Paroxysmal Nocturnal Hemoglobinuria (PNH)

Aug 1
8 min read

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hematologic disorder in which a genetic mutation in bone marrow stem cells causes the immune system to destroy red blood cells, white cells, and platelets. This uncontrolled immune activation leads to intravascular hemolysis, bone marrow dysfunction, and thrombosis, which remains the leading cause of death in untreated cases. Advances in targeted complement inhibition have transformed PNH from a fatal disease into a manageable chronic condition.

Overview

What is paroxysmal nocturnal hemoglobinuria?

Paroxysmal nocturnal hemoglobinuria (PNH) is named for its most recognizable sign—dark or reddish-brown urine noticed at night or in the early morning—caused by red blood cell breakdown and the release of hemoglobin into the urine. “Paroxysmal” means sudden, “nocturnal” means night, and “hemoglobinuria” refers to hemoglobin in the urine.

This breakdown occurs because a defective immune-regulating mechanism allows the body’s complement system to attack its own blood cells. The destruction of red blood cells (hemolysis) releases hemoglobin, depletes nitric oxide, and triggers a cascade that can lead to anemia, kidney injury, abdominal pain, and life-threatening blood clots. Complement inhibitors such as eculizumab and ravulizumab now prevent this immune destruction and have reduced the annual mortality of PNH to less than 5% (Hillmen et al., Blood, 2023).

Common Questions

What is the difference between hemoglobinuria and hematuria?

Both hemoglobinuria and hematuria refer to the presence of blood-related substances in urine, but they stem from entirely different processes and carry very different implications for diagnosis and severity.

Hematuria occurs when intact red blood cells leak into the urine, usually due to bleeding somewhere along the urinary tract—from the kidneys, ureters, bladder, or urethra. It often results from infection, inflammation, kidney stones, trauma, or malignancy. Under a microscope, red blood cells can be seen intact, confirming that the bleeding originated within the urinary system itself.

Hemoglobinuria, by contrast, signifies the presence of free hemoglobin—the oxygen-carrying pigment from destroyed red blood cells—rather than whole cells. This occurs when red blood cells rupture in the bloodstream (a process called intravascular hemolysis), releasing hemoglobin, which the kidneys then filter into urine. In paroxysmal nocturnal hemoglobinuria (PNH), this is a defining feature: as complement activation destroys red cells, massive amounts of hemoglobin enter circulation, turning the urine dark red or brown, particularly after overnight accumulation.

High-Risk Populations

Who is most at risk for paroxysmal nocturnal hemoglobinuria?

Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon but severe acquired blood disorder that affects an estimated 15–16 individuals per million worldwide, with roughly one new case diagnosed per million each year (International PNH Registry, 2024). Although it can occur at any age, PNH most often develops in adults aged 30 to 50 and shows a slight predominance in women.

The condition originates from a genetic mutation in hematopoietic stem cells, meaning it is not inherited but acquired during a person’s lifetime. For many patients, it emerges in the context of bone marrow failure syndromes such as aplastic anemia (AA) or myelodysplastic syndromes (MDS). These disorders share a common mechanism—injury to the bone marrow’s stem cells—and may precede or evolve into PNH over time. Up to 40% of patients with aplastic anemia eventually develop PNH clones, and the coexistence of these two conditions complicates both diagnosis and treatment.

PNH affects both men and women, but women face unique vulnerabilities due to the influence of hormonal and physiologic factors on the immune and coagulation systems. The disease may first manifest during pregnancy or the postpartum period, when complement activity naturally increases and the body’s coagulation balance shifts toward clot formation. These physiologic changes heighten the risk of hemolytic crises, severe anemia, and life-threatening thrombosis, particularly in the hepatic, mesenteric, and cerebral veins. Pregnancy-related PNH carries a maternal mortality rate historically reported as high as 20–30%, though modern complement inhibition therapy has reduced these rates dramatically (de Latour et al., Lancet Haematology, 2023).

Certain additional populations are also at elevated risk:

Postoperative and critically ill patients, where inflammatory triggers can exacerbate complement activation and hemolysis.
Individuals with immune-mediated marrow injury, who are more likely to harbor dormant PNH clones that can expand over time.
Patients of Asian descent, who appear slightly overrepresented in registry data, possibly due to regional differences in aplastic anemia prevalence.

Ultimately, anyone with unexplained hemolytic anemia, recurrent venous thrombosis, or bone marrow failure should be evaluated for PNH. Because the disease can remain undetected for years—especially in women whose early symptoms are misattributed to fatigue, anemia of pregnancy, or hormonal imbalance—timely recognition and testing can mean the difference between a manageable chronic condition and irreversible organ damage.

