Crises in paroxysmal nocturnal hemoglobinuria. Causes and treatment of paroxysmal nocturnal hemoglobinuria

AT 12- deficiency anemia(megaloblastic, pernicious, Addison-Birmer disease) is a disease characterized by a violation of the hematopoietic process due to a deficiency in the body of vitamin B12. It manifests itself mainly in pathological bone marrow, nervous system And gastrointestinal tract.

Why the disease develops

Hemoglobin is the protein that makes up erythrocytes - red blood cells. Its function is to transport oxygen to cells and excrete carbon dioxide. With a lack of red blood cells and an oppressed function of hemoglobin, anemia develops.

Depending on the etiological factor and clinical manifestations, there are different. Megaloblastic anemia (aka. pernicious anemia) occurs due to a lack of vitamin B12 or folic acid - substances that take Active participation in the synthesis of new red blood cells in the body. The mechanism of development of this disease is manifested by a change in the shape and an increase in the size of red blood cells.

Causes of B12 deficiency anemia:

Symptoms and how to detect the disease

As a result of anemia, there is a reduced supply of oxygen to cells. This leads to fatigue, weakness, dizziness and fainting, ringing in the ears, pallor of the skin and mucous membranes, shortness of breath, palpitations, loss of appetite and body weight.

There are three major syndromes that include the main symptoms of megaloblastic anemia:

. Manifested by weakness, dizziness, fainting, tinnitus, flashing "flies" in the eyes, shortness of breath, tachycardia, tingling in the chest.
Gastroenterological syndrome. It is characterized by a decrease in appetite and weight, nausea, vomiting, constipation, burning and discoloration (raspberry) of the tongue (glossitis).
neurological syndrome. Includes symptoms of damage to the peripheral nervous system, such as numbness and tingling of the extremities, unsteady gait, muscle weakness. With prolonged and severe deficiency of vitamin B12, damage to the spinal cord and brain is possible, which manifests itself in the loss of vibration sensitivity in the legs, convulsions.

Kinds

According to the international classification of diseases (ICD-10), they distinguish the following types:

D51.0 - Insufficiency of the internal factor of Castle, which leads to anemia of Addison-Birmer ( pernicious anemia);
D51.1 - malabsorption in combination with the excretion of protein in the urine (proteinuria);
D51.2 - pernicious anemia, the symptoms of which are numbness or tingling of the extremities (as a result of transcobalamin II deficiency);
D51.3 - anemia associated with food;
D51.8 - other types of B12 deficiency with anemia;
D51.9 - megaloblastic anemia, unspecified.

Degrees

Clinical signs of B12 deficiency anemia are an indication for a laboratory blood test.

The main criterion for classifying anemia by severity is the content of hemoglobin in the blood. Depending on the level of hemoglobin, the following degrees are distinguished:

mild (hemoglobin content in the blood from 90 to 110 g/l);
moderate (hemoglobin from 90 to 70 g/l);
severe (hemoglobin less than 70 g/l).

Normally, the level of hemoglobin in the blood is 130-160 g/l in men and 120-150 g/l in women. The content of hemoglobin from 110 to 120 g/l is intermediate between the norm and anemia.

Symptoms of B12 deficiency anemia may not yet appear, while the blood already shows abnormalities. The diagnosis of megaloblastic anemia is made mainly by the blood picture.

Diagnostic Measures

Pernicious anemia has a number of specific clinical symptoms and changes in laboratory tests Therefore, its diagnosis is not very difficult for a hematologist.

If a typical triad of anemic, gastrointestinal and neurological syndromes is detected, a hemogram and myelogram study is prescribed.

IN peripheral blood with this disease, the following characteristic changes:

color index above 1.0 (hyperchromic);
the number of red blood cells is reduced to a greater extent than the level of hemoglobin;
the content and concentration of hemoglobin in the erythrocyte is increased;
macrocytosis - large hyperchromic erythrocytes are determined in a blood smear;
anisopoikilocytosis - erythrocytes of an altered (teardrop-shaped) form are found;
basophilic granularity of erythrocytes;
erythrocytes containing Jolly bodies, Cabot bodies;
platelet anisocytosis;
hypersegmentation of neutrophil nuclei;
single erythrokaryocytes, megaloblasts;
decrease in the number of reticulocytes;
in most patients, leuko- and thrombopenia is observed - a decrease in the number of leukocytes and platelets.

The following are found in the red bone marrow: pathological changes:

hyperplasia of the red germ with megaloblastic type of hematopoiesis;
promegaloblasts, megaloblasts;
asynchronous ripening of the nucleus - the cytoplasm is oxyphilic, the nucleus is immature;
cell division (mitosis);
Cabot bodies and Jolly bodies in erythrocytes;
changes in the granulocytic series: giant metamyelocytes and stab.

A single administration of vitamin B12 leads to a complete transformation of the megaloblastic type of hematopoiesis into a normoblastic one, therefore, it is not recommended to prescribe a therapeutic course before a sternal puncture, otherwise the bone marrow examination will be uninformative.

Additional tests that may help in making a diagnosis of deficiency anemia include:

determination of the level of bilirubin in the blood - an increase is detected indirect bilirubin;
lactate dehydrogenase level - increased;
FEGDS with biopsy - atrophic gastritis;
in order to control the effectiveness of therapy and differential diagnosis, the number of reticulocytes in the blood is re-determined on the 6-7th day of therapy (an increase in their number should be observed - “reticulocyte crisis”, which is an indicator of the effectiveness and correctness of the diagnosis).

It is necessary to distinguish this disease first of all from folate deficiency anemia. These two pathologies have such a similarity of clinical and laboratory manifestations that earlier pernicious anemia (Addison-Birmer's disease) was called B12-folic deficiency.

You can immediately confirm or refute the diagnosis of folate deficiency anemia by determining the level of folate in the blood serum. Its decrease serves as the basis for establishing this diagnosis. But such a study is not available in many institutions. Therefore, more often resort to the tactics of the phased appointment of vitamin B12 and folic acid.

Treatment

Treatment of the disease can be carried out both on an outpatient basis and in a hospital, depending on the severity of the patient's condition.

medicines

Therapy for megaloblastic anemia of unspecified origin begins with the appointment of vitamin B12. Cyanocobalamin solution is injected into daily dose 500 micrograms intramuscularly daily for 2 weeks. If a “reticulocyte crisis” does not occur at the end of the first week, the diagnosis of folate deficiency anemia is most likely.

