Paroxysmal nocturnal hemoglobinuria (PNH) is a rare blood disorder in which the immune system destroys its own red blood cells. It affects roughly 38 out of every million people worldwide, with fewer than 6 new cases per million each year. The disease stems from a genetic change in blood-forming stem cells that strips red blood cells of their natural protection against a branch of the immune system called the complement system. The result is chronic anemia, dark urine, debilitating fatigue, and a dangerously high risk of blood clots.
What Causes PNH
PNH begins with a mutation in a gene called PIGA inside a single blood-forming stem cell in the bone marrow. This mutation is not inherited from a parent. It happens spontaneously at some point during a person’s life, which is why PNH can appear at any age.
The PIGA gene provides instructions for building a molecular anchor that attaches protective proteins to the surface of blood cells. When the gene is mutated, affected stem cells can no longer produce this anchor. Every red blood cell that descends from that stem cell is missing two key surface proteins that normally shield it from the complement system, a part of the immune defense that tags and destroys foreign or damaged cells. Without those protective proteins, the complement system treats healthy red blood cells as targets and punches holes in them, causing them to burst open inside blood vessels.
How Red Blood Cells Are Destroyed
In a healthy person, the complement system constantly scans blood cells but is kept in check by surface proteins that essentially say “don’t attack me.” PNH red blood cells lack these signals, so the complement cascade proceeds unchecked. The end result is a structure called the membrane attack complex, which literally punctures the cell membrane. When red blood cells rupture this way inside blood vessels, they release their hemoglobin directly into the bloodstream. This process is called intravascular hemolysis, and it is the central problem in PNH.
Free hemoglobin in the blood is toxic. It binds to nitric oxide, a molecule your body uses to relax smooth muscle in blood vessel walls, the digestive tract, and other organs. The loss of nitric oxide explains many of PNH’s seemingly unrelated symptoms: abdominal pain, difficulty swallowing, back pain, and erectile dysfunction all trace back to smooth muscle spasms triggered by hemoglobin soaking up nitric oxide.
Symptoms and Daily Impact
The disease’s full name offers a clue to one classic symptom. “Hemoglobinuria” means hemoglobin in the urine, and “nocturnal” reflects the old observation that dark or cola-colored urine was most noticeable in the morning. In practice, hemolysis happens around the clock, not just at night, and many patients never notice the urine color change at all.
The most common symptoms are far less dramatic but no less disabling:
- Fatigue and malaise that go well beyond ordinary tiredness, often severe enough to interfere with work and daily activities
- Shortness of breath from anemia, since fewer intact red blood cells means less oxygen delivery
- Dark urine from hemoglobin filtered through the kidneys
- Abdominal pain, back pain, and difficulty swallowing caused by smooth muscle spasms
- Kidney damage over time, as iron deposits from destroyed red blood cells accumulate in kidney tissue
Most patients don’t arrive at a doctor’s office with a textbook presentation. They show up with vague, nonspecific complaints like crushing fatigue or unexplained anemia, which is one reason PNH often goes undiagnosed for years.
Blood Clots: The Most Dangerous Complication
Thrombosis is the leading cause of serious illness and death in PNH. Roughly one-third of patients experience at least one blood clot during the course of their disease. In a Greek national study, 39% of patients had a clot, and nearly half of those events occurred at the time of diagnosis or before PNH was even identified.
What makes PNH clots unusual is where they form. The most common sites are the intra-abdominal veins, including the hepatic veins that drain the liver and the portal vein. Clots in these locations are rare in the general population, so an unexplained clot in the liver or abdominal veins is often the event that finally triggers PNH testing. Patients with large populations of affected cells (more than 50% of white blood cells lacking the protective surface proteins) face the highest clot risk.
How PNH Is Diagnosed
The gold standard for diagnosing PNH is a blood test called flow cytometry. This test uses fluorescent markers to check whether white blood cells, red blood cells, and their precursors are carrying the surface proteins that should be anchored by the PIGA-dependent system. A reliable screening panel checks at least two different markers on multiple cell types, typically white blood cells called granulocytes and monocytes, plus red blood cells or their immature form (reticulocytes).
