Paroxysmal nocturnal hemoglobinuria in adults. Paroxysmal nocturnal hemoglobinuria (PNH) PNH clone analysis

The essence of the pathology is changes in the structure of blood cells (mostly red blood cells), leading to premature destruction of their membranes and intravascular breakdown (hemolysis).

The prevalence is about 16 cases per million population, and the annual incidence is 1.3 per million. People aged 20 to 40 years are most often affected; no gender dependence has been identified.

The name includes the names of Italian researchers and doctors who spent years studying: Marchiafava-Micheli disease, Strübing-Marchiafava disease.

What is “hemoglobinuria” and what causes it?

Hemoglobinuria is a symptom of various diseases that cause the breakdown of red blood cells by their effect on the membrane, while hemoglobin leaves the cells and enters the plasma.

In a healthy person, it can be no more than 5% of the total blood plasma volume. An increased level of hemoglobin of 20-25% is observed in congenital disorders or hemoglobinopathies (β-thalassemia, red cell destruction in sickle cell anemia).

The causes of hemoglobinuria can be:

• acute infectious disease (flu);
• pneumonia;
• injuries;
• intoxication due to poisoning with aniline dyes, carbolic acid, Berthollet salt;
• severe hypothermia;
• strong and prolonged physical stress;
• blood diseases;
• transfusion of different types of blood;
• extensive burns;
• The role of acquired mutation of the PIG-A gene has been established.

Aniline dyes are widely used in the textile industry, batik decoration, dry cleaning and dyeing services, working with them requires caution

Hemoglobinuria does not exist without high level hemoglobin in the blood (hemoglobinemia). Pre-dawn paroxysms are associated with a physiological shift in acid-base balance towards acidosis at night. The increased content of breakdown products further contributes to acidification of the body and increased breakdown of blood cells.

Pathogenesis of disorders

The main changes in paroxysmal nocturnal hemoglobinuria occur at the complement level. It represents a chain of biochemical reactions that provide innate immunity.

Active ingredient a membrane attack complex is considered to be formed. It contains about 30 regulator components. The synthesis of complement components depends on signals received from the nervous and endocrine systems. Normally, it is controlled by special proteins that do not allow the destruction of host (human) cells.

With nocturnal hemoglobinuria, this process is lost. The lipid layer of the cell membrane of red blood cells is destroyed, which causes their death. Increased sensitivity of the erythrocyte membrane to complement components has been proven.

Complement is necessary to protect cells from infectious agents and disposal of decay products of microorganisms and own damaged cells

Other blood cells (leukocytes and platelets) also react by causing defects in the membrane. No accumulation of immunoglobulins was found on them, which proves the absence of an autoallergy mechanism and speaks in favor of damage to the common precursor cell. She is the one who gets genetic information(order) about destructive action.

The missing genetic region of the stem cell is called a GPI-AP. Its deficiency in the erythrocyte clone contributes to susceptibility to hemolysis under the influence of complement. At the same time, a normal clone of red blood cells can exist in the body.

Paroxysmal nocturnal hemoglobinuria manifests itself only if the pathological clone prevails over the normal one. Red blood cells from a clone with partial or complete absence GPI-APs are detected in patients by flow cytometry. It is important that the number of pathological cells in patients is not the same.

Increased thrombus formation in Marchiafava-Miceli disease is associated with stimulation of blood clotting by factors released during the destruction of red blood cells.

Forms of the disease

Classification clinical forms takes into account laboratory data and the cause-and-effect relationship of blood changes. It is customary to distinguish the following varieties:

1. Subclinical - laboratory signs there is no hemolysis; only highly sensitive methods can detect a small number of cells lacking GPI-AP. There is no clinical picture of the disease. Often combined with aplastic anemia.
2. Classic - everything is available clinical symptoms, occurs with periodic exacerbations, in addition to erythrocytes, leukocytes and platelets are affected, signs of hemolysis are determined in the laboratory (growth of reticulocytes, serum enzyme lactate dehydrogenase, bilirubin, with a reduced level of haptoglobin). No abnormalities of hematopoiesis were observed in the bone marrow.
3. Caused by insufficiency of bone marrow hematopoiesis in various diseases- concomitant or previous pathology is assumed bone marrow with impaired hematopoiesis (with aplastic anemia, myelodysplastic syndrome). Analysis and clinical findings reveal all manifestations of hemolysis against the background of abnormalities in bone marrow hematopoiesis.

According to another classification, it is proposed to distinguish:

• idiopathic form or paroxysmal nocturnal hemoglobinuria itself;
• pathology in the form of a syndrome for various diseases;
• a rarely observed species occurring after bone marrow hypoplasia.

Symptoms and clinical course

The disease can begin suddenly (acutely) or have a gradual chronic course. Periods of exacerbation are called hemolytic crises. They are often preceded by a previous cold, an association with infection, or contact with toxic substances.

The main symptoms of paroxysmal nocturnal hemoglobinuria include:

• stomach ache;
• pain in chest different intensity and localization - pain different localization associated with thrombosis of small branches of the arterial bed and the formation of foci of ischemia in internal organs;
• signs of anemia (weakness, dizziness, headaches) - caused by increased destruction and insufficient production of red blood cells, in addition, studies indicate a deficiency of iron and folic acid in the blood of patients;
• yellowness of the skin and sclera - an indicator of release into the blood direct bilirubin, processed by the liver from excess hemoglobin;
• swallowing disorder;
• erectile dysfunction in men - manifests itself not only against the background of crises, but becomes chronic, caused by a reduced concentration of nitric oxide in the plasma, impaired muscle and vascular tone.
• increased fatigue;
• shortness of breath, palpitations;
• local signs of thrombophlebitis (redness of the skin above the vein, swelling, pain on palpation, increased temperature);
• When examining a patient, the doctor may note an enlarged liver and spleen; this sign is especially important for diagnosing the development of thrombosis and heart attacks in them.

The chronic course of the disease contributes to the development of:

• pulmonary hypertension with thrombosis in the branches of the pulmonary vessels;
• chronic renal failure caused by deposition of the breakdown product of hemoglobin (hemosiderin) in the renal tubules, vascular thrombosis with the formation of microinfarctions;
• high sensitivity to associated infection.

These syndromes become the most likely causes of death.

Laboratory diagnostics

The diagnosis of Marchiafava-Micheli disease is made after a thorough examination in hematology centers that have the ability to conduct specific tests and analyses.

In peripheral blood are found:

• erythropenia, leukopenia, thrombocytopenia (the state of inhibition of the general growth of blood cells is called pancytopenia);
• reticulocytosis;
• increase in hemoglobin level in plasma;
• decreased iron and folate levels.

Bone marrow examination reveals:

• signs of activation of erythropoiesis (production of red blood cells) due to the accumulation of precursor cells (normoblasts, plasma and mast cells);
• decreased number of granulocytes and megakaryocytes;
• areas of hemorrhage, accumulation of hemolyzed red blood cells in the sinuses;
• at the stage of suppression of hematopoiesis, zones are visible fatty degeneration, devastation.

Both tests test the "survival" of red blood cells in a blood sample placed in a weak solution. Hem's test is positive when the destruction is 5% or more, and Hartman's is 4% or more.

The Coombs test is performed to exclude a connection with the autoimmune mechanism of cell destruction; it is negative for nocturnal hemoglobinuria.

The coloring of urine indicates a significant content of oxyhemoglobin in it.

Urine examination showed that one of the initial signs nocturnal hemoglobinuria is morning and night urine that is dark red in color. Over time, the collected urine separates into layers:

• the liquid on top is transparent, but retains color;
• particles of dead cells of organic origin are determined from below.

What diseases should nocturnal hemoglobinuria be distinguished from?

Differential diagnosis of paroxysmal nocturnal hemoglobinuria is carried out with other anemias similar in clinical course, primarily with hemolytic anemia of the autoimmune type and aplastic one.

General signs are:

• a sharp decrease in the number of red blood cells;
• reticulocytosis;
• presence of jaundice;
• fever;
• increased concentration of free bilirubin;
• tendency to thrombosis;
• moderate enlargement of the liver and spleen.

With anemia, there are no high levels of hemoglobin in the blood plasma or urobilin in the urine. The Hem and Hartman laboratory tests are negative, but the Coombs test is positive.