In the case of a positive result after 2 weeks, they switch to the dosing regimen of cyanocobalamin 500 mcg once a week. Therapy is continued until the normalization of red blood parameters: hemoglobin, the percentage of reticulocytes, the number of red blood cells.

Considering that according to modern ideas, Addison's anemia refers to autoimmune diseases(autoimmune atrophic gastritis leads to the cessation of the synthesis of the Castle factor), the treatment of pernicious anemia can only achieve stable hematological remission. To maintain remission and prevent recurrence of the disease, patients are shown the introduction of cyanocobalamin once a month at a dose of 500 mcg for life. Such patients are subject to dispensary observation by a hematologist.

Patients with pronounced neurological disorders the dose of cyanocobalamin should be increased by 50% for the first six months of therapy.

At serious condition the patient - symptoms of hypoxia, cardiovascular insufficiency, prenicious coma - an emergency transfusion of erythrocyte mass is indicated.

Folk remedies

In 1926, a method for the treatment of megaloblastic anemia was first proposed by prescribing special diet containing raw veal liver.

For this, lean raw veal liver is best suited, which must be passed through a meat grinder twice and taken 200 g before each meal.

Some other folk remedies may help relieve the symptoms of the disease. Some of them:

with severe weakness, take 1 tbsp. l. garlic with honey before each meal;
decoction of red clover inflorescences take 1 tbsp. l. 3 times a day;
a decoction of rose hips take 1 glass 3 times a day after meals as a hot drink.

In modern conditions, Addison-Birmer disease responds well to treatment. synthetic drugs vitamin B12, which are well tolerated and inexpensive. Therefore, traditional medicine has only an auxiliary value. It is possible to be treated for the diagnosis of B12 anemia with any folk recipes only after consulting with a hematologist.

Possible consequences and prognosis

The term "pernicious anemia" ("malignant anemia"), as mentioned earlier, has only historical significance. The prognosis of the disease is favorable. Despite the fact that megaloblastic anemia is most often chronic and requires lifelong maintenance therapy, the quality of life of patients in remission suffers little. These people can lead active image life.

An important prognosis remains in patients with an advanced form of anemia, accompanied by the development of hypoxia, pulmonary heart failure and coma. These conditions require the immediate initiation of intensive care, the delay of which can lead to lethal outcome.

Addison's disease has another name - bronze disease. By this is meant a violation of the functioning of the adrenal glands. In turn, this violates hormonal balance, as a result, the synthesis of glucocorticoids decreases or completely disappears.

Addison-Birmer disease has a large number of symptoms, which are mainly due to the defeat of most of the cortex. The cause of this disease can be different. In 8 out of 10 cases, Addison-Birmer disease develops due to an autoimmune process in the body.

But also sometimes the disease can be accompanied by tuberculosis, which has affected the adrenal glands. Pathology can be congenital and can be inherited. autoimmune type The disease is most common in the female half of the population.

The most common symptoms of Addison's disease are soreness, gastrointestinal disturbances, and hypotension. Pathology can lead to metabolic disorders. Such a disease can also be treated with the help of traditional medicine, which will enhance the work of the adrenal glands, as well as help in the fight against microbes and inflammation.

General characteristics of the disease

Addison's disease, the photo of which clearly shows the affected area, can be both with primary and with secondary insufficiency. As many people know, pathology affects the endocrine glands, which are responsible for the production of some of the most important hormones in the human body. These organs have 2 zones:

crust;
brain matter.

Each zone is responsible for synthesizing different types of hormones. IN medulla production of norepinephrine and adrenaline. They are especially necessary for a person in stressful situation, these hormones will help to use all the reserves of the body.

Other hormones are also synthesized in the cortex.

Corticosterone. It is necessary for the balance of water and salt metabolism in the body, and is also responsible for the regulation of electrolytes in blood cells.
Deoxycorticosterone. Its synthesis is also required for water-salt metabolism, moreover, it affects the efficiency and duration of use of muscles.
Cortisol is responsible for the regulation of carbon metabolism, as well as for the production of energy resources.

The pituitary gland, a gland located in the region of the brain, has a great influence on the adrenal cortex. The pituitary gland produces a special hormone that stimulates the adrenal glands.

As mentioned above, Addison-Birmer disease has two types. Primary this is the disease itself, when the work of the adrenal glands is completely disrupted due to negative factors. The secondary implies a decrease in the amount of ACTH synthesized, which, in turn, impairs the functioning of the endocrine glands. When the pituitary gland produces an insufficient amount hormones for a long period - dystrophic processes in the adrenal cortex can begin to develop.

Causes of the disease

The primary form of Addison-Birmer disease is quite rare. It is equally likely to be found in both men and women. In most cases, the diagnosis is made to people whose age is from 30 to 50.

There is also a chronic form of the disease. Such a development of pathology is possible with various negative processes. In almost all cases, namely in 80%, the cause of Addison-Birmer disease is an autoimmune condition of the body. In 1 out of 10 cases, the cause of the pathology is the defeat of the adrenal cortex by an infectious disease, for example, tuberculosis.

For the remaining 10% of patients, the causes may be of a different nature:

this can be affected by long-term use of drugs, in particular, glucocorticoids;
types of fungal infection;
injury to the endocrine glands;
amyloidosis;
tumors of both benign and malignant nature;
bacterial infections with a weakened human immune system;
pituitary dysfunction;
genetic predisposition to the disease.

Other syndromes can also develop due to Addison's disease, such as an adrenal crisis, which occurs when the concentration of adrenal hormones is too low.

There are the most likely causes of the crisis:

severe stressful condition;
violations in the dosage when compiling a course of treatment with hormonal drugs;
an infectious lesion of the adrenal cortex can aggravate the disease;
trauma to the adrenal glands;
circulatory disorders, such as blood clots.

Symptoms of the disease

Symptoms of Addison's disease directly depend on the violation of the synthesis of certain types of hormones. Clinical manifestations of the disease may be different. The determining factors are the form of pathology and its duration.

The most common clinical manifestations of pathology are as follows:

Addisonian pathology has its own name of bronze disease for a reason. The most obvious sign of this disease is a violation of pigmentation. The skin changes its color. The color of mucous membranes changes. It's all about too much pigmentation. With a lack of adrenal hormones, much more ACTH is produced, this is explained by the need to stimulate the work of the endocrine glands.
One of the common clinical manifestations of the disease is chronic hypotension. This can lead to dizziness and fainting state increases sensitivity to low temperatures.
With insufficient work of the endocrine glands, the whole organism weakens. If you have constant fatigue, fatigue, you should consult a medical specialist.
With this pathology, there are often disturbances in the work of the gastrointestinal tract, this can manifest itself in the form of vomiting, constant nausea and diarrhea.

