When it comes to blood diseases, paroxysmal nocturnal hemoglobinuria may be one that many people may have never heard of before. Also known as PNH, this rare blood disease is a life-threatening and acquired disease. Its most defining characteristic is the destruction of the red blood cells due to an insufficient supply of a necessary protein that protects their surface. This results in dangerous effects, such as blood clots and impaired bone marrow function.
The History of PNH
PNH was first described in 1882 when Dr. Paul Sturbing treated a 29-year-old man. His symptoms included fatigue, abdominal pain, and severe nocturnal paroxysms of hemoglobinuria, or passing dark urine overnight and the early hours of the morning. The doctor determined that hemolysis was happening within the patient intravascularly, leading to the patient’s plasma turning red following a succession of hemoglobinuria instances.
The term PNH was eventually coined in 1925 by a Dutch physician named Enneking. The very first diagnostic test that detected this disease was discovered in 1937. That year, Dr. Thomas Ham found that the erythrocytes involved in PNH hemolyzed when they were kept incubated with acidified serum. The test is now known today as the Ham Test.
The Complement System and PNH
In the 1980s, researchers discovered that the PNH cells were deficient in a group of proteins that should be found on the cell surface. It was these proteins—particularly CD55 and CD59—that regulated complement.
But what does “complement” mean?
The complement system is what doctors call a specific group of proteins that move freely within the bloodstream. These proteins aid the immune system’s work in protecting the body. This system was discovered as a component of the body’s plasma, and it supported antibodies that kill bacteria. Thus, these proteins “complement” the antibacterial activity of the body’s antibodies, which is how the system got its name.
The complement system is also responsible for inducing inflammatory responses within the body to fight off foreign invaders such as viruses and infections. Ultimately, this is the system that helps the body defend itself against other illnesses and diseases. Part of the complement system is the protein shield that protects red blood cells and prevents them from getting attacked by the body’s defensive system.
These proteins are always active at some level as the body functions normally. However, when bacteria and viruses invade the body, the proteins become far more aggressive and work in conjunction with the immune system. They go on the attack to destroy abnormal cells in their path.
People with PNH do not have enough GPI-anchored proteins that give the red blood cells a protective surface. Without it, the cells find themselves at the receiving end of the same complement system that is meant to protect them.
This is a result of a bone marrow failure, in which the marrow produces damaged or defective red blood cells. PNH patients have bone marrow that has a mutated form of the gene PIG-A that is responsible for making the protective shield for the red blood cells. The PIG-A gene is mutated by a stem cell, which clones itself and transforms the bone marrow stem cells into a collection of mutant cells.
These same cells then mature into red blood cells, leading to the growth of more red blood cells that have the same mutated gene, known as PNH red blood cells. With their lack of protective protein shield from the complement system, these same cells are then attacked and destroyed by the other proteins in the complement system.
PNH affects different individuals differently. Some people suffer from mild cases, while others will have more severe symptoms in need of immediate treatment, including blood transfusions. The majority of people with this disease can live for decades. However, individuals with more severe symptoms such as blood clots, myelodysplastic syndromes, and acute myeloid leukemia (AML), might have shorter lifespans. With advances in drugs to treat PNH, these patients may experience longer lifespans and have a better quality of life.
The Types of PNH
PNH is primarily characterized by patients who have hemolytic anemia, bone marrow failure, and a high likelihood of developing thrombosis later in the progression of the disease. It also has three specific subtypes:
- Classical PNH – Patients who exhibit the symptoms and effects of PNH despite not having other bone marrow failures;
- PNH in other diseases – PNH as seen as an effect of another major bone marrow disorder, such as aplastic anemia;
- Subclinical PNH – Patients show signs of PNH clones, but there is no clinical or laboratory evidence of hemolysis taking place in their blood. There is also a lack of blood clots.
Paroxysmal Nocturnal Hemoglobinuria
PNH is associated with a number of symptoms. This makes reaching the correct diagnosis take more time and requires careful observation from a patient’s physicians. It may take months or even years to piece together the symptoms and evidence that ultimately prove that a patient has PNH.
PNH occurs in just about any age group. However, on average the disease is diagnosed around age 42.
The rarity of the disease and variance of symptoms lead to several indicators that a person may have PNH. The more prominent symptoms of PNH occur as a result of defective blood cells. It’s important to remember that the severity of these symptoms will vary from person to person and that some people may have milder cases of the disease compared to others.
Some of these symptoms are:
Hemolysis refers to when red blood cells break apart as a result of being attacked by the body’s complement system. Their lack of a protective barrier makes them appear abnormal to the body’s defensive system, which attacks the cells. When a person is experiencing hemolysis, the broken red blood cells release hemoglobin into the body’s plasma.