Diagnosis is significantly difficult if the disease occurs in the form of temporary crises against the background acute form myeloblastic leukemia, erythromyelosis, osteomyelosclerosis, metastatic bone marrow lesions with malignant tumors.

Red blood cell mass is stored cold in special packages

Treatment

To date, there is no effective way to stop the breakdown of red blood cells. All that remains is to use the replacement option and transfuse the patient with washed red blood cells from donors.

Blood used for transfusion must be kept frozen for at least a week in order to completely destroy the leukocytes in it. Once they reach the patient, they can cause exacerbation of hemolysis due to increased sensitization and activation of complement.

With frequent transfusions, the formation of anti-erythrocyte antibodies is still possible. In such patients, subsequent transfusion is carried out after several procedures of washing red blood cells with saline and checking donated blood using the Coombs reaction.

The number of transfusions is usually prescribed at least five, but depends on the severity of the patient's condition and response to treatment.

To stimulate proper hematopoiesis, Nerobol (an anabolic hormonal drug) is used in courses of up to three months. In this case, a change in the functional state of the liver is possible.

For the purpose of treatment and prevention of thrombus formation, Heparin is used, followed by a transition to maintenance doses of indirect anticoagulants.

To compensate for iron losses, tablets are prescribed.

An indication for removal of the spleen may be a sharp increase in size and signs of a heart attack. Splenectomy is rarely performed.

To protect the liver, hepatoprotective drugs are prescribed. Sometimes steroid therapy helps.

The drug is administered only intravenously

In recent years, information has appeared on the use of the drug Eculizumab (Soliris), made from monoclonal antibodies. Judging by the available reports, it blocks hemolysis and is able to resist blood complement. The drug is considered the most expensive medicine in the world. Its action and negative effects insufficiently studied.

Nocturnal hemoglobinuria does not yet have a specific treatment. Even with sufficient supportive therapy, patients live about five years after the onset of the disease. There is no prevention. Everyone should adhere to correct behavior when working and having forced contact with toxic compounds.

How does paroxysmal nocturnal hemoglobinuria manifest?

Paroxysmal nocturnal hemoglobinuria is a severe acquired pathology of the group of hemolytic anemias. Marchiafava-Miceli disease or Strübing-Marchiafava disease, other names for this pathology, causes the destruction of red blood cells. The disease is very rare, per 500 thousand population, 1 person with this pathology may occur.

In order not to worry about development possible complications and the consequences of the pathology, you should know what the diagnosis of paroxysmal nocturnal hemoglobinuria represents, the symptoms and treatment of the pathology.

Causes of hemoglobinuria

As mentioned above, paroxysmal nocturnal hemoglobinuria is a very rare disease, moreover, the pathology is most often found in people aged 20 to 40 years. Cases of the disease developing in old age or in children are also known medical practice, but their share is a negligible percentage.

The cause of paroxysmal nocturnal hemoglobinuria (PNH) is considered to be a mutational reaction of the stem cell gene (PIG-A), which is a component of the X chromosome in the bone marrow, in response to the influence of unidentified influencing factors. Some sources claim that the reasons causing the gene mutation are unknown.

Others argue that hemoglobinuria can develop against the background of infectious diseases, pneumonia, injuries, intoxication, hypothermia and burns, and even severe physical stress.

But a unanimous opinion on the etiology of the pathology has not yet been established.

A clear connection was revealed between the development of the diagnosis of paroxysmal nocturnal hemoglobinuria as a symptom of concomitant pathologies. Medical research It has been proven that PNH develops as a consequence of aplastic anemia and other pathologies of the vascular system in 30% of cases.

A well-known argument is that even one mutated cell can lead to the development of a severe form of the pathological condition. During the formation of red blood cells, which occurs in the bone marrow, stem cells divide, mature and are released into the bloodstream. One modified gene is divided into another pair, and those into another pair, etc. That is, one cell self-replicates, gradually filling the blood with damaged red blood cells.

The essence of red blood cell damage is an incomplete or missing protein membrane, which serves to protect the cells from the immune system. At the slightest defect in the cell, the body’s immunity destroys it, resulting in a diagnosis such as hemolysis – intravascular destruction of red blood cells, which is characterized by the release of pure hemoglobin into the blood.

The same process occurs in chronic hemolytic anemia, therefore paroxysmal nocturnal hemoglobinuria is its analogue or, as medical practitioners often claim, its acute acquired form. The main and only difference between these pathologies is the principle of their development.

Hemolytic anemia is a congenital pathology, hemoglobinuria is acquired. The defectiveness of red blood cells can also extend to other solid elements of the vascular fluid: leukocytes and platelets.

Symptoms of nocturnal hemoglobinuria

Symptoms of Marchiafava-Micheli disease depend on the causal classification of the pathology. As it was found out, the disease can be independent, according to this, the idiopathic form of PNH is distinguished. Due to the development of pathology against the background of aplastic anemia, paroxysmal nocturnal hemoglobinuria takes the form of a syndrome. The rarest form is considered to be the idiomatic form of PNH, which occurs against the background of hematopoietic hypoplasia.

It is impossible to identify distinct symptoms for any form of the disease, since it is very variable. The course of the disease may be outwardly asymptomatic; in this case, pathology can only be identified through laboratory diagnosis. Other patients experience severe anemic syndrome.

In general, one can define a slight generalization of all possible manifestations nocturnal hemogloburia, thus highlighting the main symptomatic picture.

• The process of hemolysis (destruction of red blood cells and hemoglobin) occurs mainly at night (nocturnal hemoglobinuria), therefore, when urinating in the morning, the color of the urine will acquire a dark brown tint. During the day and evening time no such sign is observed.
• Due to the quantitative decrease in red blood cells, anemic syndrome is observed. Its manifestations are directly related to oxygen starvation of organs and tissues. Therefore, the patient may experience headaches, dizziness, flashing black spots before the eyes, general weakness, fatigue, attacks of angina and tachycardia.

• If concomitant infectious diseases, bleeding, physical activity, etc. occur, a hemolytic crisis may develop, which is manifested by a sharp jump in the amount of hemoglobin in the vascular fluid, as well as severe malaise, fever, bone pain, jaundice of the skin and moderate splenomegaly may appear ( enlarged spleen).
• Hemoglobinuria is accompanied by a violation of the concentration of nitric oxide in plasma, which both against the background of crises and during severe course pathology causes erectile dysfunction in men.
• Due to a defect in platelets (blood cells responsible for blood clotting), blood clots may occur, which are most often observed in the veins. The same process can be triggered by a substance that is released when solid blood cells are destroyed. It causes increased coagulability of vascular fluid, which determines the tendency to thrombus formation. Such violations can lead to death.

The most distinct symptoms of paroxysmal nocturnal hemoglobinuria can be obtained through laboratory diagnosis. Studies will show the level of hemoglobin in the blood, the condition of the cells, the presence of thrombopenia and leukopenia, the level of iron and other trace elements, etc. A complete and accurate diagnosis of hemoglobinuria takes a lot of time, since this disease can be carefully hidden under the guise of other pathologies.

Therefore, the most rational way to timely detect Marchiafava-Miceli disease is regular preventive examination.

Treatment of paroxysmal nocturnal hemoglobinuria

The period of detection of paroxysmal nocturnal hemoglobinuria determines the necessary healing methods and establishes a prognosis for the outcome of the pathology, which in most cases is unfavorable. This occurs due to the lack of a specific cause of development and the impossibility of eliminating it. Therefore, there is no specific treatment method for PNH.

All therapeutic measures are aimed at eliminating symptomatic manifestations. The only one in an effective way To completely get rid of mutated cells is a red bone marrow transplant (the place where blood cells are formed).

With the development of a hemolytic crisis, an acute form of hemolysis, the patient is prescribed multiple transfusions of red blood cells. There may be 5 or more such transfusions. The number of procedures and their frequency are determined by repeated tests and are carried out during the next multiplication of defective red blood cells.

In rare cases, the spleen is removed. Signs leading to splenectomy include a sharp enlargement of the organ and the development of an infarction.

The remaining therapeutic measures consist of taking different types of drugs that alleviate the course of the pathology. The main medications are preparations of steroid hormones, cytostatics, as well as iron and folic acid preparations.

