Brain without background. Marchiafava-Miceli disease (paroxysmal nocturnal hemoglobinuria). Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan, Kazan

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 the development of possible complications and 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 development of the disease in old age or in children are also known to 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 studies have 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, it is possible to define a small generalization of all possible manifestations of 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. In the daytime and evening, this sign is not 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 the plasma, which, both against the background of crises and in severe cases of 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 treatment methods and establishes the prognosis of 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 effective way to completely get rid of mutated cells is to transplant red bone marrow (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.

Nerobol

The most frequently prescribed drug by physicians to combat the symptomatic manifestations of 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 experiences an increase in appetite, an intensive increase in muscle mass, accelerated bone calcification, and 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 a normal level of coagulation.

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. Therapeutic therapy for 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:

Maxar;
Heptral;
Karsil.

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 the best method to prevent any pathology is to regularly undergo a full 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) is an acquired disease manifested by persistent hemolytic anemia, paroxysmal or persistent hemoglobinuria, and intravascular hemolysis. The rarity of this type of hemolytic anemia is characterized by the fact that PNH affects 1 person in half a million, mostly young people.

The causes of the disease are currently unknown. It is assumed that it occurs due to the occurrence of an abnormal clone of red blood cells prone to intravascular hemolysis. In turn, the inferiority of red blood cells is a consequence of structural and biochemical defects in their membrane. It is known that lipid peroxidation is activated in a defective membrane, which promotes rapid lysis of red blood cells; in addition, abnormal clones of granulocytes and platelets are involved in the pathological process. The main role in the occurrence of thrombotic complications of PNH belongs to the intravascular destruction of erythrocytes and the initiation of blood coagulation by factors released during this process. PNH, as a rule, begins gradually and proceeds chronically with periodic crises. Crises are provoked by viral infections, surgical interventions, psycho-emotional stress, menstruation, and the use of a number of medications and foods.

Symptoms of paroxysmal nocturnal hemoglobinuria

Symptoms of PNH during a crisis:

paroxysmal pain in the abdominal cavity;
pain in the lumbar region;
icterus of the skin and sclera; hyperthermia; facial pastiness;
black color of urine, mainly at night;
a sharp decrease in blood pressure;
transient enlargement of the spleen;
cessation of urine output.

In some cases, the hemolytic crisis ends in death.

Symptoms of PNH outside of crisis:

general weakness;
pale skin color with a jaundiced tint;
anemia;
tendency to thrombosis; hematuria; high blood pressure; liver enlargement; dyspnea; heartbeat; frequent infectious diseases.

Diagnostics

Blood test: anemia (normochromic, later hypochromic), moderate leukocytopenia and thrombocytopenia, serum iron level is significantly reduced.
Examination of urine: black staining, hemoglobinuria, hemosiderinuria, proteinuria. The Gregersen urine benzidine test is positive.
Ham's specific test is positive.
The specific Hartmann test is positive.
Bone marrow puncture: hyperplasia of the red hematopoietic lineage, but in severe cases, bone marrow hypoplasia and an increase in the amount of adipose tissue in the bone marrow can also be observed.

Treatment of paroxysmal nocturnal hemoglobinuria

Treatment of PNH is symptomatic and consists mainly of replacement blood transfusions, the volume and frequency of which depend on the “response” to these measures. In the treatment of PNH, methandrostenolone is used at a dose of 30-50 mg/day for at least 2-3 months. The fight against bone marrow hypoplasia is carried out by intravenous use of antithymocyte immunoglobulin at a dose of 150 mg/day for 4 to 10 days. It is recommended to take iron supplements per os in small dosages. Sometimes corticosteroids in high dosages have a good effect. Bone marrow hypoplasia with the development of thrombotic complications are indications for its transplantation. Isolated cases of recovery from PNH have been described; in some cases, the duration of a favorable course of the disease is several decades.

Essential drugs

There are contraindications. Specialist consultation is required.

Marchiafava-Michele disease, paroxysmal nocturnal hemoglobinuria with constant hemosiderinuria, Strübing-Marchiafava disease is a kind of acquired hemolytic anemia that occurs with constant intravascular hemolysis, hemosiderinuria, inhibition of granulo- and thrombocytopoiesis.