Because hemoglobin is what gives blood its color along with being the substance that carries oxygen to the rest of the body, hemolysis is responsible for many other symptoms of PNH, such as:
- Dark urine – This is the symptom that initially gave PNH its name, but it’s important to remember that not all people who have PNH experience it.
- Anemia – With the loss of red blood cells, patients experience anemia, which causes exhaustion, headaches, and difficulty breathing, especially during strenuous activities. It can also cause irregular heartbeats.
- Muscle spasms – When hemoglobin is released, it binds with nitric oxide and is removed from the blood. Because nitric oxide is what keeps muscled smooth and relaxed, a lack of nitric oxide in the body results in mild to severe pain in the abdominal area. Men may also experience erectile dysfunction. The spasms can also take place in the esophagus, making it hard to eat or to swallow.
Thrombosis refers to a blood clot within the veins. Approximately one out of three people who have PNH experience thrombosis.
Medical experts are not entirely sure what makes PNH patients more likely to get blood clots. Some of them believe that abnormal platelets in the body end up clotting together more often than people with healthy ones. Another possible reason is the shortage of nitric oxide. Nitric oxide makes it difficult for platelets to stick to one another, so less nitric oxide in the body (because of hemolysis) leads to more clots.
Blood clots have different symptoms depending upon where they occur. They include:
- Abdominal blood clot – This happens below the chest and above the hips. The clot may occur in the spleen, the primary vein of the liver (Budd-Chiari Syndrome), or the intestine (ischemia). The signs of an abdominal blood clot include ascites, otherwise known as swelling in the belly area, as though it is full of fluid. Other symptoms are tenderness or pain in the clot area, along with the area feeling warm to the touch. A clot in the abdomen can be very dangerous as it can lead to bowel or liver damage.
- Brain blood clot – The situation can become extremely dangerous very quickly if a blood clot appears in veins in the brain. It will immediately result in what feels like a debilitating headache and may even impair the patient’s ability to speak, see, or exhibit proper motor function.
- Blood clot in the limbs and skin – When a blood clot manifests in veins of the limbs or on the skin, the affected limb or skin may become swollen and puffy. It might feel tender and warm to touch, with some pain.
- Pulmonary embolism – This condition occurs when a clot breaks off and travels to the lungs. As a result, patients feel a sharp pain in the chest that may worsen as they breathe more deeply and feel short of breath. Coughing up blood is another indication, along with nausea, faintness, and profuse sweating.
Low Red Blood and Low White Blood Cell Count
PNH causes low red blood cell counts as well as anemia. A low white blood cell count is called neutropenia and is another primary symptom of PNH. With a low red blood cell count, people may feel exhausted and less alert. Concentration becomes difficult, and they may lose their appetite. With a low red blood cell count comes paleness, as well as difficulty in breathing or partaking in strenuous activity.
On the other hand, low white blood cell count renders people with PNH more susceptible to infections and illnesses and may cause fevers. Common infections include: bladder infections, which make urination painful; lung infections, which trigger breathing difficulties and bad coughs; sinus infections; and skin infections.
People with low white blood cell counts must always consult a physician. It can become dangerous, such as when a patient with aplastic anemia develops a fever that can quickly turn into a severe infection.
When patients have an abnormally low platelet count, they bruise and bleed easier even from minor injuries. Menstrual periods become heavier, and patients are also susceptible to nosebleeds and bleeding gums. They may also see flat red spots beneath their skin called petechiae.
Paroxysmal Nocturnal Hemoglobinuria
PNH can be caused by genetic factors that lead to a bone marrow failure. A mutated PIG-A gene creates PNH stem cells, which in turn makes PNH blood cells.
However, PNH can also be an acquired disease. Instead of being inherited, the disease occurs more among people who have no previous family history of this disease. Furthermore, the condition is not passed down to the children of individuals who do have the genetic mutation. The vast majority of cases are associated with this mutated gene, and the acquired mutation is found in a somatic cell instead of a germline cell.
Yet since PNH is so rare, the global prevalence of this disease is difficult to gauge and still unknown. It’s also not established how many people in the United States have it, although it’s estimated to affect one in every one to five million people.
What is known is that its incidence is about five to ten times less than that of aplastic anemia. Among those who have aplastic anemia, more than ten in every 100 of them will develop PNH. Since PNH is so rare, there are hardly any known risk factors aside from aplastic anemia. An expanded PNH clone can be found in approximately 70% of patients with aplastic anemia, suggesting a link between the two conditions.
Both men and women are considered equally susceptible to the disease, though it appears slightly more common in women.
While PNH is mostly seen as an adult disease, it may also manifest at just about any age. There are documented cases of children being diagnosed with the disease.