Neroball

The most common thing doctors prescribe to combat symptomatic manifestation for paroxysmal nocturnal hemoglobinuria is the drug Nerobol. This is a hormonal drug from the group of anabolic steroids. The action of the drug is directed:

• to stimulate protein synthesis in the patient’s body, which is lacking in the defective red blood cell membrane;
• has a beneficial effect on nitrogen metabolism;
• delays the excretion of potassium, sulfur and phosphorus, which are necessary for normal protein synthesis;
• provokes increased fixation of calcium in the bones.

After taking this medicine the patient feels an increase in appetite, an intense increase in muscle mass, accelerated bone calcification, as well as a much better general condition of the body.

The use of the drug begins with 10 g, gradually increasing to 30 g in 1-2 doses per day. For children, the dose of the drug is 1 tablet every other day, in severe forms daily. The course of therapy with Nerobol is from 2 to 3 months.

After stopping the use of the drug, many patients experience increased hemolysis.

The use of Nerobol can be carried out strictly as prescribed by the attending physician.

Heparin

Heparin is a direct anticoagulant - a means of inhibiting blood clotting. For paroxysmal nocturnal hemoglobinuria, it is prescribed to prevent blood clots, which complicate the course of the disease.

The dosage and frequency of administration are completely individualized, depending on the complexity of the pathology and the risk of blood clots in the vessels.

At the end of the course of Heparin, the doctor prescribes indirect anticoagulants to maintain normal level coagulability.

Eculizumab

Eculizumab is a drug that consists of humanized monochannel antibodies. The principle of action of the drug is to stop intravascular hemolysis and directly counteract the complement of blood. As a result, the natural destruction of defective red blood cells by the body’s immune system stops.

This drug is the most expensive medicine in the world. Its mechanism of action and the development of possible consequences of use have not been sufficiently studied.

Iron and folic acid supplements

If there are disturbances in the functioning of the red bone marrow, a deficiency of iron and folic acid occurs, which are necessary for normal hematopoiesis. IN curative therapy PNH includes taking preparations of these microelements to compensate for pathological losses.

The dosage and method of taking the drug is determined by the attending physician. The most often prescribed are Sorbifer, Tardiferron, Ferretab, Fenyuls, etc. These drugs contain a complex of microelements necessary for the normal creation of solid blood particles in the red bone marrow.

Liver Support

Intensified therapy in the fight against paroxysmal nocturnal hemoglobinuria has a strong effect on the liver. In the absence of supportive therapy for the liver, it may simply fail. Therefore, it is important to take hepatoprotective drugs. These may be the following drugs:

In addition, there are a number of products that help restore liver cells. These include pumpkin, dried apricots, kelp, olive oil, dairy products and much more. The main thing is, in moments of liver weakness, do not aggravate it with junk food.

After identifying the disease, doctors give inaccurate predictions. Statistics say that after diagnosis, the patient can live on maintenance therapy for about 5 years.

Due to the unknown origin of the disease and uncertainty about the causes of its development, paroxysmal nocturnal hemoglobinuria cannot be prevented.

conclusions

Marchiafava-Miceli disease or paroxysmal nocturnal hemoglobinuria is a serious disease that, even with intensive care, is fatal. The only possible recovery is the transplantation of red bone marrow, in which blood cells are formed. In addition, pathology entails the development of concomitant diseases, which are no less dangerous for the patient’s condition.

Therefore, doctors unanimously declare that best method to prevent any pathology is to regularly undergo a complete medical examination. It is possible that if the disease is only at the stage of formation, it can be permanently removed. With such serious illnesses, the main issue is time. You should take care of yourself and your body.

Paroxysmal nocturnal hemoglobinuria (PNH)

Causes:

The causes of the disease are associated with the intravascular destruction of red blood cells, which are largely defective. Along with the pathological population of erythrocytes, a part of normal cells that have a normal lifespan are also preserved. Disturbances in the structure of granulocytes and platelets were detected. The disease is not hereditary, but some external factors, provoking the formation of a defective cell population, which is a clone, i.e. the offspring of one initially modified cell are not known.

There is an increased complement sensitivity of pathological erythrocytes in PNH. Perhaps this is the basis for provoking a hemolytic crisis with a transfusion of fresh blood, which contains factors that activate complement. Transfusion of blood stored for more than a week does not provoke hemolysis.

Symptoms of paroxysmal nocturnal hemoglobinuria:

The disease develops slowly: signs of moderate anemia, weakness, fatigue, palpitations during exercise, and abdominal pain appear, often associated with thrombosis of the mesenteric vessels. The skin and mucous membranes are pale icteric, grayish due to anemia and hemosiderin deposition. Characteristic signs of intravascular hemolysis.

The morphology of erythrocytes has no characteristic features. In the bone marrow, hyperplasia of the red germ is observed, but in the trephine there is a slight increase in the cellularity of the bone marrow, which may become hypoplastic as the disease progresses.

Diagnosis:

The diagnosis is made based on signs of intravascular hemolysis (anemia, slight reticulocytosis, hemosiderin in the urine). The diagnosis is clarified by special studies (positive sucrose test, Hem's test, negative Coombs' test).

Unlike PNH, there is no leukopenia and thrombocytopenia, usually good effect gives prednisolone. PNH can be distinguished from aplastic anemia by the picture of the bone marrow: with aplasia, trepanate is characterized by a predominance of fat, with hemolysis - cellular hyperplasia, however, in rare cases of PNH, a picture of bone marrow hypoplasia can develop, although hemosiderin is constantly detected in the urine, and reticulocytosis in the blood.

Treatment of paroxysmal nocturnal hemoglobinuria:

Treatment in the absence of severe anemia is not carried out. Severe anemic syndrome requires red blood cell transfusion; The best results are obtained by transfusion of washed or aged erythrocytes for 7-10 days. For hypoplasia of hematopoiesis, anabolic steroids are indicated: Nerobol - 10-20 mg per day or Retabolil - 50 mg intramuscularly for 2-3 weeks.

Discussions

PNH(paroxysmal nocturnal hemoglobinuria) PNG

12 messages

PNG is complex disease, manifested by nonspecific and unpredictable signs and symptoms, often coinciding with those of other diseases. In addition, PNH manifests itself differently in each patient. If you have PNH, then some or all of the red blood cells in your blood are missing an important protective protein. Without this protein, red blood cells can be destroyed by a component of your body's immune system called the complement system. Even if you don't feel it, hemolysis occurs constantly, silently, and can pose a threat to your life. As with others chronic diseases such as diabetes or arterial hypertension, untreated PNH can lead to serious health problems. Typical symptoms associated with PNH include abdominal pain, difficulty swallowing, anemia, shortness of breath and fatigue. More serious complications include blood clots, kidney failure, and vital damage. important organs.

Patients with PNH may have varying manifestations of the disease, which may unpredictably worsen (for example, under the influence of stress) or improve from time to time. However, all patients with PNH experience chronic hemolysis.

People with PNH may also have other diseases that affect bone marrow function, such as aplastic anemia or myelodysplastic syndrome. Unlike PNH, in which red blood cells are destroyed, in these diseases the production of blood cells can be reduced, which further complicates the course of PNH. If you are diagnosed with PNH along with aplastic anemia or myelodysplastic syndrome, discuss with your doctor all possible effective treatment options for your medical conditions.

In PNH, red blood cells are deprived of an important protein

2. Impact of the complement system

Without this protein, some red blood cells can be destroyed under the influence of the complement system, one of the body's defense systems.

3. Destruction (hemolysis) of red blood cells in PNH

With PNH, red blood cells are destroyed, causing toxic breakdown products to enter the surrounding plasma (the yellow liquid component of blood).

Hemolysis is the medical term meaning "destruction of red blood cells." The intensity of hemolysis is assessed by determining the activity of LDH (lactate dehydrogenase - an enzyme contained in red blood cells). Increased LDH activity indicates excessive hemolysis. In healthy people, minor hemolysis is a natural, ongoing process. However, patients with PNH experience excessive hemolysis due to the absence of protective protein on the surface of some or all red blood cells. This excessive hemolysis is accompanied by the release of toxic contents of red blood cells into the blood, which over time can lead to the appearance of most of the symptoms associated with PNH, as well as damage to important organs in your body. If you have PNH, hemolysis occurs all the time, regardless of whether you feel well or have an exacerbation (paroxysm) of the disease, such as during stress or infection. Excessive and prolonged hemolysis is the main cause of serious health problems in PNH.