The disease can affect the emotional component. depressive state is one of the clinical manifestations of Addison's disease.
Patients reported increased sensitivity to stimuli. The sense of smell, hearing is aggravated, the person feels the taste of food better. In most cases, patients prefer to eat salty foods.
Pain in the muscle tissue can also be a symptom of Addisonian pathology. This is explained by an increase in the concentration of potassium in blood vessels.
As mentioned above, one of the clinical manifestations of the disease is an adrenal crisis, which occurs as a result of a sharp decrease in the level of hormones of the endocrine glands. The most popular symptoms of a crisis are pain in the abdomen, low blood pressure, and disturbed salt balance.

Diagnosis of the disease

First of all, patients pay attention to changes in the shade of the skin. This phenomenon signals an insufficient activity of adrenal hormones. When referring to a medical specialist in this situation, he determines the ability of the adrenal glands to increase the synthesis of hormones.

Diagnosis of Addison's disease occurs by the introduction of ACTH and measurements of the content of cortisol in the blood vessels before the administration of the drug and 30 minutes after vaccination. If the potential patient does not have problems with the functions of the adrenal glands, the level of cortisol will increase. If the concentration of the test substance has not changed, the person has disturbances in the functioning of the endocrine glands. In some cases, for a more accurate diagnosis, the content of the hormone in urea is measured.

Treatment of pathology

In the course of treatment, special attention should be paid to the diet. It should be varied, it should contain the necessary amount of proteins, fats and carbohydrates to provide the body. Particular attention should be paid to vitamins B and C. They can be found in bran, wheat, fruits and vegetables. In addition, the patient is advised to drink more decoctions based on wild rose or black currant.

With Addison's disease, the sodium content in the body decreases, for this reason it is recommended to focus on salty foods. In addition, the pathology is characterized by an increased concentration of potassium in the blood vessels, it is recommended not to include foods that are rich in potassium in the diet. These include potatoes and nuts. Patients are advised to eat as often as possible. Before going to bed, medical experts recommend having dinner, this will reduce the chance of hypoglycemia in the morning.

Almost all folk recipes are aimed at stimulating the adrenal cortex. ethnoscience has a mild effect side effects practically absent. Application folk recipes will not only improve the functioning of the adrenal glands, but also have a positive effect on the state of the whole organism as a whole. With the help of this approach, it is possible to normalize the work of the gastrointestinal tract, to counteract inflammatory processes. chronic nature. It is recommended to use several recipes in turn, this will avoid the addiction of the body.

Prevention and forecasting

If therapy was started in a timely manner and all the recommendations of a medical specialist were followed, the outcome of the disease will be favorable. The disease will not affect life expectancy in any way. In some cases, Addison's disease is accompanied by a complication - an adrenal crisis. In such a situation, you should immediately seek the advice of a medical specialist. A crisis can be fatal. Addison's disease is accompanied by rapid fatigue, weight loss and loss of appetite.

Changes in the shade of the skin do not occur in all cases, deterioration in the work of the endocrine glands occurs gradually, so it is difficult for a person to detect this on their own. In such situation critical condition develops abruptly and unexpectedly for the patient. Most often, the cause is some negative factor, such as stress, infection or injury.

Since Addison's disease is often autoimmune in nature, there are practically no preventive measures. You should keep track of your immune system, avoid consumption alcoholic beverages, smoking. Medical experts recommend timely attention to the manifestations of infectious diseases, especially tuberculosis.

Hemoglobinuria is a term that combines several varieties of the symptomatic condition of urine, in which free hemoglobin (Hb) appears in it. It changes the structure of the liquid and colors it in colors from pinkish to almost black.

When settling, urine is clearly divided into 2 layers: upper layer does not lose its color, but becomes transparent, while the lower one remains cloudy, increases the concentration of impurities, and sediment from detritus precipitates at the bottom.

With hemoglobinuria, in addition to Hb, urine may contain: methemoglobin, amorphous hemoglobin, hematin, protein, casts (hyaline, granular), as well as bilirubin and its derivatives.

Massive hemoglobinuria, causing blockade of the renal tubules, can lead to acute renal failure. With chronic increased breakdown of red blood cells, blood clots may form, more often in the kidneys and liver.

Causes

Normally, free hemoglobin healthy person in the blood, and even more so in the urine, does not circulate. The normal indicator is the detection of traces of Hb only in the blood plasma.

The appearance of this respiratory protein in the blood fluid - hemoglobinemia, is observed after hemolysis (destruction of red blood cells) caused by a number of diseases and external factors:

complications in blood transfusion;
ingestion of hemolytic poisons;
anemia;
pregnancy
extensive burns;
infectious diseases;
paroxysmal hemoglobinuria;
massive hemorrhages;
hypothermia;
injuries.

The above diseases, conditions and factors, causing appearance hemoglobin in plasma can lead to its appearance in urine. But, the state of hemoglobinuria occurs only after it reaches a certain concentration. Until this threshold (125-135 mg%) is reached, Hb cannot cross the renal barrier and pass into the urine.

However, the appearance of hemoglobin in urine can be caused not only by hemoglobinemia, but also occur as a result of the dissolution of erythrocytes in it, which appeared as a result of hematuria. This type of hemoglobinuria is called false or indirect.

Symptoms and Diagnosis

Signs of hemoglobinuria develop rapidly - following a change in the color of urine, skin become pale, bluish or icteric. Arthralgia occurs - aches and "flying" joint pains that are not accompanied by swelling, redness or limitation of function.

A feverish, semi-delirious state, accompanied by a sudden increase in body temperature, may be aggravated by bouts of nausea and vomiting. The liver and spleen are enlarged, pain in the kidneys and / or lower back is possible.

When diagnosing, it is necessary to exclude other conditions - hematuria, alkaptonuria, melaninuria, porphyria, myoglobinuria. To confirm the state of hemoglobinuria, first of all, tests are carried out that find out which particles colored the urine red - food coloring, erythrocytes or hemoglobin.