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 red blood cells, some 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 any external factors provoke the formation of a defective population of cells, which is a clone, i.e. the offspring of one initially modified cell are not known.

Thrombotic complications in PNH are associated with intravascular hemolysis, which provokes thrombus formation. The origin of an important, but far from obligatory sign of the disease - paroxysms of hemoglobinuria at night or in the morning - remains unclear.
Paroxysm is not associated with the time of day, but with sleep, which during the day can also cause a crisis. 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 appearance of black urine is not a permanent sign. Since PNH is often accompanied by leukopenia (mainly due to granulocytopenia), chronic infectious complications are possible. Thrombocytopenia may be complicated by hemorrhagic syndrome. Long-term excretion of hemoglobin and hemosiderin in the urine gradually leads to the development of an iron deficiency state - asthenic syndrome occurs, dry skin, and brittle nails appear.

The blood picture is characterized initially by normochromic and then hypochromic anemia, slight reticulocytosis (2-4% or more), leukopenia and thrombocytopenia. 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.

Due to constantly ongoing intravascular hemolysis, the content of free hemoglobin in the plasma is increased (normally less than 0.05 g/l). Serum iron levels are initially normal but may then be significantly reduced. Along with the typical onset of the disease, when hemolytic syndrome predominates, a picture of aplastic syndrome may develop, which after a few years can be complicated by a hemolytic crisis with typical nocturnal hemoglobinuria. More often, a hemolytic crisis provokes a blood transfusion.

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).

The hemolysin form of autoimmune hemolytic anemia, similar in external manifestations to PNH, occurs with intravascular hemolysis and is characterized by the presence of hemolysins in the blood serum and a positive Coombs test. Unlike PNH, there is no leukopenia or thrombocytopenia; prednisolone usually has a good effect. PNH can be distinguished from aplastic anemia by the picture of the bone marrow: with aplasia, the trepanate is characterized by a predominance of fat, with hemolysis - by 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.

Iron supplements are used, but they can sometimes provoke a hemolytic crisis. To prevent a crisis, iron is prescribed in small doses during treatment with anabolic steroids. For thrombosis, heparin is indicated: at the first injection, 10,000 units are administered intravenously, then 5-10 thousand units 2-3 times a day under the skin of the abdomen (with a thin needle to a depth of 2 cm into the fatty tissue) under the control of blood clotting. Contraindications to heparin treatment are a recent exacerbation of a gastric or duodenal ulcer, as well as the presence of sources of bleeding.

Materials are presented from the RUDN textbook

Anemia. Clinic, diagnosis and treatment / Stuklov N.I., Alpidovsky V.K., Ogurtsov P.P. – M.: Medical Information Agency LLC, 2013. – 264 p.

Copying and reproducing materials without indicating the authors is prohibited and is punishable by law.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hemolytic anemia associated with a defect in the blood cell membrane, therefore the disease is considered in the group of membranopathies and is the only acquired membranopathy among the diseases of this group. The mutation leading to the membrane defect in PNH occurs at the level of the pluripotent stem cell, and the cause of the mutation remains unclear.

PNH occurs with a frequency of 1:500,000 of the population. People of all age groups get sick, but more often – at the age of 30 – 40 years. Men and women get sick equally often.

Etiology and pathogenesis

Point gene mutation PIGA on chromosome 22 or the X chromosome of a pluripotent stem cell (PSC) leads to disruption of the formation of phosphatidylinolinic acid and proteins on the surface of blood cells CD 55 and CD 59, forming a system in normal cells that blocks the damaging effect on the membrane of activated complement due to the formation of a cascade CD 5b –9 – a complex that proteolytically affects the cell membrane.

Thus, the absence of factors on the surface of blood cells that interfere with complement function leads to the lysis of defective erythrocytes, neutrophils and platelets.

With PNH, there are two clones in the blood of patients: normal and pathological, and the clinical picture and severity of the disease largely depend on the ratio of these clones.

Clinic

The proteolytic action of activated complement leads to intravascular destruction of defective red blood cells, which manifests itself hemoglobinuria. Activation of complement occurs at night during sleep, due to a shift in pH to the acidic side.