When blood cells are destroyed, their toxic contents enter the bloodstream and can accumulate there, thereby causing harm to health, which can occur unexpectedly and at any time. Such violations may include renal failure and the formation of dangerous blood clots that can lead to disruption of vital organs such as the liver, brain and lungs.

Hemolysis also affects your well-being. Many patients with PNH note that the unpredictability of the onset and severity of symptoms of the disease negatively affects their quality of life. Reducing the level of chronic hemolysis is considered by doctors as the most important goal in the treatment of PNH.

The drug is an antibody that blocks the C5 component of the complement system. Experience with use has shown increased survival, decreased hemolysis and thrombosis, and improved quality of life.

The disease most often begins gradually. Patients complain of weakness, malaise, and dizziness. Subictericity of the sclera is sometimes noted. Often the first complaints are headaches and abdominal pain various localizations. The tendency to increased thrombus formation forces the patient to consult a doctor. Hemoglobinuria is quite rarely the first symptom of the disease and in some patients PNH may be completely absent. In some cases, it appears for the first time 2-3 years or even 10 years after the onset of the disease.

One of the characteristic signs of PNH is attacks of abdominal pain. Its localization can be very different. Outside the period of crisis, abdominal pain, as a rule, is not observed. It is often accompanied by vomiting. Most likely, abdominal pain in patients with PNH is associated with thrombosis of the mesenteric vessels.

Thrombosis of peripheral vessels (most often - veins of the upper and lower extremities, less often - renal vessels) also characteristic symptom paroxysmal nocturnal hemoglobinuria. Thrombophlebitis is observed in 12% of patients with PNH. Thrombotic complications are the most common cause death from this disease.

During an objective examination of the patient, pallor with a slight icteric tint most often attracts attention. Puffiness of the face, sometimes excessive fullness, is often observed. There may be a slight enlargement of the spleen and liver, although this is not typical for PNH.

Paroxysmal nocturnal hemoglobinuria is characterized by signs of intravascular hemolysis, the most important of which is an increase in free plasma hemoglobin. This symptom is periodically observed in almost all patients with PNH. However, the degree of increase in free plasma hemoglobin varies and depends on the period of the disease during which the study was conducted. During a crisis, this indicator increases significantly, and an increase in the amount of plasma metalbumin is also noted.

The level of free hemoglobin in plasma depends on the degree of hemolysis at the moment, the content of haptoglobin, the degree of filtration of hemoglobin in the urine and the rate of destruction of the hemoglobin-haptoglobin complex. In the case of a small degree of hemolysis, the level of free hemoglobin in the plasma will be insufficient to filter it through kidney filter. Therefore, hemoglobinuria is not a mandatory symptom of the disease. When passing through the nephron tubules, the released hemoglobin is partially destroyed and deposited in the epithelium of the tubules. This is the reason for the excretion of hemosiderin in the urine.

Hemosiderin is excreted in the urine in the vast majority of patients with paroxysmal nocturnal hemoglobinuria. Sometimes hemosiderinuria does not appear immediately. This is an important but not specific sign of the disease.

Laboratory parameters for paroxysmal nocturnal hemoglobinuria

The number of red blood cells in patients with PNH decreases according to the level of decrease in hemoglobin. Color index a long period remains close to unity. In cases where the patient loses a significant amount of iron in the urine in the form of hemosiderin and hemoglobin, the iron level gradually decreases. Short color index observed in approximately half of patients. Some of them have elevated hemoglobin P levels, especially during an exacerbation.

In a significant proportion of patients, the content of reticulocytes is increased, but relatively low (2-4%). The number of leukocytes in PNH is reduced in most cases. In many patients it is 1.5-3 G per 1 liter, but sometimes it drops to 0.7-0.8 G per 1 liter. Leukopenia is usually observed due to a decrease in the number of neutrophil granulocytes. Sometimes the leukocyte count in PNH is normal or increased - up to 10-11 G per 1 liter.

Paroxysmal nocturnal hemoglobinuria, also known as Strübing-Marchiafava disease, Marchiafava-Micheli disease, is a rare disease, a progressive blood pathology, life-threatening patient. It is one of the types of acquired hemolytic anemia caused by disturbances in the structure of erythrocyte membranes. Defective cells are subject to premature decay (hemolysis) that occurs inside the blood vessels. The disease is genetic in nature, but is not considered inherited.

Nocturnal paroxysmal hemoglobinuria

Epidemiology

The incidence is 2 cases per 1 million people. The incidence is 1.3 cases per million people per year. It predominantly manifests itself in older people; no dependence of the incidence on gender and race has been identified. There are isolated cases of the disease in children and adolescents.

Important: average age detection of the disease - 35 years.

What is nocturnal paroxysmal hemoglobinuria

Causes of the disease

The causes and risk factors for developing the disease are unknown. It has been established that the pathology is caused by a mutation in the PIG-A gene, located in the short arm of the X chromosome. The mutagenic factor has not yet been identified. In 30% of cases of nocturnal paroxysmal hemoglobinuria, there is a connection with another blood disease - aplastic anemia.

The formation, development and maturation of blood cells (hematopoiesis) occurs in the red bone marrow. All specialized blood cells are formed from so-called stem, unspecialized cells that have retained the ability to divide. Formed as a result of successive divisions and transformations, mature blood cells enter the bloodstream.

A mutation in the PIG-A gene even in a single cell leads to the development of PNH. Damage to the gene also changes the activity of cells in the processes of maintaining bone marrow volume; mutant cells multiply more actively than normal ones. In the hematopoietic tissue, a population of cells producing defective blood cells is quickly formed. In this case, the mutant clone does not belong to malignant formations and may disappear spontaneously. The most active replacement of normal bone marrow cells with mutant ones occurs in the processes of restoration of bone marrow tissue after significant damage caused, in particular, by aplastic anemia.

Characteristic signs of nocturnal paroxysmal hemoglobinuria

Damage to the PIG-A gene leads to disruptions in the synthesis of signaling proteins that protect body cells from the effects of the complement system. The complement system is specific blood plasma proteins that provide general immune protection. These proteins bind to damaged red blood cells and melt them, and the released hemoglobin mixes with the blood plasma.

Classification

Based on the available data on the causes and characteristics of pathological changes, several forms of paroxysmal nocturnal hemoglobinuria are distinguished:

1. Subclinical.
2. Classic.
3. Associated with hematopoiesis disorders.

The subclinical form of the disease is often preceded by aplastic anemia. Clinical manifestations there is no pathology, but the presence of a small number of defective blood cells is detected only by laboratory tests.

Clinic of nocturnal paroxysmal hemoglobinuria

On a note. There is an opinion that PNH is a more complex disease, the first stage of which is aplastic anemia.

The classic form occurs with typical symptoms; populations of defective red blood cells, platelets and some types of leukocytes are present in the patient’s blood. Laboratory methods studies confirm intravascular destruction of pathologically altered cells, hematopoiesis disorders are not detected.

After past diseases, leading to insufficiency of hematopoiesis, the third form of pathology develops. Expressed clinical picture and intravascular lysis of erythrocytes develop against the background of bone marrow lesions.

There is an alternative classification, according to which there are:

1. Actually PNH, idiopathic.
2. Developing as a concomitant syndrome with other pathologies.
3. Developing as a consequence of bone marrow hypoplasia.

Clinic of nocturnal paroxysmal hemoglobinuria. Part 2

The severity of the disease in different cases is not always related to the number of defective red blood cells. Both subclinical cases with a content of modified cells approaching 90%, and extremely severe cases with replacement of 10% of the normal population, have been described.

Development of the disease

It is currently known that in the blood of patients with paroxysmal nocturnal hemoglobinuria, three types of erythrocytes with different sensitivities to destruction by the complement system may be present. In addition to normal cells, red blood cells circulate in the bloodstream, the sensitivity of which is several times higher than normal. In the blood of patients diagnosed with Marchiafava-Micheli disease, cells were found whose sensitivity to complement was 3-5 times higher than normal.

What does nocturnal paroxysmal hemoglobinuria lead to?

Pathological changes also affect other blood cells, namely platelets and granulocytes. At the height of the disease, patients experience pancytopenia - an insufficient number of blood cells of different types.

