What is Paroxysmal Nocturnal Hemoglobinuria?
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare genetic disease that shows up with different symptoms. The most common ones include hemolytic anemia, which is a condition where the red blood cells are destroyed before their normal lifespan ends, hemoglobinuria, which is the presence of hemoglobin (a type of protein that carries oxygen in red blood cells) in the urine, and body symptoms like fatigue and difficulty in breathing. Other symptoms that may come with PNH include blood clots, kidney problems, and in severe cases, the failure of the bone marrow, which is the soft tissue inside our bones that produces blood cells.
The term PNH was first introduced in 1925 by Enneking, but we have records of similar cases dating back to the 1880s. One of the earliest was reported by Strubing, who described a young man with fatigue, abdominal pain, and occasional presence of hemoglobin in his urine. Strubing also noticed that the patient’s plasma (the liquid part of the blood) turned red during severe episodes. He made a connection between this and the destruction of red blood cells inside the blood vessels.
In 1937, Ham discovered that the red blood cells of PNH patients break down when mixed with regular urine that has been made slightly acidic. This led to the first diagnostic test for PNH, known as the Ham test. While it was suspected that this breakdown of red blood cells was caused by the activation of complement (protein components in our blood that help in destroying foreign cells), this wasn’t proven until 1954. Over time, the deficiencies in certain proteins affecting the red blood cells in PNH patients were identified, which eventually led to the discovery of the responsible genetic mutation.
Although PNH is rare, it significantly affects how a patient lives because of the severity of the symptoms. 40 or 50 years ago, the 10-year survival rate for PNH patients was only 50 percent. But with advancements in medical treatments, such as the drug eculizumab, in the past 15 years, this rate has improved to over 75 percent.
What Causes Paroxysmal Nocturnal Hemoglobinuria?
Paroxysmal nocturnal hemoglobinuria is a condition that happens when there’s a genetic mutation in the stem cells that make blood. This mutation affects a specific gene called the phosphatidylinositol glycan class A (PIGA). This leads to a shortage of a protein called glycosylphosphatidylinositol (GPI), which normally helps attach other proteins to red blood cells.
In particular, the GPI is needed to attach two proteins, called CD55 and CD59, to the red blood cells. These proteins help control the activity of the ‘complement system’, our body’s natural defense system that helps fight infections. When these proteins can’t attach to the blood cells properly, the complement system starts breaking down the cells too much, which is called hemolysis.
This constant state of hemolysis, or breaking down of cells, can become worse when the body is under stress, such as during surgery, injury, or other triggers that cause inflammation.
Risk Factors and Frequency for Paroxysmal Nocturnal Hemoglobinuria
PNH, or paroxysmal nocturnal hemoglobinuria, is a rare disease that affects people around the world. Its occurrence is estimated at about 15.9 individuals per million, but some suspect this number is possibly low since the disease often goes undiagnosed in people who show few symptoms or have other conditions that make it harder to diagnose PNH. It typically affects adults between the ages of 30 and 40, while children can also suffer from PNH, it’s quite rare.
- Based on a 2012 study of patients in the International PNH Registry, the median age for all registered patients was 42.
- The duration of the disease ranged on average around 4.6 years.
- The age of the patients in the study ranged from 3 to 99 years.
The mutation that causes PNH is located on the X chromosome. Even though this mutation is found on this sex chromosome, it is slightly more common in women than men. This frequency is due to the nature of the mutation, which affects somatic or “body” cells rather than germline cells (cells that give rise to eggs or sperm). If a girl develops the mutation, it survives in her body’s cells and can then be passed down. This pattern doesn’t occur in men because they only have one X chromosome – the one they get from their mother.
Besides, there’s another type of PNH mutation that affects germline cells. Unfortunately, this generally results in a fetus that is not viable and does not survive the pregnancy. However, a milder form of this mutation can lead to a condition known as multiple congenital anomalies-hypotonia-seizures syndromes. This disorder is severe and involves various challenges, including intellectual disabilities, abnormal facial features, seizures, and an early death.
Interestingly, PNH does not seem to be more common in some ethnic or geographic groups than others. However, where you live could affect your risk of developing blood clots if you have PNH. PNH patients from the United States and Europe have a higher tendency to develop blood clots compared to those from Asia.
- In the United States and Europe, 30 to 40% of all PNH cases are reported.
- In contrast, less than 10% of PNH cases come from Asia.
