What is png disease. Modern problems of science and education

Paroxysmal nocturnal hemoglobinuria is a rare acquired life-threatening blood disease. Pathology causes 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 scientists who described the pathology in detail.

Causes and essence of the disease

Paroxysmal nocturnal hemoglobinuria occurs infrequently - usually 1-2 cases are recorded per 1 million people in the population. This is a disease of adults at a relatively young age, average age diagnosis - 35-40 years. Manifestation of Marchiafava-Micheli disease in childhood and adolescence- a 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 cells bone marrow. The exact causes and mutagenic factors of this pathology are still unknown. The occurrence of paroxysmal nocturnal hemoglobinuria closely associated with aplastic anemia. It has been statistically proven that 30% of cases of diagnosed Marchiafava-Micheli 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 of the body. The precursors of all cellular elements of the blood are stem cells, with the gradual division of which new elements of the blood are formed. Having gone through all the processes of maturation and formation, the shaped elements enter the bloodstream and begin to perform their functions.

For the development of Marchiafava-Micheli disease, the presence of a mutation of the above-mentioned PIG-A gene in one stem cell is sufficient. The abnormal progenitor cell is constantly dividing and "cloning" itself. So the entire population becomes pathologically altered. Defective red blood cells mature, form and enter the bloodstream.

The essence of the changes is the absence of special proteins on the erythrocyte membrane that are 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 body cells are protected from their immune proteins. In paroxysmal nocturnal hemoglobinuria, there is no such protection. 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 research. The fact is that the classic symptom - dark brown urine (hemoglobinuria) occurs in only 50% of patients. Classical is the presence of hemoglobin in the morning portions of urine, during the day it usually brightens.

The excretion of hemoglobin in the urine is associated with massive resolution of erythrocytes. Doctors call this condition a hemolytic crisis. It can be provoked 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 debunked. 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:

Hemolytic anemia is a decrease in the number of red blood cells and hemoglobin due to hemolysis. Hemolytic crises are accompanied by weakness, dizziness, flashing "flies" before the eyes. The general condition at the initial stages does not correlate with the level of hemoglobin.
Thrombosis is the main cause of death in patients with Marchiafava-Micheli disease. Arterial thromboses are much less common. Hepatic, mesenteric and cerebral veins are affected. Specific clinical symptoms depend on the vein involved. 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 blockade is more common in women. Thrombosis of the dermal veins is manifested by red, painful nodes rising above the surface of the skin. Such foci capture large areas, for example, the entire skin of the back.
Insufficient hematopoiesis - a decrease in the number of erythrocytes, leukocytes and platelets in the peripheral blood. This pancytopenia makes a person susceptible to infections due to the low white blood cell count. Thrombocytopenia leads to increased bleeding.

The hemoglobin released after the destruction of red blood cells undergoes cleavage. 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 number. 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 disruption of the kidneys. Gradually develops kidney failure requiring replacement therapy.

Diagnostic and therapeutic measures

At the initial stages, it is quite difficult to make a diagnosis of Marchiafava-Micheli disease due to the diverse clinical symptoms and scattered complaints of patients. The appearance of characteristic changes in the color of urine, as a rule, directs the diagnostic search in the right direction.

Treatment of paroxysmal nocturnal hemoglobinuria

The main diagnostic tests used for paroxysmal nocturnal hemoglobinuria are:

Complete blood count - to determine the number of red blood cells, white blood cells and platelets.
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.
Flow cytometry - allows for immunophenotyping, that is, to determine the presence of a particular protein on the surface of erythrocyte membranes.
Measurement of serum hemoglobin and haptoglobin levels.
General urine analysis.

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

Steroid hormones (Prednisolone, Dexamethasone) inhibit the immune system, thereby stopping the destruction of red blood cells by complement system proteins.
Cytostatics (Eculizumab) have a similar effect. They suppress immune response and eliminate the signs of paroxysmal nocturnal hemoglobinuria.
Sometimes patients need transfusions of washed, specially selected erythrocyte mass to correct the hemoglobin level.
Maintenance therapy in the form of iron and folic acid preparations.

The described treatment of paroxysmal nocturnal hemoglobinuria cannot save the patient from the disease, but only muffles the symptoms. The 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 without appropriate treatment is potentially life-threatening. Complications in the form of thrombosis and renal failure can have serious consequences for life and health. Timely treatment can stop the development of the disease and prolong the patient's full life.

The essence of the pathology is changes in the structure of blood cells (most of all erythrocytes), leading to early destruction of their membrane and intravascular decay (hemolysis).

The prevalence is about 16 cases per million of the population, and the annual incidence is 1.3 per million. People aged 20 to 40 years are more likely to get sick, no gender dependence has been identified.

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

What is "hemoglobinuria", what causes it?

Hemoglobinuria is a symptom of various diseases that cause the breakdown of red blood cells by their action 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 volume of blood plasma. Enhanced Level hemoglobin in 20-25% is observed in congenital disorders or hemoglobinopathies (β-thalassemia, destruction of red cells in sickle cell anemia).

Causes of hemoglobinuria can be:

acute infectious disease (flu);
pneumonia;
trauma;
intoxication in case of poisoning with aniline dyes, carbolic acid, berthollet salt;
sharp hypothermia;
strong and prolonged physical stress;
blood diseases;
transfusion of different blood groups;
extensive burns;
the role of the 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, handling them requires care.

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

The pathogenesis of disorders

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

The active substance is 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 erythrocytes is destroyed, which causes their death. Proven hypersensitivity erythrocyte membranes to complement components.

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

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

The missing genetic region of a stem cell is called GPI-AP. Its deficiency in the erythrocyte clone contributes to the 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 appears only if the pathological clone prevails over the normal one. Erythrocytes from a clone with partial or total 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-Micheli disease is associated with stimulation of blood coagulation by factors released during the destruction of erythrocytes.

Forms of the disease

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

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 clinic for the disease. Often associated with aplastic anemia.
Classic - everything is available clinical symptoms, proceeds with periodic exacerbations, in addition to erythrocytes, leukocytes and platelets are affected, laboratory signs of hemolysis are determined (growth of reticulocytes, serum lactate dehydrogenase enzyme, bilirubin, with a reduced level of haptoglobin). Anomalies of hematopoiesis in the bone marrow are not observed.
Caused by insufficiency of bone marrow hematopoiesis in various diseases - concomitant or transferred pathology of the bone marrow with impaired hematopoiesis (with aplastic anemia, myelodysplastic syndrome) is assumed. According to the analyzes and the clinic, all manifestations of hemolysis are revealed against the background of anomalies of bone marrow hematopoiesis.

According to another classification, it is proposed to allocate:

idiopathic form or actually paroxysmal nocturnal hemoglobinuria;
pathology in the form of a syndrome in various diseases;
a rare species that occurs after bone marrow hypoplasia.

Symptoms and clinical course

The disease can begin suddenly (acutely) or have a gradual chronic course. Periods of exacerbations are called hemolytic crises. Often they are preceded by a cold, connection with an infection, contact with toxic substances.