The severity of the disease depends on the ratio between the populations of healthy and defective blood cells. The maximum content of red blood cells that are hypersensitive to complement-dependent hemolysis is achieved within 2-3 years from the moment of mutation. At this time, the first typical symptoms of the disease appear.

The pathology usually develops gradually; acute crisis onset is rare. Exacerbations occur against the background of menstruation, severe stress, acute viral diseases, surgical intervention, treatment with certain drugs (in particular, iron-containing ones). Sometimes the disease worsens when eating certain foods or for no obvious reason.

Paroxysmal nocturnal hemoglobinuria

There is evidence of manifestations of Marchiafava-Micheli disease due to radiation exposure.

The dissolution of blood cells to varying degrees in patients with established paroxysmal nocturnal hemoglobinuria occurs constantly. Periods of moderate flow are interspersed with hemolytic crises, massive destruction of red blood cells, which leads to sharp deterioration patient's condition.

Outside of a crisis, patients are concerned about manifestations of moderate general hypoxia, such as shortness of breath, attacks of arrhythmia, general weakness, and worsening exercise tolerance. During a crisis, abdominal pain appears, localized mainly in the navel area and in the lower back. Urine turns black, the darkest portion is in the morning. The reasons for this phenomenon have not yet been definitively established. With PNH, a slight pastiness of the face develops, and yellowness of the skin and sclera is noticeable.

On a note! A typical symptom of the disease is stained urine. In approximately half of known cases, the disease does not manifest itself.

Change in urine color from normal to pathological in paroxysmal nocturnal hemoglobinuria

In the periods between crises, patients may experience:

• anemia;
• tendency to thrombosis;
• liver enlargement;
• manifestations of myocardial dystrophy;
• tendency to inflammation of infectious origin.

When blood cells are destroyed, substances that increase clotting are released, which causes thrombosis. Blood clots may form in the vessels of the liver and kidneys; coronary and cerebral vessels are also susceptible to damage, which can lead to death. Thrombosis localized in the liver vessels leads to an increase in the size of the organ. Violations of intrahepatic blood flow entail dystrophic changes fabrics. When the portal vein system or splenic veins are blocked, splenomegaly develops. Disorders of nitrogen metabolism are accompanied by dysfunction of smooth muscles; some patients complain of difficulty swallowing, spasms of the esophagus, and erectile dysfunction is possible in men.

Important! Thrombotic complications in PNH predominantly affect the veins; arterial thrombosis rarely develops.

Video - Paroxysmal nocturnal hemoglobinuria

Mechanisms of development of complications of PNH

Hemolytic crisis is manifested by the following symptoms:

• acute abdominal pain caused by multiple thrombosis of small mesenteric veins;
• increased jaundice;
• pain in the lumbar region;
• lowering blood pressure;
• increased body temperature;
• staining urine black or dark brown.

In rare cases, “hemolytic kidney” develops, a specific transient form of renal failure accompanied by acute anuria. Due to violation excretory function Nitrogen-containing organic compounds, which are the end products of protein breakdown, accumulate in the blood, and azotemia develops. After the patient emerges from the crisis, the contents shaped elements in the blood is gradually restored, jaundice and manifestations of anemia partially fade away.

The most common course of the disease is crisis, interspersed with periods of stable, satisfactory condition. In some patients, the periods between crises are very short, insufficient to restore blood composition. Such patients develop persistent anemia. There is also a variant of the course with an acute onset and frequent crises. Over time, crises become less frequent. In especially severe cases, death is possible, which is caused by acute renal failure or thrombosis of blood vessels supplying the heart or brain.

Important! No daily patterns in the development of hemolytic crises have been identified.

In rare cases, the disease can have a long-term quiet course; isolated cases of recovery have been described.

Diagnostics

Laboratory diagnostics nocturnal paroxysmal hemoglobinuria

In the early stages of the disease, diagnosis is difficult due to the manifestation of scattered nonspecific symptoms. Diagnosis sometimes requires several months of observation. The classic symptom - specific staining of urine - appears during crises and not in all patients. Reasons to suspect Marchiafava-Miceli disease are:

• iron deficiency of unknown etiology;
• thrombosis, headaches, attacks of pain in the lower back and abdomen for no apparent reason;
• hemolytic anemia of unknown origin;
• melting of blood cells, accompanied by pancytopenia;
• hemolytic complications associated with transfusion of fresh donor blood.

In the diagnostic process, it is important to establish the fact of chronic intravascular breakdown of red blood cells and identify specific serological signs of PNH.

In a complex of studies, if nocturnal paroxysmal hemoglobinuria is suspected, in addition to general urine and blood tests, the following are carried out:

• determination of hemoglobin and haptoglobin content in the blood;
• immunophenotyping by flow cytometry to identify defective cell populations;
• serological tests, in particular the Coombs test.

Diagnostic tests for nocturnal paroxysmal hemoglobinuria

Required differential diagnosis with hemoglobinuria and anemia of other etiologies, in particular, autoimmune disease should be excluded hemolytic anemia. Common symptoms are anemia, jaundice, and increased bilirubin in the blood. Enlargement of the liver and/or spleen is not observed in all patients

Paroxysmal nocturnal hemoglobinuria is a rare acquired life-threatening blood disease. The pathology causes the destruction of red blood cells - erythrocytes. Doctors call this process hemolysis, and the term “hemolytic anemia” fully characterizes the disease. Another name for such anemia is Marchiafava-Micheli disease, after the names of the scientists who described the pathology in detail.

Causes and essence of the disease

Paroxysmal nocturnal hemoglobinuria is uncommon - usually 1-2 cases are recorded per 1 million people in the population. This is a disease of relatively young adults, the average age of diagnosis is 35-40 years. Manifestation of Marchiafava-Miceli disease in childhood and adolescence– a great rarity.

The main cause of the disease is a mutation in a single stem cell gene called PIG-A. This gene is located on the X chromosome of bone marrow cells. The exact causes and mutagenic factors of this pathology are still unknown. The occurrence of paroxysmal nocturnal hemoglobinuria is closely related to aplastic anemia. It has been statistically proven that 30% of cases of identified Marchiafava-Miceli disease are a consequence of aplastic anemia.

The process of forming blood cells is called hematopoiesis. Red blood cells, white blood cells and platelets are formed in the bone marrow, a special spongy substance located in the center of some bone structures in the body. The precursors of all cellular elements of the blood are stem cells, during the gradual division of which new blood elements are formed. Having gone through all the processes of maturation and formation, the formed elements enter the bloodstream and begin to perform their functions.

For the development of Marchiafava-Micheli disease, the presence of a mutation in the above-mentioned PIG-A gene in one stem cell is sufficient. The abnormal progenitor cell continually divides and “clones” itself. So the entire population becomes pathologically altered. Inferior red blood cells mature, form and release into the bloodstream.

The essence of the changes lies in the absence on the red blood cell membrane of special proteins responsible for protecting the cell from its own immune system - the complement system. The complement system is a set of blood plasma proteins that protect the body from various infectious agents. Normally, all cells of the body are protected from their immune proteins. With paroxysmal nocturnal hemoglobinuria, such protection is absent. This leads to the destruction or hemolysis of red blood cells and the release of free hemoglobin into the blood.

Clinical manifestations and symptoms

Due to the variety of clinical manifestations, the diagnosis of paroxysmal nocturnal hemoglobinuria can sometimes be reliably made only after several months of diagnostic search. The fact is that the classic symptom - dark brown urine (hemoglobinuria) occurs only in 50% of patients. The classic presence of hemoglobin in the morning portions of urine, during the day it usually becomes lighter.

The release of hemoglobin in the urine is associated with massive resolution of red blood cells. Doctors call this condition a hemolytic crisis. It can be triggered by an infectious disease, excessive alcohol intake, physical activity or stressful situations.

The term paroxysmal nocturnal hemoglobinuria arose from the belief that hemolysis and activation of the complement system are triggered by respiratory acidosis during sleep. This theory was later disproved. Hemolytic crises occur at any time of the day, but the accumulation and concentration of urine in bladder during the night leads to specific color changes.

