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Paroxysmal Nocturnal Hemoglobinuria (PNH)
Tuesday, 16 November 2004
Tuesday, 16 November 2004
Marchiafava-Micheli Syndrome

What

Paroxysmal nocturnal hemoglobinuria (PNH) is a general term used to describe a rare disorder that can affect many different kinds of blood cells. People with PNH will usually have three major characteristics: destruction of their red blood cells, bone marrow that is unable to make the correct cells (aplastic anemia) and an increased risk of having blood clots in their blood vessels (thrombotic events).

Who

PNH is a rare disease that can happen to anyone from the age of two to 83, but it tends to occur more in teenagers or young adults. It affects males and females equally and there are no reports of it occurring in families. There is limited evidence to suggest that it may be more common in those people from Southeast Asia or the Far East. The disease is not inherited.

Signs and Symptoms

There are three major types of symptoms in PHN that are related to the destruction of red blood cells, abnormal clotting in the blood vessels, and the inability of the bone marrow to make the correct cells. 1) Destruction of the red blood cells releases hemoglobin that causes the urine to turn dark (hemoglubinuria). This usually occurs all day long, but is concentrated in the night when someone is sleeping, giving the dark, cola-colored urine when they first urinate in the morning. The hemoglobinuria can either occur daily, in cycles of ten days, or not at all. Because the red blood cells are being destroyed, a person can become anemic and start to look pale or get tired more easily. 2) There are several blood vessels that can get clots in them. In PNH, the clots usually occur in the veins, more specifically in the liver, the abdomen, the skin, or in the brain. The symptoms are usually in relationship to where the clot is. Liver vein clots can cause sudden yellow skin, abdominal pain and a swollen belly. These symptoms are dangerous and you should see a doctor immediately if they occur. Abdominal vessel clots can cause abdominal pain or can block blood flow returning from the intestines, sometimes causing the intestine to die. This must be treated with emergency surgery. If the skin vein gets a blood clot, it can cause a red, painful bump on the skin. Usually this gets better without any long-term problems, but in rare cases the skin dies off and people may need to have a skin graft done. Clots in the veins of the brain can cause headaches, nausea or vomiting if the pressures in the fluid around the brain become elevated. It is important to remember that any time that there is a blood clot, there is an increased risk of bleeding or infection in that area. 3) The bone marrow becomes inactive and does not make the red blood cells (RBC), white blood cells (WBC) and platelets that it should. When all three blood cells are low, this is called aplastic anemia. If the RBCs get too low, then a person will have anemia and look pale or become tired more easily as mentioned above. If the WBC count drops too low, then a person is more likely to get infections and not be able to fight them off as well. Low platelets can make a person bleed for longer periods of time. They may have increased bruising, bleeding from the gums, especially bloody menstrual periods, or red or black stools. 4) Other more rare symptoms can include muscle spasms in the esophagus that occur in the morning and cause pain in the chest or difficulty swallowing. Young males can become impotent at the same time as the dark urine, but no one is quite sure why this happens.

Possible Causes

People with paroxysmal nocturnal hemoglobinuria have an altered gene that usually codes for a special enzyme called PIG-A. PIG-A is required to make special proteins that act like an anchor for the blood cells and allow membrane proteins to attach. These membrane proteins (C8 binding protein or decay-accelerating factor) stop our body’s immune system from attacking and destroying its own blood cells. If these membrane proteins cannot attach to the blood cells because the anchor is missing, then the immune system will not have any regulation and the blood cells will be destroyed by a part of the immune system called the complement system. Individuals with PNH have cells where the gene for PIG-A became damaged, making it no longer able to make the enzyme. Because the change is in a cell that is responsible for making other blood cells, many of the blood cells have the problem.

Diagnosis

The most accurate test is called flow cytometry and is designed to check for the presence of the special glycoprotein that regulates the complement system. If this glycoprotein is not on someone’s cells then that person has PNH. Other ways to make the diagnosis include the Ham test, the sucrose lysis test, and the complement lysis sensitivity test of Rosse and Dacie. In all of these tests, a person’s RBCs are placed in a solution that normal cells can tolerate, but cells from someone with PNH will be destroyed. These tests can sometimes be positive even if you don’t have PNH, so the best test is to perform flow cytometry. Other lab tests that help in the diagnosis of broken red blood cells include an increased serum LDH, an elevated reticulocyte count, low serum haptoglobin and hemoglobin or hemosiderin in the urine. A bone marrow examination should be done to determine how the bone marrow is working. If there is any concern that the person is having clots in their veins, they will need an ultrasound to look for clots, or other X-rays done to make sure the vessels are open. What test is needed depends on where the clot is suspected to be.

Treatment

Any child with PNH will need to be followed by a pediatric hematologist as well as the general pediatrician. The best treatment is to correct the stem cell with the altered gene. This can be accomplished with bone marrow transplant. This option is usually reserved for those individuals with aplastic anemia or those patients whose bone marrow becomes unregulated and go on to develop leukemia. Transplantation requires a donor with matching blood cells and has many possible complications. For less severe cases, therapy is usually aimed at treating the symptoms. The anemia can sometimes be improved by giving steroids to turn down the immune system so fewer RBCs are destroyed. The steroids are given daily when the person has dark urine and every other day once the urine has changed back to normal. Because the red blood cells are being destroyed and many more have to be made to take their place, people will have to take iron and folic acid to help make new red blood cells. Sometimes, people can also take androgenic hormones to increase their production of red blood cells. If the anemia is severe enough, blood transfusions may be required, although this is reserved for severe cases. The blood clots are treated with heparin in the beginning and then coumadin or lovenox every day to help prevent future clots. If the bone marrow fails to work correctly and there are no matched donors for a transplant, some patients can take an immune system suppressant called antithymocyte globulin (ATG). This has been shown to help the bone marrow work properly once again in many patients, but can suppress immunity and make it difficult to fight off infections.

Prognosis

In some patients, the cell with the damaged gene eventually disappears. This usually happens anywhere from five to 20 years after the disease begins. Once the affected stem cell disappears, it can sometimes reappear after certain viral infections or other stresses to the immune system. As every patient will have different degrees of involvement, the prognosis will differ for each individual. Some people will have minimal involvement other than anemia and live a normal life, needing only infrequent blood transfusions. Those with bone marrow failure or leukemic changes will have a more complicated course and will require closer monitoring.

Connect with other parents

In the spirit of community and support, Madisons Foundation offers the unique service of connecting parents of children with rare diseases. If you would like to be connected to other parents of children with this disease, please fill out this brief form.

Weblinks

PNH Support Group
Website for support group, Frequently Asked Questions, medical terms in the Glossary, or access medical articles. There is also an abundance of Web Links to other sites with information about PNH.

emedicine
A more medically inclined synopsis of paroxysmal nocturnal hemoglobinuria along with a medication summary. Support Group: Address 85 Rue du Général Donzelot 93330 NEUILLY-SUR-MARNE FRANCE Phone 01 43 08 72 79 Fax 01 43 08 72 79

Google Search for Paroxysmal Nocturnal Hemoglobinuria (PNH)

References and Sources

www.emedicine.com/med/topic2696.htm Segel, GB (2000). Chapter 467 Paroxysmal nocturnal hemoglobinuria. In: Behrman RE, Kliegman RM, Jenson HB (eds) Nelson Textbook of Pediatrics, 16th Ed, WB Saunders, p 1478 www.ncbi.nlm.nih.gov/disease/PNH.html. www.hopkinskimmelcancercenter.org/cancertypes/paroxysmal-nocturnal-hemoglobinuria.cfm?cancerid=341