The main symptoms of paroxysmal nocturnal hemoglobinuria include:

stomach ache;
pain in chest different intensity and localization - pains of different localization are 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 goes into chronic form, caused by a reduced concentration of nitric oxide in plasma, a violation of muscle and vascular tone.
increased fatigue;
shortness of breath, palpitations;
local signs of thrombophlebitis (redness of the skin area over the vein, swelling, pain on palpation, fever);
when examining a patient, a 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 the deposition of a hemoglobin breakdown product (hemosiderin) in the renal tubules, vascular thrombosis with the formation of microinfarcts;
high sensitivity to the joining infection.

These syndromes are the most likely causes of death.

Laboratory diagnostics

The diagnosis of Marchiafava-Micheli disease is made after a thorough examination in hematological 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 germ of blood cells is called pancytopenia);
reticulocytosis;
increase in plasma hemoglobin levels;
decreased iron and folate levels.

Bone marrow examination reveals:

signs of activation of erythropoiesis (erythrocyte production) due to the accumulation of progenitor cells (normoblasts, plasma and mast cells);
the number of granulocytes and megakaryocytes is reduced;
areas of hemorrhage, accumulation of hemolyzed erythrocytes in the sinuses;
at the stage of suppression of hematopoiesis, zones of fatty degeneration and devastation are visible.

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

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

Staining of urine indicates a significant content of oxyhemoglobin in it.

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

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

What diseases should be distinguished from nocturnal hemoglobinuria?

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

Common signs are:

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

With anemia, there are no high numbers of hemoglobin in the blood plasma, urobilin in the urine. Laboratory tests of Hem, Hartman are negative, but 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 myeloid leukemia, erythromyelosis, osteomyelosclerosis, bone marrow metastasis in malignant tumors.

The erythrocyte mass is stored in the cold in special packages.

Treatment

So far no effective way stop the breakdown of red blood cells. It remains only to use the replacement opportunity and transfuse the washed erythrocyte mass of donors to the patient.

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

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

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

To stimulate proper hematopoiesis, Nerobol is used (anabolic hormonal drug) courses 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 thrombosis, Heparin is used, followed by a transition to maintenance doses of indirect anticoagulants.

To compensate for the loss of iron, drugs are prescribed in tablets.

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

Hepatoprotective drugs are prescribed to protect the liver. Sometimes steroid therapy helps.

The drug is administered only intravenously

AT last years information about the use medicinal product Eculizumab (Soliris), made from monoclonal antibodies. Judging by the available reports, it blocks hemolysis, is able to resist blood complement. The drug is considered the most expensive drug in the world. Its action and negative effects are not well understood.

Nocturnal hemoglobinuria has no specific treatment yet. Even with sufficient maintenance therapy, patients live about five years after the onset of the disease. There is no prevention. Everyone should adhere to the correct behavior when working and forced contact with toxic compounds.

How does paroxysmal nocturnal hemoglobinuria manifest itself?

Paroxysmal nocturnal hemoglobinuria is a severe acquired pathology of the hemolytic anemia group. Markiafava-Mikeli disease or Strübing-Marchiafawa disease, other names for this pathology, causes the destruction of red blood cells. The disease is very rare, for 500 thousand of the population, 1 person can meet with this pathology.

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, in addition, 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 they account for a negligible percentage.

The cause of paroxysmal nocturnal hemoglobinuria (PNH) is believed 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 exposure to undefined influence factors. Some sources claim that the causes that cause the gene to mutate are unknown.

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

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

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

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

The essence of erythrocyte damage lies in an incomplete or missing protein membrane that serves to protect cells from the immune system. At the slightest defect in the cell, the body's immunity destroys it, as a result of which such a diagnosis develops 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, so paroxysmal nocturnal hemoglobinuria is its analogue or, as practitioners often say, its acute acquired form. The main and only difference between these pathologies is the principle of their development.

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

Symptoms of nocturnal hemoglobinuria

The symptoms of Markjafava-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 most rare is the idiomatic form of PNH, which occurs against the background of hematopoietic hypoplasia.

It is impossible to distinguish distinct symptoms for any of the forms of the disease, since it is very variable. The course of the disease may be outwardly asymptomatic, in which case pathology can only be detected with laboratory diagnosis. Other patients have a severe anemic syndrome.

In general, it is possible to determine 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 urine will acquire a dark brown tint. In the daytime and in the evening, such a sign is not observed.
Due to the quantitative decrease in the blood of erythrocytes, an anemic syndrome is observed. Its manifestations are directly related to oxygen starvation organs and tissues. Therefore, the patient may experience headaches, dizziness, flashing black dots before the eyes, general weakness, fatigue, angina pectoris and tachycardia.

When there are concomitant infectious diseases, bleeding, physical activity, etc., 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, yellowness of the skin and moderate splenomegaly (enlarged spleen) may appear.
Hemoglobinuria is accompanied by a violation of the concentration of nitric oxide in plasma, which, both against the background of crises and in severe pathology, causes erectile dysfunction in men.
Due to the resulting defect in platelets (blood cells responsible for blood clotting), thrombosis can occur, which are most often observed in the veins. The same process can provoke a substance that is released during the destruction of solid blood cells. It causes increased coagulability of the vascular fluid, on which the tendency to thrombosis depends. Such violations can lead to death.

The most distinct symptoms of paroxysmal nocturnal hemoglobinuria can be obtained with 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. It takes a long time to fully and accurately diagnose hemoglobinuria, since this disease can be carefully hidden under the guise of other pathologies.

Therefore, the most rational way to timely detect Markyafava-Mikeli's disease will be a regular preventive examination.

Treatment of paroxysmal nocturnal hemoglobinuria

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

All therapeutic measures are aimed at eliminating symptomatic manifestations. the only in an efficient 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 can be 5 or more such transfusions. The number of procedures and their frequency is determined by repeated analyzes and is carried out at the next reproduction of defective erythrocytes.

In rare cases, the spleen is removed. Signs leading to splenectomy are a sharp increase in the organ and a manifestation of the development of a heart attack.

The rest of the therapeutic measures consist in taking different group drugs that alleviate the course of the pathology. The main drugs are preparations of groups of steroid hormones, cytostatics, as well as preparations of iron and folic acid.

Nerobol

The most common prescription for physicians to combat the symptomatic manifestation of paroxysmal nocturnal hemoglobinuria is the drug Nerobol. This is a hormonal drug of the anabolic steroid group. The action of the drug is directed:

to stimulate protein synthesis in the patient's body, which is not enough in the defective erythrocyte membrane;
has a beneficial effect on nitrogen metabolism;
delays the withdrawal of potassium, sulfur and phosphorus, which are necessary for normal protein synthesis;
provokes increased fixation of calcium in the bones.

After taking this medicinal product the patient feels an increase in appetite, an intensive increase in muscle mass, an acceleration of bone calcification, and also a much better general state organism.

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

After the end of the drug in many patients, there is an increase in hemolysis.

The use of Nerobol can be carried out strictly according to the prescription of the attending physician.

