Paroxysmal nocturnal hemoglobinuria

The name is misleading and worth defusing first. The breakdown of red cells in PNH is usually continuous rather than nocturnal, most people never notice dark urine at all, and “paroxysm” refers to visible episodes on top of a constant background. Nothing about the disease is confined to the night.

It is acquired, not inherited. It begins with a change in a gene called PIGA in a single blood-forming stem cell during a person’s life. It is not passed from a parent and cannot be passed to a person’s own children.

PIGA helps build a molecular anchor that fastens certain proteins to the outside of a blood cell. With it broken, those proteins never reach the surface — and two of them, CD55 and CD59, are the brakes on a part of the immune system called complement. Complement circulates in the blood, tags cells it treats as foreign, and punches holes in them. Healthy cells display those two proteins as a “do not attack me” sign. PNH red cells cannot.

The family of cells descended from that one changed stem cell is called the PNH clone. It is worth being clear that this is not a cancer — the clone behaves under normal blood-production control, and the usual course is not evolution into a malignancy, though that is monitored for.

Clone size varies enormously between people, and it drives how the disease behaves. Clinicians distinguish classic PNH, with a large clone and haemolysis; PNH alongside another marrow failure disorder, usually aplastic anemia, where the low counts dominate; and subclinical PNH, a tiny clone found on testing that causes nothing.

A change in PIGA arising in one blood-forming stem cell. Nothing the person did and nothing a parent did causes it, there is no known environmental, dietary or lifestyle trigger, and it is not contagious.

A changed cell on its own is not enough. Everyone develops these clones, and they normally stay at vanishingly low levels without expanding — fewer than one such stem cell per hundred thousand normal ones.

What lets the clone grow is the surrounding situation. The usual setting is aplastic anemia, in which the immune system attacks normal blood-forming stem cells. Cells missing the anchor appear to escape some of that attack, so they gain a relative advantage and can come to dominate blood production.

That is why PNH and aplastic anemia are better understood as two views of one problem than as separate diseases. Roughly a third of people with PNH have previously been diagnosed with aplastic anemia, and most of the rest show some evidence of underlying marrow failure.

Complement attacks the unprotected red cells continuously, bursting them while they are still in the bloodstream. That is the engine of the disease.

The haemoglobin released into the plasma mops up nitric oxide, a small signalling molecule that keeps smooth muscle relaxed. Its depletion makes muscle in the gut and elsewhere clamp down — and that explains a set of symptoms people find hard to raise: difficulty swallowing, abdominal pain, audible gut rumbling, erectile dysfunction. It also explains why the fatigue in PNH is so out of proportion to the haemoglobin level. People are frequently told their count is not that bad.

Anemia and transfusion dependence can run for years. Unusually, people with PNH lose iron in the urine, so they tend not to become iron-overloaded the way other long-term transfusion recipients do — though repeated transfusion can make compatible blood harder to find.

But the thing that actually kills is clotting. NHS England names thrombosis the most common complication and the principal cause of early death. The clots occur in unusual places, which is why they are easy to miss — the veins draining the liver, other veins inside the abdomen, the veins of the brain — and there is a raised rate of stroke and heart attack at young ages. They also recur, sometimes despite anticoagulation.

Separately from all of that, the marrow failure component causes low counts across red cells, white cells and platelets. That part is driven by the failing marrow rather than by complement, which is why complement inhibitors do not fix it.

Complement inhibitors are the backbone of treatment and they are what changed the disease. They switch off the complement attack. They do not remove the PNH clone and they are not a cure — the change in the stem cell remains, and the drugs are taken indefinitely.

The older ones block the last step of the cascade, the one that punches holes in cells: eculizumab by drip every two weeks, ravulizumab roughly every eight, crovalimab by injection monthly. Newer ones act earlier in the cascade — pegcetacoplan by injection, and iptacopan and danicopan as tablets. Six are now approved.

The reason the newer ones exist is worth understanding. On the older drugs, PNH red cells survive the hole-punching step but accumulate other complement fragments on their surface and are then cleared by the spleen and liver instead. So some people stay anemic despite excellent control of the bursting-in-the-bloodstream part. The newer drugs address that.

Every one of these drugs carries a boxed warning, and it is not a formality. Blocking complement raises the risk of serious meningococcal infection, and life-threatening and fatal cases have occurred. Vaccination against the relevant strains must be completed before starting, usually with antibiotic cover as well.

A transplant is the only thing that removes the clone. EBMT grades it generally not recommended for classical PNH, and reserves it for severe marrow failure, for evolution to MDS or leukemia, and for settings where complement inhibitors are not available.

Getting the diagnosis often takes a while. PNH is rare, the test is a specialist laboratory assay rather than a routine one, and the early symptoms — fatigue, anemia, occasionally dark urine — are easily put down to something else.

The fatigue does not match the blood counts, because it is driven by nitric oxide depletion as much as by anemia. Being told your haemoglobin is not that bad, while barely able to get through a day, is a common and demoralising experience.

Several of the symptoms are hard to raise with anyone: abdominal cramping, difficulty swallowing, erectile dysfunction. They are disease rather than embarrassment, and they have a mechanism.

Treatment is a permanent schedule rather than a course — an infusion every two weeks, or every eight, or a capsule every day, depending on the drug. And living with the boxed warning is its own thing: a vaccination record, antibiotics, an instruction to seek help immediately for fever, and a number to call at any hour. That is a real ongoing anxiety rather than a footnote.

For most people diagnosed with PNH today, this is not a story about needing a donor. It is a story about a disease that medicine largely moved out of the transplant column — and if you have just been diagnosed, the most important thing this page can tell you is that you are unlikely to be looking for a match.

A transplant is not the usual treatment for PNH. EBMT grades it generally not recommended for the classical form.

Where a donor can still matter, precisely: severe marrow failure — the aplastic anemia and PNH overlap — evolution to MDS or acute myeloid leukemia, and settings where complement inhibitors are not available or affordable. In those cases the transplant is being done for the marrow failure or the malignancy, not for the haemolysis.

The connection to registry recruitment is honest but indirect. Joining a registry primarily serves people with leukemia, aplastic anemia and other marrow failure — and a minority of people with PNH arrive at a transplant through the aplastic anemia door rather than the PNH one.