Causes

What causes paroxysmal nocturnal hemoglobinuria?

Paroxysmal nocturnal hemoglobinuria (PNH) develops when a somatic mutation occurs in the PIGA gene within a bone marrow stem cell. This mutation disrupts the synthesis of glycosylphosphatidylinositol (GPI) anchors, molecules that attach protective surface proteins—most notably CD55 and CD59—to red and white blood cells. Without these proteins, cells lose their ability to regulate complement activity and become targets for immune-mediated destruction.

In the absence of CD55 and CD59, complement proteins attack and destroy unprotected red blood cells inside blood vessels, a process called intravascular hemolysis. This releases large amounts of free hemoglobin into the circulation. The free hemoglobin binds to and depletes nitric oxide (NO), a molecule essential for smooth muscle relaxation and vascular tone. Its loss causes abdominal pain, esophageal spasms, erectile dysfunction, and pulmonary hypertension.

As hemolysis accelerates, the bone marrow cannot replace destroyed red blood cells fast enough, leading to chronic hemolytic anemia. The accumulation of free hemoglobin in the kidneys damages renal tubules, making chronic kidney disease a frequent complication—reported in up to 60% of long-standing PNH cases (Sugimori et al., Haematologica, 2022). Overnight urine concentration amplifies hemoglobin excretion, explaining the characteristic dark or reddish urine noted in the morning.

The same PIGA mutation also affects platelets, creating complement-sensitive, hyperreactive cells that release procoagulant microparticles. This overactivates thrombin generation and drives a state of severe hypercoagulability. As a result, thrombosis develops in approximately 40% of patients, most often in the hepatic, mesenteric, or cerebral veins, where it can be fatal if untreated (de Latour et al., Lancet Haematology, 2023).

Symptoms

What are the most common symptoms of paroxysmal nocturnal hemoglobinuria?

Although named for its urinary presentation, paroxysmal nocturnal hemoglobinuria (PNH) affects multiple organ systems and rarely begins with hemoglobinuria alone. Most patients initially seek care for fatigue, weakness, or anemia-related symptoms. The disease evolves as complement-mediated damage extends beyond red blood cells to platelets and the vascular endothelium.

Common symptoms include:

Fatigue, weakness, or pallor
Shortness of breath (dyspnea) or decreased exercise tolerance
Abdominal or back pain due to nitric oxide depletion
Difficulty swallowing (dysphagia) or esophageal spasms
Dark or reddish-brown urine, particularly overnight or upon waking
Kidney impairment or elevated creatinine
Erectile dysfunction or menstrual irregularities from vascular instability
Unexplained or recurrent blood clots, especially in hepatic or cerebral veins

PNH symptoms often fluctuate in severity and may worsen with infection, surgery, or pregnancy—periods when complement activity naturally increases.

Diagnosis and Tests

How do healthcare providers diagnose paroxysmal nocturnal hemoglobinuria?

Diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) requires a combination of clinical suspicion, laboratory evidence of hemolysis, and confirmatory flow cytometry testing. Because PNH can mimic other causes of anemia or thrombosis, healthcare providers rely on a stepwise evaluation to identify the characteristic pattern of red blood cell destruction and complement sensitivity.

Initial laboratory studies help detect evidence of ongoing hemolysis and organ involvement:

Complete Blood Count (CBC with Differential): Reveals anemia, leukopenia, or thrombocytopenia—common findings in PNH due to bone marrow injury.
Basic Metabolic Panel (BMP): Evaluates kidney function, which can decline from chronic hemoglobin-mediated injury.
Urinalysis: Detects hemoglobinuria (free hemoglobin in urine) and hemosiderin deposition, reflecting repeated intravascular hemolysis.
Reticulocyte Count: Measures bone marrow response. Elevated reticulocytes suggest compensation for ongoing red cell loss.
Haptoglobin: Low or undetectable levels indicate hemolysis, as haptoglobin binds and removes free hemoglobin from circulation.
Lactate Dehydrogenase (LDH): Markedly elevated LDH is a hallmark of intravascular red blood cell destruction.
Bilirubin and Liver Function Tests: Indirect bilirubin rises as the liver processes the byproducts of red cell breakdown.

The definitive diagnostic tool for PNH is flow cytometry, which identifies red and white blood cells lacking GPI-anchored surface proteins such as CD55 and CD59. Modern high-sensitivity flow cytometry can detect very small PNH cell populations—as low as 0.01%—allowing for early diagnosis even in patients with mild or overlapping bone marrow disorders.