Heparin

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

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

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

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 resist the blood compliment. As a result, the natural destruction of defective red blood cells stops immune system organism.

This drug is the most expensive drug in the world. Its mechanism of action and development possible consequences applications are not well understood.

Iron and folic acid preparations

With violations in the work of the red bone marrow, there is a deficiency of iron and folic acid, which are necessary for normal hematopoiesis. AT medical 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. Most often, Sorbifer, Tardiferron, Ferretab, Fenyuls, etc. are prescribed. These drugs include a complex of microelements necessary for the normal creation of solid blood particles in the red bone marrow.

Liver Support

Strengthened therapy in the fight against paroxysmal nocturnal hemoglobinuria strongly affects the liver. In the absence of supportive therapy for the liver, it may simply refuse. Therefore, it is important to take hepatoprotective drugs. These can be such 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 not to aggravate it with junk food in moments of liver weakness.

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

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

conclusions

Markjafava-Micheli disease or paroxysmal nocturnal hemoglobinuria is serious disease, which even when intensive care leads to death. 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, physicians unanimously declare that best method to prevent any pathology is the regular passage of a complete medical examination. Perhaps, 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)

The reasons:

The causes of the disease are associated with the intravascular destruction of erythrocytes, which are largely defective. Along with the pathological population of erythrocytes, a part of normal cells with a normal lifespan is also preserved. Violations in the structure of granulocytes and platelets were found. The disease is not hereditary, but any external factors, provoking the formation of a defective population of cells, which is a clone, i.e. offspring of a single originally altered cell are not known.

There is an increased complement sensitivity of pathological erythrocytes in PNH. Perhaps this is the basis for the provocation of a hemolytic crisis by 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: there are signs of moderate anemia, weakness, fatigue, palpitations during exercise, abdominal pain, often associated with thrombosis of mesenteric vessels. The skin and mucous membranes are pale icteric, grayish due to anemia and hemosiderin deposition. Characterized by signs of intravascular hemolysis.

The morphology of erythrocytes does not have characteristic features. In the bone marrow, hyperplasia of the red germ is observed, but in the trepanate there is a slight increase in the cellularity of the bone marrow, which, as the disease progresses, may become hypoplastic.

Diagnosis:

The diagnosis is established on the basis of signs of intravascular hemolysis (anemia, slight reticulocytosis, hemosiderin in the urine). Clarify the diagnosis by special studies (positive sucrose test, Hem test, negative Coombs test).

Unlike PNH, it does not have leukopenia or thrombocytopenia, usually good effect give prednisone. The picture of the bone marrow allows to distinguish PNH from aplastic anemia: with aplasia, trepanat is characterized by a predominance of fat, with hemolysis - by cellular hyperplasia, however, in rare cases, PNH may develop a picture of bone marrow hypoplasia, although hemosiderin is constantly found 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. With 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

PNH is a complex disease characterized by nonspecific and unpredictable signs and symptoms, often overlapping with those of other diseases. In addition, PNH manifests itself differently in each patient. If you have PNH, some or all of your red blood cells 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 happens all the time, invisibly, and can be life threatening. As in the case of others chronic diseases such as diabetes or arterial hypertension, the lack of treatment of 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 damage to vital organs.

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

Patients 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, these diseases can reduce the production of blood cells, further complicating the course of PNH. If you are diagnosed with PNH at the same time as aplastic anemia or myelodysplastic syndrome, discuss with your doctor all possible effective treatment options for your diseases.

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

2. Impact of the complement system

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

3. Destruction (hemolysis) of erythrocytes in PNH

In PNH, erythrocytes are destroyed, as a result of which toxic decay products enter the surrounding plasma (yellow liquid component of blood).

Hemolysis is medical term, meaning "destruction of red blood cells". The intensity of hemolysis is estimated by the results of determining the activity of LDH (lactate dehydrogenase - an enzyme contained in erythrocytes). Elevated LDH activity indicates excessive hemolysis. At healthy people slight hemolysis is a natural ongoing process. However, patients with PNH experience excessive hemolysis due to the absence of a protective protein on the surface of some or all of the red blood cells. This excessive hemolysis is accompanied by the release of toxic red blood cells into the blood, which over time can lead to 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, 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 appear unexpectedly and at any time. These disorders can include kidney failure and the formation of dangerous blood clots that can lead to damage to vital organs such as the liver, brain, and lungs.

Hemolysis also affects how you feel. Many patients with PNH report that the unpredictability of the onset and severity of symptoms negatively impacts 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. Application experience has shown an increase in survival, a decrease in hemolysis and thrombosis, and an increase in the quality of life.

The disease most often begins gradually. Patients complain of weakness, malaise, dizziness. Sometimes there is a subicteric sclera. Often the first are complaints of headache, abdominal pain of various localization. The tendency to increased thrombosis makes the patient consult a doctor. Hemoglobinuria is rarely the first symptom of the disease and in some patients PNH may be absent altogether. In some cases, it appears for the first time in 2-3 years and even 10 years after the onset of the disease.

One of the characteristic signs of PNH is bouts of abdominal pain. Its localization can be very different. Outside the crisis period, abdominal pain, as a rule, is not observed. Often it is 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 - the vessels of the kidneys) 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.

In an objective examination of the patient, pallor with a slight icteric tint most often attracts attention. Often there is puffiness of the face, sometimes excessive fullness. There may be a slight increase in the spleen and liver, although this is not characteristic of 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 noted 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 the crisis, this figure increases significantly, there is also an increase in the amount of plasma metalbumin.

The level of free plasma hemoglobin 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 plasma hemoglobin will be insufficient to filter it through the renal filter. Therefore, hemoglobinuria is not a mandatory symptom of the disease. When passing through the tubules of nephrons, the secreted 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 for PNH sign of the disease.

Laboratory indicators for paroxysmal nocturnal hemoglobinuria

The number of erythrocytes in patients with PNH decreases according to the level of decrease in hemoglobin. The color index remains close to unity for a long period. In cases where the patient loses a significant amount of iron in the urine in the form of hemosiderin and hemoglobin, the level of iron gradually decreases. A low color index is observed in about half of the 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 in most cases is reduced. 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 neutrophilic granulocytes. Sometimes the content of leukocytes in PNH is normal or increased - up to 10-11 G per 1 liter.

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

Nocturnal paroxysmal hemoglobinuria

Epidemiology

The frequency of occurrence is 2 cases per 1 million people. The incidence is 1.3 cases per million people during the year. It is predominantly manifested in persons of age, the dependence of the incidence on gender and race has not been identified. There are isolated cases of the disease in children and adolescents.

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

What is nocturnal paroxysmal hemoglobinuria

Causes of the disease

Causes and risk factors for the development of the disease are unknown. It has been established that the pathology is caused by a mutation of 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) takes place in the red bone marrow. All specialized blood cells are formed from the so-called stem, non-specialized, cells that have retained the ability to divide. Formed as a result of successive divisions and transformations, mature blood cells enter the bloodstream.