Clinically, hemolysis during sleep is manifested by the release of black urine during morning diuresis, complaints of malaise, dizziness, and the appearance of yellowness of the sclera. In addition, hemolysis can be provoked by infectious diseases and certain medications.

In addition to anemic symptoms associated with hemolysis, PNH plays an important role in the clinic. thrombotic complications, caused by the release of thromboplastin and a number of active enzymes from destroyed cells.

Often, one of the first complaints of the patient is abdominal pain, simulating a variety of acute abdominal pathologies. Abdominal pain is associated with thrombosis of small mesenteric arteries.

Thrombophlebitisoccurs in 12% of patients with PNH and can occur in different ways. In one of the options, the condition of patients outside of crises is quite satisfactory, the content Hb – about 80 – 90 g/l. In other patients, severe hemolytic crises follow one after another, leading to severe anemia. They are often accompanied by thrombotic complications.

Laboratory data

During a hemolytic crisis, a sharp decrease in hemoglobin levels to 20 g/l or lower, and a parallel decrease in the number of red blood cells, can be observed. During the period of remission, content Hb and erythrocytes increases, however, in rare cases it reaches the lower limit of normal. Unlike most membranopathies, a defect in the erythrocyte membrane in PNH is not accompanied by characteristic changes in the shape of pathological erythrocytes. Anemia in most cases is normocytic and normochromic in nature. However, with significant loss of iron in the urine (as a result of hemoglobinuria and hemosiderinuria), hypochromia of erythrocytes develops. The content of reticulocytes is increased, but to a much lesser extent than in congenital membranopathies with a similar intensity of hemolysis. Abnormal hemoglobins and decreased enzyme activity (except for acetylcholinesterase) were not detected in erythrocytes in PNH. The osmotic resistance of erythrocytes is not changed. When erythrocytes from patients with PNH are incubated under sterile conditions, greater than normal autohemolysis is observed, which, however, does not decrease with the addition of glucose.

The number of leukocytes in most cases is reduced due to neutropenia. Sometimes there is a left shift in the leukogram.

The platelet count is also usually low. Platelet functions are not impaired.

When examining the bone marrow, erythroid hyperplasia and signs of bone marrow hematopoiesis deficiency are detected in the form of impaired ripening of red cells and granulocytic elements, as well as a decrease in the number of megakaryocytes, often with impaired lacing of blood platelets. In some patients with PNH, along with signs of dyshematopoiesis, bone marrow hypoplasia, characteristic of aplastic anemia, is detected.

In cases where complement-sensitive PNH erythrocytes and symptoms of intravascular hemolysis are detected in patients with previously established hematopoietic aplasia, PNH syndrome, which has developed against the background of aplastic anemia, is diagnosed.

However, one should remember about rare cases of PNH, which end in aplastic anemia due to depletion of bone marrow hematopoiesis by severe hemolytic crises and other adverse effects (infections, certain medicinal agents, etc.).

An important laboratory sign of PNH is hemoglobinuria. The content of free hemoglobin in plasma due to intravascular destruction of erythrocytes in PNH, depending on the severity of hemolysis, ranges from 11 to 280 mg% (with a norm of up to 4 mg%).

The bilirubin content is usually slightly increased, mainly due to the unconjugated fraction. The level of serum iron in PNH depends on the phase of the disease: during hemolytic crises, due to the release of hemoglobin iron into the plasma, ferritinemia is observed, and during a quiet period, due to the loss of iron in the urine, hypoferritinemia is observed. Iron deficiency in PNH, in contrast to iron deficiency anemia, is accompanied by a simultaneous decrease in total and latent iron-binding capacity, apparently due to a violation of transferrin synthesis in the liver.

Urine examination reveals hemoglobinuria in most patients with PNH. With PNH, hemoglobin appears in the urine at its relatively low concentration in plasma, which is associated with a decrease in the content of plasma haptoglobin. During excretion of hemoglobin by the kidneys, part of it is reabsorbed and deposited in the tubular epithelium in the form of hemosiderin, which is then excreted in the urine. Interestingly, hemosiderinuria in PNH can be detected more often than hemoglobinuria, since it also develops outside of a hemolytic crisis.