Depending on the severity of the symptoms and the general condition of the patient, the attending physician chooses necessary examinations and their sequence from the following laboratory studies and methods of functional diagnostics:

clinical general analyzes (hemogram) of urine and blood;
biochemical analysis of urine;
ammonium sulfate test;
analysis for the content of hemosedrin and detritus in the sediment;
"paper test" - urine electrophoresis and immunoelectrophoresis;
bacteriuria - bacterioscopic analysis of urine sediment;
coagulogram (hemostasiogram) - a study of coagulation;
Coombas test;
myelogram (bone marrow puncture from the sternum or ilium);
Ultrasound of the genitourinary system;
radiograph of the kidneys.

Differentiation of varieties of hemoglobinuria is based on the difference in causal-significant factors.

Marchiafava-Micheli disease

With paroxysmal nocturnal hemoglobinuria difficulty and pain in swallowing

Marchiafava-Micheli disease or in another way, paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia caused by the destruction of defective red blood cells inside the vessels. This is a rare form of hemolytic anemia (1:500,000), diagnosed for the first time between the ages of 20 and 40 years.

Marchiafava-Micheli disease is caused by a somatic mutation of a gene on the X chromosome in one of the stem cells that is responsible for normal development membranes of erythrocytes, platelets and leukocytes.

Paroxysmal nocturnal hemoglobinuria is distinguished by special characteristic features that are unique to it, which include an increase in blood clotting, also in the case of its classical course, note:

destruction of red blood cells (Hb) occurs during sleep;
spontaneous hemolysis;
yellowness or bronze coloration of the skin;
difficulty and pain in swallowing;
the level of A-hemoglobin - less than 60 g / l;
leukopenia and thrombocytopenia;
increase in the number of immature forms of erythrocytes;
negative antiglobulin test result;
possible abdominal pain.

Paroxysmal nocturnal hemoglobinuria can often lead to impaired perception and brain function. In case of ignoring the symptoms and lack of adequate treatment, thrombosis occurs, which in 40% of cases becomes the cause of death.

To clarify the diagnosis of Marchiafava-Micheli disease, additional tests are used - flow cytometry, the Hem test (acid test) and the Hartman test (sucrose test). They are used to determine hypersensitivity PNH-defective red blood cells, which is characteristic only for this type of hemoglobinuria.

In the treatment of the disease, as a rule, the following methods are used:

Conducting a transfusion of washed 5 times or thawed erythrocytes - the volume and frequency of transfusion are strictly individual and additionally depend on the current state.
Intravenous administration of antithymocyte immunoglobulin - 150 mg / kg per day, a course of 4 to 10 days.
Reception of tocopherol, androgens, corticosteroids and anabolic hormones. For example, nerabol - 30 50 mg per day for a course of 2 to 3 months. Replenishment of iron deficiency - taking drugs only orally and in small doses.
Anticoagulant therapy - after surgical interventions.

IN extreme cases a related bone marrow transplant is performed.

Count's disease

Alimentary-toxic paroxysmal myoglobinuria (Count's, Yukov's, Sartlan's disease) causes almost all the signs of hemoglobinuria. In addition to humans, livestock, domestic animals, five species of fish are sick. It is characterized by damage to the skeletal muscles, nervous system and kidneys. severe forms diseases lead to the destruction of muscle tissue.

The primary cause of disease in humans and mammals is toxic poisoning affected river fish, especially its fat and entrails.

Important! The toxic fraction is particularly aggressive and thermally stable - heat treatment, including boiling for an hour at 150 ° C, and / or prolonged deep freezing do not neutralize this toxin. It collapses only after special degreasing.

In a sick person, treatment is aimed at general intoxication, blood purification and an increase in the level of A-hemoglobin.

Paroxysmal hemoglobinuria - Harley's disease

This name hides a whole group, uniting almost identical, sharply severe symptoms, and which is additionally divided into subspecies depending on the reasons that caused them.

Paroxysmal cold hemoglobinuria - Donath-Laidsteiner syndrome

This variety causes prolonged cooling or a sharp hypothermia of the body caused by being in cold water(less often in frosty air). It differs in the Donotan-Laidsteiner syndrome - the appearance in the plasma of two-phase hemolysins, which trigger the complement activation system and cause hemolysis inside the vessels.

Activation of the complement system is the main effector mechanism of inflammation and immune dysfunction, which begins with betaglobulin (component C3), and in an increasing cascade, affects other significant immunoglobulins.

The cold variety caused by hypothermia proceeds paroxysmal. Description typical attack, which can occur even after slight cooling (already at<+4°C воздуха) открытых частей тела:

sudden and severe chills - up to one hour;
body t jump –> 39°C;
dark red urine is excreted during the day;
always - severe pain in the kidneys;
spasm of small vessels;
possible - vomiting, yellowness of the skin, a sharp increase in the liver and spleen;

The attack ends with the fall of the body and the release of profuse sweat. Attacks can be strong and frequent (in winter - up to several times a week).

It should be noted that some patients have seizures with "sluggish" manifestations of all symptoms, pulling dull pains in the extremities and small traces of free hemoglobin in the urine.

The diagnosis is specified by the Donotan-Laidsteiner laboratory test - the presence of hemolysin, the amboceptor of which binds to erythrocytes only at low temperatures, and the presence of DL-antibodies specific to the P-blood group antigen are determined.

Rosenbach's test may be especially valuable - when hands are immersed (on both shoulders along the tourniquet) in ice water, in a positive case, after 10 minutes, the appearance of Hb in the serum (> 50%) is observed and it is possible short attack hemoglobinuria.

Treatment consists in the strict exclusion of exposure to cold. Immunosuppressive therapy is carried out only as prescribed by a doctor.

As antipodes to cold varieties, there are autoimmune hemolytic anemias caused by thermal hemolysins.

Infectious paroxysmal cold hemoglobinuria can be caused by infectious diseases such as the flu

A symptom that occurs against the background of a number of infectious diseases:

flu;
monoculosis;
measles;
mumps;
malaria;
sepsis.

This also includes separately isolated Hemoglobinuria syphilitic (haemoglobinuria syphilitica). Each type of infection has its own specifics, for example, the presence of hemoglobin in the urine caused by cooling by tertiary syphilis, in contrast to the usual "cold variant", is not accompanied by the presence of "cold" agglutins in the blood plasma.

Due to globalization trends, hemoglobinuric fever is gaining actualization.

Treatment is carried out according to the underlying disease. Clarification of the diagnosis is carried out in order to exclude other pathologies.