Mutation of 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 the volume of the bone marrow, mutant cells multiply more actively than normal ones. In the hematopoietic tissue, a population of cells producing defective blood cells is rather quickly formed. In this case, the mutant clone does not belong to malignant formations and may spontaneously disappear. The most active replacement of normal bone marrow cells by mutant ones occurs in the processes of bone marrow tissue recovery after significant lesions caused, in particular, by aplastic anemia.

Characteristic signs of nocturnal paroxysmal hemoglobinuria

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

Classification

Based on the available data on the causes and features pathological changes There are several forms of paroxysmal nocturnal hemoglobinuria:

Subclinical.
Classic.
Associated with disorders of hematopoiesis.

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

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 classical form proceeds with manifestations of typical symptoms, in the patient's blood there are populations of defective erythrocytes, platelets and some types of leukocytes. Laboratory methods studies confirm intravascular destruction of pathologically altered cells, hematopoiesis disorders are not detected.

After the transferred 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 they distinguish:

Actually PNG, idiopathic.
Developing as a concomitant syndrome in other pathologies.
Developing as a consequence of bone marrow hypoplasia.

Clinic of nocturnal paroxysmal hemoglobinuria. Part 2

The severity of the course of the disease in different cases is not always interconnected with the number of defective erythrocytes. Both cases of a subclinical course with a content of modified cells approaching 90%, and extremely severe cases, with a replacement of 10% of the normal population, are described.

Development of the disease

At the moment, it is known that in the blood of patients with paroxysmal nocturnal hemoglobinuria, three types of erythrocytes with different sensitivity to destruction by the complement system can be present in the blood. In addition to normal cells, erythrocytes circulate in the bloodstream, the sensitivity of which is several times higher than normal. In the blood of patients diagnosed with Marchiafava-Micheli's 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, pancytopenia is detected in patients - an insufficient content of blood cells of different types.

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

Pathology usually develops gradually, acute crisis onset is rare. Exacerbations are manifested against the background of menstruation, severe stress, acute viral diseases, surgical intervention, treatment with certain drugs (in particular, iron-containing). Sometimes the disease is exacerbated by the use of certain foods or for no apparent reason.

Paroxysmal nocturnal hemoglobinuria

There is evidence of manifestations of Marchiafava-Micheli disease due to 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 a sharp deterioration in the patient's condition.

Outside the crisis, patients are concerned about manifestations of moderate general hypoxia, such as shortness of breath, arrhythmias, general weakness, and tolerance worsens. physical activity. During a crisis, abdominal pains are manifested, localized mainly in the navel, 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 pastosity of the face develops, yellowness of the skin and sclera is noticeable.

On a note! A typical symptom of the disease is urine staining. Approximately half of the known cases of the disease do not manifest themselves.

Urine color change from normal to abnormal in paroxysmal nocturnal hemoglobinuria

In 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. Perhaps the formation of blood clots in the vessels of the liver, kidneys, coronary and cerebral vessels are also affected, which can lead to death. Thrombosis localized in the vessels of the liver leads to an increase in the size of the organ. Violations of intrahepatic blood flow entail dystrophic changes fabrics. With blockage of the portal vein system or the veins of the spleen, splenomegaly develops. Nitrogen metabolism disorders are accompanied by dysfunctions of smooth muscles, some patients complain of difficulty in swallowing, spasms of the esophagus, erectile dysfunction is possible in men.

Important! Thrombotic complications in PNH predominantly affect the veins, arterial thrombosis is rare.

Video - Paroxysmal nocturnal hemoglobinuria

Mechanisms for the 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;
urine staining black or dark brown.

In rare cases, a "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 emerges 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 variant of the course of the disease is a crisis, interspersed with periods of a stable satisfactory state. In some patients, the periods between crises are very short, insufficient to restore blood composition. These patients develop persistent anemia. There is also a variant of the flow with an acute onset and frequent crises. Over time, crises become less frequent. In especially severe cases, a fatal outcome is possible, which is caused by acute renal failure or thrombosis of the vessels that feed the heart or brain.

Important! Daily regularities in the development of hemolytic crises were not revealed.

In rare cases, the disease can also have a long calm course, isolated cases of recovery are described.

Diagnostics

Laboratory diagnosis of nocturnal paroxysmal hemoglobinuria

On the early stages Diagnosis of the disease is difficult due to the manifestation of scattered non-specific symptoms. It sometimes takes several months of observation to make a diagnosis. The classic symptom - specific staining of urine - appears during crises and not in all patients. Grounds for suspicion of Marchiafava-Micheli disease are:

iron deficiency of unknown etiology;
thrombosis, headaches, bouts 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 process of diagnosis, it is important to establish the fact of chronic intravascular breakdown of erythrocytes and to identify specific serological signs of PNH.

In the complex of studies with suspicion of nocturnal paroxysmal hemoglobinuria, in addition to general analyzes urine and blood are carried out:

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

Diagnostic tests for nocturnal paroxysmal hemoglobinuria

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

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

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

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

A clear connection between the development of the diagnosis of paroxysmal nocturnal hemoglobinuria as a symptom of concomitant pathologies was revealed. Medical studies have shown 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 a single mutated cell can lead to the development of a severe form of the pathological condition. During the formation of red blood cells, which is performed in the bone marrow, stem cells divide, mature and are released into the bloodstream. One modified gene is divided into a couple, and those into a couple, etc. That is, one cell reproduces itself, gradually filling the blood with damaged red blood cells.

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

Symptoms of nocturnal hemoglobinuria

In general, it is possible to determine 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 urine will acquire a dark brown tint. In the daytime and in the evening, such a sign is not observed.
Due to the quantitative decrease in the blood of erythrocytes, an 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 dots before the eyes, general weakness, fatigue, angina pectoris and tachycardia.

In the event of concomitant infectious diseases, bleeding, physical exertion, etc., 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, yellowness of the skin and moderate splenomegaly may appear ( enlargement of the spleen).
Hemoglobinuria is accompanied by a violation of the concentration of nitric oxide in plasma, which, both against the background of crises and in severe pathology, causes erectile dysfunction in men.
Due to the resulting defect in platelets (blood cells responsible for blood clotting), thrombosis can occur, which are most often observed in the veins. The same process can provoke a substance that is released during the destruction of solid blood cells. It causes increased coagulability of the vascular fluid, on which the tendency to thrombosis depends. Such violations can lead to death.

Therefore, the most rational way to timely detect Markyafava-Mikeli's disease will be a regular preventive examination.

Treatment of paroxysmal nocturnal hemoglobinuria

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

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

In rare cases, the spleen is removed. Signs leading to splenectomy are a sharp increase in the organ and a manifestation of the development of a heart attack.

Nerobol

to stimulate protein synthesis in the patient's body, which is not enough in the defective erythrocyte membrane;
has a beneficial effect on nitrogen metabolism;
delays the withdrawal of potassium, sulfur and phosphorus, which are necessary for normal protein synthesis;
provokes increased fixation of calcium in the bones.

After taking this drug, the patient feels an increase in appetite, an intensive increase in muscle mass, an acceleration of bone calcification, and a much better general condition of the body.