DiagnosticsThe disease is associated with the identification of a characteristic clinical picture, laboratory signs of intravascular hemolysis (hemoglobinemia (red color of blood serum after centrifugation), decreased haptoglobin in the blood, slight indirect billirubinemia, increased LDH, hemoglobinuria, hemosiderinuria). The diagnosis of PNH is based on the detection of complement-sensitive erythrocytes characteristic of this disease. For this purpose they are used Hema acid test and more sensitive sucrose test.

When performing the Hem test, the red blood cells being tested are incubated in normal serum acidified to pH 6.4. Under these conditions, only complement-sensitive erythrocytes are lysed. It should be remembered that with a low content of PNH red blood cells in the patient’s blood and with low complement activity in the serum, the Hem test can give negative results.

More sensitive is the sucrose test, in which the red blood cells being tested and a small amount of normal serum are placed in an isotonic sucrose solution. Under conditions of reduced voltage in a sucrose environment, more active fixation of complement on the surface of erythrocytes and lysis of complement-sensitive PNH erythrocytes occurs.

Evidence of the presence of a PNH clone is the detection on the cell membrane of signs characteristic of damage to the PIG A gene. Modern methods of flow cytometry make it possible to determine the presence of erythrocytes with a complete or partial deficiency of CD59 molecules on the membrane, however, pathological erythrocytes cannot always be detected, given the presence of their pronounced hemolysis. The most reliable is the study of monocyte granulocytes, since nucleated cells are less susceptible to the action of complement.

Treatment

Due to the lack of clear ideas about the pathogenesis of PNH, treatment of this disease is currently symptomatic.

To combat anemia, replacement blood transfusions are used, the frequency of which depends on the severity of hemolysis and compensatory activity of the bone marrow. It should be remembered that transfusion of fresh whole blood to patients with PNH is often accompanied by increased hemolysis. The reason for this reaction is unclear. Patients with PNH better tolerate transfusions of whole blood or red blood cells with long storage periods (more than 7–8 days) and transfusions of 3–5 times washed red blood cells freed from leukocytes and platelets. The use of washed red blood cells is the best transfusion method in the treatment of PNH. When a reaction occurs to washed red blood cells due to the development of isosensitization, individual selection of a donor is necessary according to the indirect Coombs reaction (Fig. 12).

An important place in the treatment of PNH is occupied by iron supplements and androgenic hormones. Therapy with iron supplements is recommended for patients with PNH when hypochromia of erythrocytes and a decrease in serum iron levels are detected during the quiet course of the disease. Iron supplements should be used carefully (in small doses and only peros ), since their ability to provoke severe hemolytic crises in some patients with PNH is known.

The use of androgens in PNH is based on the stimulating effect of these hormones on erythropoiesis. The administration of Nerabol or its analogues at a dose of 30–40 mg/day promotes a more rapid recovery of hemoglobin levels after a hemolytic episode and thereby significantly reduces the need for blood transfusions. The use of androgens is especially effective in PNH with hematopoietic hypoplasia.

The treatment tactics for thrombotic complications depend on the location of thrombosis, their duration and the state of the coagulation system. In cases where this complication threatens the patient’s life, it is necessary to use complex thrombolytic and anticoagulant therapy (fibrinolysin or urokinase, nicotinic acid, heparin and indirect anticoagulants) according to general therapeutic rules and in sufficient dosages.

Since there are reports of increased hemolysis after heparin administration, this anticoagulant should be used with great caution.

Splenectomy for PNH is not indicated, since the postoperative period is often complicated by thrombosis of the mesenteric vessels. The risk of surgery is acceptable only in the presence of severe symptoms of hypersplenism: deep leukopenia, complicated by frequent infections and/or thrombocytopenia, accompanied by severe hemorrhagic syndrome.

A modern genetic technology drug Eculizumab (Soliris, SOLIRIS®) has been developed, which is registered by the FDA (Food and Drug Administration) for the treatment of children and adults suffering from PNH. Eculizumab is a glycosylated humanized monoclonal antibody - immunoglobulin kappa (IgG2/4k) that binds to human complement protein C5 and inhibits the activation of complement-mediated cell lysis. The antibody consists of human immunoglobulin constant regions and mouse immunoglobulin complementary-determined regions embedded in the variable regions of the light and heavy chains of the human antibody. Eculizumab contains two heavy chains of 448 amino acids each and two light chains of 214 amino acids each. The molecular weight is 147870 Da. Eculizumab is produced in cultured murine myeloma cell line NS0 and purified using affinity and ion exchange chromatography. The production process of the substance also includes processes of specific inactivation and removal of viruses.