It should be noted that with Harley's disease, in the anamnesis of all patients there are almost always indications of lues and a positive RW reaction, and for cold hemoglobinuria, cases of hereditary transmission of the symptom in luetics are described.

Marching hemoglobinuria

A paradox that is not fully understood. It is believed that the basis increased loads on the feet, which, with the obligatory presence of lordosis of the spine, cause a violation of the renal circulation. Marching hemoglobinuria may occur for the following reasons:

after running marathons;
hiking or other long and heavy physical exertion (with emphasis on the legs);
horse riding;
rowing lessons;
during pregnancy.

In symptoms, in addition to lumbar lordosis, the absence is always noted feverish state, and when laboratory research a positive benzidine reaction and the absence of erythrocytes in urine are detected.

Marching hemoglobinuria does not cause complications and goes away by itself. It is recommended to take a break from sports (other) activities.

Traumatic and transient hemoglobinuria

To establish such a diagnosis, the presence of destroyed fragments of erythrocytes in the blood becomes decisive. unusual shape. During the clarification of the diagnosis, it is important to find out due to what, what are the reasons, and in what place did the destruction of red blood cells occur:

crash syndrome - prolonged squeezing;
marching hemoglobinuria;
stenosis of the aortic heart valve;
artificial heart valve defects;
malignant arterial hypertension;
mechanical damage to blood vessels.

Transient hemoglobinuria occurs in patients taking iron supplements. If detected, a consultation is necessary to adjust the doses and treatment regimen for the underlying disease.

If you find in yourself the main symptom of hemoglobinuria - red urine, you need to contact a therapist or hematologist.

Paroxysmal nocturnal hemoglobinuria (Marchiafava-Mikeli disease, Strübing-Marchiafava disease) is an acquired hemolytic anemia associated with intravascular destruction of defective erythrocytes.

Paroxysmal nocturnal hemoglobinuria is a rare acquired disease caused by disruption of the erythrocyte membrane and characterized by chronic hemolytic anemia, intermittent or persistent hemoglobinuria and hemosiderinuria, events, thrombosis, and bone marrow hypoplasia. Paroxysmal nocturnal hemoglobinuria is one of the rare forms of hemolytic anemia. There is 1 case of this disease per 500,000 healthy individuals. The disease is usually first diagnosed in individuals age group 20-40 years old, but can also occur in the elderly.

What provokes Paroxysmal nocturnal hemoglobinuria (Marquiafava-Micheli disease): Paroxysmal nocturnal hemoglobinuria is an acquired disease, apparently due to an inactivating somatic mutation in one of the stem cells. The mutant gene (PIGA) is located on the X chromosome; the mutation disrupts the synthesis of glycosylphosphatidylinositol. This glycolipid is required for fixation to cell membrane a number of proteins, including CD55 (a factor that accelerates complement inactivation), and protectin.

To date, in patients with paroxysmal nocturnal hemoglobinuria, the absence of about 20 proteins on blood cells has been revealed. Along with the pathological clone, patients also have normal stem cells and blood cells. The share of pathological cells differs in different patients and even in the same patient at different times.

It is also suggested that paroxysmal nocturnal hemoglobinuria results from the proliferation of a defective bone marrow stem cell clone; such a clone gives rise to at least three populations of erythrocytes that differ in sensitivity to activated complement components. Increased complement sensitivity is most characteristic of young circulating erythrocytes.

In paroxysmal nocturnal hemoglobinuria, leukocytes and platelets, as well as erythrocytes, are also characterized by structural defects in their membranes. The absence of immunoglobulins on the surface of these cells speaks in favor of the fact that paroxysmal nocturnal hemoglobinuria does not belong to autoaggressive diseases. The accumulated data indicate the presence of two independent populations of erythrocytes - pathological (not surviving to maturity) and healthy. The uniformity of damage to the membrane of erythrocytes, leukocytes and platelets is an argument in favor of the fact that with most likely pathological information is received by the common precursor cell of myelopoiesis. The leading role in the genesis of thrombotic complications belongs to the intravascular destruction of erythrocytes and stimulation of the coagulation process by factors released during their decay.

Pathogenesis (what happens?) during Paroxysmal nocturnal hemoglobinuria (Marquiafava-Micheli disease): Due to the absence of two proteins - the decay accelerating factor (CD55) and protectin (CD59, an inhibitor of the membrane attack complex), the sensitivity of erythrocytes to the lytic action of complement is increased. The decay accelerating factor destroys the C3-convertases and C5-convertases of the classical and alternative pathways, and protectin prevents the polymerization of the C9 component catalyzed by the C5b-8 complex and, therefore, disrupts the formation of the membrane attack complex.
Platelets also lack these proteins, but their lifespan is not shortened. On the other hand, complement activation indirectly stimulates platelet aggregation and increases blood clotting. This probably explains the tendency to thrombosis.

Symptoms of Paroxysmal nocturnal hemoglobinuria (Marquiafava-Micheli disease): Allocate an idiopathic form of paroxysmal nocturnal hemoglobinuria and paroxysmal nocturnal hemoglobinuria as a syndrome that accompanies a number of diseases. Rarely, a peculiar variant of idiomatic paroxysmal nocturnal hemoglobinuria is also encountered, the development of which is preceded by a phase of hematopoietic hypoplasia.

Symptoms of paroxysmal nocturnal hemoglobinuria are very variable - from mild benign to severe aggressive. In the classical form, hemolysis occurs while the patient is sleeping (nocturnal hemoglobinuria), which may be due to slight decline blood pH at night. However, hemoglobinuria is observed only in about 25% of patients, and in many not at night. In most cases, the disease is manifested by symptoms of anemia. Hemolytic flares may occur after infection, severe physical activity, surgery, menstruation, blood transfusions and the introduction of iron preparations for therapeutic purposes. Hemolysis is often accompanied by bone and muscle pain, malaise, and fever. Characterized by such signs as pallor, icterus, bronze coloration of the skin and moderate splenomegaly. Many patients complain of difficulty or pain in swallowing, and spontaneous intravascular hemolysis and infections often occur.