After the end of the drug in many patients, there is an increase in hemolysis.

The use of Nerobol can be carried out strictly according to the prescription of the attending physician.

Heparin

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

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

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

Iron and folic acid preparations

With violations in the work of the red bone marrow, there is a deficiency of iron and folic acid, which are necessary for normal hematopoiesis. Therapeutic therapy of PNH includes taking preparations of these microelements to compensate for pathological losses.

Liver Support

Maksar;
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 more. The main thing is not to aggravate it with junk food in moments of liver weakness.

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

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

conclusions

Markjafava-Micheli 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 way to prevent any pathology is to regularly undergo a complete medical examination. Perhaps, 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.

In this group of patients, there is no familial tendency to anemia, no associated congenital anomalies, and no abnormalities in the neonatal period. Aplastic anemia can occur at any age in children and adults, sometimes it can be associated with a specific intoxication or infection, but often there is no such connection, and then the anemia is considered "idiopathic".

Some drugs, such as 6-mercaptopurine, methotrexate, cyclophosphamine, and busulfan, have a specific, predictable, dose-dependent ability to depress the bone marrow. If this inhibition continues, it will lead to bone marrow aplasia, which usually disappears quickly after the drug is discontinued. These drugs damage normal bone marrow cells through the same mechanism as when they inhibit the growth of leukemic cells. The biochemical principles of their action are fairly well understood. This category also includes radiation damage to the bone marrow.

Other drugs, such as acriquine, chloramphenicol, phenylbutazone, and anticonvulsants, used at normal therapeutic doses, can cause profound bone marrow aplasia in a very small number of people, and this aplasia cannot be predicted in advance. Often it is irreversible and about half of the patients die. This category also includes intoxication with insecticides such as DDT and some organic solvents. It is often unclear whether anemia can be linked to a particular medication. Necessary condition for such a connection is the use of medications within the last 6 months. The most famous and studied of them is chloramphenicol. This drug is at the top of the list of known etiological agents in the group of patients with acquired aplastic anemia described by Scott et al., and in the same groups of sick children in Shahidi. Gurman observed in Sydney for 8 years 16 cases in which the disease was associated, as expected, with the intake of chloramphenicol. Absolute incidence of fatal acquired aplastic anemia in populations with no known exposure to any hazardous drug and known exposure to various drugs, including chloramphenicol.

Treatment with chloramphenicol increases the likelihood of developing aplastic anemia by 13 times, but it is also clear that this increase is small. For other medicines, the risk is even less. However, the British Medicines Safety Board recommends systemic chloramphenicol for all diseases except typhoid fever and haemophilic influenza meningitis, only after careful clinical and usually laboratory investigation indicating that another antibiotic will not be sufficient. It should never be used systemically for a banal infection.

The mechanism of development of aplastic anemia under the influence of chloramphenicol is unclear. The occurrence of aplastic anemia is not related to the dose and duration of treatment, nor can it be explained by insufficient excretion in susceptible individuals. In vitro inhibition of nucleic acid synthesis in normal bone marrow cells can be demonstrated, but only at a drug concentration that exceeds that used in vivo. It has been suggested that small amounts of chloramphenicol may be ingested in milk from cows treated for mastitis, that these small amounts may sensitize the bone marrow to therapeutic doses subsequently applied. It has also been suggested that there is as yet undiscovered synergism with other drugs that are probably harmless when used alone. In discussing the etiology of pancytopenic lethal aplasia caused by chloramphenicol, it should be noted that a significant proportion of patients receiving this drug have a completely different, reversible and dose-dependent depression of the bone marrow. In 10 of 22 patients treated with chloramphenicol, multiple large vacuoles were found in early bone marrow erythroblasts, which was often accompanied by a drop in the number of erythrocytes and reticulocytes. These changes disappear a week after the drug is discontinued. Their development, apparently, is facilitated by increased doses, delayed clearance from plasma and accelerated erythropoiesis. The same vacuoles can be seen with a deficiency of phenylalanine or riboflavin.

With regard to the etiology of other drug-induced aplasias, it has always been tempting to assume the action of immune mechanisms, perhaps of the drug-hapten type. However, these mechanisms have never been demonstrated. Only in one clinical situation, namely, graft-versus-host disease in immunologically incompetent infants who received transfusions, the immunological origin of aplastic anemia has been established. The development of a pronounced anaphylactoid reaction after accidental re-exposure to DDT in a sensitive patient also suggests an immune mechanism. Newig proposed three explanations for drug-induced aplasia: a) direct and toxic effects on bone marrow cells, for example, after chronic industrial contact with benzene; b) true allergy, the manifestations of which occur quickly after contact with a small dose; c) prolonged contact with high doses, i.e. "high dose allergy". This is the most common form. The author explains this primarily by damage to cell membranes. A genetic predisposition may also be suggested, as indicated by a case of blood dyscrasia following contact with chloramphenicol in identical twins. Review articles on drug-induced aplastic anemia by Neuwig have recently been published in the Lancet.

Similar problems arise in connection with the viral infection preceding the development of aplastic anemia. This phenomenon has been well studied in infectious hepatitis. Aplastic anemia in 5 patients aged 4 to 19 years developed 1-7 weeks after the onset of hepatitis. A number of similar cases have been described, including 3 cases by Schwartz et al. These authors noted that in infectious hepatitis there is often a temporary decrease in the number of granulocytes, platelets and hemoglobin and that progressive changes leading to bone marrow aplasia in a very small number of patients may represent a continuation of the whole process, probably depending on the genetic predisposition. Here you can see an analogy with chloramphenicol intoxication. Pancytopenia with temporary bone marrow hypoplasia has also been described in association with a number of infections caused by RNA viruses, including rubella and influenza microviruses, parainfluenza viruses, mumps and measles viruses. Two experimental viral infections in mice, ie, MVH-3 and the Trinidadian strain of Venezuelan equine encephalitis cause pancytopenia and bone marrow hypoplasia, and the virus can be isolated from the bone marrow. As with other causes of aplastic anemia, an autoimmune process is suspected.

In about half of cases of acquired aplastic anemia, no history of serious previous infection or exposure to toxic agents can be detected. Wolf published a large material, including 334 cases of acquired pancytopenia, and in 191 cases, i.e. 57.2%, anemia was recognized as idiopathic.

In Gurman's material, the relative number of patients with idiopathic anemia was less, i.e., 28 out of 104 who suffered from acquired aplasia. In 5 out of 17 cases according to Shahidi's material and in 5 out of 9 cases according to Desposito's material the anemia was idiopathic. It is not yet clear whether the illnesses in these cases are caused by infection with an unidentified virus. At least some of the idiopathic cases seem to fit into a distinct group that might be called pre-leukemia or leukemia in the aplastic phase.