Eculizumab suppresses the terminal activity of human complement, having high affinity for its C5 component. As a consequence, the cleavage of the C5 component into C5a and C5b and the formation of the terminal complement complex C5b–9 are completely blocked. Thus, eculizumab restores the regulation of complement activity in the blood and prevents intravascular hemolysis in patients with PNH. On the other hand, terminal complement deficiency is accompanied by an increased incidence of infections with encapsulated microorganisms, mainly meningococcal infection. At the same time, eculizumab maintains the content of early complement activation products necessary for the opsonization of microorganisms and the removal of immune complexes. Prescribing Soliris to patients is accompanied by a rapid and stable decrease in terminal complement activity. In most patients with PNH, a plasma eculizumab concentration of about 35 μg/ml is sufficient to completely inhibit intravascular hemolysis induced by terminal complement activation.

Thanks to the unique new clinical results and the opening therapeutic opportunities for doctors to preserve the full life and health of patients, Eculizumab was registered in an accelerated manner, without conducting a third phase of clinical trials - this will save many lives, both children and adults.

In this regard, following registration in the USA, the European Medicines Committee issued a positive opinion on the accelerated registration of Eculizumab in Europe, which is also expected in the near future.

Considering the high cost of eculizumab, the impossibility of using it to influence the cause of the disease and the fact that it must be used for life, a reserve strategy is most applicable to it, intended specifically for patients with a high number of PNH cells or for patients with a tendency to thrombus formation, not depending on the size of the PNG clone.

Currently, the only radical treatment for PNH is allogeneic bone marrow transplantation.

Course and prognosis

The prognosis depends on the severity of the underlying disease, worse in patients dependent on blood transfusions, with severe thrombosis. In 10% of patients, spontaneous remissions of the disease are observed, in others it transforms into aplastic anemia, MDS, and in 5% - into acute leukemia. On average, life expectancy is 10 – 15 years.

PNH is a chronic and currently completely incurable disease. The severity of PNH and prognosis largely depend on the size of the complement-sensitive erythrocyte population, the compensatory ability of the bone marrow and the occurrence of complications, especially venous thrombosis. The idea of a severe prognosis for PNH has recently changed due to the introduction of active symptomatic therapy.

The number of patients who have been in a state of clinical and hematological compensation for a long time and leading a normal lifestyle at this time has increased. The incidence of severe, life-threatening thrombosis has decreased. In some patients, over time, there is a mitigation of the disease with a decrease in the proportion of complement-sensitive erythrocytes. In rare cases, the complete disappearance of pathological red blood cells is described, which indicates the fundamental possibility of curing the disease.

Catad_tema Blood diseases - articles

ICD 10: D61.1, D61.2, D61.3, D61.8, D61.9

Year of approval (revision frequency): 2014 (reviewed every 2 years)

ID: KR121

Professional associations:

National Society of Hematology

Approved

Russian Society of Hematologists

Agreed

Scientific Council of the Ministry of Health of the Russian Federation__ __________201_

Quality criteria

Level of evidence

Diagnostic measures

Perform an advanced clinical blood test

Morphological and cytochemical studies of the bone marrow preparation were performed

A cytogenetic study of bone marrow cells was performed

A morphological (histological) study of a bone marrow preparation was performed

A chest X-ray and/or computed tomography scan of the chest and brain was performed

Event-based (semantic, content, process) quality criteria

A morphological and/or histological and/or standard cytogenetic study of a bone marrow specimen was performed

Combined immunosuppressive therapy was carried out (in the absence of contraindications)

HLA typing of siblings was performed

A consultation was performed at the transplant center within 3 months from the moment the refractory course was determined

Temporary quality assessment criteria

Immunosuppressive therapy was performed within 1 month after histological and/or cytogenetic confirmation of the diagnosis (in the absence of medical contraindications)

