Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease of the blood. The disease is characterized by destruction of red blood cells (hemolytic anemia), blood clots (thrombosis), impaired bone marrow function, and a 3 to 5% risk of developing leukemia. PNH affects only 1-2 persons per million of the population and is a disease of young adults (median age of diagnosis 35-40 years of age) with occasional cases diagnosed in childhood or adolescence. PNH is closely related to aplastic anemia. In fact, up to 30% of newly diagnosed cases of PNH evolve from aplastic anemia. Similarly, the risk 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, some patients can survive for decades with only minor symptoms.
The genetic defect responsible for causing PNH has recently been identified. Knowledge of the genetic defect will allow researchers to study the disease in a manner that was not previously possible, and may give insight for developing more effective therapies. 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. Therefore, the affected stem cell passes the PIG-A mutation to all cells derived from the abnormal stem cell (see figure). Cells harboring PIG-A mutations are deficient in a class of proteins called, GPI-anchored proteins. Certain GPI-anchored proteins protect red blood cells from destruction, others are involved in blood clotting, while others are involved in fighting infection. Therefore, the majority of the disease manifestations i.e., hemolytic anemia, thrombosis, and infection result from a deficiency of these GPI-anchored proteins.
If your doctor suspects PNH he may order a variety of blood tests to confirm the diagnosis. The sucrose hemolysis (sugar water) test and Ham test are available at almost all institutions, but can be falsely negative if you have received recent red blood cell transfusions. Over the past several years flow cytometry has become the gold standard for making the diagnosis. Like the sucrose hemolysis and Ham tests, this is a relatively easy blood test, but the result is not affected by blood transfusions. Unfortunately, not all laboratories perform this test.
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 50% or less of patients. Frequently patients notice their urine is a dark tea-color. 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 of thrombosis; however, all veins, especially those in the abdomen are susceptible.
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 supportive care may be indicated depending on the patients' symptoms. For example, in the anemic patient with signs of hemolysis, prednisone is often given in an attempt to slow the rate of red blood cell destruction. Although prednisone will not cure the disease, in a minority of patients it can be useful. Prednisone should be discontinued if the patient does not show significant benefit in four to six weeks, because of the numerous side-effects associated with the drug. Patients with acute thrombosis are often treated with thrombolytic therapy (streptokinase, urokinase, or tissue plasminogen activator) and placed on long-term anticoagulation drugs to help prevent further blood clots. Antiplatelet agents such as aspirin and ibuprofen may also help prevent blood clots. Unfortunately, some patients will continue to develop blot clots despite aggressive anti-coagulation agents. Medications that increase the risk for thrombosis, such as oral birth control pills, should be avoided. PNH, like aplastic anemia, is often associated with bone marrow failure resulting in very low blood counts. Occasionally these patients will respond to antithymocyte globulin (ATG), but frequently they will continue to require red cell and/or platelet transfusions.
Allogeneic (from a donor) bone marrow transplantation (BMT) has been the mainstay of curative therapy for PNH for some time. BMT replaces all of the bone marrow stem cells with those of a healthy brother or sister. Nevertheless, BMT has been offered to patients with severe disease (i.e., patients with life threatening thrombosis or dangerously low blood counts) because of the risks of this procedure (15-20% chance of death). Unfortunately, the majority of PNH patients are not eligible for BMT because they lack a suitable donor. Rarely, bone marrow from an unrelated donor is used, but this approach is best reserved for young patients with very severe disease. Recently, the drug eculizumab (brand name Soliris) was approved by the FDA to treat symptoms of the disease.