Besides, within the United States, the complications of PNH differ among different ethnic groups. For instance, African-Americans with PNH have a 73% rate of developing blood clots, Latin Americans have a 50% rate, while White and Asian Americans have a 36% rate. It’s also worth noting that the risk of developing bone marrow failure – another complication of PNH – varied with geography. It is more common in residents of Asia, the Pacific Islands, and Latin America for reasons that are not yet clear.
Signs and Symptoms of Paroxysmal Nocturnal Hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) used to be identified by repeated bouts of blood cell destruction, blood clots formation, and low blood cell counts related to failed bone marrow. However, extensive research has shown us that patient symptoms can be varied and often difficult to categorize under specific conditions. People with this condition often experience general discomfort like tiredness, shortness of breath, dark urine due to excessive hemoglobin in the urine, kidney problems resulting from iron build-up which causes inflammation in the kidney tissues, difficulty swallowing or esophageal cramps, stomach pain, back pain and problems with sexual activity, which all come as a result of muscle tension. These symptoms vary widely, making diagnosis difficult and frequently delayed.
- Tiredness
- Shortness of breath
- Dark urine due to high levels of hemoglobin
- Kidney problems due to iron build-up causing inflammation
- Difficulty swallowing or esophageal cramps
- Stomach pain
- Back pain
- Issues with sexual activity due to muscle tension
Testing for Paroxysmal Nocturnal Hemoglobinuria
The ‘gold standard’, or best test, for diagnosing Paroxysmal Nocturnal Hemoglobinuria (PNH) is called flow cytometry. This involves using a particular reagent, or a testing substance, called fluorescent aerolysin reagent (FLAER) and various monoclonal antibodies. FLAER sticks directly to a type of protein found on the surface of our cells, known as glycosylphosphatidylinositol (GPI) anchored protein. This test can evaluate several kinds of GPI-anchored proteins, especially CD55 and CD59, with high accuracy.
Aerolysin, the main element of virulence (or disease-causing ability) found in Aeromonas hydrophila — a type of bacteria, is introduced into the body in an inactive form known as proaerolysin. This inactive form binds exceptionally well with GPI anchor proteins. When FLAER is used in a test, it can confirm whether there is a lack of GPI anchor protein in certain types of cells. One thing to note here is that at least two GPI linked proteins must be studied in this test to avoid any false negatives due to uncommon congenital deficiencies of single antigens like CD55 or CD59. In this test, all GPI negative red blood cells, white blood cells and granulocytes are identified.
There are two types of flow cytometry tests: low sensitivity and high sensitivity. While the low sensitivity tests are good enough for diagnosing PNH, the high sensitivity test is better for diagnosing PNH along with another bone marrow disorder. PNH can be classified into three types based on the findings of the test and the patient’s condition: Classic PNH, PNH with another bone marrow disorder and, Subclinical PNH—where there are no obvious signs. It’s good practice to reassess patients every 6 to 12 months to keep an eye on the progression of the disease.
Even though they are not diagnostic tests, other lab work like complete blood count with differential, basic metabolic panel, and urinalysis can provide useful information. This can include signs of intravascular hemolysis (breaking down of red blood cells), low counts of several types of blood cells, and hemoglobinuria or hemosiderosis (conditions caused by excess levels of hemoglobin or iron in the blood). These tests might indicate the need for a more specific test for PNH, such as flow cytometry.
Generally, if flow cytometry testing shows that more than 20% of the tested granulocytes, a type of white blood cell, are ‘clones’ or identical, detailed assessment of hemolysis, silent thrombosis (blood clots), and organ damage are required. Depending on the findings, additional tests may be performed.
Imaging like an echocardiogram, Doppler abdominal ultrasound, computerized tomography pulmonary angiography (CTPA), CT scan of the abdomen, and MRI of the head may also be performed to assess any complications like pulmonary hypertension, hepatic blood flow abnormalities and clots in the veins, lungs or brain.
Treatment Options for Paroxysmal Nocturnal Hemoglobinuria
In the past, treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH), a rare blood disease, was largely supportive. Patients were given blood transfusions and iron supplements to deal with a continuous breakdown of red blood cells and resulting anemia. To prevent blood clots, anti-thrombosis medication was used. In cases where the bone marrow was affected, a bone marrow transplant was offered.
The main issues in PNH are ongoing red blood cell destruction and an unstable immune response, where part of the immune system (complement pathway) is excessively active. This results from the loss of specific proteins (CD55 and CD59) that typically protect the cells from being destroyed by the immune system. This destruction leads to complications like blood clots, which can cause severe disease and death.
