Paroxysmal Nocturnal Hemoglobinuria: Symptoms, Types, Causes and Treatment

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare and complex blood disorder that affects both patients and clinicians due to its variable symptoms, unpredictable progression, and evolving treatment landscape. Understanding PNH requires a close look at its symptoms, types, underlying causes, and the latest advances in therapy. This article will guide you through each aspect, providing a comprehensive, evidence-based overview for patients, caregivers, and health professionals.

Symptoms of Paroxysmal Nocturnal Hemoglobinuria

PNH is notorious for its wide array of symptoms, which can range from mild fatigue to life-threatening complications. Many symptoms arise from chronic destruction of red blood cells (hemolysis), blood clots (thrombosis), and bone marrow dysfunction. Because symptoms can fluctuate daily, individuals with PNH often face challenges in daily life and work.

Symptom	Frequency/Impact	Significance	Sources
Fatigue	Most common (80–88%)	Major cause of disability	1 3 5
Hemoglobinuria	Up to 62%	Classic PNH feature	1 5
Abdominal Pain	44–60%	Correlates with severity	1 4 5
Dyspnea	64%	May signal severe anemia	1 2 5
Thrombosis	10–23% (on treatment)	Leading cause of mortality	1 2 3 10

Table 1: Key Symptoms

Fatigue: The Most Pervasive Burden

Fatigue is reported by more than 80% of PNH patients and is often the most disabling symptom, impacting quality of life, work ability, and emotional health. Even patients receiving state-of-the-art therapies often experience significant fatigue, reflecting the chronic nature of the disease and possible ongoing anemia 1 3 5.

Hemoglobinuria and Anemia

Hemoglobinuria—dark-colored urine due to the release of hemoglobin from destroyed red blood cells—is one of the hallmark signs of PNH. It's not only a diagnostic clue but also reflects ongoing intravascular hemolysis, which leads to chronic anemia. This anemia can be severe, requiring transfusions even in treated patients 1 3 5.

Abdominal and Chest Pain

Abdominal pain is frequently reported and is often associated with severe hemolysis or blood clots in abdominal veins. Chest pain may also occur, sometimes as a warning sign of thrombotic events 1 2 4 5.

Shortness of Breath (Dyspnea) and Other Symptoms

Shortness of breath is common, especially with anemia or when blood clots affect the lungs. Other reported symptoms include headaches, difficulty swallowing, muscle weakness, and cognitive difficulties 2 3 5.

Thrombosis: The Most Serious Complication

Thrombosis—formation of blood clots in veins or arteries—is the most feared and potentially fatal complication of PNH. It can occur in unusual sites such as abdominal veins and is a leading cause of death among PNH patients 1 2 3 10 11. Early identification and treatment are critical.

Types of Paroxysmal Nocturnal Hemoglobinuria

PNH is not a one-size-fits-all disease. It presents in several different clinical forms, which are crucial for diagnosis, management, and prognosis. The main types are based on the predominance of hemolysis, bone marrow failure, or a combination of both.

Type	Main Characteristics	Clinical Relevance	Sources
Classic	Severe hemolysis, thrombosis risk	Most symptomatic, treated	6 7 8
Overlap	With marrow failure disorders	Shares features with AA/MDS	6 7 8 14
Subclinical	Small PNH clone, few/no symptoms	Often detected incidentally	6 7 14

Table 2: Types of PNH

Classic (Hemolytic) PNH

This type is marked by active hemolysis, leading to severe anemia, hemoglobinuria, and high risk of thrombosis. Most patients with classic PNH will need targeted therapy and are at greatest risk for complications 6 7 8.

PNH with Bone Marrow Failure (Overlap)

Here, PNH coexists with bone marrow failure syndromes such as aplastic anemia (AA) or myelodysplastic syndrome (MDS). These patients may have fewer symptoms of hemolysis but suffer from low blood cell counts (cytopenias), and their management often requires immunosuppressive therapy or bone marrow transplantation 6 7 8 14.

Subclinical (Asymptomatic) PNH

Some individuals have small PNH clones without symptoms. These are often detected during testing for other reasons (e.g., unexplained cytopenias). They rarely require treatment unless progression occurs 6 7 14.

Clinical Heterogeneity

The type of PNH a patient has is determined by the size of the affected (GPI-deficient) clone and the degree of bone marrow involvement. The clinical picture can evolve over time, with overlap between types 6 7 14.

Causes of Paroxysmal Nocturnal Hemoglobinuria

Understanding what causes PNH sheds light on why the disease is so variable and how it can be targeted for treatment. PNH is an acquired—not inherited—disorder that arises from mutations in blood-forming stem cells.

