Cracking the PNH Code: Exploring its History and Breakthrough Treatments

The Rare360 Editorial Team

Oct 26, 20238 min read

Updated: Jan 16, 2024

The Genetic Mystery Behind PNH

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare chronic blood disorder that happens when part of your immune system attacks and damages your red blood cells and platelets. People living with PNH have abnormal red blood cells that are easily destroyed by their own immune system, leading to anemia, blood clots, and bone marrow failure. Our body's cells have proteins on their surfaces that help them communicate with their surroundings. Some of these proteins are anchored to the cell's surface using glycolipids like GPI (glycosyl phosphatidylinositols). In people living with PNH, there's a problem with how these glycolipid-protein structures are put together on the surface of blood cells.

A mutation in an X-linked gene phosphatidylinositol glycan class A (PIGA) results in the acquired hematopoietic stem cell disorder, PNH. This gene is necessary to make GPI, and a mutation in the PIGA gene can cause the absence of GPI anchors on the cell membrane. The cell membrane proteins anchored by GPI usually protect the cells from being destroyed by the complement system, which is part of our immune system. Without these anchors, the cells become more vulnerable to attack by the complement system, especially red blood cells.

When this mutation happens in a bone marrow stem cell, all the cells it produces will have the same defect. The mutation occurs randomly in a single stem cell in the bone marrow, which then multiplies and expands, causing the disease. This mutation occurs randomly, making it difficult to predict who is at risk of developing PNH in the general population.

It’s important to note that PNH is not an inherited disease. The mutation occurs spontaneously and cannot be passed on from parents to children.

Exploring the History and Prevalence of PNH Over Time

PNH has a history that spans several centuries, with significant developments in our understanding of the condition over time. Here's a timeline of the history of PNH:

Early References (Before 19th Century): Some historical records suggest that symptoms resembling PNH may have been observed as far back as the 16th century. However, there were no formal diagnoses or understanding of the condition during this period.
First Clinical Description (19th Century): The first recognized clinical description of PNH can be attributed to Paul Strübing, a German physician, in 1882. Strübing documented a case of hemoglobinuria (the presence of hemoglobin in the urine) and jaundice (yellowing of the skin and eyes) that occurred in paroxysms or sudden attacks, typically at night. This laid the foundation for the term "paroxysmal nocturnal hemoglobinuria."
Early Research and Discovery (20th Century): It wasn't until the 20th century that further research and understanding of PNH began to develop. In the 1930s and 1940s, scientists like Ham, Dacie, and Johnson made significant contributions to the understanding of PNH by describing its characteristics, such as hemolysis (destruction of red blood cells) and susceptibility to blood clots.
Discovery of the PNH Clone (1960s): In the 1960s, the discovery of the PNH clone, which is a population of blood cells with a genetic mutation responsible for PNH, marked a significant milestone in the understanding of the condition. This genetic mutation affects the ability of blood cells to anchor protective proteins on their surfaces.
Elucidation of the Complement System (1970s): Researchers in the 1970s made significant progress in understanding the role of the complement system in PNH. They found that PNH red blood cells are more vulnerable to attack by the complement system, contributing to the condition's symptoms.
Molecular Understanding (Late 20th Century): Advances in molecular genetics and genetic testing in the latter part of the 20th century allowed for a more precise understanding of the genetic mutations responsible for PNH.
Treatment Advances (Late 20th Century and Beyond): The development of therapies, such as eculizumab (Soliris), has transformed the management of PNH by reducing the risk of hemolysis and blood clot formation.

Today, PNH is better understood, with improved diagnostic methods and treatment options. Ongoing research continues to shed light on the condition's underlying mechanisms and potential future therapies. Despite its rarity, PNH's history reflects the progress made in our understanding of hematological disorders and the development of effective treatments.

Prevalence of PNH

Due to its rarity, the exact prevalence and incidence are unknown for PNH. However, some estimates suggest that in the US, PNH has an incidence rate that is 5 to 10 times less than that of aplastic anemia, which is around 0.6 to 6.1 cases per million people. The estimated prevalence of PNH in the US is between 1 and 9 in every 100,000 people. In the U.S., only about 500 people are diagnosed with PNH each year. A study conducted in the UK estimated the overall incidence of detectable PNH clones to be 0.35 cases per 100,000 individuals per year, equivalent to 220 cases diagnosed annually in the UK. The overall prevalence rate was estimated to be 3.81 per 100,000 individuals, equivalent to 2400 cases in the UK.

These numbers can vary due to factors such as geographical location and age. Most patients with PNH are initially diagnosed in their 30s.

