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

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

Why does the disease develop?

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

Depending on the etiological factor and clinical manifestations, they are different. Megaloblastic anemia (also known as 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 increase in the size of red blood cells.

Causes of B12 deficiency anemia:

Symptoms and how to detect the disease

Anemia results in decreased oxygen supply to cells. This leads to rapid fatigue, weakness, dizziness and fainting, ringing in the ears, pallor of the skin and mucous membranes, shortness of breath, palpitations, decreased appetite and body weight.

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

. Manifested by weakness, dizziness, fainting, tinnitus, flickering “spots” in the eyes, shortness of breath, tachycardia, tingling in the chest.
Gastroenterological syndrome. Characterized by decreased appetite and weight, nausea, vomiting, constipation, burning sensation and discoloration (raspberry) of the tongue (glossitis).
Neurological syndrome. Includes symptoms of peripheral nervous system damage, such as numbness and tingling of the extremities, unsteadiness of gait, muscle weakness. With prolonged and severe deficiency of vitamin B12, damage to the spinal cord and brain may develop, which manifests itself in the loss of vibration sensitivity in the legs and convulsions.

Kinds

According to the international classification of diseases (ICD-10) there are the following types:

D51.0 - deficiency of intrinsic factor Castle, which leads to Addison-Biermer anemia ( pernicious anemia);
D51.1 - malabsorption in combination with protein excretion 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 - food-associated anemia;
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 laboratory blood tests.

The main criterion for classifying anemia by severity is the hemoglobin content 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. A hemoglobin content of 110 to 120 g/l is intermediate between normal and anemia.

Symptoms of B12 deficiency anemia may not yet appear, while abnormalities are already visible in the blood. 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, so 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 occur 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 red blood cells are detected in the blood smear;
anisopoikilocytosis - red blood cells of a changed (droplet-shaped) shape are detected;
basophilic granularity of erythrocytes;
red blood cells containing Jolly bodies, Cabot bodies;
platelet anisocytosis;
hypersegmentation of neutrophil nuclei;
single erythrokaryocytes, megaloblasts;
decrease in the number of reticulocytes;
Most patients experience leukopenia and thrombopenia - a decrease in the number of leukocytes and platelets.

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

hyperplasia of the red sprout 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 granulocyte series: giant metamyelocytes and band cells.

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

Additional tests that may help make the diagnosis of deficiency anemia:

determining 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 monitor 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 similarities in clinical and laboratory manifestations that previously pernicious anemia (Addison-Birmer disease) was called B12-folate deficiency.

The diagnosis of folate deficiency anemia can be immediately confirmed or refuted by determining the level of folate in the blood serum. Its decrease serves as the basis for establishing this diagnosis. But such research is not available at many institutions. Therefore, they often resort to the tactics of phased administration 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

Treatment of megaloblastic anemia of unspecified origin begins with the administration of vitamin B12. A solution of cyanocobalamin is injected into daily dose 500 mcg 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.

If the result is positive, after 2 weeks they switch to a dosage regimen of cyanocobalamin 500 mcg once a week. Therapy is continued until normalization of red blood parameters: hemoglobin, percentage of reticulocytes, 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 Castle factor synthesis), treatment of pernicious anemia only allows achieving stable hematological remission. To maintain remission and prevent relapses of the disease, patients are advised to administer cyanocobalamin once a month at a dose of 500 mcg for life. Such patients are subject to clinical observation by a hematologist.

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

At in serious condition patient - symptoms of hypoxia, cardiovascular failure, precarious coma - emergency transfusion of red blood cells is indicated.

Folk remedies

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

For this, low-fat raw veal liver is best suited, which must be minced twice and taken 200 g before each meal.

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

for 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;
Take 1 glass of rosehip decoction 3 times a day after meals as a hot drink.

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

Possible consequences and prognosis

The term “pernicious anemia” (“pernicious anemia”), as mentioned earlier, has only historical significance. The prognosis of the disease is favorable. Despite the fact that megaloblastic anemia most often occurs chronically and requires a lifelong maintenance therapeutic course, 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 immediate initiation of intensive care, delay of which may lead to fatal outcome.

Addison's disease has another name - bronze disease. This means 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-Biermer disease has a large number of symptoms, which mainly arise from the involvement of most of the crust. 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 sometimes the disease can be accompanied by tuberculosis, which affects the adrenal glands. Pathology can be congenital and inherited. Autoimmune type The disease is most common in the female half of the population.

