home Endocrinology Hemolytic anemia: what is it? Acquired hemolytic anemia

Hemolytic anemia: what is it? Acquired hemolytic anemia

Hemolytic anemia in children it is about 5.3% among other blood diseases, and 11.5% among anemic conditions. In the structure of hemolytic anemia, hereditary forms of diseases predominate.

Hemolytic anemia is a group of diseases, the most characteristic of which is increased destruction of red blood cells due to a reduction in their life expectancy. It is known that the normal lifespan of red blood cells is 100-120 days; About 1% of red blood cells are removed from the peripheral blood each day and replaced by an equal number of new cells coming from the bone marrow. This process creates, under normal conditions, a dynamic equilibrium that ensures a constant number of red blood cells in the blood. As the lifespan of red blood cells decreases, their destruction in the peripheral blood occurs more intensively than their formation in the bone marrow and release into the peripheral blood. In response to a reduction in the lifespan of erythrocytes, bone marrow activity increases 6-8 times, as evidenced by reticulocytosis in the peripheral blood. Continued reticulocytosis in combination with varying degrees of anemia or even stable hemoglobin levels may indicate the presence of hemolysis.

In addition to the above symptoms, common to all hemolytic anemias, there are symptoms that are pathognomonic for a specific form of the disease. Each hereditary form of hemolytic anemia has its own differential diagnostic features. A differential diagnosis between various forms of hemolytic anemia should be carried out in children over the age of one year, since at this time the anatomical and physiological features characteristic of the blood of young children disappear: physiological macrocytosis, fluctuations in the number of reticulocytes, the predominance of fetal hemoglobin, a relatively low limit of minimum osmotic resistance red blood cells

Hereditary hemolytic anemias

Hereditary hemolytic anemia associated with disruption of the erythrocyte membrane (membranopathy)

Membranopathies are characterized by a hereditary defect in the structure of the membrane protein or a disorder of the lipids of the erythrocyte membrane. Inherited autosomal dominant or autosomal recessive.

Hemolysis is localized, as a rule, intracellularly, that is, the destruction of red blood cells occurs mainly in the spleen, and to a lesser extent in the liver.

Classification of hemolytic anemia associated with disruption of the erythrocyte membrane:

Disturbance of the protein structure of the erythrocyte membrane
1. hereditary elliptocytosis;
2. hereditary stomatocytosis;
3. hereditary pyropoikilocytosis.
Red blood cell membrane lipid disorder
1. hereditary acanthocytosis;
2. hereditary hemolytic anemia caused by deficiency of lecithin-cholesterol acyl-transferase activity;
3. hereditary non-spherocytic hemolytic anemia caused by an increase in phosphatidylcholine (lecithin) in the erythrocyte membrane;
4. childhood infantile pycnocytosis.

Disturbance of the protein structure of the erythrocyte membrane

Rare forms of hereditary anemia caused by a violation of the structure of erythrocyte membrane proteins

Hemolysis in these forms of anemia occurs intracellularly. Hemolytic anemia has varying degrees severity - from mild to severe, requiring blood transfusions. There is pallor of the skin and mucous membranes, jaundice, splenomegaly, possible development cholelithiasis.

Diagnosis of hemolytic anemia

Hemolysis is suspected in patients with anemia and reticulocytosis, especially in the presence of splenomegaly, as well as other possible causes of hemolysis. If hemolysis is suspected, a peripheral blood smear is examined and serum bilirubin, LDH, and ALT are determined. If these studies do not yield results, hemosiderin, urine hemoglobin, and serum haptoglobin are determined.

With hemolysis, one can assume the presence of morphological changes in red blood cells. The most typical for active hemolysis is spherocytosis of erythrocytes. Red blood cell fragments (schistocytes) or erythrophagocytosis on blood smears suggest intravascular hemolysis. With spherocytosis, there is an increase in the MSHC index. The presence of hemolysis can be suspected when serum LDH and indirect bilirubin levels are elevated with normal ALT and the presence of urinary urobilinogen. Intravascular hemolysis is suspected when a low level of serum haptoglobin is detected, but this indicator can be reduced in liver dysfunction and increased in the presence of systemic inflammation. Intravascular hemolysis is also suspected when hemosiderin or hemoglobin is detected in the urine. The presence of hemoglobin in the urine, as well as hematuria and myoglobinuria, is determined by a positive benzidine test. Differential diagnosis of hemolysis and hematuria is possible based on the absence of red blood cells on urine microscopy. Free hemoglobin, unlike myoglobin, can stain the plasma brown, which appears after centrifugation of the blood.

