What causes PNH?

It is not fully understood why people develop PNH. Inside the bone marrow, blood cells are made by stem cells (the seed cells of the marrow). PNH occurs due to a change (or mutation) in a gene in one of the stem cells in the bone marrow. This mutation happens in a gene called PIG-A and the cells made by this stem cell lack certain proteins on their surface making them ‘weaker’ than normal blood cells. The mutation is “acquired” meaning that it develops in the bone marrow stem cell whilst it is multiplying but is not present from birth. We have evidence that almost all people in the population will develop a PNH mutation at some time but as the resulting PNH cells are weak they rarely grow to a level that they can be routinely detected. Normal blood cells have proteins on the surface that protect the cells from part of the immune system. PNH cells don’t have these protective proteins, which is what makes them ‘weaker’ and causes them to be either destroyed (red cell haemolysis) or activated or stimulated (white blood cells and platelets).

Who gets PNH?

PNH is an extremely rare condition and is thought to affect around 16 people per million in the United Kingdom. It is not an inherited condition, meaning it cannot be passed on from parents to children. Equally, you cannot catch PNH from someone who has it. It can occur at any age. Men and women are affected equally.

PNH and bone marrow failure

PNH is associated with other blood conditions, particularly Aplastic Anaemia (AA) and Myelodysplasia (MDS). Both AA and MDS are types of bone marrow failure meaning the bone marrow is unable to make blood cells normally. In AA, the bone marrow cells look normal but there are just too few present to make enough blood cells whereas in MDS the marrow cells look abnormal and cannot make blood efficiently. In AA and MDS, patients usually have reduced levels of platelets, red and white blood cells. These are the different blood cells normally produced in the bone marrow. Treatment for patients with PNH may be directed at the bone marrow failure as well as PNH itself.

The function of the bone marrow

The main purpose of the bone marrow is to produce blood cells. There are three main types of blood cells made by the bone marrow: red blood cells, white blood cells and platelets.

• Red blood cells carry oxygen around the body as they contain haemoglobin which binds and transports oxygen. Anaemia is where the level of red cells, and therefore the haemoglobin, is low. The symptoms of anaemia include tiredness, palpitations, breathlessness and looking pale.
• White blood cells are responsible for fighting infections and a low white cell count can mean people are more prone to develop infections.
• Platelets are blood cells involved in blood clotting. Low platelet counts are associated with increased bruising and bleeding. Activated (or stimulated) platelets can clump together in the wrong place leading to the formation of blood clots (also known as thromboses).

Why PNH?

PNH was named a long time ago after a description of the symptoms observed in patients. However, the name does not fit for all people who have PNH. “Paroxysmal” refers to symptoms occurring intermittently, “haemoglobinuria” to haemoglobin seen in urine (discolouring it dark red or black urine) and “nocturnal” to it occurring at night (or usually first thing in the morning). In reality the condition is present all the time and not everyone experiences dark urine.

Symptoms

There can be a marked variation in the signs and symptoms observed due to PNH both between patients and in the same patient at different times. Some people exhibit no symptoms whereas others may be affected by a number of very different disease symptoms and complications. Patients with no or few symptoms can still sometimes suffer from complications. These can dramatically affect people’s everyday lives and without treatment some of them can be life threatening. Over time the symptoms experienced by anyone with PNH can change. In some people, symptoms occur all the time and in others only when an episode of haemolysis is experienced. Some of the more common symptoms are listed below:

