Nocturnal paroxysmal hemoglobinuria – causes, symptoms, treatment

Nocturnal paroxysmal hemoglobinuria is one of the very rare blood diseases. Contrary to its name, it does not have to appear after dark. A person suffering from NNH must take into account a number of unpleasant symptoms, as well as the risk of developing ailments that are dangerous to health and life.

1. Nocturnal paroxysmal hemoglobinuria belongs to the group of diseases of the circulatory system
2. It is estimated that, on average, one person in a million suffers from it
3. NNH most often affects young people below 45 years of age
4. More current information can be found on the Onet homepage.

Nocturnal paroxysmal hemoglobinuria (NNH) is a rare disease. The annual incidence is about 1 per million population – these are data from the USA, as there is no Polish registry. The disease can occur at any age, but mainly in people from 25 to 45 years of age, and equally common in men and women. It is an acquired clonal defect of the hematopoietic stem cell. This defect is caused by a mutation of the PIGA gene on the X chromosome. The result is a deficiency of glycosylphosphatidylinositol (GPI) in hematopoietic stem cells. The abnormality is passed on to their daughter cells, that is, red blood cells, white blood cells and platelets.

Unprotected blood cells

GPI plays an important role – as an anchor holds proteins on cell membranes that protect blood cells from being aggravated by their own immune system, especially complement (complement). The erythrocytes created from mutated hematopoietic stem cells show the absence or deficiency of two important proteins that protect them against complement attack: CD55 – a factor accelerating decay, and CD59 – an inhibitor of passive membrane disintegration. Since the blood cell is not protected, activation of the complement system causes perforation of the erythrocyte membrane and their accelerated destruction (haemolysis). This leads to haemolytic anemia, the only one caused by intracellular factors. In NNH there is constant destruction of red blood cells (haemolytic anemia), thrombosis, and bone marrow failure. Some patients with NNH may have bone marrow failure manifested by deficiency of cells of one line, e.g. only platelets (cytopenia), or three lines (pancytopenia), i.e. red, white and platelets. You may also develop full-blown aplastic anemia.

Although the altered NNH cell clone with the PIGA mutation is very expansive and displaces the normal clone, nocturnal paroxysmal hemoglobinuria is not cancerous. It is still not fully understood how the displacement of normal cells occurs, but it is known that an additional mutation must occur in abnormal hematopoietic cells in order for them to dominate healthy cells.

Variety of NNH Symptoms

The haemolysis leading to anemia is chronic, although there are exacerbations (seizures) that often occur in the morning and are associated with lowering the pH but caused by infection, stress, or considerable exercise.

Changes in NNH occur that the patient experiences and evaluates. These are: fatigue, weakness, feeling sick, shortness of breath, headache, pain in the chest and / or abdomen, painful swallowing, erectile dysfunction. On the other hand, the objective signs include: dark urine (hemoglobinuria) – found in 25% of respondents. sick people, jaundice and thrombosis in unusual places. The dark color of the urine results from the presence of a dye – hemoglobin (hemoglobinuria) or hemosiderin.

Symptoms of NNH can be more closely related to the pathomechanism of the disease and distinguish those related to hemolysis, thrombosis or bone marrow failure. The symptoms from the first group include: yellowing of the integuments, dark urine at night or in the morning (25% of patients), smooth muscle dystonia (abdominal pain, dysphagia, impotence). This group also includes renal symptoms, such as acute kidney damage as a result of severe haemolysis followed by hemoglobinuria or chronic kidney disease in patients with a longer course of NNH, resulting from renal tubular dysfunction caused by iron deposits. Symptoms related to thrombosis (mainly venous) often relate to a sudden and relapsing disease. Visceral vein thrombosis may occur – especially with severe haemolysis or after surgery. It is atypically located, e.g. in the skin, visceral veins, and brain veins. The consequences of bone marrow failure are mainly infections and bleeding.