Morphological changes in erythrocytes in hemolytic anemia

Morphology
Spherocytes	Transfused red blood cells, hemolytic anemia with warm antibodies, hereditary spherocytosis
Schistocytes	Microangiopathy, intravascular prosthetics
Target-shaped	Hemoglobinopathies (Hb S, C, thalassemia), liver pathology
Crescent	Sickle cell anemia
Agglutinated cells	Cold agglutinin disease
Heinz corpuscles	Activation of peroxidation, unstable Hb (eg, G6PD deficiency)
	Beta thalassemia major
Acanthocytes	Spurred red blood cell anemia

Although the presence of hemolysis can be determined using these simple tests, the decisive criterion is to determine the lifespan of red blood cells by testing with a radioactive label such as 51 Cr. Determining the lifespan of labeled red blood cells can reveal the presence of hemolysis and the location of their destruction. However, this study is rarely used.

When hemolysis is detected, it is necessary to establish the disease that provoked it. One way to limit the differential search for hemolytic anemia is to analyze the patient’s risk factors (for example, geographical position countries, heredity, existing diseases), detection of splenomegaly, determination of the direct antiglobulin test (Coombs) and examination of the blood smear. Most hemolytic anemias have abnormalities in one of these variants, which may guide further search. Other laboratory tests that can help determine the cause of hemolysis are quantitative hemoglobin electrophoresis, red blood cell enzyme testing, flowcytometry, cold agglutinins, red blood cell osmotic resistance, acid hemolysis, and glucose testing.

Haemophilus influenzae If possible, splenectomy is delayed by 2 weeks.

The erythrocyte membrane consists of a double lipid layer, permeated with various proteins that act as pumps for various microelements. TO inner surface cytoskeletal elements are attached to membranes. Located on the outer surface of the red blood cell a large number of glycoproteins that act as receptors and antigens - molecules that determine the uniqueness of the cell. To date, more than 250 types of antigens have been discovered on the surface of erythrocytes, the most studied of which are antigens of the ABO system and the Rh factor system.

According to the AB0 system, there are 4 blood groups, and according to the Rh factor - 2 groups. The discovery of these blood groups marked the beginning of a new era in medicine, as it allowed the transfusion of blood and its components to patients with malignant blood diseases, massive blood loss, etc. Also, thanks to blood transfusion, the survival rate of patients after massive surgical interventions has significantly increased.

According to the ABO system, the following blood groups are distinguished:

agglutinogens ( antigens on the surface of red blood cells that, when in contact with the same agglutinins, cause precipitation of red blood cells) are absent on the surface of red blood cells;
agglutinogens A are present;
agglutinogens B are present;
agglutinogens A and B are present.

Based on the presence of the Rh factor, the following blood groups are distinguished:

Rh positive – 85% of the population;
Rh negative – 15% of the population.

Despite the fact that, theoretically, pouring completely compatible blood from one patient to another anaphylactic reactions It shouldn't happen; they happen from time to time. The reason for this complication is incompatibility with other types of erythrocyte antigens, which, unfortunately, have been practically unstudied to date. In addition, the cause of anaphylaxis may be some components of plasma - the liquid part of the blood. Therefore, according to the latest recommendations of international medical guides, whole blood transfusions are not recommended. Instead, blood components are transfused - red blood cells, platelets, albumins, fresh frozen plasma, coagulation factor concentrates, etc.

The previously mentioned glycoproteins, located on the surface of the red blood cell membrane, form a layer called the glycocalyx. An important feature of this layer is the negative charge on its surface. The surface of the inner layer of blood vessels also has a negative charge. Accordingly, in the bloodstream, red blood cells are repelled from the walls of the vessel and from each other, which prevents the formation of blood clots. However, as soon as a red blood cell is damaged or the vessel wall is injured, their negative charge gradually changes to positive, healthy red blood cells group around the site of damage, and a blood clot forms.

The concept of deformability and cytoplasmic viscosity of an erythrocyte is closely related to the functions of the cytoskeleton and the concentration of hemoglobin in the cell. Deformability is the ability of a red blood cell cell to arbitrarily change its shape to overcome obstacles. Cytoplasmic viscosity is inversely proportional to deformability and increases with increasing hemoglobin content relative to the liquid part of the cell. An increase in viscosity occurs during erythrocyte aging and is a physiological process. In parallel with the increase in viscosity, the deformability decreases.