Mehlhorn et al describe 6 children who were diagnosed with aplastic anemia between the ages of 1 year 11 months and 6 years on the basis of strong, indisputable evidence, but all of these children later developed acute lymphoblastic leukemia after 9 weeks - 20 months. . These 6 patients had one common feature- faster than usual therapeutic effect compared with aplastic anemia to initial corticosteroid therapy. The same was noted by Gurman, and we also observed this effect in one case, in which acute lymphoblastic leukemia developed after 3 months. This rapid response of pancytopenia to treatment with corticosteroids alone is markedly different from the usual lack of response in other cases of aplastic anemia. It should be noted that a similar leukemic transformation of aplastic anemia induced by benzene and chloramphenicol has been described.

Symptoms of acquired aplastic anemia

Acquired aplastic anemia is characterized by approximately the same symptoms and objective signs as the constitutional form, but there is no pigmentation, short stature and congenital anomalies of the skeleton or internal organs. The age range in which the disease occurs is wider, with the possible exception of aplasia caused by chloramphenicol, in which the "peak" of maximum incidence lies between the 3rd and 7th year. 43% of patients with the acquired form of the disease in the large Wolf: and 67% in the large Gurman summary had a history of contact, sometimes repeated, usually within the previous 6 months, with drugs or chemicals known to be predispose to aplastic anemia.

Newman and co-authors described 14 children with idiopathic pancytopenia and noted that, in addition to the three main signs - anemia, fever and purpura, there are important negative signs, i.e. the absence of hepatosplenomegaly, lymphadenopathy, oral ulcers and jaundice. However, purpura of the oral mucosa and bleeding from the gums can be observed. Sometimes there may be inflammatory lymphadenopathy associated with local sepsis.

If the child has red urine, then the development of paroxysmal nocturnal hemoglobinuria should be assumed.

Laboratory diagnostics

The picture of peripheral blood is approximately the same as in the constitutional form, but the neutropenia is deeper, sometimes approaching agranulocytosis. In addition, there is a more pronounced aplasia of the bone marrow, which consists almost entirely of fatty areas devoid of hemic cells. In 5-90% of erythroid precursors that are still in the bone marrow, megaloblastic changes and other signs of "dyserythropoiesis" are observed. In patients with dose-related chloramphenicol-induced reversible bone marrow suppression, vacuolization of erythroid and myeloid progenitors in the bone marrow is observed, similar to that seen in phenylalanine deficiency. The level of fetal hemoglobin may be elevated to the same extent as in constitutional forms, but less permanently. Levels above 400 µg% (or 5%) were thought to indicate a better prognosis for acquired disease, but analyzes of later cases treated at the same institution did not confirm these findings, possibly due to the use of a different method.

Aminaciduria, observed in about half of patients with a constitutional form, is absent and there is no lag in bone age.

More than half of adult patients with this disease have lymphopenia and hypogammaglobulinemia with subnormal IgG levels.

Associated hemolysis, including paroxysmal nocturnal hemoglobinuria. In some patients with aplastic anemia, the life span of erythrocytes is shortened. This suggests that the defect in erythrocytes is sometimes not only quantitative, but also qualitative. At the same time, increased sequestration in the spleen can be observed. Reticulocytosis, which in this case should have been, is usually excluded due to bone marrow aplasia. In some cases, the content of haptoglobin is reduced. One of the causes of hemolysis in this disease is an unusual combination of paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia. This syndrome should be assumed when a patient with aplastic anemia has elevated bilirubin or spontaneous reticulocytosis. Diagnosis is confirmed by a serum acid hemolysis (SHA) test for PNH, as well as tests for hemosiderinuria. In some cases, PNH can only be detected by examining the most sensitive population of erythrocytes, i.e., reticulocytes and young erythrocytes, obtained by carefully removing the layer below the leukocyte-platelet clot with a pipette after centrifuging 20-35 ml of blood at 500 G.

Usually, in this syndrome, PNH is detected against the background of aplastic anemia, often after erythropoiesis has recovered to a certain extent. In several cases, the reverse sequence was observed, i.e., against the background of PNH, severe or fatal bone marrow failure developed. Lewis and Days systematically tested all of their patients with aplastic anemia and found that 7 out of 46 (15%) had laboratory criteria for PNH. Two of them subsequently developed a typical picture of PNH. Approaching this issue from a different point of view, the authors found that at least 15 out of 60 patients with PNH initially had signs of aplasia. PNH is usually a disease of adult men. However, the form that occurs with aplasia seems to occur at a younger age and may affect children. Gardner observed 11 such patients, including 6 to 25 years old, 2 patients were 7 and 9 years old. These two were boys. They had aplastic anemia before the diagnosis of PNH lasted 2 years and 5 years.

An interesting feature of this combined syndrome is that aplastic anemia can be of the Fanconi type, can be acquired after contact with chloramphenicol, tranquilizers, insecticides, herbicides and other substances, and can be idiopathic. Lewis and Days believe that the main link exists between bone marrow aplasia and PNH, and not between the etiological factors that caused bone marrow damage and PNH. Both of these authors, as well as Gardner and Bloom, suggest that during the period of aplasia, somatic mutation of bone marrow stem cells occurs, which leads to the appearance of a secondary clone of pathological erythrocytes inherent in PNH, which begin to be produced during subsequent bone marrow regeneration. It should be added that although the characteristic defect in PNH is concentrated in the erythrocytes, the granulocytes are also altered. The "skin window" method shows a decrease in their phagocytic activity and alkaline phosphatase activity. In contrast, in uncomplicated aplastic anemia, alkaline phosphatase activity in granulocytes is usually elevated.

Treatment

Treatment is in principle the same as for constitutional aplastic anemia, but care must be taken to stop all contact with the drug or toxic agent, if known. Re-exposure can cause a fatal relapse in patients who have experienced a first attack of aplasia, and may even provoke fatal anaphylactic shock.

Supportive measures also include blood transfusions while the anemia is severe enough to cause symptoms, usually at a hemoglobin level of 4-6 g%. Erythrocyte mass is used not only for the treatment of obvious bleeding, and one should strive to increase the level to 8-9 g%. Higher hemoglobin levels lead to more severe inhibition of erythropoiesis. Thrombocytopenic bleeding is treated with rapid infusions of platelet-rich plasma or platelet concentrates (4 units/m2). Intramuscular injections should be avoided. All procedures require strict asepsis and vigorous treatment of infections with bactericidal antibiotics. Since neutropenia is usually especially deep in acquired forms of aplastic anemia, a special neutropenic regimen can be used during the neutropenic phase: washing the mouth with a 0.1% solution of gibitan 4 times a day after meals (made from a pure antiseptic without detergents and dyes); lubrication of the nostrils with naseptin ointment 3 times a day; bath daily. Lubrication of the gums with 1% gibitan tooth gel 2 times a day (instead of brushing the teeth). When patients are in the hospital, some kind of isolation with a reversible barrier is needed to reduce the risk of infection with hospital microflora. Prophylactic systemic antibiotic therapy should be absolutely rejected, as it increases the susceptibility to fungal infections and infections resistant to antibiotics. Incipient infection may present with an increased tendency to bleed. With infection, not only does the number of platelets decrease, but the hemorrhagic tendency increases with a given number of platelets.