Recognizing the Signs and Symptoms of PNH

The signs and symptoms of PNH can vary in severity among individuals, but they generally result from the lack of protective proteins on the surface of red blood cells due to a mutation in the PIGA gene. This mutation leads to increased sensitivity to a process called complement-mediated hemolysis. Here are some of the common signs and symptoms associated with PNH:

Hemolytic Anemia: This is the hallmark of PNH. Hemolysis refers to the destruction of red blood cells, which can lead to anemia. Symptoms of anemia may include fatigue, weakness, pale skin, and shortness of breath.
Dark Urine: Hemoglobin released during the breakdown of red blood cells can be excreted in the urine, causing it to appear dark or discoloured, often described as "cola-coloured" urine.
Fatigue: Ongoing anemia and reduced oxygen-carrying capacity of the blood can lead to persistent fatigue.
Blood Clots (Thrombosis): People living with PNH are at an increased risk of developing blood clots, which can occur in various parts of the body, including deep vein thrombosis (DVT), pulmonary embolism, and abdominal or cerebral veins. These can result in symptoms such as pain, swelling, or neurological symptoms, depending on the location of the clot.
Abdominal Pain: Blood clots in the abdomen can cause severe abdominal pain, and in some cases, it may lead to gastrointestinal symptoms like nausea and vomiting.
Bleeding: PNH can be associated with increased bleeding tendencies, particularly in the presence of blood-thinning medications.
Difficulty Swallowing: Sometimes, blood clots in the throat can lead to difficulty in swallowing.
Headaches and Neurological Symptoms: In cases where blood clots affect cerebral veins, individuals may experience headaches, dizziness, confusion, and other neurological symptoms.
Bone Marrow Failure: PNH can lead to bone marrow failure, which results in a shortage of various types of blood cells (pancytopenia). This can lead to increased susceptibility to infections and unexplained bleeding.

There are some additional symptoms that may be associated with PNH:

Shortness of Breath
Irregular Heartbeats
Chest Pain
Back Pain
Erectile Dysfunction
Pulmonary Hypertension
Gastrointestinal Symptoms

It's important to note that the symptoms of PNH can be variable, and not all individuals will experience all of these symptoms. The severity of PNH can also vary from person to person.

Diagnosing PNH: Key Steps and Crucial Tests

PNH can be challenging to diagnose due to its rarity and the similarity of its symptoms to many other diseases. PNH is typically diagnosed through a combination of clinical evaluation, physical examination, and specific laboratory tests. Here are the key steps involved:

Physical Exam and Health History: The diagnostic process usually starts with a physical exam and a health history. The doctor will ask about symptoms and overall health.
Flow Cytometry: This is the most accurate way to diagnose PNH. This test uses a sample of blood and proteins called antibodies attached to a fluorescent dye to find other proteins called antigens on the surface of blood cells. The flow cytometry test measures how many blood cells are missing a protein called GPI, which protects red blood cells from destruction and stops blood clots from forming.
Bone Marrow Tests: These tests show whether the body makes enough healthy blood cells. A bone marrow test won’t confirm PNH, but it can rule out other bone marrow problems that might cause symptoms, like aplastic anemia or myelodysplastic syndrome.
Urinalysis: For the most accurate results, you should see your doctor for a special urine test (urinalysis).
Laboratory testing: Here is a list of tests and their description that are crucial in your diagnostic journey with PNH.

Test	Description
LDH level	LDH is an enzyme found in various tissues that is abundant in red blood cells. In PNH when red blood cells are destroyed, LDH is released into the bloodstream. Therefore, the level of LDH in a person with PNH can indicate the amount of haemolysis that is occurring. An LDH level ≥1.5 times the upper limit of normal (normal range = 105–333 IU/L) indicates an elevated level of haemolysis.
Reticulocyte count	This test measures how fast red blood cells made by the bone marrow (reticulocytes) are released into the blood. The reticulocyte count rises when red blood cells are destroyed prematurely, for example during hemolysis. A reticulocyte level >1.5% indicates elevated haemolysis, or additional bone marrow dysfunction.
Haemoglobin level	Patients with PNH often, or in many cases, have a low haemoglobin level (<12.1 g/dL in females and <13.8 g/dL in males).
Haptoglobin level	Haptoglobin is a protein that binds to haemoglobin. Haptoglobin levels <41 mg/dL provide evidence of elevated intravascular haemolysis in patients with PNH.
Tests of kidney function	As PNH can cause kidney problems, people with PNH should have their kidney function measured by blood tests. A low estimated glomerular filtration rate (<90 mL/min/1.73m2) and elevated levels of serum creatinine (>1.1 mg/dL in females and >1.3 mg/dL in males) are indicators of impaired renal function. This is especially true during haemolytic crisis due to the risk of acute renal failure.
Bilirubin level	Bilirubin is a waste product of the breakdown of red blood cells. Levels of bilirubin can be elevated in PNH due to increased haemolysis. Direct and total levels of bilirubin that indicate elevated haemolysis are >0.3 mg/dL and >1.9 mg/dL, respectively.
Serum ferritin test	Ferritin is a protein that stores iron within cells. In PNH, due to the destruction of red blood cells, the levels of ferritin can be higher than normal. In patients with haemolytic PNH without complement inhibition and without an accompanying bone marrow failure syndromes, patients usually present with low iron levels. If there is a shift to extravascular haemolysis or additional bone marrow failure syndromes, an iron overload can occur.
Low platelet count	In PNH, activation of the complement system results in platelet activation which in turn leads to platelet aggregation and possibly thrombosis. Therefore, in patients with PNH, platelet levels are lower than normal (<150 x 109/L).
NT-proBNP level	N-terminal pro-brain natriuretic peptide (NT-proBNP) is a marker of pulmonary vascular resistance and right ventricular function, both of which are indicators for PHT. Almost half of patients with PNH have elevated levels of NT-proBNP.
D-dimer level	A D-dimer is a protein fragment produced during the degradation of a thrombus. Elevated D-dimer levels (>250 ng/mL) are a sign of thrombosis.
Folate and vitamin B12	Measuring levels of folate and vitamin B12 can help to diagnose anaemia. Folate levels <4.5 nmol/L and vitamin B12 levels <200 pg/mL are indicative of anaemia.