Paroxysmal nocturnal hemoglobinuria often accompanies aplastic anemia, preleukemia, myeloproliferative disorders, and acute myeloid leukemia. Detection of splenomegaly in a patient with aplastic anemia should serve as the basis for examination in order to detect paroxysmal nocturnal hemoglobinuria.
Anemia is often severe, with hemoglobin levels of 60 g/L or lower. Leukopenia and thrombocytopenia are common. In a peripheral blood smear, as a rule, a picture of normocytosis is observed, however, with prolonged hemosiderinuria, iron deficiency occurs, manifested by signs of anisocytosis and the presence of microcytic hypochromic erythrocytes. The number of reticulocytes is increased, except in cases where there is bone marrow failure. The bone marrow is usually hyperplastic at the onset of the disease, but hypoplasia and even aplasia may develop later.

Level alkaline phosphatase in neutrophils is reduced, sometimes up to its complete absence. All signs of intravascular hemolysis may be present, but severe hemosiderinuria is usually observed, leading to iron deficiency. In addition, chronic hemosiderinuria causes iron deposition in the renal tubules and dysfunction of their proximal parts. Antiglobulin test is usually negative.

Venous thrombosis occurs in about 40% of patients and is the main cause of death. The veins of the abdominal cavity (hepatic, portal, mesenteric, and others) are usually affected, which is manifested by Budd-Chiari syndrome, congestive splenomegaly, and abdominal pain. Thrombosis of the sinuses of the dura mater is less common.

Diagnosis of Paroxysmal nocturnal hemoglobinuria (Marquiafava-Micheli disease): The diagnosis of paroxysmal nocturnal hemoglobinuria should be suspected in patients with hemolytic anemia, accompanied by black urine, leukocytopenia and thrombocytopenia, and thrombotic complications. Importance has microscopy of urine sediment stained for iron in order to detect hemosiderinuria, a positive benzidine Gregersen test with urine.

In the blood, normochromic anemia is detected, which can later become hypochromic. The number of reticulocytes increased slightly. The number of leukocytes and platelets is reduced. In plasma, the content of free hemoglobin is increased. In some cases, there is a decrease in the content of serum iron and an increase in the level of bilirubin. Proteinuria and hemoglobin count can be detected in the urine.

The myelogram usually shows signs of increased erythropoiesis. In the bone marrow biopsy, hyperplasia of the hematopoietic tissue due to an increase in the number of erythro- and normoblasts, accumulation of hemolyzed erythrocytes in the lumen of the dilated sinuses, areas of hemorrhage. An increase in the number of plasma and mast cells is possible. The number of granulocytes and megakaryocytes is usually reduced. In some patients, devastation fields can be detected, represented by edematous stroma, fat cells. A marked increase in adipose tissue in the bone marrow is found when the disease is accompanied by the development of hematopoietic hypoplasia.

The Ham test (acid test) and the Hartman test (sucrose test) are specific for paroxysmal nocturnal hemoglobinuria, since they are based on the most characteristic sign for this disease - increased sensitivity of PNH-defective erythrocytes to complement.

Paroxysmal nocturnal hemoglobinuria may begin with previous hematopoietic hypoplasia, sometimes it occurs at later stages. At the same time, there are cases with the appearance at various stages of the disease of signs of intravascular hemolysis, with positive acid and sugar tests. In such cases, one speaks of PNH syndrome or hypoplastic anemia. Patients who developed acute myeloid leukemia and erythromyelosis against the background of paroxysmal nocturnal hemoglobinuria, transient syndrome of paroxysmal nocturnal hemoglobinuria in acute myeloblastic leukemia, osteomyelosclerosis, and cancer metastases to the bone marrow were described. In hereditary dyserythropoietic anemia with multinucleated normoblasts, a positive Hem test may be detected.

In some cases, it is necessary to differential diagnosis between paroxysmal nocturnal hemoglobinuria and autoimmune hemolytic anemia with thermal hemolysins, when a sucrose test can give a false positive result. Correct diagnosis a cross-sucrose test using the patient's blood serum and donor erythrocytes helps, which reveals the presence of hemolysins. In the sucrose sample, complement activation is provided by the low ionic strength of the incubation solution. This test is more sensitive but less specific than the Ham test.

The most sensitive and specific method is flow cytometry, which allows you to establish the absence of protectin and a factor that accelerates complement inactivation on erythrocytes and neutrophils.

Differential diagnosis is carried out with some forms of autoimmune hemolytic anemia, occurring with intravascular hemolysis, kidney disease (with severe proteinuria), aplastic anemia, lead intoxication. With severe anemia, transfusions of erythrocytes washed with isotonic sodium chloride solution are indicated; for the prevention and treatment of thrombosis - anticoagulant therapy. Iron deficiency is treated with iron supplements. Tocopherol preparations are useful, as well as anabolic hormones (nerobol, retabolil).

Treatment of Paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli disease): Treatment of paroxysmal nocturnal hemoglobinuria is symptomatic, since there is no specific therapy. The main method of therapy for patients with paroxysmal nocturnal hemoglobinuria are transfusions of washed (at least 5 times) or thawed erythrocytes, which, as a rule, are well tolerated by patients for a long time and do not cause isosensitization. Transfusions of freshly prepared whole blood or red blood cells with a shelf life of less than 7 days are contraindicated due to the possibility of increased hemolysis, the development of hemoglobinuria crises due to the presence of leukocytes in these transfusion media, which leads to the formation of antileukocyte antibodies and complement activation.

The volume and frequency of transfusions depend on the patient's condition, the severity of anemia and the response to ongoing blood transfusion therapy. Patients with paroxysmal nocturnal hemoglobinuria frequent transfusions anti-erythrocyte and anti-leukocyte antibodies can be produced.
In these cases, the erythrocyte mass is selected according to the indirect Coombs test, it is washed many times with saline.

In the treatment of paroxysmal nocturnal hemoglobinuria, nerobol is used at a daily dose of 30-50 mg for at least 2-3 months. However, in a number of patients, after discontinuation of the drug or during treatment, a rapid increase in hemolysis is observed. Sometimes taking this group of drugs is accompanied by a change in liver function tests, usually reversible.

To combat bone marrow hypoplasia, antithymocyte immunoglobulin is usually used, as in aplastic anemia. A total dose of 150 mg/kg is administered intravenously for 4-10 days.

In patients with paroxysmal nocturnal hemoglobinuria, due to the constant loss of iron, its deficiency in the body often develops. Since an increase in hemolysis is often observed against the background of taking iron preparations, they should be used per os and in small doses. Anticoagulants are indicated after surgery, but they should not be administered for a long time. There are a number of reports about sudden development hemolysis after heparin administration.

It has been reported that some patients good effect given high doses of corticosteroids; androgens may be helpful.