The main clinical aspects of paroxysmal nocturnal hemoglobinuria:

1. Hemolytic anemia is a decrease in the number of red blood cells and hemoglobin due to hemolysis. Hemolytic crises are accompanied by weakness, dizziness, and “spots” flashing before the eyes. General condition on initial stages does not correlate with hemoglobin levels.
2. Thrombosis is the main cause of death in patients with Marchiafava-Micheli disease. Arterial thrombosis is much less common. The hepatic, mesenteric and cerebral veins are affected. Specific clinical symptoms depend on the vein involved in the process. Budd-Chiari syndrome occurs with thrombosis of the hepatic veins, blockade of cerebral vessels has neurological symptoms. A scientific review on paroxysmal nocturnal hemoglobinuria published in 2015 suggests that hepatic vascular blockage is more common in women. Dermal vein thrombosis is manifested by red, painful nodes that rise above the surface of the skin. Such lesions cover large areas, for example, the entire skin of the back.
3. Insufficient hematopoiesis - a decrease in the number of red blood cells, leukocytes and platelets in the peripheral blood. This pancytopenia makes a person susceptible to infections due to the low number of white blood cells. Thrombocytopenia leads to increased bleeding.

The hemoglobin released after the destruction of red blood cells undergoes splitting. As a result, the degradation product, haptoglobin, enters the bloodstream, and hemoglobin molecules become free. Such free molecules bind irreversibly to nitric oxide (NO) molecules, thereby reducing their quantity. NO is responsible for smooth muscle tone. Its deficiency causes the following symptoms:

• stomach ache;
• headache;
• spasms of the esophagus and swallowing disorders;
• erectile dysfunction.

Excretion of hemoglobin in the urine leads to impaired kidney function. Kidney failure gradually develops, requiring replacement therapy.

Diagnostic and therapeutic measures

At the initial stages, making a diagnosis of Marchiafava-Miceli disease is quite difficult due to the diverse clinical symptoms and scattered complaints of patients. The appearance of characteristic changes in the color of urine usually leads to diagnostic search V the right direction.

Basic diagnostic tests used for paroxysmal nocturnal hemoglobinuria:

1. Complete blood count - to determine the number of red blood cells, white blood cells and platelets.
2. The Coombs test is an analysis that allows you to determine the presence of antibodies on the surface of red blood cells, as well as antibodies circulating in the blood.
3. Flow cytometry allows for immunophenotyping, that is, to determine the presence of a particular protein on the surface of red blood cell membranes.
4. Measurement of serum hemoglobin and haptoglobin levels.
5. General urine analysis.

An integrated diagnostic approach makes it possible to identify Strübing-Marchiafava disease in a timely manner and begin its treatment before the manifestation of thrombotic complications. Treatment of paroxysmal nocturnal hemoglobinuria is possible with the following groups of drugs:

1. Steroid hormones (Prednisolone, Dexamethasone) inhibit the functioning of the immune system, thereby stopping the destruction of red blood cells by proteins of the complement system.
2. Cytostatics (Eculizumab) have similar action. They suppress the immune response and eliminate the signs of paroxysmal nocturnal hemoglobinuria.
3. Sometimes patients need transfusions of washed red blood cells, specially selected by hematologists, to correct hemoglobin levels.
4. Maintenance therapy in the form of iron and folic acid supplements.

The described treatment of paroxysmal nocturnal hemoglobinuria cannot relieve the patient of the disease, but only muffles the symptoms. A real therapeutic option is bone marrow transplantation. This procedure completely replaces the pool of abnormal stem cells, curing the disease.

The disease described in the article is potentially life-threatening without appropriate treatment. Complications in the form of thrombosis and renal failure can have serious consequences for life and health. Timely treatment can stop the progression of the disease and prolong the patient’s full life.

Paroxysmal nocturnal hemoglobinuria is a very rare disease from the group of hemolytic anemias and is not considered inherited. It is acquired during life, although it has a genetic basis. The essence of the pathology is changes in the structure of blood cells (mostly red blood cells), leading to premature destruction of their membranes and intravascular breakdown (hemolysis).

The prevalence is about 16 cases per million population, and the annual incidence is 1.3 per million. People aged 20 to 40 years are most often affected; no gender dependence has been identified.

The name includes the names of Italian researchers and doctors who spent years studying: Marchiafava-Micheli disease, Strübing-Marchiafava disease.

What is “hemoglobinuria” and what causes it?

Hemoglobinuria is a symptom of various diseases that cause the breakdown of red blood cells by their effect on the membrane, while hemoglobin leaves the cells and enters the plasma.

In a healthy person, it can be no more than 5% of the total blood plasma volume. An increased level of hemoglobin of 20-25% is observed in congenital disorders or hemoglobinopathies (β-thalassemia, red cell destruction in sickle cell anemia).

Severe hemoglobinuria is caused by conditions when the permissible hemoglobin levels are significantly exceeded due to hemolysis of red blood cells. The macrophage system is not able to process such a large volume of pigment, and hemoglobin enters the urine.

The causes of hemoglobinuria can be:

• acute infectious disease (flu);
• pneumonia;
• injuries;
• intoxication due to poisoning with aniline dyes, carbolic acid, Berthollet salt;
• severe hypothermia;
• strong and prolonged physical stress;
• transfusion of different types of blood;
• extensive burns;
• The role of acquired mutation of the PIG-A gene has been established.

Aniline dyes are widely used in the textile industry, batik decoration, dry cleaning and dyeing services, working with them requires caution

Hemoglobinuria does not exist without a high level of hemoglobin in the blood (hemoglobinemia). Pre-dawn paroxysms are associated with a physiological shift in acid-base balance towards acidosis at night. The increased content of breakdown products further contributes to acidification of the body and increased breakdown of blood cells.

Pathogenesis of disorders

The main changes in paroxysmal nocturnal hemoglobinuria occur at the complement level. It represents a chain of biochemical reactions that provide innate immunity.

The active substance is considered to be the formed membrane attack complex. It contains about 30 regulator components. The synthesis of complement components depends on signals received from the nervous and endocrine systems. Normally, it is controlled by special proteins that do not allow the destruction of host (human) cells.

With nocturnal hemoglobinuria, this process is lost. The lipid layer of the cell membrane of red blood cells is destroyed, which causes their death. Increased sensitivity of the erythrocyte membrane to complement components has been proven.

Complement is necessary to protect cells from infectious agents and utilize the breakdown products of microorganisms and their own damaged cells.

Other blood cells (leukocytes and platelets) also react by causing defects in the membrane. No accumulation of immunoglobulins was found on them, which proves the absence of an autoallergy mechanism and speaks in favor of damage to the common precursor cell. It is she who receives genetic information (order) about the destructive action.

The missing genetic region of the stem cell is called a GPI-AP. Its deficiency in the erythrocyte clone contributes to susceptibility to hemolysis under the influence of complement. At the same time, a normal clone of red blood cells can exist in the body.

Paroxysmal nocturnal hemoglobinuria occurs only if the pathological clone prevails over the normal one. Red blood cells from a clone with partial or complete absence of GPI-AP are detected in patients by flow cytometry. It is important that the number of pathological cells in patients is not the same.

Increased thrombus formation in Marchiafava-Miceli disease is associated with stimulation of blood clotting by factors released during the destruction of red blood cells.

Forms of the disease

The classification of clinical forms takes into account laboratory data and the cause-and-effect relationship of blood changes. It is customary to distinguish the following varieties:

1. Subclinical - there are no laboratory signs of hemolysis; only highly sensitive methods can detect a small number of cells lacking GPI-AP. There is no clinical picture of the disease. Often combined with aplastic anemia.
2. Classic - all clinical symptoms are present, it occurs with periodic exacerbations, in addition to erythrocytes, leukocytes and platelets are affected, signs of hemolysis are determined in the laboratory (growth of reticulocytes, serum enzyme lactate dehydrogenase, bilirubin, with a reduced level of haptoglobin). No abnormalities of hematopoiesis were observed in the bone marrow.
3. Caused by insufficiency of bone marrow hematopoiesis in various diseases- concomitant or previous pathology of the bone marrow with a disorder of hematopoiesis is assumed (with aplastic anemia, myelodysplastic syndrome). Analysis and clinical findings reveal all manifestations of hemolysis against the background of abnormalities in bone marrow hematopoiesis.

