Introduction
Since the English physician Sir William Gull described the first instance of Paroxysmal Nocturnal Hemoglobinuria (PNH) in the mid-19th century, medical interest has stirred up. The 'intermittent hematuria' that Gull's patient experienced in the mornings was eventually identified as the breakdown of red blood cells in the bloodstream. In most hemolytic anemias, reticuloendothelial system destruction of erythrocytes occurs, making intravascular hemolysis (rupture of the red blood cells) uncommon.
What Is PNH?
Paroxysmal Nocturnal Hemoglobinuria (PNH) is an acquired condition where the red blood cells (erythrocytes) are destroyed prematurely. As a result, hemoglobin is lost through urine. A condition that is not present at birth but develops as life advances is called an acquired condition. Being a rare condition, it can often be overlooked by healthcare professionals.
The condition affects platelets (thrombocytes), which are involved in blood clotting; white blood cells (leukocytes), which guard the body against infections; and red blood cells (erythrocytes), which carry oxygen. Even though PNH can strike at any age, it is usually diagnosed among young adults. There are fewer red blood cells in the blood due to the premature breakdown of these cells. Fatigue, weakness, unusually pale skin, shortness of breath, and an elevated heart rate are some of the signs and symptoms that may result from this. Leukopenia (a lack of white blood cells), can make people with PNH more vulnerable to infections.
What Is the Genetic Cause of PNH?
The phosphatidylinositol glycan class A (PIGA) gene is located on chromosome X. Mutations in this gene are the major cause of PNH. Although the PIGA gene is found on chromosome X, it is not a sex-linked disorder. Some hematopoietic stem cells in patients with this type of PNH develop somatic PIGA mutations throughout their lifetime. Normal blood cells are produced by unaffected hematopoietic stem cells, but abnormal PNH blood cells are produced by mutated stem cells. The phosphatidylinositol glycan class T (PIGT) gene is on chromosome 20. Very rarely, a mutation in this gene can cause PNH. This variation is usually an inflammatory form of the condition. In contrast to the PIGA-caused PNH, PIGT mutation-related PNH patients receive a mutant allele from one parent and a normal PIGT allele from the other.
The exact cause of PIGA mutations is unknown. However, researchers have concluded that the immune system can affect the hematopoietic stem cells in response to an injury or an infection. They believe this to be a reason for the mutations.
What Are the Other Genetic Causes of PNH?
Most of the clinical signs and symptoms in PNH are caused by the lack of CD59. (The CD59 encodes a glycoprotein on the cell surface that controls complement-mediated cell lysis). Consequently, there is ample documentation of the rare instances where inherited mutations in CD59 result in the loss of CD59 on the cell surface. These patients' phenotype is similar to that of PNH in that they tend to thrombosis, paroxysmal hemolysis (an autosomal condition where the red blood cells are destroyed) flare-ups, and chronic intravascular hemolysis (a condition where the red blood cells rupture due to the attack of surface antibodies). Individuals with inherited CD59 deficiency also exhibit relapsing immune-mediated peripheral neuropathy, unlike PNH patients.
What Are the Symptoms of PNH?
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Anemia: Hemolysis and bone marrow failure can contribute to anemia in PNH, which is frequently multifactorial. Classical PNH is frequently accompanied by intravascular hemolysis, up to a 10-fold lactate dehydrogenase (LDH) increase, moderate to severe anemia, and an elevated reticulocyte count.
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Thrombosis: Thrombosis (formation of blood clots within blood vessels) is the most common cause of death in PNH and is associated with severe morbidity. Venous thrombosis is more common than arterial thrombosis, but thrombosis in PNH can occur at any site. The most common site of thrombosis in PNH is hepatic vein thrombosis (Budd-Chiari syndrome). For unknown reasons, other common sites include cerebral (sagittal and cavernous sinus) and intraabdominal (hepatic, portal, mesenteric, splenic, etc.) veins.
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Dystonia of Smooth Muscles: The common symptoms of classical PNH include dysphagia (difficulty in swallowing), esophageal spasm, abdominal pain, and erectile dysfunction. These are directly related to intravascular hemolysis and the release of free hemoglobin. Haptoglobin, CD163, and hemopexin typically remove free hemoglobin from the body. When PNH overwhelms these clearing mechanisms, high levels of free hemoglobin accumulate in the plasma, which causes Nitric Oxide (NO) to be depleted. The two molecules quickly and irreversibly react to produce methemoglobin and nitrate, with free hemoglobin acting as a potent scavenger of NAD+. The scavenging of free hemoglobin leads to a deficiency of nitric oxide. This, in turn, disrupts smooth muscle tone and platelet activation. It has been reported that patients with a large PNH clone size are more likely to experience smooth muscle dystonias.
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Other Symptoms: Patients with PNH are at higher risk of kidney diseases. The accumulation of iron deposits and microvascular thrombosis cause damage to the renal tubules. Some people are found to have mild to moderate pulmonary hypertension. Fatigue and symptoms of dyspnea are partly due to hemolysis-associated nitric acid scavenging and subclinical microthrombi. As a result, there is an elevation in pulmonary pressures and a decrease in right ventricular function.
How Is PNH Treated?
Allogeneic Bone Marrow Transplantation (BMT) and terminal complement inhibition with Eculizumab (a type of monoclonal antibody) are the only treatments for patients with classical PNH that are generally found to be successful. Corticosteroids can lower hemolysis and raise hemoglobin levels in certain PNH patients. However, they have limited efficacy and long-term toxicity, which made these medications less popular.
Conclusion
Over the past 20 years, improvements in the understanding of the cellular and molecular foundations of PNH have led to a better comprehension of the condition. In recent studies using the monoclonal antibody Eculizumab, terminal complement inhibition has been shown to regulate most PNH symptoms and potentially fatal complications. Novel inhibitors of the alternative pathway of complement and complement inhibitors with longer half-lives are expected to enhance the quality of life of people with PNH further in the years to come.