Cause	Mechanism	Pathophysiological Outcome	Sources
PIGA Mutation	Loss of GPI anchor synthesis	Missing CD55/CD59 on blood cells	8 9 14
Autoimmunity	T-cell mediated attack	Selective survival of mutant cells	9 14
Clone Expansion	Mutant stem cell dominates	Varying symptoms, risk factors	6 9 14

Table 3: Key Causes of PNH

The Genetic Defect: PIGA Mutation

Almost all cases of PNH begin with an acquired (not inherited) mutation in the PIGA gene in a single hematopoietic stem cell. This gene is essential for producing the GPI anchor—a structure that attaches protective proteins (like CD55 and CD59) to the surface of blood cells 8 9 14. Without these proteins, blood cells are vulnerable to attack by the body's complement system.

Immune-Mediated Selection and Clone Expansion

While PIGA mutations can occur in anyone, for PNH to develop, the mutant stem cell must outcompete normal cells. This happens most often when the immune system (particularly T cells) attacks and destroys normal stem cells, sparing those with PIGA mutations. This "survival advantage" allows the mutant clone to expand and produce large numbers of susceptible blood cells 9 14.

Pathophysiological Cascade

• Complement Activation: GPI-deficient red cells are destroyed by uncontrolled complement activation, leading to hemolysis.
• Thrombosis: The loss of GPI-anchored proteins on platelets and other cells creates a prothrombotic state.
• Bone Marrow Failure: The underlying immune-mediated damage can lead to inadequate production of all blood cells 6 8 9 14.

Relationship with Bone Marrow Failure Syndromes

PNH shares close ties with disorders like aplastic anemia, both in pathogenesis and clinical presentation. The immune environment that favors PNH clone expansion is often the same that causes marrow failure 6 9 14.

Treatment of Paroxysmal Nocturnal Hemoglobinuria

The management of PNH has evolved dramatically in recent years, moving from supportive care to targeted therapies that address the underlying disease process. Treatment is tailored to disease severity, type, and patient needs.

Treatment	Main Approach	Key Benefits/Limitations	Sources
Supportive Care	Transfusions, anticoagulation	Symptom relief, not curative	1 14
Eculizumab	C5 complement inhibitor	Reduces hemolysis, thrombosis	1 3 8 13 14
Ravulizumab	Long-acting C5 inhibitor	Similar to eculizumab, less frequent dosing	3 15
Pegcetacoplan	C3 complement inhibitor	Controls intra/extravascular hemolysis	12 13 16
Bone Marrow Transplant	Stem cell replacement	Only cure; high risk	8 14 15

Table 4: Main Treatment Approaches

Supportive Care

Before the era of targeted therapies, PNH management focused on transfusions for anemia, anticoagulation for clot prevention, and general supportive measures. While still important for symptom control, these do not address the underlying disease 1 14.

Complement Inhibition: Eculizumab and Ravulizumab

Eculizumab is a monoclonal antibody that inhibits the terminal complement component C5, preventing destruction of red blood cells and dramatically reducing the risk of thrombosis. It has transformed the prognosis for many patients, improving survival and quality of life 1 3 8 13 14. Ravulizumab is a newer, longer-acting C5 inhibitor requiring less frequent infusions, with similar efficacy 3 15.

However, not all patients achieve normalization of blood counts. Some remain anemic due to residual hemolysis or underlying bone marrow failure 3 13 15.

Proximal Complement Inhibition: Pegcetacoplan

Pegcetacoplan targets complement protein C3, blocking both intravascular and extravascular hemolysis. Clinical trials show it can improve anemia and reduce transfusion needs in patients not fully controlled by C5 inhibitors 12 13 16. Other proximal inhibitors (targeting factor D or factor B) are in development 13 16.

Bone Marrow Transplantation

The only curative option, bone marrow (stem cell) transplantation, is reserved for patients with severe marrow failure or those who do not respond to complement inhibitors. It carries significant risks and is not suitable for most patients 8 14 15.

Ongoing Challenges and Future Directions

• Some patients continue to experience fatigue, anemia, or breakthrough hemolysis despite optimal therapy 3 13.
• Thrombosis risk, while greatly reduced, is not eliminated 3 10 11.
• New therapies are focusing on more proximal complement inhibition and personalized care 13 16.

Conclusion

PNH is a rare, multifaceted disease that requires individualized, multidisciplinary care. Advances in our understanding of its causes and treatment have transformed outcomes, but challenges remain.

Main Points Covered:

• Symptoms: Fatigue, hemoglobinuria, abdominal pain, dyspnea, and thrombosis are key symptoms, with fatigue being the most common and thrombosis the most severe complication 1 2 3 5 10 11.
• Types: PNH can present as classic (hemolytic), overlap with bone marrow failure, or subclinical, with clinical heterogeneity determined by clone size and marrow function 6 7 8 14.
• Causes: PNH arises from an acquired PIGA mutation, immune-mediated stem cell selection, and subsequent clone expansion, leading to complement-mediated hemolysis and thrombosis 8 9 14.
• Treatment: Modern therapy centers on complement inhibition (C5 and C3), with eculizumab and ravulizumab as established options and pegcetacoplan representing a new frontier. Bone marrow transplantation is curative but high-risk and reserved for select cases 3 8 12 13 14 15 16.

PNH care continues to evolve, with ongoing research promising even better outcomes and quality of life for those affected by this rare disease.