The most common symptoms of Addison's disease are pain, disturbances in the functioning of the gastrointestinal tract and hypotension. Pathology can lead to metabolic disorders. This disease can also be treated with the help of traditional medicine, which will strengthen the functioning of the adrenal glands and also help in the fight against microbes and inflammation.

General characteristics of the disease

Addison's disease, photos of which clearly show the affected area, can be either primary or secondary. secondary failure. As many people know, the 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 norepinephrine and adrenaline are produced. They are especially necessary for people in stressful situation, these hormones will help use all the body's reserves.

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, in addition, it affects the efficiency and duration of muscle use.
Cortisol is responsible for the regulation of carbon metabolism, as well as the production of energy resources.

The pituitary gland has a great influence on the adrenal cortex; it is a gland that is located in the area of the brain. The pituitary gland produces a special hormone that stimulates the adrenal glands.

As mentioned above, Addison-Biermer disease has two types. Primary is the disease itself, when the functioning of the adrenal glands is completely disrupted due to negative factors. Secondary involves a decrease in the amount of ACTH synthesized, which, in turn, impairs the functioning of the endocrine glands. In a situation where the pituitary gland produces an insufficient amount hormones for a long period - degenerative processes may begin to develop in the adrenal cortex.

Causes of the disease

The primary form of Addison-Birmer disease is quite rare. It can be found with equal probability in both men and women. In most cases, the diagnosis is made to people aged between 30 and 50.

There is also a chronic form of the disease. Such development of pathology is possible due to 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 damage to the adrenal cortex by an infectious disease, for example, tuberculosis.

For the remaining 10% of patients, the causes may vary:

this may be affected by long-term use of medications, 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.

Addison's disease can also cause other syndromes, such as adrenal crisis, which occurs when the concentration of adrenal hormones is too low.

There are the most likely causes of the crisis:

severe stress condition;
violations in dosage when preparing a course of treatment with hormonal drugs;
infection of the adrenal cortex can aggravate the disease;
adrenal gland injury;
circulatory problems, such as blood clots.

Symptoms of the disease

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

The most common clinical manifestations of the pathology are as follows:

Addison's pathology has its name bronze disease for a reason. The most obvious sign of this disease is pigmentation disorder. The skin changes its color. The shade of the mucous membranes changes. It's all about too much pigmentation. With a lack of adrenal hormones, significantly more ACTH is produced, this is explained by the need to stimulate the functioning of the endocrine glands.
One of the common clinical manifestations of the disease is chronic hypotension. This may lead to dizziness and fainting, sensitivity to low temperatures increases.
If the endocrine glands are not functioning sufficiently, the entire body as a whole weakens. If you have constant fatigue, fatigue, you should consult a medical specialist.
With this pathology, disturbances in the functioning of the gastrointestinal tract often occur; 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 noted increased sensitivity to irritants. The sense of smell and hearing are enhanced, and a person feels the taste of food better. In most cases, patients prefer to eat salty foods.
Painful sensations in muscle tissue can also be a symptom of Addison's pathology. This is explained by an increase in potassium concentration in blood vessels.
As mentioned above, one of the clinical manifestations of the disease is 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 insufficient activity of adrenal hormones. When contacting 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 administering ACTH and measuring the cortisol content in the blood vessels before administration of the drug and 30 minutes after vaccination. If a potential patient does not have problems with adrenal function, cortisol levels 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 hormone content in urea is measured.

Treatment of pathology

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

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 eating dinner to 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 will also have a positive effect on the condition of the entire body as a whole. Using this approach, it is possible to normalize the functioning of the gastrointestinal tract and counteract inflammatory processes chronic. It is recommended to use several recipes in turn, this will avoid the body becoming addicted.

Prevention and prognosis

If therapy was started in a timely manner and all 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 - adrenal crisis. In such a situation, you should immediately seek advice from a medical specialist. A crisis can be fatal. Addison's disease is accompanied by fatigue, weight loss and loss of appetite.

Changes in the shade of the skin do not occur in all cases; deterioration in the functioning 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 sharply and unexpectedly for the patient. Most often, the reason 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 watch your immune system, avoid consumption alcoholic drinks, smoking. Medical experts recommend paying attention to the manifestations of infectious diseases, especially tuberculosis, in a timely manner.