However, changes in these indicators can occur not only during the physiological process of erythrocyte aging, but also in many congenital and acquired pathologies, such as hereditary membranopathies, enzymopathies and hemoglobinopathies, which will be described in more detail below.

Red blood cell, like any other living cell, needs energy to function successfully. The red blood cell receives energy through redox processes occurring in the mitochondria. Mitochondria have been compared to the powerhouses of the cell because they convert glucose into ATP through a process called glycolysis. A distinctive ability of the erythrocyte is that its mitochondria produce ATP only through anaerobic glycolysis. In other words, these cells do not need oxygen to ensure their vital functions and therefore deliver to the tissues exactly as much oxygen as they received when passing through the pulmonary alveoli.

Despite the fact that red blood cells are considered to be the main carriers of oxygen and carbon dioxide, in addition to this, they perform a number of important functions.

The secondary functions of red blood cells are:

regulation of the acid-base balance of the blood through the carbonate buffer system;
hemostasis is a process aimed at stopping bleeding;
determination of the rheological properties of blood - a change in the number of red blood cells in relation to the total amount of plasma leads to thickening or thinning of the blood.
participation in immune processes - on the surface of the erythrocyte there are receptors for the attachment of antibodies;
digestive function - when breaking down, red blood cells release heme, which independently transforms into free bilirubin. In the liver, free bilirubin is converted into bile, which is used to break down dietary fats.

Life cycle of a red blood cell

Red blood cells are formed in the red bone marrow, going through numerous stages of growth and maturation. All intermediate forms of erythrocyte precursors are combined into a single term - erythrocyte germ.

As erythrocyte precursors mature, they undergo a change in the acidity of the cytoplasm ( liquid part of the cell), self-digestion of the nucleus and accumulation of hemoglobin. The immediate predecessor of an erythrocyte is a reticulocyte - a cell in which, when examined under a microscope, one can find some dense inclusions that were once the nucleus. Reticulocytes circulate in the blood for 36 to 44 hours, during which they get rid of the remnants of the nucleus and complete the synthesis of hemoglobin from the residual chains of messenger RNA ( ribonucleic acid).

Regulation of the maturation of new red blood cells is carried out through a direct mechanism feedback. The substance that stimulates the growth of the number of red blood cells is erythropoietin, a hormone produced by the kidney parenchyma. During oxygen starvation, the production of erythropoietin increases, which leads to accelerated maturation of red blood cells and, ultimately, restoration of the optimal level of tissue oxygen saturation. Secondary regulation of the activity of the erythrocyte germ is carried out through interleukin-3, stem cell factor, vitamin B 12, hormones ( thyroxine, somatostatin, androgens, estrogens, corticosteroids) and microelements ( selenium, iron, zinc, copper, etc.).

After 3–4 months of the erythrocyte’s existence, its gradual involution occurs, manifested by the release of intracellular fluid from it due to the wear and tear of most transport enzyme systems. Following this, the erythrocyte becomes compacted, accompanied by a decrease in its plastic properties. A decrease in plastic properties impairs the permeability of red blood cells through capillaries. Ultimately, such a red blood cell enters the spleen, gets stuck in its capillaries and is destroyed by white blood cells and macrophages located around them.

After the destruction of the red blood cell, free hemoglobin is released into the bloodstream. When the rate of hemolysis is less than 10% of the total number of red blood cells per day, hemoglobin is captured by a protein called haptoglobin and deposited in the spleen and the inner layer of blood vessels, where it is destroyed by macrophages. Macrophages destroy the protein part of hemoglobin, but release heme. Heme, under the influence of a number of blood enzymes, is transformed into free bilirubin, after which it is transported to the liver by the protein albumin. The presence of a large amount of free bilirubin in the blood is accompanied by the appearance of lemon-colored jaundice. In the liver, free bilirubin binds to glucuronic acid and is released into the intestine as bile. If there is an obstruction to the outflow of bile, it flows back into the blood and circulates in the form of bound bilirubin. In this case, jaundice also appears, but of a darker shade ( mucous membranes and skin are orange or reddish in color).