Androgens. Specific therapy with androgens + corticosteroids is carried out in the same way as with constitutional forms, i.e. oxymetalone orally - 4-5 mg / kg per day + prednisolone 5 mg 2 times a day in children weighing up to 20 kg, 5 mg 3 once a day with a body weight of 20 to 40 kg and 4 times a day with a body weight of more than 40 kg. The difference lies in the fact that with acquired forms of anemia, the effect is achieved in a smaller percentage of patients, the response to treatment is slower, but remission in patients who can be treated continues after the withdrawal of androgen and corticosteroids. In Fanconi anemia, bone marrow failure recurs rapidly after discontinuation of this therapy. It was even pointed out that this circumstance can be used in difficult cases when differentiating an acquired form from a constitutional one.

The first results of treatment with androgens and steroids were very impressive. Of 17 children with acquired aplastic anemia (toxic in 12, idiopathic in 5), 10 had persistent reticulocytosis, which peaked at 5-15% after 1-7 months of combined treatment with androgens and corticosteroids. Of these children, 9 survived, and subsequently their hemoglobin content increased. In 3 children transient reticulocytosis was observed without other reactions. The discrepancy between the timing of the appearance of reticulocytosis and the increase in hemoglobin in these patients was explained by hemolysis. In addition, erythrocytes, which are formed in the early stage of bone marrow regeneration, are hypochromic in normal level iron in serum and increased, the content of free protoporphyrin in erythrocytes, which indicates a cellular block in the synthesis of hemoglobin. Max Boost hemoglobin was observed 2-15 months after the start of androgen treatment. In the study of the bone marrow in dynamics in the early stage of treatment, groups of reticular cells were found that mature and turn into erythroid foci in those patients who later develop a response to treatment. In all patients with an increase in hemoglobin, an increase in the number of segmented cells to more than 1500 in 1 μl was also observed, however, the platelet reaction was less pronounced and they reached only 25,000-90,000 in 1 μl. Usually, the number of segmented neutrophils increased more slowly than the level of hemoglobin, the number of platelets increased even more slowly. The total duration of androgen treatment in these patients ranged from 2 to 15 months, after stopping treatment, they remained in remission indefinitely. 2 patients who responded positively to treatment had idiopathic aplasia, 8 had toxic aplasia. Among the patients who did not respond, 3 had idiopathic and 4 had a toxic form of aplasia. The authors hypothesized that long-term treatment high doses of corticosteroids can impair bone marrow function due to an increase in the amount of adipose tissue in the bone marrow.

Similar results were obtained by Desposito et al using androgens + steroids. In 5 out of 9 children with acquired aplastic anemia, a pronounced hematological improvement occurred, which turned out to be stable. 2 children had an idiopathic form and 3 had a toxic form. (Of the patients who did not respond to treatment, 3 had idiopathic and 1 toxic anemia.) Similar timing ratios were observed. The number of platelets increased significantly only 9-17 months after the start of treatment, and even then it reached only 50,000 in one patient and 100,000 in 1 μl in 2 patients, while hemoglobin and segmented cells were normal. Treatment was stopped after 7-11 months; in 4 out of 5 patients, the hemoglobin level temporarily dropped for 1-3 months. The patients were followed up from 1 to 3 years. During this time they had no relapses.

According to these two posts, positive reaction was observed in slightly more than half of the children, and the treatment was effective in both idiopathic and toxic forms of aplastic anemia. Among patients with toxic forms, the frequency of reactions was perhaps somewhat higher.

Until the last of these articles appeared, the impression was that without androgen treatment, patients rarely survived. The increased survival noted in the two most recent reports is attributed to the success of symptomatic therapy, including antibiotics and platelet transfusions. In particular, the material of Hayne et al. sheds new light on the natural course of the disease and seems to fill the gap between patients treated with androgens and without androgens (in 30 of 33 patients, the etiology of anemia was toxic, not idiopathic, which may be explains the better prognosis). Gurman, in a review of 104 sick children with acquired aplastic anemia from Boston and Sydney, indicates that overall survival was 34% with combined treatment androgens and corticosteroids and 19% with corticosteroids alone or supportive care.

In newer reports, including results from the same Boston Children's Hospital, the data are less satisfactory. Mortality was 70-80% despite androgens, corticosteroids, and supportive care. The survival curve is biphasic. Many patients in early period die from infections and bleeding within the first 6 months. Currently, the effectiveness of androgens in patients with severe acquired aplasia is being questioned.

Prognostic signs. According to Gurman's work, the prognosis appears to be worse in aplastic anemia after infections, especially infectious hepatitis, or after one short course of chloramphenicol. The prognosis is better in idiopathic cases, as well as in patients with anemia that can be explained by taking anticonvulsants or repeated courses of chloramphenicol. It has been suggested that the bone marrow of a child who develops aplastic anemia after one short course is often more depressed than in a child whose pancytopenia is caused only by repeated courses of medication. It is known that in children with severe hypocellularity of the bone marrow, a particularly severe prognosis is indicated by the number of lymphocytes more than 85% in the bone marrow, the number of neutrophils less than 200 per 1 μl or platelets less than 20,000 per 1 μl. Based on these data, Hamitt et al suggested that severe aplasia after hepatitis should be considered an indication for early bone marrow transplantation, given that only about 10% of patients of this genus survive on maintenance therapy + androgens and steroids.

Bone marrow transplant . Due to the failure of androgen treatment in severe acquired aplastic anemias, researchers have turned to the possibilities of the prospect of bone marrow transplantation. After intravenous infusions of bone marrow from identical twins in 5 out of 10 cases, there was a rapid recovery of bone marrow function. If there are no identical twin donors, then a serious obstacle is the possible rejection of the graft or, if it takes root, graft-versus-host disease. However, among normal sibs, there is a one in 4 chance that a histocompatible donor will be found, matched by HL-A typing and mixed lymphocytic culture to reveal the remaining histocompatibility loci. These precautions reduce the problem of graft incompatibility but do not completely solve it. In order to reduce or eliminate the possibility of rejection, additional immunosuppressive therapy is required, such as high doses of cyclophosphamide before bone marrow transplantation and a course of methotrexate after transplantation. Before attempting this therapeutic measure, massive supportive care must be carried out, including nursing the patient in a sterile environment, leukocyte and platelet transfusions during the critical first days, and the presence of a medical team with extensive experience. Thomas et al. describe techniques for harvesting, processing, and infusing bone marrow. 24 patients (including 8 under 14 years old) with severe aplastic anemia (14 cases of idiopathic anemia, 4 cases of anemia after hepatitis, 4 cases of drug-induced anemia, 1 case of PNH, 1 case of Fanconi anemia), who did not respond to conventional treatment, received transplants from sibs identical in HL-A. In 21 patients, rapid regeneration of the bone marrow was observed, which in most cases, as was established using genetic markers, was due to donor cells. In 4 patients, the graft was rejected and they died. Four patients died from a secondary disease, 11 people live with functioning transplants. The observation period is from 141 days to 823 days. Ten patients returned to a normal active lifestyle. These results, obtained by a group of researchers from Seattle, have encouraged others to use this method. On fig. 25 shows the transplant result in the first case in the UK, performed by the bone marrow transplant team at the Royal Marsden Hospital. It is possible that this will be the further treatment of individual patients with poor prognostic signs at the first request for help.