Hemoglobinuria is a term that combines several types of symptomatic conditions in the 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, and the lower one remains cloudy, increases the concentration of impurities, and a sediment of detritus falls 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 blockage 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 is healthy person it does not circulate in the blood, much less in the urine. A normal indicator is the detection of traces of Hb only in 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 during blood transfusion;
exposure to hemolytic poisons;
anemia;
pregnancy;
extensive burns;
infectious diseases;
paroxysmal hemoglobinuria;
massive hemorrhages;
hypothermia;
injuries.

The above diseases, conditions and factors, causing the appearance hemoglobin in plasma may lead to its appearance in urine. But, the state of hemoglobinuria occurs only after it reaches a certain concentration. Before reaching this threshold (125-135 mg%), Hb cannot cross the renal barrier and enter 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 red blood cells in it that appear 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 urine color, skin acquire a pale, bluish or jaundiced tint. Arthralgia occurs - aches and “flying” joint pains that are not accompanied by swelling, redness or limitation of function.

A febrile, semi-delirious state, accompanied by a sudden increase in body temperature, can be aggravated by attacks 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, tests are first performed to determine which particles colored the urine red - food coloring, red blood cells 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 tests and functional diagnostic methods:

clinical general tests (hemogram) of urine and blood;
biochemical urine analysis;
ammonium sulfate test;
analysis for the content of hemosederin and detritus in sediment;
“paper test” – electrophoresis and immunoelectrophoresis of urine;
bacteriuria – bacterioscopic analysis of urine sediment;
coagulogram (hemostasiogram) – study of coagulation;
Coombas test;
myelogram (bone marrow puncture from the sternum or ilium);
Ultrasound of the genitourinary system;
X-ray of the kidneys.

Differentiation of types of hemoglobinuria is based on the difference in causally significant factors.

Marchiafava-Miceli disease

With paroxysmal nocturnal hemoglobinuria there is difficulty and pain in swallowing

Marchiafava-Miceli disease or in other words, 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), first diagnosed 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 red blood cells, platelets and leukocytes.

Paroxysmal nocturnal hemoglobinuria is distinguished by special, unique characteristic signs, which include increased blood clotting, also in the case of its classic 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;
A-hemoglobin level – less than 60 g/l;
leukopenia and thrombocytopenia;
increase in the number of immature forms of red blood cells;
negative antiglobulin test result;
Possible abdominal pain.

Paroxysmal nocturnal hemoglobinuria can often lead to disturbances in perception and brain function. If symptoms are ignored and there is no adequate treatment, thrombosis occurs, which in 40% of cases causes death.

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

When treating the disease, the following methods are usually used:

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

IN extreme cases related bone marrow transplantation 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, and five species of fish are also affected. Characterized by damage to 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 by river fish, especially its fat and entrails.

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

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

Paroxysmal hemoglobinuria - Harley's disease

Under this name lies a whole group that unites almost identical, pronounced symptoms, and which is further divided into subtypes depending on the reasons that caused them.

Paroxysmal cold hemoglobinuria – Donath-Laidsteiner syndrome

This variety causes prolonged cooling or sudden hypothermia of the body caused by being in cold water(less often in frosty air). It differs in Donothan-Laidsteiner syndrome - the appearance in the plasma of biphasic 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 immunity disorders, which begins with betaglobulin (component C3), and in an increasing cascade, affects other significant immunoglobulins.

The cold variety, caused by hypothermia, occurs in attacks. 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 temperature jump –> 39°C;
dark red urine is excreted throughout the day;
always – severe pain in the kidney area;
spasm of small vessels;
possible - vomiting, yellowing of the skin, sharp enlargement of the liver and spleen;

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

It should be noted that some patients experience attacks with “sluggish” manifestations of all symptoms, dragging dull pain in the extremities and small traces of free hemoglobin in the urine.

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

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

Treatment consists of strictly avoiding 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 warm hemolysins.

Infectious paroxysmal cold hemoglobinuria may be caused by infectious diseases such as influenza

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

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

This also includes the separately isolated syphilitic hemoglobinuria (haemoglobinuria syphilitica). Each type of infection has its own specifics, for example, the presence of hemoglobin in the urine caused by cooling with tertiary syphilis, unlike 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 popularity.

