as opposed to arteries, and are the leading cause of death in PNH. Hepatic vein thrombosis (also referred to as Budd-Chiari syndrome) and sagittal vein (a vein in the head) thrombosis are the most common sites for blood clots; however, all veins, especially those in the abdomen, are susceptible. Other common symptoms of PNH may include difficulty swallowing. Males may experience erectile dysfunction.
The appropriate treatment for PNH depends on the severity of symptoms. Some patients will experience few or no symptoms from PNH and do not require treatment other than folic acid and sometimes iron supplementation to increase red blood cell production. Over time, the disease may progress and more aggressive care may be necessary depending on the patients’ symptoms.
Medications -- Eculizumab (Solirus) is the only FDA-approved drug for the treatment of PNH. Eculizumab is administered intravenously every two weeks over 30 minutes. It is highly effective is reducing, or in many cases eliminating, the need for blood transfusions. Eculizumab also greatly reduces the risk of blood clots and in most cases greatly improves quality of life. The medication generally is safe and well-tolerated. The major adverse consequence of the drug is that it increases the risk for acquiring meningitis; therefore, all patients need to be vaccinated against meningitis. Even with the vaccine there is a 0.5% risk per year of acquiring meningitis, so many patients are also placed on penicillin to help prevent meningitis.
Bone marrow transplantation (BMT) is the only curative therapy for PNH. It is offered primarily only to patients who don’t have a good response to eculizumab. This is because of the potential risks of BMT and because eculizumab in most cases controls the disease.
At Johns Hopkins:
Articles by Robert Brodsky, M.D., Director of Hematology and professor of medicine and oncology at Johns Hopkins:
How I treat paroxysmal nocturnal hemoglobinuria. Blood. 2009; 113(26):6522-7.
Narrative review: Paroxysmal Nocturnal Hemobloginuria: the physiology of complement-related hemolytic anemia. Annals of Internal Medicine. 2008; 148(8):587-95.