Because PNH can appear alongside aplastic anemia or myelodysplastic syndromes, clinicians often perform bone marrow evaluation to assess cellularity and exclude other hematologic conditions. Early recognition through this combination of laboratory and cytometric testing allows timely initiation of life-saving therapy.

Management and Treatment

How do healthcare providers treat paroxysmal nocturnal hemoglobinuria?

The cornerstone of paroxysmal nocturnal hemoglobinuria (PNH) management is complement inhibition therapy, which blocks the immune cascade responsible for red blood cell destruction. These targeted biologic agents—eculizumab and ravulizumab—bind to complement protein C5, preventing it from triggering hemolysis and thrombosis.

Before complement inhibitors became available, treatment centered on supportive transfusions and immunosuppressive therapy, and average survival ranged from 10 to 22 years after diagnosis. Today, with complement blockade, life expectancy approaches that of the general population (Hillmen et al., Blood, 2023).

Additional management may include:

Iron and folate supplementation to support red cell production
Anticoagulation in patients with a history of thrombosis
Allogeneic stem cell transplantation, reserved for severe cases with marrow failure, remains the only curative option, though it carries significant risk

Treatment Side Effects

What risks and side effects should I be aware of while receiving complement inhibitor therapy?

Complement inhibitors such as eculizumab and ravulizumab have revolutionized the management of PNH, but they come with real risks that patients must fully understand before beginning therapy. These medications work by blocking the complement protein C5, a key part of the immune system that attacks pathogens. While this prevents destruction of red blood cells, it also weakens one of the body’s front-line defenses against certain bacteria.

The most serious risk is life-threatening infection, particularly from Neisseria meningitidis, the bacteria that cause meningococcal meningitis and sepsis. The complement system is critical for killing these encapsulated organisms, and once it is suppressed, patients become far more vulnerable. Infections can progress rapidly—sometimes within hours—and are fatal in 10–15% of cases even with treatment. For this reason, vaccination against meningococcus is mandatory before starting therapy, including both the MenACWY and MenB vaccines. Some patients also require prophylactic antibiotics, especially during the first few weeks of therapy or if vaccination cannot be completed in time.

Complement blockade may also increase susceptibility to other encapsulated bacteria, such as Streptococcus pneumoniae and Haemophilus influenzae, making broader immunization and vigilant infection monitoring essential. Patients should be instructed to seek emergency care immediately if they experience symptoms like sudden fever, headache, neck stiffness, rash, or chills.

Other side effects are generally mild but should not be dismissed:

Infusion-related reactions (flushing, nausea, back pain, or mild fever) occur in up to 10% of patients during administration.
Headaches are common early in therapy and are attributed to changes in nitric oxide metabolism once hemolysis subsides.
Fatigue or muscle aches may persist temporarily as the body stabilizes after prolonged anemia and inflammation.
Breakthrough hemolysis can occur if doses are delayed or if the complement system reactivates between infusions, sometimes causing sudden fatigue, dark urine, or abdominal pain.

Though complement inhibitors are highly effective, they require lifelong commitment, vaccination maintenance, and continuous monitoring. Patients must be empowered with the knowledge that their immune system is permanently altered while on therapy—and that survival now depends on proactive infection prevention, adherence to infusion schedules, and immediate action at the first sign of illness.

Outlook and Prognosis

Can paroxysmal nocturnal hemoglobinuria be cured?

While complement inhibitors do not cure PNH, they effectively halt red blood cell destruction, prevent thrombosis, and restore near-normal quality of life. Most patients develop some degree of anemia, which can require ongoing supportive therapy. The only definitive cure is stem cell transplantation, but it is reserved for patients with severe marrow failure or refractory disease due to its high complication rate.

Prevention

Can I prevent paroxysmal nocturnal hemoglobinuria?

PNH cannot be prevented, as it arises from a random, acquired mutation in the PIGA gene of bone marrow stem cells. However, early recognition and treatment can prevent the life-threatening complications of the disease. Regular monitoring, particularly in patients with aplastic anemia or unexplained hemolysis, ensures that any emerging PNH clone is detected promptly and managed before irreversible organ damage occurs.

The IWBCA provides the information and materials on this site for educational and informational purposes only. The content is not a substitute for professional medical evaluation, diagnosis, or treatment. Always consult your physician or another qualified healthcare provider regarding any questions you may have about a medical condition, diagnosis, or course of treatment. Do not disregard, delay, or alter medical advice based on information obtained from this site. If you believe you are experiencing a medical emergency, call 911 or your local emergency services immediately.