Treatment is carried out according to the underlying disease. The diagnosis is clarified to exclude other pathologies.

It should be noted that with Harley’s disease, the history of all patients almost always contains indications of lues and a positive RW reaction, and for cold hemoglobinuria, cases of hereditary transmission of the symptom in luetics have been described.

March hemoglobinuria

A paradox that is not fully understood. It is believed that they are based on increased loads on the feet, which, in the presence of spinal lordosis, cause impaired renal circulation. March hemoglobinuria may occur for the following reasons:

after running marathons;
walking or other long and intense physical activity (with emphasis on the legs);
horseback 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 red blood cells in the urine are detected.

March hemoglobinuria does not cause complications and goes away on its own. 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 red blood cells in the blood is determining. unusual shape. When clarifying the diagnosis, it is important to find out why, what are the reasons, and where the destruction of red blood cells occurred:

crash syndrome - prolonged compression;
march hemoglobinuria;
aortic heart valve stenosis;
artificial heart valve defects;
malignant arterial hypertension;
mechanical damage to blood vessels.

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

If you notice the main symptom of hemoglobinuria - red urine, you should consult a therapist or hematologist.

Paroxysmal nocturnal hemoglobinuria (Marchiafava-Miceli disease, Strübing-Marchiafava disease) is an acquired hemolytic anemia associated with intravascular destruction of defective red blood cells.

Paroxysmal nocturnal hemoglobinuria is a rare acquired disease caused by a violation of the erythrocyte membrane and characterized by chronic hemolytic anemia, intermittent or constant hemoglobinuria and hemosiderinuria, phenomena of 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. This disease is usually first diagnosed in people age group 20-40 years, but can also occur in older people.

What provokes Paroxysmal nocturnal hemoglobinuria (Marchiafava-Miceli disease): Paroxysmal nocturnal hemoglobinuria is an acquired disease, apparently caused by 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 necessary for fixation on cell membrane a number of proteins, including CD55 (a factor that accelerates complement inactivation) and protectin.

To date, patients with paroxysmal nocturnal hemoglobinuria have been found to lack about 20 proteins on their blood cells. Along with the pathological clone, patients also have normal stem cells and blood cells. The proportion of pathological cells differs in different patients and even in the same patient at different times.

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

In paroxysmal nocturnal hemoglobinuria, leukocytes and platelets, like erythrocytes, are also characterized by structural defects in their membranes. The absence of immunoglobulins on the surface of these cells suggests that paroxysmal nocturnal hemoglobinuria does not belong to autoaggressive diseases. Accumulated data indicate the presence of two independent populations of erythrocytes - pathological (not surviving to maturity) and healthy. The uniformity of damage to the membranes of erythrocytes, leukocytes and platelets is an argument in favor of the fact that 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 red blood cells and stimulation of the coagulation process by factors released during their decay.

Pathogenesis (what happens?) during Paroxysmal nocturnal hemoglobinuria (Marchiafava-Micheli disease): Due to the absence of two proteins - decay accelerating factor (CD55) and protectin (CD59, membrane attack complex inhibitor), the sensitivity of erythrocytes to the lytic action of complement is increased. The decay accelerating factor destroys 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 (Marchiafava-Micheli disease): There is an idiopathic form of paroxysmal nocturnal hemoglobinuria and paroxysmal nocturnal hemoglobinuria in the form of a syndrome accompanying a number of diseases. A unique variant of idiomatic paroxysmal nocturnal hemoglobinuria, the development of which is preceded by a phase of hematopoietic hypoplasia, is also rare.

Symptoms of paroxysmal nocturnal hemoglobinuria are very variable - from mild benign to severe aggressive. In the classic form, hemolysis occurs while the patient is sleeping (nocturnal hemoglobinuria), which may be due to slight decrease at night blood pH. However, hemoglobinuria is observed only in approximately 25% of patients, and in many not at night. In most cases, the disease manifests itself with symptoms of anemia. Hemolytic outbreaks may occur after severe infection physical activity, surgery, menstruation, blood transfusions and the administration of iron supplements for therapeutic purposes. Hemolysis is often accompanied by bone and muscle pain, malaise and fever. Characteristic signs include pallor, jaundice, 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 diseases and acute myeloid leukemia. The detection of splenomegaly in a patient with aplastic anemia should serve as a basis for examination to identify 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, but with prolonged hemosiderinuria, iron deficiency occurs, manifested by signs of anisocytosis and the presence of microcytic hypochromic erythrocytes. The reticulocyte count is elevated unless there is bone marrow failure. The bone marrow at the onset of the disease is usually hyperplastic, but later hypoplasia and even aplasia may develop.