According to another classification, it is proposed to distinguish:

• idiopathic form or paroxysmal nocturnal hemoglobinuria itself;
• pathology in the form of a syndrome for various diseases;
• a rarely observed species occurring after bone marrow hypoplasia.

No classification is based on a quantitative indicator of the prevalence of an abnormal clone in the blood. It has been shown that a subclinical course is possible with 90% replacement of normal cells. And in other patients, severe thrombosis occurs in the presence of only 10% of altered red blood cells.

Symptoms and clinical course

The disease can begin suddenly (acutely) or have a gradual chronic course. Periods of exacerbation are called hemolytic crises. They are often preceded by a previous cold, an association with infection, or contact with toxic substances.

The main symptoms of paroxysmal nocturnal hemoglobinuria include:

• stomach ache;
• pain in the chest of varying intensity and localization - pain of different localization is associated with thrombosis of small branches of the arterial bed and the formation of foci of ischemia in the internal organs;
• signs of anemia (weakness, dizziness, headaches) - caused by increased destruction and insufficient production of red blood cells, in addition, studies indicate a deficiency of iron and folic acid in the blood of patients;
• yellowness of the skin and sclera - an indicator of the release of direct bilirubin into the blood, processed by the liver from excess hemoglobin;
• swallowing disorder;
• erectile dysfunction in men - manifests itself not only against the background of crises, but becomes chronic, caused by a reduced concentration of nitric oxide in the plasma, impaired muscle and vascular tone.
• increased fatigue;
• shortness of breath, palpitations;
• local signs of thrombophlebitis (redness of the skin above the vein, swelling, pain on palpation, increased temperature);
• When examining a patient, the doctor may note an enlarged liver and spleen; this sign is especially important for diagnosing the development of thrombosis and heart attacks in them.

The chronic course of the disease contributes to the development of:

• pulmonary hypertension with thrombosis in the branches of the pulmonary vessels;
• chronic renal failure caused by deposition of the breakdown product of hemoglobin (hemosiderin) in the renal tubules, vascular thrombosis with the formation of microinfarctions;
• high sensitivity to associated infection.

These syndromes become the most likely causes of death.

Laboratory diagnostics

The diagnosis of Marchiafava-Micheli disease is made after a thorough examination in hematology centers that have the ability to conduct specific tests and analyses.

In peripheral blood are found:

• erythropenia, leukopenia, thrombocytopenia (the state of inhibition of the general growth of blood cells is called pancytopenia);
• reticulocytosis;
• increase in hemoglobin level in plasma;
• decreased iron and folate levels.

Bone marrow examination reveals:

• signs of activation of erythropoiesis (production of red blood cells) due to the accumulation of precursor cells (normoblasts, plasma and mast cells);
• decreased number of granulocytes and megakaryocytes;
• areas of hemorrhage, accumulation of hemolyzed red blood cells in the sinuses;
• at the stage of suppression of hematopoiesis, zones of fatty degeneration and devastation are visible.

Specific tests based on the increased sensitivity of defective erythrocytes to complement under conditions that are most favorable in terms of the composition of the medium are the Hem (acidic) and Hartmann (with sucrose) tests.

Both tests test the "survival" of red blood cells in a blood sample placed in a weak solution. Hem's test is positive when the destruction is 5% or more, and Hartman's is 4% or more.

The Coombs test is performed to exclude a connection with the autoimmune mechanism of cell destruction; it is negative for nocturnal hemoglobinuria.

The coloring of urine indicates a significant content of oxyhemoglobin in it.

A urine test showed that one of the initial signs of nocturnal hemoglobinuria is morning and night urine, colored dark red. Over time, the collected urine separates into layers:

• the liquid on top is transparent, but retains color;
• particles of dead cells of organic origin are determined from below.

What diseases should nocturnal hemoglobinuria be distinguished from?

Differential diagnosis of paroxysmal nocturnal hemoglobinuria is carried out with other anemias similar in clinical course, primarily with hemolytic anemia of the autoimmune type and aplastic one.

Common features are:

• a sharp decrease in the number of red blood cells;
• reticulocytosis;
• presence of jaundice;
• fever;
• increased concentration of free bilirubin;
• tendency to thrombosis;
• moderate enlargement of the liver and spleen.

With anemia, there are no high levels of hemoglobin in the blood plasma or urobilin in the urine. The Hem and Hartman laboratory tests are negative, but the Coombs test is positive.

Diagnosis is significantly difficult if the disease occurs in the form of temporary crises against the background of an acute form of myeloblastic leukemia, erythromyelosis, osteomyelosclerosis, metastatic bone marrow lesions in malignant tumors.

Red blood cell mass is stored cold in special packages

Treatment

To date, there is no effective way to stop the breakdown of red blood cells. All that remains is to use the replacement option and transfuse the patient with washed red blood cells from donors.

Important feature is a good “attitude” of the patient’s body towards the injected foreign cells, there is practically no rejection reaction. Considering the presence of healthy GPI-AP cells in the membranes and the absence of genetic mutations in them, it is possible to support the patient’s hematopoiesis.

Blood used for transfusion must be kept frozen for at least a week in order to completely destroy the leukocytes in it. Once they reach the patient, they can cause exacerbation of hemolysis due to increased sensitization and activation of complement.

With frequent transfusions, the formation of anti-erythrocyte antibodies is still possible. In such patients, subsequent transfusion is carried out after several procedures of washing red blood cells with saline and checking the donor blood using the Coombs test.

The number of transfusions is usually prescribed at least five, but depends on the severity of the patient's condition and response to treatment.

To stimulate proper hematopoiesis, Nerobol (an anabolic hormonal drug) is used in courses of up to three months. In this case, a change in the functional state of the liver is possible.

For the purpose of treatment and prevention of thrombus formation, Heparin is used, followed by a transition to maintenance doses of indirect anticoagulants.

To compensate for iron losses, tablets are prescribed.

An indication for removal of the spleen may be a sharp increase in size and signs of a heart attack. Splenectomy is rarely performed.

To protect the liver, hepatoprotective drugs are prescribed. Sometimes steroid therapy helps.

The drug is administered only intravenously

In recent years, information has appeared on the use of the drug Eculizumab (Soliris), made from monoclonal antibodies. Judging by the available reports, it blocks hemolysis and is able to resist blood complement. The drug is considered the most expensive medicine in the world. Its action and negative effects have not been sufficiently studied.

Nocturnal hemoglobinuria does not yet have a specific treatment. Even with sufficient supportive therapy, patients live about five years after the onset of the disease. There is no prevention. Everyone should adhere to correct behavior when working and having forced contact with toxic compounds.

Paroxysmal nocturnal hemoglobinuria, also known as Strübing-Marchiafava disease, Marchiafava-Micheli disease, is a rare disease, a progressive blood pathology that threatens the patient’s life. It is one of the types of acquired hemolytic anemia caused by disturbances in the structure of erythrocyte membranes. Defective cells are subject to premature decay (hemolysis) that occurs inside the blood vessels. The disease is genetic in nature, but is not considered inherited.

The incidence is 2 cases per 1 million people. The incidence is 1.3 cases per million people per year. It mainly manifests itself in people aged 25-45 years; no dependence of incidence on gender and race has been identified. There are isolated cases of the disease in children and adolescents.

Important: the average age at which the disease is diagnosed is 35 years.

Causes of the disease

The causes and risk factors for developing the disease are unknown. It has been established that the pathology is caused by a mutation in the PIG-A gene, located in the short arm of the X chromosome. The mutagenic factor has not yet been identified. In 30% of cases of nocturnal paroxysmal hemoglobinuria, there is a connection with another blood disease - aplastic anemia.

The formation, development and maturation of blood cells (hematopoiesis) occurs in the red bone marrow. All specialized blood cells are formed from so-called stem, unspecialized cells that have retained the ability to divide. Formed as a result of successive divisions and transformations, mature blood cells enter the bloodstream.

A mutation in the PIG-A gene even in a single cell leads to the development of PNH. Damage to the gene also changes the activity of cells in the processes of maintaining bone marrow volume; mutant cells multiply more actively than normal ones. In the hematopoietic tissue, a population of cells producing defective blood cells is quickly formed. In this case, the mutant clone is not a malignant tumor and can disappear spontaneously. The most active replacement of normal bone marrow cells with mutant ones occurs in the processes of restoration of bone marrow tissue after significant damage caused, in particular, by aplastic anemia.