Clinical and hematological parameters were assessed during therapy at least 2 times a week until a complete hematological response was achieved

A morphological study of a bone marrow preparation was performed with an assessment of bone marrow hematopoiesis after completion of the therapy program

A standard cytogenetic study of a bone marrow preparation was performed (study of at least 20 metaphases) and/or a bone marrow study using fluorescent hybridization (in case the cytogenetic study was not informative to identify abnormalities characteristic of myelodysplastic syndrome)

The clone of paroxysmal nocturnal hemoglobinuria was determined using highly sensitive flow cytometry every 6-12 months, clinical and laboratory signs of hemolysis were assessed

A morphological and/or histological and/or standard cytogenetic study was performed before the next stage of treatment

A repeated course of antithymocyte globulin and HLA typing were carried out (to determine the availability of allogeneic bone marrow donors, in the absence of a response after 3-6 months)

Bibliography

1. Kokhno A.V., Pimenova M.A., Parovichnikova E.N., Domracheva E.V. S.V.G. Detection of hidden karyotype abnormalities in myelodysplastic syndrome. / S. V. G. Kokhno A.V., Pimenova M.A., Parovichnikova E.N., Domracheva E.V. // Hematology and transfusiology – 2014. – T. 59 – No. 1 – 25–28 p.

Kulagin A.D. Aplastic anemia / Kulagin A.D. / ed. K.V.A. Lisukov I.A. – – Novosibirsk: Nauka, 2008. Vol. The science.
Mikhailova E.A. Protocol for program treatment of patients with aplastic anemia: combined immunosuppressive therapy / ed. V.G.Savchenko. Moscow: Praktika, 2012. – 135–150 pp.
Afable M.G. Clonal evolution in aplastic anemia. / M. G. Afable, R. V Tiu, J. P. Maciejewski // Hematology Am. Soc. Hematol. Educ. Program – 2011. – T. 2011 – 90–5 p.
Bacigalupo A. Treatment strategies for patients with severe aplastic anemia. / A. Bacigalupo // Bone Marrow Transplant. – 2008. – T. 42 Suppl 1 – No. SUPPL.1 – S42–S44с.
Borowitz M.J. Guidelines for the diagnosis and monitoring of paroxysmal nocturnal hemoglobinuria and related disorders by flow cytometry. / M. J. Borowitz, F. E. Craig, J. A. Digiuseppe, A. J. Illingworth, W. Rosse, D. R. Sutherland, C. T. Wittwer, S. J. Richards // Cytometry B. Clin. Cytom. – 2010. – T. 78 – No. 4 – 211–30 p.
Kulagin A. Prognostic value of paroxysmal nocturnal haemoglobinuria clone presence in aplastic anemia patients treated with combined immunosuppression: Results of two-centre prospective study / A. Kulagin, I. Lisukov, M. Ivanova, I. Golubovskaya, I. Kruchkova, S. Bondarenko, V. Vavilov, N. Stancheva, E. Babenko, A. Sipol, N. Pronkina, V. Kozlov, B. Afanasyev // Br. J. Haematol. – 2014. – T. 164 – No. 4 – 546–554 p.
Marsh J.C.W. Guidelines for the diagnosis and management of aplastic anemia / J. C. W. Marsh, S. E. Ball, J. Cavenagh, P. Darbyshire, I. Dokal, E. C. Gordon-Smith, J. Keidan, A. Laurie, A. Martin, J. Mercieca, S. B. Killick, R. Stewart, J. A. L. Yin // Br. J. Haematol. – 2009. – T. 147 – No. 1 – 43–70 p.
Marsh J.C.W. Guidelines for the diagnosis and management of aplastic anemia. / J. C. W. Marsh, S. E. Ball, J. Cavenagh, P. Darbyshire, I. Dokal, E. C. Gordon-Smith, J. Keidan, A. Laurie, A. Martin, J. Mercieca, S. B. Killick, R. Stewart, J. A. L. Yin / / Br. J. Haematol. – 2009. – T. 147 – No. 1 – 43–70 p.
Marsh J.C.W. Management of the refractory aplastic anemia patient: what are the options? J. C. W. Marsh, A. G. Kulasekararaj – 2014. – T. 122 – 3561–3567 pp.
Scheinberg P. Horse antithymocyte globulin as salvage therapy after rabbit antithymocyte globulin for severe aplastic anemia / P. Scheinberg, D. Townsley, B. Dumitriu, P. Scheinberg, B. Weinstein, O. Rios, C. O. Wu, N. S. Young // Am . J. Hematol. – 2014. – T. 89 – No. 5 – 467–469 p.
Scheinberg P. How I treat acquired aplastic anemia. / P. Scheinberg, N. S. Young // Blood – 2012. – T. 120 – No. 6 – 1185–96 p.
Young N.S. Epidemiology of Aplastic Anemia // Bone Marrow Fail. Syndr. – 1–46s.
Young N.S. The problem of clonality in aplastic anemia: Dr Dameshek’s riddle, rested // Blood. – 1992. – T. 79. – No. 6. – 1385–1392 p.
Young N.S. Pathophysiologic mechanisms in acquired aplastic anemia. // Hematology Am. Soc. Hematol. Educ. Program. – 2006. – 72–77 p.
Young N.S. The relationship of aplastic anemia and PNH. //Int. J. Hematol. – 2002. – T. 76 Suppl 2. – 168–172 p.
Zeng Y. The complex pathophysiology of acquired aplastic anemia. / Y. Zeng, E. Katsanis // Clin. Exp. Immunol. – 2015. – T. 180 – No. 3 – 361–70 p.
Vinogradova M.A. Infectious complications in patients with aplastic anemia / Vinogradova M.A. – Moscow: dissertation for the degree of candidate of medical sciences / State Institution “Hematological Research Center of the Russian Academy of Medical Sciences”, 2009.