• Haemoglobinuria – Dark or black urine due to free haemoglobin in the urine. This occurs due to the destruction of red blood cells (haemolysis) that occurs in the circulation so that the red cells effectively burst. This leads to the release of haemoglobin, that is usually packaged inside the red cells, into the plasma (the liquid part of the blood) and this then overflows through the kidneys into the urine. Haemoglobinuria can be confused with haematuria (bleeding into the urine) which often leads to some patients having investigation to look for bleeding.
• Anaemia – Anaemia occurs commonly in PNH due to the constant destruction of red blood cells. It can also be aggravated by bone marrow failure which co-exists in some patients with PNH. Anaemia in turn causes increased tiredness, fatigue and breathlessness.
• Breathlessness – This is in part due to anaemia but can also be experienced due to increased blood pressure in the lungs (pulmonary hypertension) that may occur in PNH. If breathlessness occurs suddenly then it is important to exclude other causes such as infection or blood clots going to the lungs. These are rare but important alternative explanations.
• Difficulty swallowing and abdominal pain – As PNH red blood cells are destroyed, their contents, particularly the haemoglobin, are released into the circulation. Haemoglobin is not meant to be free in the plasma as it binds other gases as well as oxygen. One of these, called nitric oxide, is used by the body to help the muscles of the intestine (amongst other muscles) to work properly. If there is free haemoglobin in the plasma and therefore a low level of nitric oxide this leads to spasm in the muscles of the intestinal/digestive system. This can affect the oesophagus (gullet) causing difficulty swallowing and/or the intestines causing abdominal pain. Occasionally, the abdominal pain is due to a blood clot and this will also need investigations for exclusion.
• Erectile dysfunction – Around half of men with PNH are affected by erectile dysfunction. This also appears to be due to the depletion of nitric oxide by free haemoglobin and is generally worse during an attack of haemoglobinuria.
• Fatigue – Fatigue and tiredness are very common in PNH. Fatigue is something that is difficult to quantify but can be extremely debilitating meaning that some patients at times cannot even manage very mild activity. This is also possibly a symptom of nitric oxide depletion and can occur even when the haemoglobin level is relatively good.
• Jaundice – Yellow discolouration of the sclera (whites of the eye) and the skin due to the continued destruction of red blood cells. The yellow colour is due a substance called bilirubin which is a breakdown product of haemoglobin and is usually processed by the liver. When the level of haemolyis is very high the liver has difficulty processing the bilirubin quickly enough leading to jaundice.
• Kidney damage – This can vary from those mildly affected to kidney failure requiring dialysis treatment (this severity is very rare). The kidney problems in PNH can occur due to the haemolysis, blood clots as well as due to other therapies that might be necessary to treat associated conditions such as aplastic anaemia. Most patients with PNH do not develop significant kidney problems but this needs to be carefully monitored. Occasionally, during an episode of severe haemolysis and haemoglobinuria the kidneys have difficult dealing with the haemoglobin that they are filtering and this can cause a sudden (acute), but usually temporary, kidney failure. It is important during episodes of haemoglobinuria that patients drink plenty of fluid to keep the kidneys well hydrated and to reduce the risk of acute kidney problems.
• Blood clots – Blood clots (thromboses) are a common complication of PNH occurring in up to half of patients. Thrombosis is something we are always keen to exclude as if they occur they need specific treatment and may be serious or even life-threatening. The symptoms of thrombosis are highly variable and depend largely on where they develop and it’s extent. Clots can occur anywhere including in unusual places such as in the veins of the liver and around the brain.

Pregnancy & Contraception

• Contraception – The safest methods of contraception are either the use of progesterone-implanted coils (like the Mirena coil) or using a barrier contraception (i.e. condoms). The combined oral contraceptive pill should ideally be avoided as it can increase the risk of developing a blood clot.
• Fertility – Neither men nor women with PNH have reduced fertility specifically due to their disease. PNH is not an inherited disorder and there is no additional risk of the baby developing PNH. The major risk to the unborn baby is if the mother with PNH becomes unwell during pregnancy. It is therefore critical to closely manage pregnancy in women with PNH to prevent any potential complications (see below).
• Pregnancy – Pregnancy is associated with an increased risk of complications in PNH. In rare cases it may be that pregnancy is not advisable but after full information the PNH Service will support the patient in making decisions regarding pregnancy. It is therefore important to discuss the decision to become pregnant at the PNH clinic if at all possible. In almost all patients with PNH, pregnancy is potentially high risk and will be followed much more closely by both the local obstretric team in collaboration with the PNH Centre to prevent complications occurring and to reduce this risk. Treatment during pregnancy may include blood and platelet transfusions, folic acid, heparin (a drug to reduce the risk of developing blood clots) and eculizumab. During pregnancy it is important to be reviewed regularly both by haematology and obstetric specialists.