Bone marrow hypoplasia and thrombosis, especially in young patients, are indications for transplantation of HLA-compatible bone marrow from sibling or sisters (if any) already at an early stage of the disease. To destroy the pathological clone of cells, conventional preparatory chemotherapy is sufficient.

The effectiveness of splenectomy has not been established, and the operation itself is poorly tolerated by patients.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare (orphan) disease with a variety of clinical picture. The loss of the GPI-AP protein, due to somatic mutation on the cell surface, is a leading link in the pathogenesis. Hemolysis, thrombosis and cytopenias are characteristic clinical manifestations. The gold standard for diagnosis is flow cytometry. Stem cell transplantation and the biological agent eculizumab are the most current treatments.

Modern methods of diagnosis and treatment of paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (APG) — rare (orphan) diseases with varied clinical presentation. The loss of protein GPI-AP, due to somatic mutation on the cell surface, is the leading players in the pathogenesis. Hemolysis, thrombosis and cytopenia are characteristic symptoms. The gold standard of diagnosis is flow cytometry. Transplantation of stem cells and biological agent ekulizumab are the most modern methods of treatment.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare (orphan) disease. Mortality in PNH is about 35% within 5 years of onset. Unfortunately, most cases remain undiagnosed. Clinical manifestations are varied and patients can be observed with diagnoses such as aplastic anemia, thrombosis unclear etiology, hemolytic anemia, refractory anemia (myelodysplastic syndrome). The average age of patients is 30-35 years.

The leading link in pathogenesis is the loss, due to somatic mutation, of the GPI-AP protein (glycosyl-phosphatidylinositol anchor protein) on the cell surface. This protein is an anchor, in the event of the loss of which some of the important proteins cannot attach to the membrane. Many proteins lose the ability to join, which is used to diagnose PNH by immunophenotyping (CD59 - erythrocytes, CD16 -, CD24 - granulocytes, CD14 - monocytes). Cells with signs of the absence of the studied proteins are called a PNH clone. All these proteins must interact with complement system proteins, in particular with C3b and C4b, destroying the enzymatic complexes of the classical and alternative complement pathways, and thereby stop the complement chain reaction. The absence of the above proteins leads to cell destruction upon activation of the complement system.

There are three main clinical syndromes in PNH: hemolytic, thrombotic, and cytopenic. Each patient may have one, two or all three syndromes. The “classic” form is the manifestation of the disease in the form of severe hemolysis ± thrombosis, the bone marrow in this form is hypercellular. There is a separate form of combination of PNH and bone marrow failure (PNH + aplastic anemia, PNH + myelodysplastic syndrome), when there are no pronounced clinical manifestations, but there are indirect laboratory signs of hemolysis. Finally, there is a third, subclinical form, in which there are no clinical and laboratory signs hemolysis, but there is bone marrow failure and a small (≤ 1%) PNH clone.

Hemolysis is largely associated with the absence of CD59 protein (membrane inhibitor of reactive lysis (MIRL)) on the surface of erythrocytes. Hemolysis in PNH is intravascular, so dark urine (hemosiderinuria) and great weakness. A decrease in haptoglobin is recorded in the laboratory (reaction physiological protection with hemolysis), an increase in lactate dehydrogenase (LDH), a positive test for free hemoglobin in the urine (hemosiderinuria), a decrease in hemoglobin with a subsequent increase in reticulocytes, an increase in the unbound fraction of bilirubin. The Hem's test (red blood cell hemolysis when a few drops of acid are added to a blood sample) and the sucrose test (the addition of sucrose activates the complement system) are used to diagnose PNH.

Currently, it is believed that hemolysis flows almost constantly, but has periods of intensification. A large number of free hemoglobin triggers a cascade of clinical manifestations. Free hemoglobin actively binds to nitric oxide (NO), leading to dysregulation of smooth muscle tone, platelet activation and aggregation (abdominal pain, dysphagia, impotence, thrombosis, pulmonary hypertension). Free hemoglobin that does not bind to haptoglobin damages the kidneys (acute tubulonecrosis, pigmentary nephropathy) and can lead to kidney failure after a few years. Dark urine in the morning is due to activation of the complement system due to respiratory acidosis during sleep. The absence of dark urine in some patients in the presence of other laboratory signs of hemolysis (increased LDH) does not contradict the diagnosis and is explained by the binding of free hemoglobin to haptoglobin and nitric oxide, and hemoglobin reabsorption in the kidneys.

Thrombosis is diagnosed in 40% of patients and is the main cause of death, more often thrombosis of the liver's own veins (Budd-Chiari syndrome) and PE. Thrombosis in PNH has specific features: it often coincides with episodes of hemolysis and occurs despite ongoing anticoagulant therapy and a small PNH clone. In the pathophysiological substantiation of thrombosis, platelet activation due to CD59 deficiency, endothelial activation, impaired fibrinolysis, microparticle formation, and the entry of phospholipids into the blood as a result of activation of the complement system are discussed. A number of authors point to an increase in D-dimers and abdominal pain as the main predictors of thrombosis.

The pathogenesis of bone marrow failure syndrome in PNH is unclear. Normal stem cells (GPI+) and mutated stem cells (GPI-) coexist in the bone marrow. The appearance of a small (less than 1%) PNH clone is often observed in patients with aplastic anemia and myelodysplastic syndrome.

The gold standard for diagnosing PNH is the immunophenotyping of peripheral blood cells for the presence of a PNH clone. In the conclusion of the study, the size of the PNH clone in erythrocytes (CD 59 -), granulocytes (CD16 -, CD24 -) and monocytes (CD14 -) is indicated. Another diagnostic method is FLAER (fluorescently labeled inactive toxin aerolysin), a fluorescently labeled bacterial toxin aerolysin that binds to the GPI protein and initiates hemolysis. The advantage of this method is the ability to test all cell lines in one sample, the disadvantage is the impossibility of testing with a very low number of granulocytes, which is observed in aplastic anemia.

Treatment can be divided into maintenance therapy, thrombosis prophylaxis, immunosuppression, erythropoiesis stimulation, stem cell transplantation, treatment with biological agents. Maintenance therapy includes erythrocyte transfusions, the appointment of folic acid, vitamin B12, iron preparations. Most patients with "classic" PNH are transfusion dependent. Hemochromatosis, with damage to the heart and liver, is rare in patients with PNH, as hemoglobin is filtered into the urine. Cases of renal hemosiderosis have been described.

