Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria
Description, Causes and Risk Factors:
Paroxysmal nocturnal hemoglobinuria is a rare clonal blood disorder that manifests with hemolytic anemia, bone marrow failure, and thrombosis. Many of the clinical manifestations of the disease result from complement-mediated intravascular hemolysis.
The disease originates from a multipotent hematopoietic stem cell that acquires a mutation of the PIG-A gene. Expansion and differentiation of the PIG-A mutant stem cell lead to clinical manifestations of the disease. The PIG-A gene product is required for the biosynthesis of glycophosphatidylinositol anchors, a glycolipid moiety that attaches dozens of proteins to the plasma membrane of cells. Consequently, the PNH stem cell and all of its progeny have a reduction or absence of glycosylphosphatidylinositol (gpi)-anchored proteins. Two of these proteins, CD55 and CD59, are complement regulatory proteins; the absence of these proteins is fundamental to the pathophysiology of the disease. CD55 inhibits C3 convertases and CD59 blocks formation of the membrane attack complex (MAC) by inhibiting incorporation of C9 into the MAC. The loss of complement regulatory proteins renders PNH erythrocytes susceptible to both intravascular and extravascular hemolysis, but it is the intravascular hemolysis that contributes to much of the morbidity and mortality from the disease. Intravascular hemolysis releases free hemoglobin into the plasma. Free plasma hemoglobin scavenges nitric oxide and depletion of nitric oxide at the tissue level contributes to numerous PNH manifestations, including esophageal spasm, male erectile dysfunction, renal insufficiency, and thrombosis.
The natural history of PNH is highly variable, ranging from indolent to life-threatening. The median survival is 10 to 15 years, but with a wide range. Thrombosis is the leading cause of death, but others may die of complications of bone marrow failure, renal failure, myelodysplastic syndrome, and leukemia.
Paroxysmal nocturnal hemoglobinuria estimated to affect approximately 50 per million people. Prognosis depends upon severity of symptoms and complications. The abnormal clone responsible for the disease may die out, but this usually takes at least five years and may be 15 to 20 years. Acute infection can reactivate the clone.
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.
Patients with a Coombs-negative hemolytic anemia, refractory anemia, and unexplained thrombosis in conjunction with cytopenias or hemolysis should be screened for PNH. If your hematologist/oncologist suspects PNH he/she 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 cytometryblood test to detect CD59 (MIRL), a glycoprotein, and CD55 (DAF) in regulation of complement action. Absence or reduced expression of both CD59 and CD55 on PNH red blood cells is diagnostic. This is the latest diagnostic test which may replace the Ham and sugar-water tests as the 'gold standard' for diagnosis.
Venography can show thrombosis of major veins.
MRI, ultrasound or technetium 99mTc colloid scan of the liver and spleen may demonstrate hypoperfusion.
MRI with contrast can demonstrate sagittal vein thrombosis.
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.
NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.
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