Remember, it’s important to consult with healthcare professionals who can provide you with the most accurate information and help manage your condition.

Managing PNH: Treatment Options and Strategies

The treatment for PNH depends on the severity of your symptoms and the characteristics of the disease itself. Several treatment options are available, which include:

Medicines to Protect Blood Cells: The primary approach to managing PNH involves medications aimed to stop the breakdown of red blood cells, thus reducing the chances of blood clots, and enhancing the overall quality of life. Medicines like Eculizumab (Soliris) and Ravulizumab (Ultomiris) function in a similar manner and are typically administered intravenously (IV). You’ll need to take medicine for the rest of your life (long-term), or until your disease goes into remission. For those newly commencing treatment or transitioning from Soliris or Ultomiris, Pegcetacoplan (Empaveli) is another targeted therapy that may be prescribed.
Stem Cell Transplant: Stem cell transplantation is the sole curative option for PNH, but it carries inherent risks. This procedure involves replacing damaged stem cells with healthy ones from a compatible donor, often a close relative due to the higher likelihood of genetic compatibility.
Symptom Alleviation Treatments: In addition to specific PNH-targeted therapies, your doctor may recommend you other treatments to ease PNH symptoms by helping your body make new blood cells. These adjunct treatments may include supplements like iron and folic acid, blood transfusions, growth factors, and androgen hormones.
Blood Thinners: These may be used on some patients to help reduce the chance of having blood clots.
Immunosuppressive Therapy: In cases where PNH coexists with aplastic anemia, a condition characterized by reduced blood cell production, immunosuppressive therapy may be considered. This treatment modulates the body's immune response.

Each patient's treatment plan is tailored to their unique circumstances and the progression of their PNH.

FDA-Approved Treatments for PNH

Currently, there are three FDA-approved treatments for the management of PNH:

Eculizumab (Soliris): Approved in 2007, Eculizumab is a monoclonal antibody that blocks terminal complement at C5. Its approval marked a transformative milestone in altering the course of PNH by impeding the natural disease progression.
Ravulizumab (Ultomiris): Approved on December 21, 2018, Ravulizumab is also used for adult patients with PNH. It is administered every 8 weeks. The most common side effects of ULTOMIRIS in people treated for PNH are upper respiratory tract infection and headache.
Pegcetacoplan (Empaveli): Approved in 2021, Pegcetacoplan is the first PNH treatment that binds to complement protein C3. The effectiveness of Empaveli was evaluated in a study enrolling 80 patients with PNH and anemia who had been taking eculizumab. The most common side effects are injection site reactions, infections, diarrhea, abdominal pain, respiratory tract infection, viral infection, and fatigue.
Iptacopan (Fabhalta): Approved on December 05, 2023, Iptacopan is the only FDA-approved factor B inhibitor targeting the immune system’s complement pathway for the treatment of PNH in adults. The FDA approval was supported by two late-stage clinical trials.

It’s crucial to understand that these treatments do not cure PNH but may reduce symptoms, lower the risk of complications, and improve the quality of life. It's important to note that all these medications may elevate the risk of infection, including potentially serious meningococcal infection. As a precaution, healthcare providers often recommend receiving the meningococcal vaccine before initiating these treatments.

Conclusion

In conclusion, Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare and complex blood disorder that has seen remarkable advancements in our understanding and management over the years. From its early historical references to the first clinical descriptions by physicians like Paul Strübing, the 20th century witnessed significant research that elucidated the condition's characteristics and the role of the complement system.

The discovery of the PNH clone in the 1960s marked a turning point in our understanding, and researchers in the 1970s further elucidated the complement system's involvement. With the advent of molecular genetics and advanced diagnostic tools, we gained more precise insights into PNH's genetic underpinnings.

Today, the management of PNH has been transformed with the advent of FDA-approved treatments such as Eculizumab (Soliris), Ravulizumab (Ultomiris), and Pegcetacoplan (Empaveli). These therapies, while not providing a cure, significantly alleviate symptoms, reduce complications, and enhance the quality of life for individuals living with PNH.

Despite its rarity, PNH has come a long way in terms of understanding, diagnosis, and treatment. Ongoing research continues to shed light on this enigmatic disorder, offering hope for more effective therapies and improved outcomes in the future.

References

Updated on December 12, 2023