Different types of treatment. Patients who are not amenable to other treatment, with cellular bone marrow, splenectomy is indicated. However, the supposed effect of this operation has not been confirmed in the analysis of a large group of cases, and since splenectomy is quite dangerous in these patients with thrombocytopenia, it is generally not recommended. A possible exception are patients with an element of hemolysis and with detected sequestration of erythrocytes in the spleen. Splenectomy has been shown to increase platelet survival in patients with aplasia who are no longer helped by platelet transfusion.

In aplastic anemia, intravenous phytohemagglutinin has been suggested, but data collected to date do not support the suggestion that this method is appropriate. Treatment with iron is contraindicated, as is treatment with cobalt, which causes nausea, vomiting, and enlargement. thyroid gland. Folic acid and vitamin B12 are ineffective even in patients with megaloblastic changes.

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

The frequency of occurrence is 2 cases per 1 million people. The incidence is 1.3 cases per million people during the year. It is predominantly manifested in persons aged 25-45 years, the dependence of the incidence on gender and race has not been identified. There are isolated cases of the disease in children and adolescents.

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

Causes of the disease

Mutation of 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 the volume of the bone marrow, mutant cells multiply more actively than normal ones. In the hematopoietic tissue, a population of cells producing defective blood cells is rather quickly formed. At the same time, the mutant clone does not belong to malignant formations and can spontaneously disappear. The most active replacement of normal bone marrow cells by mutant ones occurs in the processes of bone marrow tissue recovery after significant lesions caused, in particular, by aplastic anemia.

Classification

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

Subclinical.
Classic.
Associated with disorders of hematopoiesis.

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

The classical form proceeds with manifestations of typical symptoms, in the patient's blood there are populations of defective erythrocytes, platelets and some types of leukocytes. Laboratory research methods confirm intravascular destruction of pathologically altered cells, hematopoiesis disorders are not detected.

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

There is an alternative classification, according to which they distinguish:

Actually PNG, idiopathic.
Developing as a concomitant syndrome in other pathologies.
Developing as a consequence of bone marrow hypoplasia.

Development of the disease

At the moment, it is known that in the blood of patients with paroxysmal nocturnal hemoglobinuria, three types of erythrocytes with different sensitivity to destruction by the complement system can be present in the blood. In addition to normal cells, erythrocytes 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.

Pathology usually develops gradually, acute crisis onset is rare. Exacerbations are manifested against the background of menstruation, severe stress, acute viral diseases, surgery, treatment with certain drugs (in particular, iron-containing ones). Sometimes the disease is exacerbated by the use of certain foods or for no apparent reason.

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

Outside the crisis, patients are concerned about manifestations of moderate general hypoxia, such as shortness of breath, attacks of arrhythmia, general weakness, and exercise tolerance worsens. During a crisis, abdominal pains are manifested, localized mainly in the navel, 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 pastosity of the face develops, yellowness of the skin and sclera is noticeable.

On a note! A typical symptom of the disease is urine staining. Approximately half of the known cases of the disease do not manifest themselves.
In 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. Perhaps the formation of blood clots in the vessels of the liver, kidneys, coronary and cerebral vessels are also affected, which can lead to death. Thrombosis localized in the vessels of the liver leads to an increase in the size of the organ. Violations of intrahepatic blood flow entail dystrophic tissue changes. With blockage of the portal vein system or the veins of the spleen, splenomegaly develops. Nitrogen metabolism disorders are accompanied by dysfunctions of smooth muscles, some patients complain of difficulty in swallowing, spasms of the esophagus, erectile dysfunction is possible in men.
Important! Thrombotic complications in PNH predominantly affect the veins, arterial thrombosis is rare.

Video - Paroxysmal nocturnal hemoglobinuria
Mechanisms for the 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;
urine staining black or dark brown.

In rare cases, a "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 emerges 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 variant of the course of the disease is a crisis, interspersed with periods of a stable satisfactory state. In some patients, the periods between crises are very short, insufficient to restore blood composition. These patients develop persistent anemia. There is also a variant of the flow with an acute onset and frequent crises. Over time, crises become less frequent. In especially severe cases, a fatal outcome is possible, which is caused by acute renal failure or thrombosis of the vessels that feed the heart or brain.
Important! Daily regularities in the development of hemolytic crises were not revealed.

In rare cases, the disease can also have a long calm course, isolated cases of recovery are described.
Diagnostics
In the early stages of the disease, diagnosis is difficult due to the manifestation of disparate nonspecific symptoms. It sometimes takes several months of observation to make a diagnosis. The classic symptom - specific staining of urine - appears during crises and not in all patients. Grounds for suspicion of Marchiafava-Micheli disease are:
iron deficiency of unknown etiology;
thrombosis, headaches, bouts 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 process of diagnosis, it is important to establish the fact of chronic intravascular breakdown of erythrocytes and to identify specific serological signs of PNH.
In the complex of studies, if paroxysmal nocturnal hemoglobinuria is suspected, in addition to general urine and blood tests, the following are performed:
determination of the content of hemoglobin and haptoglobin in the blood;
immunophenotyping by flow cytometry to identify populations of defective cells;
serological tests, in particular, the Coombs test.

Differential diagnosis with hemoglobinuria and anemia of a different etiology is necessary, in particular, autoimmune hemolytic anemia should be excluded. Common symptoms are anemia, jaundice, increased bilirubin in the blood. Enlargement of the liver or / and 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) - +
Ham test (acid) - +
Hemosiderin in urine - +
Thrombosis ± +
Hepatomegaly ± ±
Splenomegaly ± ±
The results of the Hartman and Hem test are specific for PNH and are the most important diagnostic features.
Treatment
Relief of hemolytic crisis is carried out by repeated transfusions of erythrocyte mass, thawed or previously washed many times. It is believed that at least 5 transfusions are needed to achieve a stable result, however, the number of transfusions may differ from the average and is determined by the severity of the patient's condition.
Attention! It is impossible to transfuse blood without preliminary preparation in such patients. Donor blood transfusion exacerbates the course of the crisis.

For symptomatic elimination of hemolysis, patients may be prescribed nerobol, but after discontinuation of the drug, relapses are possible.
Additionally, folic acid, iron, hepatoprotectors are prescribed. With the development of thrombosis, direct-acting anticoagulants and heparin are used.
In extremely rare cases, the patient is shown 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.
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signs	Autoimmune hemolytic anemia	PNG
Coombs test	+	-
Increased content of free hemoglobin in blood plasma	-	+
Hartmann test (sucrose)	-	+
Ham test (acid)	-	+
Hemosiderin in urine	-	+
Thrombosis	±	+
Hepatomegaly	±	±
Splenomegaly	±	±