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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), and impaired bone marrow function (not making enough of the three blood components). PNH affects 1-1.5 persons per million of the population and is primarily a disease of younger adults. The median age of diagnosis is 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 of developing PNH after treatment for aplastic anemia with immunosuppressive therapy (anti-thymocyte globulin and cyclosporine) is approximately 20-30%. The median survival after diagnosis is 10 years; however, some patients can survive for decades with only minor symptoms.
PNH occurs when mutations of a gene called PIG-A occur in a bone marrow stem cell. Stem cells give rise to all the mature blood elements including red blood cells , which carry oxygen to our tissues; white blood cells , which fight infection; and platelets, which are involved in forming blood clots. In PNH, 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 protect red blood cells from destruction, some are involved in blood clotting, and others are involved in fighting infection. The majority of PNH-related issues, including destruction of red blood cells (hemolytic anemia), blood clots (thrombosis), and infection, result from a deficiency of these proteins.
The genetic defect responsible for causing PNH has 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.
If your doctor suspects PNH, he or she may order a variety of blood tests to confirm the diagnosis.. Over the past several years, flow cytometry has become the gold standard for making the diagnosis. This laboratory technique allows clinicians to count blood cells in a sample.
PNH is characterized by hemolytic anemia, bone marrow failure and a tendency toward the development of thrombosis. The condition has three main subtypes: classical PNH, which includes patients who have evidence of PNH in the absence of another bone marrow failure disorder; PNH in the context of other primary bone marrow disorders, such as aplastic anemia or myelodysplastic syndrome; and subclinical PNH, in which patients have small PNH clones but no clinical or laboratory evidence of hemolysis (red blood cell destruction) or thrombosis (blood clots).
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. Overall, the most common symptoms of PNH include:
- Significant fatigue or weakness
- Bruising or bleeding easily
- Shortness of breath
- Recurring infections and/or flu-like symptoms
- Difficulty in controlling bleeding, even from very minor wounds
- The appearance of small red dots on the skin that indicates bleeding under the skin
- Severe headache
- Fever due to infection
- Blood clots (thrombosis)
Other issues include abdominal pain crises and back pain. The classic symptom of bright red blood in the urine (hemoglobinuria) occurs in 50% or less of patients. Frequently patients notice their urine is the color of dark tea. Typically, hemoglobinuria will be most noticeable in the morning, and clear as the day progresses. Attacks of hemoglobinuria may be brought on 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. The most common sites for blood clots are in the hepatic vein (a vein that drains the liver. Clots here are also referred to as Budd-Chiari syndrome) and in the sagittal vein (a vein in the head). However, they can occur in any vein, especially those in the abdomen.
At the Johns Hopkins Kimmel Cancer Center, PNH patients are managed by experts from the Bone Marrow Failures Disorders Program. 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.
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 patients will respond to anti-thymocyte globulin (ATG), but frequently they will continue to require red cell and/or platelet transfusions.
Medical Therapy The mainstay of PNH treatment is the drug eculizumab (Soliris). It is a humanized monoclonal antibody that binds to proteins in the blood that can destroy red blood cells. The drug reduces the risk of thrombosis and can improve quality of life in PNH patients. It is the only medical therapy for PNH approved by the U.S. Food and Drug Administration.
Bone marrow transplantation Allogeneic (from a donor) bone marrow transplantation (BMT) is the only cure for PNH. BMT replaces all of a patient’s bone marrow stem cells with those from a donor, usually a healthy brother or sister. It may be appropriate for patients who do not respond to eculizumab or for those who have severe reductions in red blood cells, white blood cells and platelets. The allogeneic BMT approach is best reserved for young patients with very severe disease in whom the marrow failure component is most significant.