Paroxysmal nocturnal hemoglobinuria, or PNH, is a rare blood disease in which your immune system destroys your own red blood cells. It affects roughly 38 per million people worldwide, with fewer than 6 new cases per million diagnosed each year. The destruction happens because affected red blood cells are missing protective surface proteins that normally shield them from a part of the immune system called the complement system.
What Causes PNH
PNH starts with a mutation in a gene called PIGA, which provides instructions for building a protein involved in the very first step of creating tiny molecular anchors on cell surfaces. These anchors, called GPI anchors, act like hooks that hold dozens of different protective proteins in place on the outside of blood cells. When the PIGA gene is mutated, cells either make a defective version of this protein or produce one so small and unstable that it breaks down almost immediately. Without functional anchors, the protective proteins never attach to the cell surface.
Two of those missing protective proteins are especially important. One normally breaks apart immune molecules before they can build up on the cell. The other blocks the final step of an immune attack, preventing a destructive structure called the membrane attack complex from punching holes in the cell membrane. Without these two shields, red blood cells are left completely vulnerable to the complement system, which is always running at a low level in the bloodstream. The result is a steady, ongoing destruction of red blood cells inside blood vessels.
Unlike most genetic diseases, PNH is not inherited. The PIGA mutation happens spontaneously in a single blood-forming stem cell in the bone marrow. That mutant cell then multiplies, producing a growing population of defective blood cells alongside normal ones. The proportion of affected cells, often called the “PNH clone,” varies widely between patients and largely determines how severe symptoms are.
Symptoms and How They Feel
The most recognizable symptom is dark or cola-colored urine, especially first thing in the morning. This happens because hemoglobin released from destroyed red blood cells gets filtered through the kidneys overnight. The disease’s name literally describes this pattern: paroxysmal (sudden episodes), nocturnal (at night), hemoglobinuria (hemoglobin in the urine). That said, not everyone with PNH notices dark urine, and the hemolysis actually occurs around the clock, not just during sleep.
Fatigue is the most common complaint and often the most disabling. It goes beyond ordinary tiredness. Because red blood cells are constantly being destroyed, oxygen delivery throughout the body drops, leading to persistent exhaustion, shortness of breath, and general malaise. Many patients also experience abdominal pain, back pain, difficulty swallowing, and esophageal spasms. These symptoms arise because the free hemoglobin released during red blood cell destruction scavenges nitric oxide, a molecule that keeps smooth muscles relaxed. Without enough nitric oxide, smooth muscles in the gut, esophagus, and blood vessels can go into spasm. Erectile dysfunction can occur through the same mechanism.
Over time, the iron released from destroyed red blood cells deposits in the kidneys, causing a type of kidney damage called tubulointerstitial inflammation. This can progress to kidney insufficiency if left untreated.
Blood Clots: The Most Dangerous Complication
Thrombosis is the leading cause of death and serious disability in PNH. Up to 40% of people with the classic form of the disease will experience at least one blood clot. About 85% of these clots are venous, and they tend to strike in unusual locations that set PNH apart from typical clotting disorders.
The most common sites are the intra-abdominal veins, including the hepatic veins. A clot in the hepatic veins causes Budd-Chiari syndrome, which can lead to liver failure. Clots also occur in the mesenteric veins (serving the intestines), renal veins, cerebral veins, and skin veins. Arterial clots are less common but still occur more frequently than in healthy individuals, with coronary arteries among the most affected. Roughly one in five patients who experience a clot will have clots in more than one location at the same time.
How PNH Is Diagnosed
The gold standard for diagnosing PNH is a blood test called flow cytometry. This technology uses laser light to examine individual blood cells and detect whether GPI-anchored proteins are present on their surfaces. Doctors look at both red blood cells and white blood cells (specifically neutrophils and monocytes). Guidelines require that at least two different GPI-linked proteins be missing on white blood cells to confirm the diagnosis.
The test also classifies affected cells into types. Type III PNH cells are completely missing all GPI-anchored proteins, while Type II cells have a partial deficiency. A specialized reagent called FLAER, a fluorescent version of a bacterial toxin that naturally binds to GPI anchors, is particularly effective at identifying affected white blood cells. For red blood cells, a protein called CD59 is the primary marker tested, since it gives the clearest signal.
PNH is often discovered during workups for unexplained anemia, unusual blood clots in young people, or bone marrow failure syndromes like aplastic anemia. Roughly 2 to 6% of PNH patients will develop severe bone marrow failure within 10 years of diagnosis, sometimes progressing to a pre-leukemic condition or acute leukemia.
Treatment With Complement Inhibitors
The standard treatment for PNH targets the complement system directly. The first breakthrough came with a C5 inhibitor, a medication given by infusion every two weeks that blocks the complement cascade right before it can form the membrane attack complex. This drug improved survival by at least 75% compared to the era of supportive care alone, when about 35% of patients died within five years.
A longer-acting version of this C5 inhibitor was approved in 2018. It works through the same mechanism but requires infusions only every eight weeks after an initial loading dose, with dosing based on body weight. Both medications dramatically reduce the destruction of red blood cells inside blood vessels and lower the risk of blood clots.
However, C5 inhibitors have a limitation. While they prevent intravascular hemolysis (the explosive destruction of red blood cells in the bloodstream), they don’t stop a subtler process called extravascular hemolysis. When C5 is blocked, fragments of a complement protein called C3b still accumulate on PNH red blood cells. These tagged cells get recognized and consumed by immune cells in the spleen and liver. For many patients, this residual destruction is why they still need blood transfusions and still feel fatigued despite treatment.
Newer Approaches Targeting C3
A newer class of treatment works further upstream in the complement cascade by targeting C3, the protein that feeds into both the intravascular and extravascular destruction pathways. Pegcetacoplan, an FDA-approved C3 inhibitor, binds to both C3 and C3b, providing broader suppression of complement activity. In clinical trials, patients who had never received complement inhibitors reached normal hemoglobin levels by around day 85 of treatment. The drug also reduced C3 deposition on PNH red blood cells, directly addressing the extravascular hemolysis that C5 inhibitors leave behind.
This represents a meaningful shift in treatment, since data show that neither of the C5 inhibitors fully controls the disease on their own. Patients who continue to have significant anemia despite C5 inhibitor therapy are candidates for C3-targeted treatment.
Bone Marrow Transplant as a Cure
The only potential cure for PNH is an allogeneic bone marrow transplant, which replaces the patient’s defective stem cells with healthy donor cells. A multicenter analysis of 78 transplanted PNH patients found that the procedure effectively eliminated the PNH clone with acceptable toxicity and satisfactory overall survival. It remains a valid option, particularly for patients with bone marrow failure or those whose disease cannot be controlled with complement inhibitors. However, transplant carries significant risks, including graft-versus-host disease and infection, so it is typically reserved for patients with severe or refractory disease rather than offered as a first-line treatment.