Paroxysmal nocturnal hemoglobinuria (PNH) is a very rare hemolytic anemia caused by a defective red blood cell structure. The disease has several characteristic symptoms, yet diagnosis is always very difficult. Find out when to suspect paroxysmal nocturnal hemoglobinuria and what life-threatening complications this disease can have.

Paroxysmal nocturnal hemoglobinuria( PNH ,Marchiafava-Michelie syndrome , eng. paroxysmal nocturnal hemoglobinuria ) belongs to a group of diseases called hemolytic anemia. It is an acquired disease, usually occurs in young people, around 30 years of age. It is a very rare disease, its symptoms and complications can occur in many other conditions, so diagnosis is very difficult.

It is a diverse, large group of diseases in which red blood cells - erythrocytes - are destroyed and broken down too quickly, usually this process is so intense that there is a deficiency - anemia.

A symptom of PNH is the occurrence of ailments after the triggering factor, which may be difficult to perceive, e.g. sleep or infection. The symptoms are weakness, jaundice, and complications are thrombosis, usually in an atypical location.

Haemolytic anemia can be congenital or acquired, and the cause of the breakdown is blood cell defects or extracellular factors, whether or not dependent on the immune system.

Paroxysmal nocturnal hemoglobinuria belongs to the group of acquired, non-immune hemolytic anemia, and is caused by an abnormal structure of the cell membrane, and more specifically of the erythrocyte membrane proteins.

Damage to red blood cells occurs during the activation of the complement system, which is one of the non-specific immune mechanisms responsible for inactivating and destroying pathogens, as well as supporting their phagocytosis, i.e. absorption.

Unfortunately, at the point of activation, complement acts on all cells, and if they are he althy, they have systems to protect against its effects. Damaged erythrocytes, however, do not have an effective defense and occur due to the activity of complementcytolysis, i.e. the breakdown of blood cells.

Paroxysmal nocturnal hemoglobinuria is relapsing, this is because in people with normal circumstances the process of formation, metabolism and production of blood cells is stable and balanced, unfortunately, this delicate balance is disturbed from time to time, which results in the occurrence of an attack of hemolysis .

It should be remembered that this disease can lead to many chronic diseases and life-threatening conditions, including Buddha-Chiari syndrome, kidney failure and cerebral vein thrombosis. Initial diagnostics can be performed with the help of basic laboratory tests, but they never allow a diagnosis to be made, and very specialized tests are necessary for a reliable diagnosis.

Unfortunately, treatment is difficult and rarely effective, survival over 5 years from diagnosis is estimated at approx. 35%, and mortality is not related to the disease itself, but to its complications. The most effective drug is eculizumab, but due to its severe side effects, the lack of response in some patients, and its high cost, its availability is limited.

  • Why do relapses and breakdown of blood cells occur at night?

The name of the disease indicates that blood cells are damaged and broken down at night while sleeping, but this is not the only time this process occurs.

A seizure can also be caused by infection, stress, exercise, certain medications, or even pregnancy. All these situations lead to a decrease in blood pH in different ways, in the case of sleep, breathing is often slower, and sometimes also to apnea, which in turn leads to the retention of carbon dioxide in the body, which lowers the pH.

Then erythrocytes become more susceptible to complement damage and the breakdown process intensifies. As a result, hemoglobin is released from damaged blood cells. If the amounts are large enough that the liver's metabolism is not efficient enough to break it down, hemoglobin is excreted unchanged through the kidneys in the urine. This has many consequences as described below.

There are 3 types of paroxysmal nocturnal hemoglobinuria, which are distinguished by measuring the activity of cholinesterase (an enzyme present in the plasma).

Symptoms of paroxysmal nocturnal hemoglobinuria

Occasionally paroxysmal nocturnal hemoglobinuria remains asymptomatic, especially when hemolysis is mild and has been going on for many years, so you can be sick without knowing it for a long time.

Symptoms begin to become noticeable once the levelhemoglobin drops below a certain level (usually 8 g / dl), or when the anemia develops very quickly.

Then there are symptoms common to many types of anemia: weakness and fatigue, which often prevent normal functioning, in addition, inability to concentrate, headaches, dizziness, and sometimes also shortness of breath.

One of the main and most obvious symptoms is jaundice. It occurs as a result of the increased destruction of red blood cells and is an indicator of insufficient disposal of their breakdown products. In addition, in a medical examination, it is not uncommon to find rapid heart beat (tachycardia), as well as an enlarged liver and an enlarged spleen.

Recognition of the symptoms described above raises the suspicion of anemia, but it requires laboratory confirmation.

A certain group of symptoms is characteristic of paroxysmal nocturnal hemoglobinuria and facilitates the diagnosis of this disease. These include:

  • dark color of urine passed in the morning
  • sometimes also leukopenia and thrombocytopenia in laboratory tests (decrease in the number of white blood cells and platelets, respectively).

Paroxysmal nocturnal hemoglobinuria also manifests itself with impaired smooth muscle function, which causes abdominal pain, swallowing disorders and erectile dysfunction. Unfortunately, this disease is associated with many complications.

The effects of paroxysmal nocturnal hemoglobinuria

The complications of paroxysmal nocturnal hemoglobinuria are hemolytic and aplastic crises, which are characterized by a sudden worsening of the disease caused by the breakdown of blood cells.

The above-mentioned symptoms are joined by

  • fever
  • chills
  • often loss of consciousness
  • and breakdown products of blood cells can damage the kidneys, causing acute kidney failure

For this reason, people with chronic kidney disease are also more likely to suffer from chronic kidney disease, because every time a person passes dark urine, their kidneys are exposed to hemoglobin that damages them.