Flow cytometry can detect even very small populations of affected cells and quantify their size. The clone size matters because it correlates with disease severity. Patients whose red blood cells show more than 20% of the most severely deficient type generally have clinically significant anemia. Standard blood work will also show signs of ongoing red blood cell destruction: elevated lactate dehydrogenase (LDH), elevated indirect bilirubin, and very low or undetectable haptoglobin, a protein that normally mops up free hemoglobin.
Connection to Bone Marrow Failure
PNH sits in a family of bone marrow failure diseases that includes aplastic anemia and myelodysplastic syndromes (MDS). These conditions overlap in significant ways. Many people diagnosed with aplastic anemia carry small PNH clones that may or may not expand over time. Conversely, some PNH patients develop signs of broader bone marrow failure, producing too few white blood cells or platelets alongside their anemia. Patients who develop MDS or acute myeloid leukemia in addition to PNH tend to have a shorter lifespan, which is why ongoing monitoring of blood counts matters even after PNH treatment begins.
Treatment With Complement Inhibitors
The introduction of drugs that block the complement system transformed PNH from a disease with poor survival into one most patients can manage for decades. These medications work by intercepting the complement cascade before it can destroy red blood cells.
The first generation of treatment targets a complement protein called C5. One option requires an intravenous infusion every two weeks. A longer-acting version, approved more recently, needs a loading dose followed by infusions every eight weeks, which significantly reduces the treatment burden. Both effectively stop intravascular hemolysis, raising hemoglobin levels, lowering the need for transfusions, and dramatically reducing clot risk. Four- to five-year survival on C5 inhibitor therapy ranges from 95.5% to 98.3%, compared with 66.8% to 79.7% in untreated patients.
However, C5 inhibitors have a limitation. By blocking the late stage of complement activation, they allow an earlier part of the cascade to deposit complement fragments on red blood cells. These tagged cells aren’t destroyed inside blood vessels, but they are removed by the spleen and liver in a process called extravascular hemolysis. Some patients remain anemic despite C5 treatment for this reason.
Newer Options Targeting C3
A newer class of treatment targets complement protein C3, which sits earlier in the cascade. By blocking complement at this higher level, these drugs control both intravascular and extravascular hemolysis. In a head-to-head trial published in the New England Journal of Medicine, a C3 inhibitor produced significantly greater improvements in hemoglobin than a standard C5 inhibitor in patients who were already on C5 therapy. This option is given as an injection under the skin rather than intravenously, which some patients prefer.
Vaccination Before Starting Treatment
Blocking complement activity does come with a tradeoff: it weakens the body’s defense against certain bacteria, particularly the ones that cause meningococcal disease. Before starting any complement inhibitor, you need vaccination against meningococcal bacteria. The CDC recommends both the MenACWY vaccine (covering four strains) and the MenB vaccine (covering a fifth), ideally completed at least two weeks before the first drug dose. You’ll also need booster shots for as long as treatment continues: every five years for MenACWY and every two to three years for MenB. Some doctors also prescribe a daily antibiotic as an added layer of protection.
Long-Term Outlook
Before complement inhibitors were available, PNH carried a 10-year survival rate of about 68%, with blood clots as the primary killer. Modern treatment has shifted those numbers dramatically, with survival now approaching that of the general population for many patients. Most people with PNH today live for decades after diagnosis.
The disease does require lifelong management. Complement inhibitors control symptoms but do not eliminate the underlying mutant stem cell clone, so stopping treatment allows hemolysis to return. The only potentially curative option is a bone marrow transplant, which replaces the defective stem cells entirely. Transplant carries its own serious risks, though, so it is generally reserved for patients with severe bone marrow failure or life-threatening complications that don’t respond to complement inhibitor therapy.