PNH FAQs

What test will I need to have to diagnose PNH?

PNH can be diagnosed through a simple blood test that is sent to the laboratory. Both PNH Centres also act as reference laboratories for diagnosis.

Will I have to have a Bone Marrow biopsy?

Due to the relationship of PNH and bone marrow failure, most commonly aplastic anaemia, it is likely that you will need to have a bone marrow biopsy at some point. The bone marrow is the organ (like a factory) of the body that produces the blood cells. Therefore, a bone marrow biopsy allows your medical team to see under the microscope a more detailed picture of your disease. There is much more information that we can gain from the bone marrow examination compared to the blood which can have an impact on the treatment required.

Will I need a Bone Marrow Transplant?

The treatment of PNH is decided on an individual patient basis and depends on the specific issues for that patient. For example, some patients are usually very well with only occasional episodes of symptoms whereas other patients suffer from haemolysis (rapid breakdown of PNH red cells) and anaemia with red or black urine or can have thrombosis as their main clinical problem. These are the classical symptoms of PNH and are not an indication for a bone marrow transplant. However if individual patients suffer mainly from bone marrow failure (e.g. severe aplastic anaemia or a weak bone marrow) then this may be an indication for a bone marrow transplant but this is relatively rarely necessary.

What does the PNH clone size mean?

PNH cells are not found in individuals without PNH or bone marrow failure and their detection is how we diagnose the disease. The machine that we use to detect PNH cells (called a flow cytometer) allows us to count the exact proportion of PNH cells compared to normal cells for all the blood cell types. We mainly concentrate on the white cells (neutrophils or granulocytes and monocytes) and on the red cells. The percentage of PNH granulocytes is usually the best way to assess the actual size of the PNH clone, as unlike red cells this is not affected by haemolysis (destruction of PNH red cells) or transfusions. The proportion of PNH granulocytes (or “PNH clone”) can vary in size from 0.01- 100% between different patients. The size of the PNH clone tends to have an impact on the symptoms an individual patient experiences but can be very variable.

Will my PNH clone always be the same size?

No, the PNH clone size can change over time with the number of PNH cells either staying stable, increasing or decreasing. For example we sometimes detect a small PNH clone in a patient with aplastic anaemia and this can over time increase in size so that the patient starts to experience symptoms of PNH. Most patients who have had PNH for a long period of time have relatively stable clone sizes although in some the clone can gradually reduce in size. In a small proportion of patients (less than 20% of patients in our experience) the clone can disappear altogether although this generally occurs over several years. It is not yet clear why some patients get better and there is nothing that we have found that predicts for which patient will improve.

How often will the size of my PNH clone be measured?

We will test the size of your PNH clone at most clinic visits. This allows us to monitor for any significant changes in your PNH and for us to consider any treatments that might be necessary to prevent complications.

Are my children at risk of getting PNH?

PNH is not an inherited condition (there is no increased risk in family members). PNH cannot be passed from one person to another.

If seen by the National PNH Service, do I still need to see my local haematologist?

The National PNH Service offers a shared care approach to managing your PNH but you still remain under the care of the local haematologist. It is therefore advisable that you continue to see your local haematologist. They will be looking after you should you become unwell and will often manage any problems separate to the PNH related to the underlying bone marrow failure, although we are happy to be involved as needed. The PNH Centre will work with your local haematologist to treat any problems that might arise related to your PNH but often the treatment will be delivered by your local team. Patients who are being treated with eculizumab need to be seen at least every 3 months either at a PNH Centre or an outreach clinic. Other patients will be seen in the PNH clinic as is necessary.

What can I do if I have further questions about my condition that I didn’t ask at my appointment?

It is not uncommon to either forget to ask a specific question during your consultation or to think of other questions that you want to ask about once you are back home. The National PNH Service are always happy to be contacted about you and your PNH. Please call the PNH service and ask to speak to one of the Clinical Nurse Specialists.