Appendix A1. Composition of the working group

Voitsekhovsky V.V. doctor, Blagoveshchensk

Vopilina N.A. GBUZ Tambov Regional Clinical Hospital named after. V.D.Babenko", Tambov

Gaponova T.V. Candidate of Medical Sciences, Deputy General Director of the Federal State Budgetary Institution Hematological Scientific Center of the Ministry of Health of Russia, Moscow

Golubeva M.E.. "City Hematology Center" at the Municipal Budgetary Healthcare Institution "GKP No. 5", Perm

Kaporskaya T.S. Candidate of Medical Sciences, Head of the Department of Hematology, Irkutsk Order of the Badge of Honor Regional Clinical Hospital, Irkutsk,

Klyasova G.A. Doctor of Medical Sciences, Professor, Head of the Scientific and Clinical Laboratory of Microbiology, Federal State Budgetary Institution Hematological Research Center of the Ministry of Health of Russia, Moscow,

Konstantinova T.S. Head of the Department of Hematology, Regional Hematology Center, Sverdlovsk Regional Clinical Hospital No. 1, Yekaterinburg,

Kulagin A.D. Doctor of Medical Sciences, Deputy Chief Physician at the Clinic of the State Budgetary Educational Institution of Higher Professional Education "St. Petersburg State Medical University named after. acad. I.P. Pavlov" Ministry of Health of Russia, St. Petersburg Research Institute of Pediatric Hematology and Transplantology named after. R.M.Gorbacheva,

Lapin V.A. Candidate of Medical Sciences, Head of the Department of Hematology, Yaroslavl Regional Clinical Hospital, Yaroslavl

Mikhailova E.A. Doctor of Medical Sciences, Professor, Leading Researcher at the Department of Chemotherapy for Hematological Malignancies and Hematopoietic Depressions, Federal State Budgetary Institution Hematological Scientific Center of the Ministry of Health of Russia, Moscow,

Parovichnikova E.N. Doctor of Medical Sciences, Head of the Scientific and Clinical Department of Chemotherapy of Hemoblastosis, Hematopoietic Depression and Bone Marrow Transplantation, Federal State Budgetary Institution Hematological Research Center of the Ministry of Health of Russia, Moscow,

Ploskikh M.A. GBUZ PC "Perm Regional Clinical Hospital", Perm

Savchenko V.G. Academician, Doctor of Medical Sciences, Professor, General Director of the Federal State Budgetary Institution Hematological Research Center of the Ministry of Health of Russia, Moscow,