After the release of bound bilirubin into the intestine in the form of bile, it is restored to stercobilinogen and urobilinogen with the help of intestinal flora. Most of the stercobilinogen is converted to stercobilin, which is excreted in the stool and turns it brown. The remaining portion of stercobilinogen and urobilinogen is absorbed in the intestine and enters back into the bloodstream. Urobilinogen is transformed into urobilin and excreted in the urine, and stercobilinogen reenters the liver and is excreted in bile. This cycle may seem meaningless at first glance, however, this is a misconception. When red blood cell breakdown products re-enter the bloodstream, the activity of the immune system is stimulated.

With an increase in the rate of hemolysis from 10% to 17–18% of the total number of red blood cells per day, haptoglobin reserves become insufficient to capture the released hemoglobin and utilize it in the manner described above. In this case, free hemoglobin enters the renal capillaries through the bloodstream, is filtered into primary urine and is oxidized to hemosiderin. Hemosiderin then enters secondary urine and is excreted from the body.

With extremely severe hemolysis, the rate of which exceeds 17 - 18% of the total number of red blood cells per day, hemoglobin enters the kidneys in too large quantities. Because of this, its oxidation does not have time to occur and pure hemoglobin enters the urine. Thus, the determination of excess urobilin in urine is a sign of mild hemolytic anemia. The appearance of hemosiderin indicates a transition to a medium degree of hemolysis. The detection of hemoglobin in the urine indicates a high intensity of destruction of red blood cells.

What is hemolytic anemia?

Hemolytic anemia is a disease in which the lifespan of red blood cells is significantly shortened due to a number of external and internal red blood cell factors. Internal factors leading to the destruction of red blood cells are various anomalies in the structure of red blood cell enzymes, heme or the cell membrane. External factors that can lead to the destruction of red blood cells are various types of immune conflicts, mechanical destruction of red blood cells, as well as infection of the body with certain infectious diseases.

Hemolytic anemias are classified into congenital and acquired.

Distinguish the following types congenital hemolytic anemias:

membranopathy;
fermentopathy;
hemoglobinopathies.

The following types of acquired hemolytic anemia are distinguished:

immune hemolytic anemia;
acquired membranopathies;
anemia due to mechanical destruction of red blood cells;
hemolytic anemia caused by infectious agents.

Congenital hemolytic anemias

Membranopathies

As described previously, the normal shape of the red blood cell is a biconcave disc shape. This shape corresponds to the correct protein composition of the membrane and allows the red blood cell to penetrate through capillaries, the diameter of which is several times smaller than the diameter of the red blood cell itself. The high penetrating ability of red blood cells, on the one hand, allows them to most effectively perform their main function - the exchange of gases between the internal environment of the body and the external environment, and on the other hand, to avoid their excessive destruction in the spleen.

A defect in certain membrane proteins leads to disruption of its shape. With a violation of the shape, there is a decrease in the deformability of red blood cells and, as a consequence, their increased destruction in the spleen.

Today, there are 3 types of congenital membranopathies:

microspherocytosis
ovalocytosis

Acanthocytosis is a condition in which red blood cells with numerous outgrowths, called acanthocytes, appear in the patient’s bloodstream. The membrane of such red blood cells is not round and under a microscope resembles an edging, hence the name of the pathology. The causes of acanthocytosis have not been fully studied to date, but there is a clear connection between this pathology and severe damage liver with high levels of blood fat content ( total cholesterol and its fractions, beta lipoproteins, triacylglycerides, etc.). The combination of these factors can occur in such hereditary diseases as Huntington's chorea and abetalipoproteinemia. Acanthocytes are unable to pass through the capillaries of the spleen and are therefore soon destroyed, leading to hemolytic anemia. Thus, the severity of acanthocytosis directly correlates with the intensity of hemolysis and clinical signs of anemia.

Microspherocytosis- a disease that in the past was known as familial hemolytic jaundice, since it involves a clear autosomal recessive inheritance of a defective gene responsible for the formation of a biconcave red blood cell. As a result, in such patients, all formed red blood cells are spherical in shape and have a smaller diameter compared to healthy red blood cells. The spherical shape has less surface area compared to the normal biconcave shape, so the efficiency of gas exchange of such red blood cells is reduced. Moreover, they contain less hemoglobin and are less easily modified when passing through capillaries. These features lead to a shortening of the lifespan of such red blood cells through premature hemolysis in the spleen.

Since childhood, such patients experience hypertrophy of the erythrocyte bone marrow sprout, compensating for hemolysis. Therefore, with microspherocytosis, mild to moderate anemia is more often observed, appearing mainly at moments when the body is weakened by viral diseases, malnutrition or intense physical labor.