Prevention of thrombosis is carried out with warfarin and low molecular weight heparin, the INR should be at the level of 2.5-3.5. The risk of thrombosis does not depend on the size of the PNH clone.

Immunosuppression is carried out with cyclosporine and antithymocyte immunoglobulin. During acute hemolysis, prednisolone is used in a short course.

Stem cell transplantation is the only method that gives a chance complete cure. Unfortunately, complications and difficulties in donor selection associated with allogeneic transplantation limit the application of this method. Mortality in patients with PNH with allogeneic transplantation is 40%.

Since 2002, the drug eculizumab, which is a biological agent, has been used in the world. 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. .

Clinical case of the "classic" variant of PNH.

Patient D., 29 years old. Complaints of weakness, yellow coloration of the sclera, dark urine in the morning, some days - the urine is yellow, but cloudy, with an unpleasant odor. In May 2007, dark urine appeared for the first time. In September 2007, she was examined at the Hematological Research Center (SSC), Moscow. Based on the presence of a positive Hema test and a sucrose test, detection in the blood of 37% (normal - 0) of an erythrocyte clone with the immunophenotype CD55- / CD59-, hemosiderinuria, anemia, reticulocytosis in the blood up to 80% (normal - 0.7-1%), hyperbilirubinemia due to indirect bilirubin, the diagnosis was made: PNH, secondary folic and iron deficiency anemia.

Hemolysis increased against the background of pregnancy in 2008. In June 2008, at a period of 37 weeks, C-section due to partial placental abruption and the threat of fetal hypoxia. The postoperative period was complicated by acute kidney failure, severe hypoproteinemia. Against the background of intensive therapy, acute renal failure resolved on the fourth day, blood counts returned to normal, edematous syndrome was stopped. A week later, the temperature rises to 38-39 ˚С, weakness, chills. A diagnosis of metroendometritis was made. The therapy was ineffective, the uterus was extirpated with tubes. The postoperative period was complicated by liver failure with syndromes of cholestasis, cytolysis, mesenchymal inflammation, severe hypoproteinemia, and thrombocytopenia. Ultrasonography revealed thrombosis of the liver's own veins and portal vein. Conducted antibacterial and anticoagulant therapy, the introduction of hepatoprotectors, prednisolone, replacement therapy FFP, EMOLT, thromboconcentrate.

She was re-hospitalized at the State Scientific Center due to thrombosis of the portal and own veins of the liver, thrombosis of small branches pulmonary artery, development infectious complications with rapidly growing ascites. Conducted intensive anticoagulant therapy, antibiotic therapy led to partial recanalization of the portal vein and proper veins of the liver, a decrease in ascites was noted. In the future, the patient was long-term injected with low molecular weight heparin - clexane.

Currently, according to laboratory parameters, the patient has hemolysis - a decrease in hemoglobin to 60-65 g / l (normal 120-150 g / l), reticulocytosis up to 80% (normal - 0.7-1%), an increase in LDH levels to 5608 U / l (norm -125-243 U / l), hyperbilirubinemia up to 300 μmol / l (norm - 4-20 μmol / l). Immunophenotyping of peripheral blood - the total value of the erythrocyte PNH clone 41% (normal - 0), granulocytes - FLAER-/CD24- 97.6% (normal - 0), Monocytes - FLAER-/CD14- 99.3% (normal - 0) . Continuous replacement therapy is carried out with washed erythrocytes (2-3 transfusions every 2 months), folic acid, iron preparations, vitamin B12. Given the very high thrombogenic risk, warfarin therapy (INR - 2.5) is carried out. The patient was included in the national registry of PNH for planning therapy with eculizumab.

Clinical case of combination of aplastic anemia and PNH.

Patient E., 22 years old. Complaints of general weakness, tinnitus, bleeding gums, bruises on the body, weight loss of 3 kg, fever up to 38 g.

The onset of the disease is gradual, about 1 year old, when bruises began to appear on the body. Six months ago, bleeding gums joined, general weakness intensified. In April 2012, a decrease in hemoglobin to 50 g/l was registered. In the Central District Hospital, the therapy with vitamin B12 and iron preparations did not give a positive effect. In the hematology department of the Republican Clinical Hospital - severe anemia, Hb - 60 g / l, leukopenia 2.8 × 10 9 / l (norm - 4.5-9 × 10 9 / l), thrombopenia 54 × 10 9 / l (norm - 180-320 × 10 9 /l), increase in LDH - 349 U / l (norm 125-243 U / l).

According to bone marrow aspiration biopsy, a decrease in megakaryocytic germ. Immunophenotyping of peripheral blood - the total value of the erythrocyte PNH clone 5.18%, granulocytes - FLAER-/CD24- 69.89%, Monocytes - FLAER-/CD14- 70.86%.

The patient underwent erythrocyte transfusion three times. Currently, the possibility of allogeneic stem cell transplantation or the appointment of biological therapy is being considered.

A.V. Kosterina, A.R. Akhmadeev, M.T. Savinova

Kazan State Medical University

Republican Clinical Hospital of the Ministry of Health of the Republic of Tatarstan, Kazan

Kosterina Anna Valentinovna – Assistant of the Department of Hospital Therapy, KSMU

Literature:

1. Luzzatto L. Paroxysmal nocturnal hemoglobinuria. Hematology 2000 // American Society of Hematology Education Program. - 2000. - R. 28-38.

2. Parker C., Omine M., Richards S. et. al. for the International PNH Interest Group. Diagnosis and management of paroxysmal nocturnal hemoglobinuria // Blood. - 2005. - Vol. 106, No. 12. - R. 3699-709.

3. Hillman P., Lewis S.M., Bessler M., Luzzatto L., Dacie J.V. Natural history of paroxysmal nocturnal hemoglobinuria // N. Engl. J. Med. - 1995. - Vol. 333, No. 19. - R. 1253-8.

4. Brodsky R.A., Mukhina G.L., Li S. et. al. Improved detection and characterization of paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin // Am. J.Clin. Pathol. - 2000. - Vol. 114, No. 3. - R. 459-66.

5. Hall C., Richards S., Hillman P. Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) // Blood. - 2003. - Vol. 102, No. 10. - R. 3587-91.

6. Kelly R.J., Hill A., Arnold L.M. et. al. Long-term treatment with eculizumab in paroxysmal nocturnal hemoglobinuria: sustained efficacy and improved survival // Blood. - 2011. - Vol. 117, No. 25. - R. 6786-92.