Another very dangerous complication of PNH is aplastic anemia, which leads to pancytopenia, i.e. a deficiency of not only erythrocytes, but also leukocytes and thrombocytes.

This process occurs when similar damage to the membrane as in red blood cells also occurs in these blood cells, the deficiency of white blood cells leads to a tendency to infection and severe infection, while platelets to bleeding tendency and difficulty in stopping bleeding.

Another dangerous complicationparoxysmal nocturnal hemoglobinuria is prone to blood clots and emboli, they arise in less typical locations: in the hepatic veins (the so-called Buddha-Chiari syndrome), the brain veins, as well as the portal vein, the mesenteric vein, and the skin veins.

These clots result in liver damage, blood stasis in the brain, and skin necrosis, respectively. PNH rarely contributes to the typical venous thromboembolism - lower extremity venous thrombosis and pulmonary embolism, which, however, can be life-threatening.

Typical, but much more serious, is the formation of blood clots and blockages in the arteries, which in turn can lead to strokes and heart attacks.

Gallstone is a less dangerous condition. Normally produced bile contains bilirubin, a substance made from the breakdown of hemoglobin contained in red blood cells. In the course of paroxysmal nocturnal hemoglobinuria, the excess of its metabolites causes the formation of an unnaturally large amount of bilirubin, which may lead to the formation of gallbladder stones, and thus biliary colic, and subsequently bladder inflammation.

Another complication of PNH is pulmonary hypertension, which is characterized by shortness of breath, exercise intolerance, and the cause is increased blood pressure in the pulmonary arteries, sometimes it is a complication of pulmonary embolism.

In the course of PNH, a deficiency of folic acid is also observed, resulting from the increased demand associated with intense haemopathy.

This deficiency, in turn, can aggravate anemia and its symptoms, because the lack of a substrate for the production of erythrocytes impairs the process of their production.

Secondary hemosiderosis, i.e. the accumulation of haemosiderin, which is a carrier of iron, in macrophages and other cells of various organs, including the liver, may also be a consequence of paroxysmal nocturnal hemoglobinuria, without affecting organ function.

Who should be suspected of having nocturnal paroxysmal hemoglobinuria?

It is believed that detailed diagnostics for this disease should be started in people with:

• hemoglobinuria
• markers of intravascular hemolysis (breakdown of blood cells in the vessels) - increase in reticulocytes and LDH, decrease in haptoglobin
• thromboembolism, especially in unusual localization
• swallowing disorders and abdominal pain

Research in paroxysmal nocturnal hemoglobinuria and complications

The basic laboratory test in suspected paroxysmal nocturnal hemoglobinuria is the peripheral blood count, which shows a reduction in the number of red blood cells (RBC) and hemoglobin (hgb).

This is itso-called normocytic anemia normochromic, i.e. erythrocytes have the correct size and color, but there are too few of them, unfortunately this is a very non-specific result, which means that such a deviation from the norm may occur in many other diseases. As an expression of the intense formation of new blood cells, the number of reticulocytes - forms of juvenile red blood cells - increases.

If the disease develops aplastic anemia and pancytopenia, the levels of leukocytes (WBC) and platelets (PLT) also fall.

In addition, levels of LDH, or lactate dehydrogenase, are often elevated, an enzyme found in all blood cells that is released when cell damage occurs. Haptoglobin activity, on the other hand, decreases as an indicator of the protein's ability to capture free hemoglobin.

Haptoglobin is a carrier of a blood pigment, when erythrocytes break down, the released hemoglobin is captured by this transporter - the more hemoglobin binds to haptoglobin, the less its activity.

There is also an increase in the concentration of bilirubin in the blood, i.e. the component of bile that is a product of hemoglobin metabolism.

Among the very specialized tests, flow cytometry is performed, in which the expression of proteins related to glycosylphosphatidylinositol (CD55 and CD 59) on granulocytes and erythrocytes is measured, its absence indicates excessive sensitivity of cells to complement and confirms the diagnosis.

Other specialized tests are: the Ham test and the sucrose test, in which the blood cells of patients are broken down in acid and sucrose, respectively.

In the diagnosis of PNH, a general urine test is helpful, as mentioned, morning urine is most often dark, and the analysis also shows the presence of hemoglobin.

In some cases, a bone marrow biopsy is also necessary, most often to exclude other, serious hematological diseases.

The diagnosis of complications includes laboratory and imaging tests: abdominal ultrasound is necessary to assess the presence of gallstones, Doppler ultrasound allows to confirm the suspicion of lower limb thrombosis, and computed tomography to suspect pulmonary embolism.

In the case of the latter two, it is also necessary to determine serum D-Dimers. The peripheral blood morphology also allows to identify a possible folic acid deficiency - in this case the blood count is disturbed, there is no typical PNH normocytic normochromic anemia, macrocytic normochormic anemia, which can be confusing and make diagnostics difficult.

Treatment of the paroxysmnight hemoglobinuria

Treatment is complicated and usually not very effective. First of all, the most troublesome symptoms are controlled and possible complications of the disease are treated, as well as prophylaxis of their occurrence, e.g. anticoagulants in the event of blood clots, sometimes they are also used prophylactically.

In addition, folic acid is used long-term to provide a substrate for the production of new blood cells and prevent the development of a possible deficiency. In the event of a deficiency, iron preparations are also taken. In the case of very severe anemia, it is necessary to transfuse red blood cells.

Specific treatment is primarily eculizumab, i.e. a monoclonal antibody that acts immunosuppressive - blocking the complement system, unfortunately, the use of this drug has serious consequences - a much greater risk of serious infections (especially bacterial and meningococcal infections).

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Unfortunately, an effective cure is only possible after bone marrow transplantation.

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Category:

Cardiology