Ovalocytosis is a hereditary disease transmitted in an autosomal dominant manner. More often, the disease occurs subclinically with the presence of less than 25% of oval red blood cells in the blood. Much less common are severe forms, in which the number of defective red blood cells approaches 100%. The cause of ovalocytosis lies in a defect in the gene responsible for the synthesis of the spectrin protein. Spectrin is involved in the construction of the erythrocyte cytoskeleton. Thus, due to insufficient plasticity of the cytoskeleton, the erythrocyte is not able to restore its biconcave shape after passing through the capillaries and circulates in the peripheral blood in the form of ellipsoidal cells. The more pronounced the ratio of the longitudinal and transverse diameter of the ovalocyte, the sooner its destruction occurs in the spleen. Removal of the spleen significantly reduces the rate of hemolysis and leads to remission of the disease in 87% of cases.

Enzymepathies

The red blood cell contains a number of enzymes, with the help of which the constancy of its internal environment is maintained, glucose is processed into ATP and the acid-base balance of the blood is regulated.

According to the above directions, 3 types of enzymopathies are distinguished:

deficiency of enzymes involved in the oxidation and reduction of glutathione ( see below);
deficiency of glycolysis enzymes;
deficiency of enzymes that use ATP.

Glutathione is a tripeptide complex involved in most redox processes in the body. In particular, it is necessary for the functioning of mitochondria - the energy stations of any cell, including red blood cells. Congenital defects of enzymes involved in the oxidation and reduction of glutathione in erythrocytes lead to a decrease in the rate of production of ATP molecules, the main energy substrate for most energy-dependent cellular systems. ATP deficiency leads to a slowdown in the metabolism of red blood cells and their rapid spontaneous destruction, called apoptosis.

Glycolysis is the process of breakdown of glucose with the formation of ATP molecules. Glycolysis requires the presence of a number of enzymes that repeatedly convert glucose into intermediate compounds and ultimately release ATP. As stated earlier, a red blood cell is a cell that does not use oxygen to produce ATP molecules. This type of glycolysis is anaerobic ( airless). As a result, from one glucose molecule in an erythrocyte, 2 ATP molecules are formed, which are used to maintain the functionality of most enzyme systems of the cell. Accordingly, a congenital defect in glycolytic enzymes deprives the red blood cell of the necessary amount of energy to maintain life, and it is destroyed.

ATP is a universal molecule, the oxidation of which releases the energy necessary for the functioning of more than 90% of the enzyme systems of all body cells. The red blood cell also contains many enzyme systems whose substrate is ATP. The released energy is spent on the process of gas exchange, maintaining constant ionic equilibrium inside and outside the cell, maintaining constant osmotic and oncotic pressure of the cell, as well as on active work cytoskeleton and much more. Violation of glucose utilization in at least one of the above-mentioned systems leads to loss of its function and a further chain reaction, the result of which is the destruction of the erythrocyte.

Hemoglobinopathies

Hemoglobin is a molecule that occupies 98% of the volume of a red blood cell, responsible for ensuring the processes of capture and release of gases, as well as for their transportation from the pulmonary alveoli to peripheral tissues and back. With some hemoglobin defects, red blood cells carry gases much worse. In addition, against the background of changes in the hemoglobin molecule, the shape of the red blood cell itself also changes, which also negatively affects the duration of their circulation in the bloodstream.

There are 2 types of hemoglobinopathies:

quantitative – thalassemia;
qualitative – sickle cell anemia or drepanocytosis.

Thalassemia are hereditary diseases associated with impaired hemoglobin synthesis. In its structure, hemoglobin is a complex molecule consisting of two alpha monomers and two beta monomers linked to each other. The alpha chain is synthesized from 4 sections of DNA. Beta chain – from 2 sections. Thus, when a mutation occurs in one of the 6 regions, the synthesis of the monomer whose gene is damaged decreases or stops. Healthy genes continue the synthesis of monomers, which over time leads to a quantitative predominance of some chains over others. Those monomers that are in excess form weak compounds, the function of which is significantly inferior to normal hemoglobin. According to the chain whose synthesis is impaired, there are 3 main types of thalassemia - alpha, beta and mixed alpha-beta thalassemia. The clinical picture depends on the number of mutated genes.