Samoilova O.S. Candidate of Medical Sciences, Head of the Department of Hematology, Nizhny Novgorod Region Nizhny Novgorod Regional Clinical Hospital. N.A. Semashko, Nizhny Novgorod,

Skripkina N.S. hematologist GAUZ JSC "Amur Regional Clinical Hospital", Blagoveshchensk,

Tikunova T.S. OGBUZ "Belgorod Regional Clinical Hospital of St. Joasaph", Belgorod

Troitskaya V.V. Candidate of Medical Sciences, Head of the Scientific and Clinical Department of Chemotherapy of Hemoblastoses and Depressions of Hematopoiesis, Federal State Budgetary Institution Hematological Scientific Center of the Ministry of Health of Russia, Moscow,

Ustinova E.N. Candidate of Medical Sciences, Researcher at the Department of Chemotherapy for Hematological Malignancies and Depressions of Hematopoiesis, Federal State Budgetary Institution Hematological Research Center of the Ministry of Health of Russia, Moscow,

Chagorova T.V. GBUZ "Regional Oncology Dispensary", Penza

Hematology specialists;

Oncology specialists;

Specialist therapists;

Evidence collection methodology

Methods used for collecting/selecting evidence: searching electronic databases.

Description of the methods used for collecting/selecting evidence: the evidence base for the recommendations is publications included in the Cochrane Library, the EMBASE and MEDLINE databases. The search depth was 10 years.

Levels of Evidence	Description
	High-quality meta-analyses, systematic reviews of randomized controlled trials (RCTs), or RCTs with very low risk of bias
	Well-conducted meta-analyses, systematic ones, or RCTs with low risk of bias
	Meta-analyses, systematic, or RCTs with a high risk of bias
	High-quality systematic reviews of case-control or cohort studies. High-quality reviews of case-control or cohort studies with very low risk of confounding effects or bias and moderate probability of causality
	Well-conducted case-control or cohort studies with moderate risk of confounding effects or bias and moderate probability of causality
	case-control or cohort studies with a high risk of confounding effects or bias and a moderate probability of causation
	Non-analytical studies (for example: case reports, case series
	Expert opinion

Methods used to assess the quality and strength of evidence:

Expert consensus;

Methods used to analyze evidence:

Systematic reviews with evidence tables.

Description of methods used to analyze evidence:

When selecting publications as potential sources of evidence, the methodology used in each study is examined to ensure its validity. The outcome of the study influences the level of evidence assigned to the publication, which in turn influences the strength of the recommendations resulting from it.

Methodological examination is based on several key questions that focus on those features of the study design that have a significant impact on the validity of the results and conclusions.

The assessment process can undoubtedly be affected by the subjective factor. To minimize potential bias, each study was assessed independently, i.e. at least two independent members of the working group. Any differences in assessments were discussed by the entire group. If it was impossible to reach consensus, an independent expert was involved.

Evidence tables:

evidence tables were completed by members of the working group.

Methods used to formulate recommendations:

expert consensus.

Good Practice Points (GPPs):

Economic analysis:

No cost analysis was performed and pharmacoeconomics publications were not reviewed.

External expert assessment;

Internal expert assessment.

	Description
	At least one meta-analysis, systematic review, or RCT rated 1++, directly applicable to the target population and demonstrating robustness of the results, or body of evidence that includes study results rated 1+, directly applicable to the target population, and demonstrating overall robustness of the results

	a body of evidence consisting of study results rated 2++, directly applicable to the target population and demonstrating overall robustness of the results, or extrapolated evidence from studies rated 1++ or 1+

	a body of evidence consisting of study results rated 2+, directly applicable to the target population, and demonstrating overall robustness of the results; or extrapolated evidence from studies rated 2++

	Level 3 or 4 evidence; or extrapolated evidence from studies rated 2+

These draft recommendations were peer-reviewed by independent experts who were asked to comment primarily on the extent to which the interpretation of the evidence underlying the recommendations was clear.

Comments were received from primary care physicians and local therapists regarding the clarity of the recommendations and their assessment of the importance of the recommendations as a working tool in daily practice.

A preliminary version was also sent to a non-medical reviewer for comments from a patient perspective.