Level alkaline phosphatase in neutrophils it is reduced, sometimes to the point of 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, as a rule, is negative.

Venous thrombosis occurs in approximately 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 dural sinuses is less common.

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

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

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

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

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

In some cases it is necessary to carry out differential diagnosis between paroxysmal nocturnal hemoglobinuria and autoimmune hemolytic anemia with warm 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 red blood cells helps, revealing the presence of hemolysins. In the sucrose test, complement activation is ensured 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 cytofluorimetry, which allows one to determine the absence of protectin and factor accelerating 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. In case of severe anemia, transfusions of red blood cells washed with isotonic sodium chloride solution are indicated; for the prevention and treatment of thrombosis - anticoagulant therapy. For iron deficiency, iron supplements are prescribed. 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 treatment for patients with paroxysmal nocturnal hemoglobinuria is transfusion of washed (at least 5 times) or thawed red blood cells, 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 and the development of hemoglobinuria crises due to the presence of leukocytes in these transfusion media, which leads to the formation of anti-leukocyte antibodies and complement activation.

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

When treating paroxysmal nocturnal hemoglobinuria, Nerobol is used in 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 drugs of this group is accompanied by changes in liver function tests, which are usually reversible.

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

In patients with paroxysmal nocturnal hemoglobinuria, due to constant loss of iron, iron deficiency often develops in the body. Since increased hemolysis is often observed when taking iron supplements, they should be used orally 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 corticosteroids in high doses; The use of androgens may be helpful.

Bone marrow hypoplasia and thrombosis, especially in young patients, are indications for transplantation of HLA-matched 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. Loss of the GPI-AP protein, due to somatic mutation on the cell surface, is a leading link in 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 modern treatment options.

Modern methods of diagnosis and treatment of paroxysmal nocturnal hemoglobinuria

Paroxysmal nocturnal hemoglobinuria (APG) is a rare (orphan) disease 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. The mortality rate for PNH is about 35% within 5 years of the onset of the disease. Unfortunately, most cases remain undiagnosed. Clinical manifestations are varied and patients can be observed with diagnoses such as aplastic anemia, thrombosis unknown 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, if lost, some important proteins cannot attach to the membrane. Many proteins lose their ability to join, which is used to diagnose PNH by immunophenotyping (erythrocytes CD59 -, granulocytes CD16 -, CD24 -, monocytes CD14 -). Cells with signs of the absence of the studied proteins are called PNH clone. All these proteins must interact with proteins of the complement system, in particular with C3b and C4b, destroying the enzymatic complexes of the classical and alternative complement pathways, and thereby stopping the complement chain reaction. The absence of the above proteins leads to cell destruction when the complement system is activated.

There are three main clinical syndromes in PNH: hemolytic, thrombotic, cytopenic. Each patient may have one, two, or all three syndromes. The “classical” 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 the CD59 protein (membrane inhibitor of reactive lysis (MIRL)) on the surface of red blood cells. Hemolysis in PNH is intravascular, so dark urine may appear (hemosiderinuria) and severe weakness. A decrease in haptoglobin is detected 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 bilirubin fraction. The Hem test (hemolysis of red blood cells by adding a few drops of acid to a blood sample) and the sucrose test (the addition of sucrose activates the complement system) are used to diagnose PNH.

It is currently believed that hemolysis occurs 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 impaired regulation of smooth muscle tone, platelet activation and aggregation (abdominal pain, dysphagia, impotence, thrombosis, pulmonary hypertension). Free hemoglobin that is not bound to haptoglobin damages the kidneys (acute tubulonecrosis, pigmentary nephropathy) and after a few years can lead to kidney failure. 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, reabsorption of hemoglobin in the kidneys.