Sickle cell anemia is a hereditary disease in which abnormal hemoglobin S is formed instead of normal hemoglobin A. This abnormal hemoglobin is significantly inferior in functionality to hemoglobin A, and also changes the shape of the red blood cell to sickle-shaped. This form leads to the destruction of red blood cells in a period of 5 to 70 days in comparison with the normal duration of their existence - from 90 to 120 days. As a result, a proportion of sickle-shaped red blood cells appears in the blood, the value of which depends on whether the mutation is heterozygous or homozygous. With a heterozygous mutation, the proportion of abnormal red blood cells rarely reaches 50%, and the patient experiences symptoms of anemia only with significant physical exertion or in conditions of reduced oxygen concentration in the atmospheric air. With a homozygous mutation, all the patient's red blood cells are sickle-shaped and therefore the symptoms of anemia appear from the birth of the child, and the disease is characterized by a severe course.

Acquired hemolytic anemia

Immune hemolytic anemias

With this type of anemia, the destruction of red blood cells occurs under the influence of the body's immune system.

There are 4 types of immune hemolytic anemia:

autoimmune;
isoimmune;
heteroimmune;
transimmune.

For autoimmune anemia The patient’s own body produces antibodies to normal red blood cells due to a malfunction of the immune system and a violation of the lymphocytes’ recognition of their own and foreign cells.

Isoimmune anemias develop when a patient is transfused with blood that is incompatible with the ABO system and Rh factor or, in other words, with blood of a different group. In this case, the red blood cells transfused the day before are destroyed by cells of the immune system and antibodies of the recipient. A similar immune conflict develops when the Rh factor is positive in the blood of the fetus and negative in the blood of the pregnant mother. This pathology is called hemolytic disease of newborns.

Heteroimmune anemias develop when foreign antigens appear on the erythrocyte membrane, which are recognized by the patient’s immune system as foreign. Foreign antigens may appear on the surface of the red blood cell if certain medications are taken or after acute viral infections.

Transimmune anemias develop in the fetus when antibodies against red blood cells are present in the mother’s body ( autoimmune anemia). In this case, both maternal and fetal red blood cells become the target of the immune system, even if Rh incompatibility is not detected, as in hemolytic disease newborns.

Acquired membranopathies

A representative of this group is paroxysmal nocturnal hemoglobinuria or Marchiafava-Miceli disease. At the core of this disease There is a constant formation of a small percentage of red blood cells with a defective membrane. Presumably, the erythrocyte germ of a certain part of the bone marrow undergoes a mutation caused by various harmful factors, such as radiation, chemical agents, etc. The resulting defect makes the erythrocytes unstable to contact with proteins of the complement system ( one of the main components of the body's immune defense). Thus, healthy red blood cells are not deformed, and defective red blood cells are destroyed by complement in the bloodstream. As a result, a large amount of free hemoglobin is released, which is excreted in the urine mainly at night.

Anemia due to mechanical destruction of red blood cells

This group of diseases includes:

march hemoglobinuria;
microangiopathic hemolytic anemia;
anemia during transplantation of mechanical heart valves.

March hemoglobinuria, as the name suggests, develops during long marching. The formed elements of blood located in the feet, with prolonged regular compression of the soles, are subject to deformation and even destruction. As a result, a large amount of unbound hemoglobin is released into the blood, which is excreted in the urine.

Microangiopathic hemolytic anemia develops due to deformation and subsequent destruction of red blood cells in acute glomerulonephritis and disseminated intravascular coagulation syndrome. In the first case, due to inflammation of the renal tubules and, accordingly, the capillaries surrounding them, their lumen narrows, and the red blood cells are deformed due to friction with their inner membrane. In the second case, throughout circulatory system lightning-fast platelet aggregation occurs, accompanied by the formation of many fibrin threads blocking the lumen of the vessels. Some of the red blood cells immediately get stuck in the resulting network and form multiple blood clots, and the rest high speed slips through this network, becoming deformed along the way. As a result, erythrocytes deformed in this way, called “crowned,” still circulate in the blood for some time, and then are destroyed on their own or when passing through the capillaries of the spleen.

Anemia during mechanical heart valve transplantation develops when red blood cells moving at high speed collide with the dense plastic or metal that makes up the artificial heart valve. The rate of destruction depends on the speed of blood flow in the valve area. Hemolysis intensifies during physical work, emotional experiences, a sharp increase or decrease in blood pressure and an increase in body temperature.