Suspected NNH – detailed investigation necessary

A person who has symptoms that could suggest NNH should see their GP. If your blood count shows anemia with an increased number of reticulocytes (and many also have decreased numbers of neutrophils and platelets), you will likely be referred to a haematologist. The bone marrow test result will indicate that, in addition to a possible increase in the red cell line, there are no changes indicative of NNH and that there are no other abnormalities suggesting the presence of bone marrow failure or myelodysplastic syndrome. Thanks to biochemical tests, it is possible to assess whether there are changes indicative of intravascular haemolysis, which results in accelerated destruction of red blood cells – this will be indicated by an increased concentration of the enzyme lactate dehydrogenase (LDH), while the direct antiglobulin test (formerly known as the Coombs test) will be negative. The gold standard confirming the diagnosis of NNH is the lack of expression of GPI-related proteins, i.e. CD55 and CD59, in cells from at least two lines (leukocytes and erythrocytes) in the flow cytometer test.

Due to the possibility of expansion or disappearance of a mutant cell clone, systematic monitoring of its size is recommended in each patient with newly diagnosed NNH. In the first year after diagnosis, these tests should be performed every 3-6 months, and then every 6-12 months. Patients after allogeneic haematopoietic stem cell transplantation require monitoring for the presence of the NNH clone and residual disease.

Treatment is not always a cure

The only cure method – by removing (eradicating) the mutant NNH clone – is allogeneic hematopoietic stem cell transplantation. This option is especially considered in the presence of bone marrow failure and ineffective pharmacological treatment. However, it is associated with a high risk of complications in the early post-transplant period. Currently, the treatment of choice is monoclonal antibodies inhibiting the C5 component of complement, which significantly reduce the need for red blood cell transfusions and the risk of thromboembolic complications. Two drugs are registered – one of them, which is used intravenously every 2 weeks, is available in Poland under the National Health Fund program. The drug should be administered continuously or until the NNH clone is significantly reduced and the symptoms of the disease disappear. All patients should be vaccinated 2 weeks prior to this treatment to reduce the risk of enveloped bacterial infections, including particularly severe Neisseria meningitidis infections. Every infection in a patient with NNH should be taken very seriously and treated intensively.

Complement inhibition is of utmost importance in the treatment of thrombosis. In the event of acute thrombosis, heparin is used, followed by drugs from the group of vitamin K antagonists or oral drugs that are not vitamin K antagonists, directly inhibiting the factors involved in the blood clotting process – factor Xa or thrombin.

NNH – threat to life and its quality

NNH is a life-threatening disease. The average survival time is around 15 years. Observations indicate that 5% of people survive 78 years after diagnosis. patients, and 15 years from diagnosis – only 48 percent. For 40-67 percent. deaths in the NNH patient population correspond to venous thromboembolism. About 29-44 percent. patients experience at least one thromboembolic event and the first one increases the risk of death by 5-10 times. It is worth remembering that about 64 percent. patients with NNH have chronic kidney disease, which is responsible for 8-18 percent. deaths. Pulmonary hypertension occurs in approximately 47% of patients. patients, often caused by a history of pulmonary microembolism.

The quality of life in patients with NNH is poorer for a number of reasons. Due to the disease itself, incl. constant feeling of fatigue (80%), weakness, pain of various localization, incl. headaches (63%). Treatment is also burdensome, as some patients have to visit the hospital due to the necessity of frequent transfusions of blood components and cyclical administration of drugs. This often requires traveling to another city, and having days off from work or school. Fear for one’s own future and the future of the family, as well as anxiety related to the course of the disease and treatment are also of great importance. The situation of patients with NNH improved after the introduction of the drug program of the National Health Fund, thanks to which patients suffering from NNH can lead a normal life and feel safer.

We encourage you to listen to the latest episode of the RESET podcast. This time, Dr. Agnieszka Bolikowska – the founder of Linguistics, creator of the 6oMethod® method, will tell us about what slow learning is. How to break the language barrier? How to learn to make mistakes? You will learn about this and other aspects of language learning in today’s episode. Listen!