Modern treatments for PNH focus on drugs such as eculizumab and ravulizumab that block the overactive immune response, along with stem cell transplantation.
Eculizumab is a medication that can save lives, reducing the need for transfusions by over 50% and decreasing the risk of blood clots and severe vascular complications by nearly 70%. It works by inhibiting a component of the immune system (factor C5), preventing it from forming complexes that attack and burst cells. However, some patients might not respond to treatment and may have an increased risk of certain bacterial infections, such as meningococcal meningitis. Hence, patients need to be vaccinated and are usually given preventative antibiotics (prophylaxis).
About 11 to 27% of patients on eculizumab experience fatigue and an ongoing breakdown of red blood cells even while on the standard treatment dose because the immune reactions are not wholly inhibited. Additionally, eculizumab can be expensive and must be given frequently, which might reduce patients’ quality of life.
Acknowledging these issues, a new drug, ravulizumab, was developed and approved by the US Food and Drug Administration for PNH treatment in December 2018. Ravulizumab, which has a longer effect and is given less frequently, appears to be more cost-effective and effective than eculizumab. Nonetheless, it’s a relatively new drug, and long-term data are not yet available. In the future, it’s expected that ravulizumab will likely be the first choice for treating PNH. There are also many other therapies under investigation that focus on different parts of the immune system.
Another potential cure for PNH is stem cell transplantation from a donor (allogeneic hematopoietic stem cell transplantation). This option is considered for high-risk patients, considering the benefits versus the risks of possible adverse outcomes such as graft versus host disease.
Other PNH treatments target complications related to the disease. For example, if PNH leads to acute kidney injury, the best treatment may be continuous renal replacement therapy, which is a type of dialysis that filters the kidneys continuously.
What else can Paroxysmal Nocturnal Hemoglobinuria be?
The process of diagnosing medical conditions often involves ruling out other diseases with similar symptoms. This is known as a differential diagnosis. When dealing with conditions that might involve hemolytic anemias, bone marrow failure or unusual cases of blood clotting, there’s a range of possible diseases that doctors need to consider. These include:
- Paroxysmal cold hemoglobinuria (a rare condition where the body’s immune system destroys its own red blood cells after exposure to cold temperatures)
- Autoimmune hemolytic anemia (another condition where your body destroys its own red blood cells)
- Bone Marrow disorders like aplastic anemia (where your bone marrow doesn’t produce enough new blood cells), myelodysplastic syndrome (a group of disorders caused by poorly formed blood cells or cells that don’t work properly), or primary myelofibrosis (a disorder where your bone marrow is replaced with scar tissue)
- Microangiopathic hemolytic anemia (a disorder that causes clotting in the small blood vessels in your body)
- Disseminated intravascular coagulation (a condition that causes abnormal blood clotting throughout the body)
- Other hereditary anemias (genetic disorders that affect the body’s ability to produce healthy red blood cells)
What to expect with Paroxysmal Nocturnal Hemoglobinuria
Prior to the development of treatments known as complement inhibitors, such as eculizumab, people with Paroxysmal Nocturnal Hemoglobinuria (PNH), a rare blood disease, typically lived for 10 to 22 years. The primary reason for their death was typically a condition called thrombotic events, where blood clots form in the bloodstream.
However, with the creation of new medicines such as eculizumab and ravulizumab, those with PNH now have a life expectancy closer to those who don’t have the disease. These advancements underline the importance of ongoing medical research for improving patient outcomes.
Possible Complications When Diagnosed with Paroxysmal Nocturnal Hemoglobinuria
Common problems related to PNH involve blood clots that can occur in the liver, brain, and abdomen, and can either be in the veins or arteries. Other issues include acute or chronic kidney disease, high blood pressure in the lungs, difficulty in maintaining an erection, and trouble swallowing.
Common Complications:
- Blood clots in the liver, brain, and abdomen
- Venous and arterial blood clots
- Acute or chronic kidney disease
- High blood pressure in the lungs
- Difficulty maintaining an erection
- Difficulty swallowing
Preventing Paroxysmal Nocturnal Hemoglobinuria
It’s essential that patients follow their prescribed medication routines, show up for any lab tests or imaging that’s needed, and consistently attend their appointments. This is particularly critical with your main healthcare provider as well as any specialist appointments, like those for blood diseases (hematology). It’s essential to fully explain to you, the patient, the positives and negatives of the suggested treatment. You need to be aware of what the future could hold for your health and understand any decisions for future treatment that may be needed. There will also be a time to discuss your preferences for emergency medical care and your thoughts on life-sustaining measures.