Hemolytic anemia caused by infectious agents

Microorganisms such as Plasmodium malaria and Toxoplasma gondii ( causative agent of toxoplasmosis) use red blood cells as a substrate for the reproduction and growth of their own kind. As a result of infection with these infections, pathogens penetrate the red blood cell and multiply in it. Then, after a certain time, the number of microorganisms increases so much that it destroys the cell from the inside. At the same time, an even larger amount of the pathogen is released into the blood, which settles into healthy red blood cells and repeats the cycle. As a result, with malaria every 3 to 4 days ( depending on the type of pathogen) a wave of hemolysis is observed, accompanied by a rise in temperature. In toxoplasmosis, hemolysis develops according to a similar scenario, but more often has a non-wave course.

Causes of hemolytic anemia

Summarizing all the information from the previous section, we can say with confidence that there are a huge number of causes of hemolysis. The reasons may lie in both hereditary diseases and acquired ones. It is for this reason that great importance is attached to searching for the cause of hemolysis not only in the blood system, but also in other systems of the body, since often the destruction of red blood cells is not an independent disease, but a symptom of another disease.

Thus, hemolytic anemia can develop for the following reasons:

entry into the blood of various toxins and poisons ( toxic chemicals, pesticides, snake bites, etc.);
mechanical destruction of red blood cells ( during long hours of walking, after implantation of an artificial heart valve, etc.);
disseminated intravascular coagulation syndrome;
various genetic abnormalities in the structure of red blood cells;
autoimmune diseases;
paraneoplastic syndrome ( cross-immune destruction of red blood cells together with tumor cells);
complications after donor blood transfusion;
infection with some infectious diseases (malaria, toxoplasmosis);
chronic glomerulonephritis;
severe purulent infections accompanied by sepsis;
infectious hepatitis B, less often C and D;
avitaminosis, etc.

Symptoms of hemolytic anemia

Symptoms of hemolytic anemia fit into two main syndromes - anemic and hemolytic. In cases where hemolysis is a symptom of another disease, the clinical picture is complicated by its symptoms.

Anemic syndrome is manifested by the following symptoms:

pallor of the skin and mucous membranes;
dizziness;
severe general weakness;
rapid fatigue;
shortness of breath during normal physical activity;
heartbeat;

Hemolytic syndrome is manifested by the following symptoms:

yellowish-pale color of the skin and mucous membranes;
urine that is dark brown, cherry or scarlet in color;
increase in the size of the spleen;
pain in the left hypochondrium, etc.

Diagnosis of hemolytic anemia

Diagnosis of hemolytic anemia is carried out in two stages. At the first stage, hemolysis occurring in the vascular bed or in the spleen is diagnosed directly. At the second stage, numerous additional research to determine the cause of red blood cell destruction.

First stage of diagnosis

Hemolysis of red blood cells is of two types. The first type of hemolysis is called intracellular, that is, the destruction of red blood cells occurs in the spleen through the absorption of defective red blood cells by lymphocytes and phagocytes. The second type of hemolysis is called intravascular, that is, the destruction of red blood cells takes place in the bloodstream under the influence of lymphocytes, antibodies and complement circulating in the blood. Determining the type of hemolysis is extremely important because it gives the researcher a hint in which direction to continue searching for the cause of the destruction of red blood cells.

Confirmation of intracellular hemolysis is carried out using the following laboratory indicators:

hemoglobinemia– the presence of free hemoglobin in the blood due to the active destruction of red blood cells;
hemosiderinuria– the presence of hemosiderin in the urine, a product of oxidation of excess hemoglobin in the kidneys;
hemoglobinuria– the presence of unchanged hemoglobin in the urine, a sign of an extremely high rate of destruction of red blood cells.

Confirmation of intravascular hemolysis is carried out using the following laboratory tests:

general blood test - decrease in the number of red blood cells and/or hemoglobin, increase in the number of reticulocytes;
biochemical blood test - increase in total bilirubin due to the indirect fraction.
peripheral blood smear - with various methods of staining and fixing the smear, most anomalies in the structure of the erythrocyte are determined.

Once hemolysis is ruled out, the researcher switches to searching for another cause of anemia.

Second stage of diagnosis

There are a huge number of reasons for the development of hemolysis, so finding them can take an prohibitively long time. In this case, it is necessary to find out the medical history of the disease in as much detail as possible. In other words, it is necessary to find out the places that the patient visited in the last six months, where he worked, in what conditions he lived, the order in which the symptoms of the disease appeared, the intensity of their development, and much more. Such information may be useful in narrowing down the search for the causes of hemolysis. In the absence of such information, a series of tests are carried out to determine the substrate of the most common diseases leading to the destruction of red blood cells.