Diagnosis & Testing
The rarity of the disease, combined with the numerous possible symptoms, pose a challenge when it comes to diagnosing PNH. Doctors must consider multiple symptoms and rule out a lot of diagnoses to confirm that it is PNH. They must also extensively examine the patient’s medical history to find evidence that either proves or disproves the presence of PNH.
Some of the telltale signs that they look for is the presence of anemia, discolored urine, and unexplained blood clots.
To that end, there are several tests that doctors may use to determine the presence of PNH. They are:
Flow cytometry is considered the gold standard in diagnosing PNH. It is used to tell doctors if red blood cells are missing the crucial protective proteins, or any proteins, from their surface. PNH cells tend to indicate that CD55 and CD59 proteins are missing. Flow cytometry divides cells into three subtypes: healthy cells; cells sensitive to the complement system; and cells that are extremely sensitive and more susceptible to breaking apart.
Bone Marrow Test
This is one of the essential tests in diagnosing PNH. It shows how much bone marrow is occupied by different types of cells and precisely what kinds of cells the bone marrow is now making. It also checks the level of iron in the bone marrow, as well as relevant abnormalities in DNA.
Other blood tests
- Complete blood count - Used to look for signs of low hemoglobin.
- Lactate dehydrogenase test - Performed to detect high levels of LDH, which means red blood cells have been breaking apart easily or that there is tissue damage within the body.
- Bilirubin test - High levels of bilirubin in the blood may suggest that PNH is destroying red blood cells.
- Reticulocyte count – This counts young red blood cells in the blood. Elevated counts may indicate bone marrow is creating a large number of new red blood cells.
- EPO level – Measures the amount of erythropoietin in the body in response to low oxygen levels caused by low red blood cell count.
- Ferritin test – Measures the amount of iron in the blood. This test is performed more to determine the kind of treatment a patient can receive.
- Vitamin B12 and Folate level test – Performed to rule out any other causes of anemia.
Paroxysmal Nocturnal Hemoglobinuria
Medical therapy for PNH is mainly dependent on the patient’s symptoms. For some, the disease can be mild enough that they won’t need treatment other than taking folic acid and iron supplements to increase red blood cell production. For others, more targeted therapy may be necessary, such as eculizumab, which simulates the antibody that binds essential proteins in the blood that could destroy red blood cells.
Patients may also take androgens or natural male hormones that increase the number of red blood cells. Erythropoietin, a naturally-derived protein that can also be administered by injection, may be used to induce bone marrow to make red blood cells.
Diet and Lifestyle:
The recommended diet for people with PNH is the same as that of people with aplastic anemia. Maintaining a healthy weight is important, and the patient’s diet should be based on sensible food portions that have minimally processed food products. Non-starchy fruits and vegetables, whole grains, and legumes are recommended. It’s vital for people with PNH to limit their consumption of energy-dense processed, starchy, or salt-preserved foods. Doctors also advise avoiding fast food.
Therapy and Procedures:
Treatment options for people with PNH include blood transfusions to replace their red blood cells with normal red blood cells from a donor. A bone marrow transplant is also possible to replace the patient’s marrow with that of a donor’s. However, a bone marrow transplant is not a perfect cure, and there are still significant risks and long-term side-effects from the treatments.
Research & Advancement
Clinical research remains the heart of the process of finding a cure for PNH. Scientists and researchers are always looking for new ways to prevent bone marrow failure, aplastic anemia, and PNH. Investigational therapies are also being performed to seek out new and better treatments that would improve the quality of life of people with PNH.
This is where the importance of a comprehensive medical history comes in. For doctors to determine how effective a treatment is, and to identify new signs and symptoms, they need to carefully study and document the patient’s history and update it accordingly. An electronic health record or electronic medical record can be incredibly useful in this regard. Both doctors and patients can keep careful track of the progress of the disease, the efficacy of treatment, and how the disease developed in them.
The disease is genetic. Can I pass it down to my children?
No. Even though genes play a significant factor in PNH, the mutation is not one that you can pass down to offspring.
What would happen to me if I get pregnant when I have PNH?
There is an increased risk of complications for both the mother and the fetus. There may be an increase in thrombotic events, infections, bleeding, anemia, and risk of miscarriage.
Can I take an anticoagulant to prevent blood clots?
The doctor needs to prescribe you an anticoagulant if required. But the use of them remains risky, so you will need to consult your doctor to determine if you need it.
Part of understanding and finding better treatments for PNH is through the careful study of patient records and tests. PicnicHealth makes it easier to get your complete medical records to aid in managing the disease. Visit PicnicHealth.com/pnh to sign up for a free PicnicHealth account if you have been diagnosed with PNH.