Thrombosis is diagnosed in 40% of patients and is the main cause of death; thrombosis of the liver's own veins (Budd-Chiari syndrome) and pulmonary embolism are more common. Thrombosis in PNH has its own characteristics: it often coincides with episodes of hemolysis and occurs despite anticoagulant therapy and a small PNH clone. The pathophysiological basis for thrombosis discusses platelet activation due to CD59 deficiency, endothelial activation, impaired fibrinolysis, microparticle formation, and the release of phospholipids into the blood as a result of activation of the complement system. 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. In the bone marrow, normal stem cells (GPI+) and cells with a mutation (GPI-) coexist. 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 immunophenotyping of peripheral blood cells for the presence of the PNH clone. The study conclusion indicates the size of the PNH clone in erythrocytes (CD 59 -), granulocytes (CD16 -, CD24 -) and monocytes (CD14 -). Another diagnostic method is FLAER (fluorescently labeled inactive toxin aerolysin), a bacterial toxin aerolysin labeled with fluorescent tags 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 prevention, immunosuppression, stimulation of erythropoiesis, stem cell transplantation, and treatment with biological agents. Maintenance therapy includes red blood cell transfusions, administration of folic acid, vitamin B12, and iron supplements. Most patients with the “classic” form of PNH are dependent on blood transfusions. Hemochromatosis, with damage to the heart and liver, is rarely observed in patients with PNH, since hemoglobin is filtered into the urine. Cases of hemosiderosis of the kidneys have been described.

Prevention of thrombosis is carried out with warfarin and low molecular weight heparin, 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 use of this method. The mortality rate of patients with PNH after allogeneic transplantation is 40%.

Since 2002, the drug eculizumab, which is a biological agent, has been used worldwide. The drug is an antibody that blocks the C5 component of the complement system. Experience with use has shown increased survival, decreased hemolysis and thrombosis, and improved quality of life. .

Clinical case of the “classic” variant of PNH.

Patient D., 29 years old. Complaints of weakness, yellow 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 Hematology Research Center (HRC), Moscow. Based on the presence of a positive Hem test and sucrose test, detection in the blood of 37% (norm - 0) of a clone of erythrocytes with the immunophenotype CD55-/CD59-, hemosiderinuria, anemia, reticulocytosis in the blood up to 80% (norm - 0.7-1%), hyperbilirubinemia Due to indirect bilirubin, a diagnosis was made: PNH, secondary folate and iron deficiency anemia.

Hemolysis intensified during pregnancy in 2008. In June 2008, at 37 weeks, a C-section due to partial placental abruption and the threat of fetal hypoxia. The postoperative period was complicated by acute renal failure, severe hypoproteinemia. Against the background of intensive therapy, acute renal failure resolved on the fourth day, blood counts returned to normal, and the edema syndrome was relieved. A week later, the temperature rises to 38-39 ° C, weakness, chills. A diagnosis of metroendometritis was made. The therapy was ineffective, extirpation of the uterus and tubes was performed. The postoperative period was complicated by liver failure with syndromes of cholestasis, cytolysis, mesenchymal inflammation, severe hypoproteinemia, and thrombocytopenia. According to ultrasound data, thrombosis of the liver’s own veins was diagnosed and portal vein. Antibacterial and anticoagulant therapy, administration of hepatoprotectors, prednisolone, replacement therapy FFP, EMOLT, thromboconcentrate.

She was readmitted to the State Scientific Center due to thrombosis of the portal and native veins of the liver, thrombosis of small branches pulmonary artery, development infectious complications, with rapidly growing ascites. Intensive anticoagulant therapy and antibiotic therapy led to partial recanalization of the portal vein and the liver's own veins, and a decrease in ascites was noted. Subsequently, the patient was administered low molecular weight heparin – Clexane – for a long time.

Currently, according to laboratory indicators, the patient continues to have 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 level to 5608 U/ l (normal -125-243 U/l), hyperbilirubinemia up to 300 µmol/l (normal - 4-20 µmol/l). Immunophenotyping of peripheral blood - the total value of the erythrocyte PNH clone is 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 red blood cells (2-3 transfusions every 2 months), folic acid, iron supplements, and vitamin B12. Given the very high thrombogenic risk, warfarin therapy is carried out (INR – 2.5). The patient was entered into the national register of PNG for planning treatment with eculizumab.

Clinical case of a 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, increased body temperature to 38 degrees.

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

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

The patient received red blood cell transfusions three times. The possibility of allogeneic stem cell transplantation or biological therapy is currently 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

Anna Valentinovna Kosterina – assistant at the Department of Hospital Therapy of 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.