Damage to the PIG-A gene leads to disruptions in the synthesis of signaling proteins that protect body cells from the effects of the complement system. The complement system is specific blood plasma proteins that provide general immune protection. These proteins bind to damaged red blood cells and melt them, and the released hemoglobin mixes with the blood plasma.

Classification

Based on the available data on the causes and characteristics of pathological changes, several forms of paroxysmal nocturnal hemoglobinuria are distinguished:

1. Subclinical.
2. Classic.
3. Associated with hematopoiesis disorders.

The subclinical form of the disease is often preceded by aplastic anemia. There are no clinical manifestations of the pathology, but the presence of a small number of defective blood cells is detected only during laboratory tests.

On a note. There is an opinion that PNH is a more complex disease, the first stage of which is aplastic anemia.

The classic form occurs with typical symptoms; populations of defective red blood cells, platelets and some types of leukocytes are present in the patient’s blood. Laboratory research methods confirm intravascular destruction of pathologically altered cells; hematopoiesis disorders are not detected.

After suffering from diseases leading to hematopoietic insufficiency, a third form of pathology develops. A pronounced clinical picture and intravascular lysis of red blood cells develop against the background of bone marrow lesions.

There is an alternative classification, according to which there are:

1. Actually PNH, idiopathic.
2. Developing as a concomitant syndrome with other pathologies.
3. Developing as a consequence of bone marrow hypoplasia.

The severity of the disease in different cases is not always related to the number of defective red blood cells. Both subclinical cases with a content of modified cells approaching 90%, and extremely severe cases with replacement of 10% of the normal population, have been described.

Development of the disease

It is currently known that in the blood of patients with paroxysmal nocturnal hemoglobinuria, three types of erythrocytes with different sensitivities to destruction by the complement system may be present. In addition to normal cells, red blood cells circulate in the bloodstream, the sensitivity of which is several times higher than normal. In the blood of patients diagnosed with Marchiafava-Micheli disease, cells were found whose sensitivity to complement was 3-5 and 15-25 times higher than normal.

Pathological changes also affect other blood cells, namely platelets and granulocytes. At the height of the disease, patients experience pancytopenia - an insufficient number of blood cells of different types.

The severity of the disease depends on the ratio between the populations of healthy and defective blood cells. The maximum content of red blood cells that are hypersensitive to complement-dependent hemolysis is achieved within 2-3 years from the moment of mutation. At this time, the first typical symptoms of the disease appear.

The pathology usually develops gradually; acute crisis onset is rare. Exacerbations occur against the background of menstruation, severe stress, acute viral diseases, surgery, treatment with certain drugs (in particular, iron-containing ones). Sometimes the disease worsens when eating certain foods or for no obvious reason.

There is evidence of manifestations of Marchiafava-Micheli disease due to radiation exposure.

The dissolution of blood cells to varying degrees in patients with established paroxysmal nocturnal hemoglobinuria occurs constantly. Periods of moderate progression are interspersed with hemolytic crises, massive destruction of red blood cells, which leads to a sharp deterioration in the patient’s condition.

Outside of a crisis, patients are concerned about manifestations of moderate general hypoxia, such as shortness of breath, attacks of arrhythmia, general weakness, and worsening exercise tolerance. During a crisis, abdominal pain appears, localized mainly in the navel area and in the lower back. Urine turns black, the darkest portion is in the morning. The reasons for this phenomenon have not yet been definitively established. With PNH, a slight pastiness of the face develops, and yellowness of the skin and sclera is noticeable.

On a note! A typical symptom of the disease is stained urine. In approximately half of known cases, the disease does not manifest itself.

In the periods between crises, patients may experience:

• anemia;
• tendency to thrombosis;
• liver enlargement;
• manifestations of myocardial dystrophy;
• tendency to inflammation of infectious origin.

When blood cells are destroyed, substances that increase clotting are released, which causes thrombosis. Blood clots may form in the vessels of the liver and kidneys; coronary and cerebral vessels are also susceptible to damage, which can lead to death. Thrombosis localized in the liver vessels leads to an increase in the size of the organ. Disturbances in intrahepatic blood flow lead to degenerative changes in tissue. When the portal vein system or splenic veins are blocked, splenomegaly develops. Disorders of nitrogen metabolism are accompanied by dysfunction of smooth muscles; some patients complain of difficulty swallowing, spasms of the esophagus, and erectile dysfunction is possible in men.

Important! Thrombotic complications in PNH predominantly affect the veins; arterial thrombosis rarely develops.

Video - Paroxysmal nocturnal hemoglobinuria

Mechanisms of development of complications of PNH

Hemolytic crisis is manifested by the following symptoms:

• acute abdominal pain caused by multiple thrombosis of small mesenteric veins;
• increased jaundice;
• pain in the lumbar region;
• lowering blood pressure;
• increased body temperature;
• staining urine black or dark brown.

In rare cases, “hemolytic kidney” develops, a specific transient form of renal failure accompanied by acute anuria. Due to impaired excretory function, nitrogen-containing organic compounds accumulate in the blood, which are the end products of protein breakdown, and azotemia develops. After the patient recovers from the crisis, the content of formed elements in the blood is gradually restored, jaundice and manifestations of anemia partially fade away.

The most common course of the disease is crisis, interspersed with periods of stable, satisfactory condition. In some patients, the periods between crises are very short, insufficient to restore blood composition. Such patients develop persistent anemia. There is also a variant of the course with an acute onset and frequent crises. Over time, crises become less frequent. In especially severe cases, death is possible, which is caused by acute renal failure or thrombosis of blood vessels supplying the heart or brain.

Important! No daily patterns in the development of hemolytic crises have been identified.

In rare cases, the disease can have a long-term quiet course; isolated cases of recovery have been described.

Diagnostics

In the early stages of the disease, diagnosis is difficult due to the manifestation of scattered nonspecific symptoms. Diagnosis sometimes requires several months of observation. The classic symptom - specific staining of urine - appears during crises and not in all patients. Reasons to suspect Marchiafava-Miceli disease are:

• iron deficiency of unknown etiology;
• thrombosis, headaches, attacks of pain in the lower back and abdomen for no apparent reason;
• hemolytic anemia of unknown origin;
• melting of blood cells, accompanied by pancytopenia;
• hemolytic complications associated with transfusion of fresh donor blood.

In the diagnostic process, it is important to establish the fact of chronic intravascular breakdown of red blood cells and identify specific serological signs of PNH.

In a complex of studies, if nocturnal paroxysmal hemoglobinuria is suspected, in addition to general urine and blood tests, the following are carried out:

• determination of hemoglobin and haptoglobin content in the blood;
• immunophenotyping by flow cytometry to identify defective cell populations;
• serological tests, in particular the Coombs test.

Differential diagnosis with hemoglobinuria and anemia of other etiologies is necessary; in particular, autoimmune hemolytic anemia should be excluded. Common symptoms are anemia, jaundice, and increased bilirubin in the blood. Enlargement of the liver and/or spleen is not observed in all patients

Signs	Autoimmune hemolytic anemia	PNG
Coombs test	+	-
Increased content of free hemoglobin in blood plasma	-	+
Hartmann test (sucrose)	-	+
Hem's test (acidic)	-	+
Hemosiderin in urine	-	+
Thrombosis	±	+
Hepatomegaly	±	±
Splenomegaly	±	±

The results of the Hartmann and Hem test are specific for PNH and are the most important diagnostic signs.

Treatment

Relief of a hemolytic crisis is carried out by repeated transfusions of red blood cells, thawed or previously washed many times. It is believed that at least 5 transfusions are needed to achieve a lasting result, however, the number of transfusions may differ from the average and is determined by the severity of the patient’s condition.

Attention! Blood cannot be transfused to such patients without prior preparation. Transfusion of donor blood aggravates the crisis.

For symptomatic relief hemolysis, patients can be prescribed Nerobol, but after discontinuation of the drug, relapses are possible.

Additionally, folic acid, iron, and hepatoprotectors are prescribed. When thrombosis develops, direct-acting anticoagulants and heparin are used.

In extremely rare cases, the patient is indicated for splenectomy - removal of the spleen.

All of these measures are supportive; they alleviate the patient’s condition, but do not eliminate the population of mutant cells.

0