PNH and aplastic anaemia: how the two conditions connect

A rare disorder that often turns up beside aplastic anaemia

Some people with aplastic anaemia are later found to have a second condition called paroxysmal nocturnal haemoglobinuria, usually shortened to PNH. The two can overlap, and the connection confuses many families when they first hear about it. This page explains what PNH is, why it tends to come up in people with bone marrow failure, how it is tested for, and what treatment and monitoring usually involve.

PNH is rare. StatPearls quotes estimates as high as 15.9 cases per million people worldwide and notes that many cases probably go unrecognised. Americans will often see the spelling "anemia" and the longer name paroxysmal nocturnal hemoglobinuria, but the condition is the same.

What PNH is, in plain terms

PNH is an acquired condition. It is not something a person is born with, and it is not passed from parent to child. During a person's lifetime, a change in the PIGA gene occurs in one blood-forming stem cell in the bone marrow. MedlinePlus Genetics explains that most cases come from new changes in this gene, usually in people with no earlier family history.

The altered stem cell copies itself, and its descendants make red cells that lack a protective layer. The PIGA gene normally helps build an anchor that holds protective proteins on the surface of cells. Two of these proteins, CD55 and CD59, guard red cells against the complement system, a group of blood proteins that attack abnormal cells. Without them, complement destroys the red cells early. Doctors call this haemolysis, and it is the main reason PNH causes anaemia.

Signs that often lead to a diagnosis

The name can mislead. Paroxysmal means sudden and irregular, and dark urine from haemoglobin is the sign that gave the condition its name. AAMDS points out that many people with PNH never notice dark urine, so its absence does not rule the condition out.

The most common features are tiredness, shortness of breath and pale skin, all linked to the shortage of red cells. Blood clots are another key feature. StatPearls reports that about 40 per cent of people with PNH have a clot at some point, and that clots in the veins of the abdomen, especially the hepatic vein, are the most common type. Symptoms vary a great deal, which is one reason diagnosis is often delayed.

• Dark urine, sometimes most noticeable first thing in the morning
• Tiredness, breathlessness and pale skin
• Blood clots, often in veins of the abdomen
• Tummy pain or difficulty swallowing

If you notice dark urine or an unexplained clot, tell your haematology team promptly.

Why PNH so often shows up with aplastic anaemia

This is the question most people want answered. AAMDS describes aplastic anaemia as the only known risk factor for developing PNH, and estimates that more than 10 in every 100 people with aplastic anaemia go on to develop it. Some people with PNH later develop aplastic anaemia as well, and the two conditions share features such as low blood counts.

Nobody fully understands the reason. One idea is that a marrow weakened by aplastic anaemia, or by mild marrow failure that has not been diagnosed, gives PNH cells room to grow. MedlinePlus adds that some abnormal immune cells may mistakenly attack normal blood-forming cells, a process called autoimmunity, and that this may also favour the PNH clone. The wider overlap between these conditions is discussed in acquired and inherited bone marrow failure, and the marrow side of aplastic anaemia is covered in what aplastic anaemia is.

StatPearls describes three groups. Classic PNH shows haemolysis alone. PNH with another marrow disorder shows haemolysis together with a marrow problem such as aplastic anaemia or MDS. Subclinical PNH is a PNH clone found without signs of haemolysis. Specialists often reassess a clone of that kind every 6 to 12 months.

How doctors test for PNH

The standard test is flow cytometry. Cells are tagged with antibodies and with a labelled reagent called FLAER, which binds to the anchor molecules. StatPearls calls flow cytometry the gold standard. Testing for at least two anchored proteins helps avoid a false negative caused by a rare inherited absence of a single protein.

Routine blood tests often give the first clue. Low counts, raised LDH, low haptoglobin and signs of haemoglobin or iron in the urine all point towards PNH, according to StatPearls. Where the PNH granulocyte clone is above 20 per cent, specialists look more closely for hidden clots and organ damage. A bone marrow sample may also be taken to check for a second marrow disorder, as described in diagnosing bone marrow failure.

Treatment and what has changed

Treatment used to be mostly supportive, with transfusions, iron, blood thinners to reduce clots, and a stem cell transplant reserved for serious marrow complications. The picture changed with complement inhibitors. Eculizumab and ravulizumab work by blocking part of the complement pathway, so the attack on red cells is reduced. StatPearls reports that eculizumab cut transfusion needs by more than half and reduced the risk of clotting events by close to 70 per cent.

Ravulizumab, which was approved for PNH in the United States in December 2018, was developed to address some limits of eculizumab. These drugs raise the risk of serious infection, particularly from encapsulated bacteria such as meningococcus, so people are usually vaccinated and given preventive antibiotics before they start. A transplant from a donor, called an allogeneic stem cell transplant, is also an option in some cases. The broader treatment picture for marrow failure is set out in aplastic anaemia treatment.

Living with a rare condition raises practical questions about work, travel and planning around tiredness or clots. Many people find it useful to bring a written list of questions to each appointment.

Monitoring and the outlook

Monitoring usually means regular blood counts, kidney and liver checks, and a close watch for clots and haemolysis. Scans of the abdomen, heart or head are used when a clot is suspected, according to StatPearls.

The outlook has improved. StatPearls notes that 10-year survival was about 50 per cent four or five decades ago and rose above 75 per cent in the era of eculizumab. AAMDS says many people with PNH live for decades, and it describes older estimates of 15 to 20 years as out of date. PNH is not a cancer, but AAMDS estimates that on average 2 in 100 people with PNH go on to develop MDS, and MedlinePlus notes an increased risk of leukaemia. That is why regular blood tests matter.

The ongoing support available to people with PNH in England, Wales and Northern Ireland is described by PNH Support, a patient community that also shares information about the condition.

The takeaway for families facing both diagnoses

PNH is a separate, acquired problem in a set of blood cells, and it is most often found because it sits alongside marrow failure. Flow cytometry is the test that settles the question, and the treatments now available have changed what people can expect. If you have aplastic anaemia, ask your team whether PNH testing has been done and when any clone will be checked again.