The analyzes of the second stage of diagnosis are:

direct and indirect Coombs test;
circulating immune complexes;
osmotic resistance of erythrocytes;
study of erythrocyte enzyme activity ( glucose-6-phosphate dehydrogenase (G-6-PDH), pyruvate kinase, etc.);
hemoglobin electrophoresis;
test for sickling of red blood cells;
Heinz body test;
bacteriological culture blood;
examination of a “thick drop” of blood;
myelogram;
Hem's test, Hartmann's test ( sucrose test).

Direct and indirect Coombs test
These tests are performed to confirm or rule out autoimmune hemolytic anemia. Circulating immune complexes indirectly indicate the autoimmune nature of hemolysis.

Osmotic resistance of red blood cells
A decrease in the osmotic resistance of erythrocytes often develops when congenital forms hemolytic anemias such as spherocytosis, ovalocytosis and acanthocytosis. In thalassemia, on the contrary, there is an increase in the osmotic resistance of erythrocytes.

Study of erythrocyte enzyme activity
For this purpose, they first carry out qualitative analyzes for the presence or absence of the desired enzymes, and then resort to quantitative analyzes carried out using PCR ( polymerase chain reaction) . Quantitative determination of erythrocyte enzymes allows us to identify their decrease in relation to normal values and diagnose latent forms of erythrocyte enzymopathies.

Hemoglobin electrophoresis
The study is carried out to exclude both qualitative and quantitative hemoglobinopathies ( thalassemia and sickle cell anemia).

Test for sickling of red blood cells
The essence of this study is to determine the change in the shape of red blood cells as the partial pressure of oxygen in the blood decreases. If the red blood cells take on a sickle shape, the diagnosis of sickle cell anemia is confirmed.

Heinz body test
The purpose of this test is to detect special inclusions in the blood smear, which are insoluble hemoglobin. This test is carried out to confirm such fermentopathy as G-6-FDG deficiency. However, it must be remembered that Heinz bodies can appear in a blood smear with an overdose of sulfonamides or aniline dyes. Determination of these formations is carried out in a dark-field microscope or in a conventional light microscope with special staining.

Bacteriological blood culture
Buck culture is carried out to determine the types of infectious agents circulating in the blood that can interact with red blood cells and cause their destruction directly or through immune mechanisms.

Study of a “thick drop” of blood
This study is carried out to identify malaria pathogens, the life cycle of which is closely associated with the destruction of red blood cells.

Myelogram
A myelogram is the result of a bone marrow puncture. This paraclinical method allows us to identify pathologies such as malignant diseases blood, which, through a cross-immune attack in paraneoplastic syndrome, destroy red blood cells. In addition, in the bone marrow punctate, the proliferation of the erythroid germ is determined, which indicates a high rate of compensatory production of erythrocytes in response to hemolysis.

Hem's test. Hartmann's test ( sucrose test)
Both tests are carried out to determine the duration of the existence of red blood cells of a particular patient. In order to speed up the process of their destruction, the tested blood sample is placed in a weak solution of acid or sucrose, and then the percentage of destroyed red blood cells is assessed. The Hem test is considered positive when more than 5% of red blood cells are destroyed. The Hartmann test is considered positive when more than 4% of red blood cells are destroyed. A positive test indicates paroxysmal nocturnal hemoglobinuria.

In addition to the laboratory tests presented, other additional tests may be performed to determine the cause of hemolytic anemia and instrumental studies, prescribed by a specialist in the field of the disease that is believed to be the cause of hemolysis.

Treatment of hemolytic anemia

Treatment of hemolytic anemia is a complex multi-level dynamic process. It is preferable to begin treatment after a full diagnosis and establishment of the true cause of hemolysis. However, in some cases, the destruction of red blood cells occurs so quickly that there is not enough time to establish a diagnosis. In such cases, as a necessary measure, lost red blood cells are replenished through transfusion of donor blood or washed red blood cells.

Treatment of primary idiopathic ( unknown reason) hemolytic anemia, as well as secondary hemolytic anemia due to diseases of the blood system, is dealt with by a hematologist. Treatment of secondary hemolytic anemia due to other diseases falls to the specialist whose field of activity is this disease. Thus, anemia caused by malaria will be treated by an infectious disease specialist. Autoimmune anemia will be treated by an immunologist or allergist. Anemia due to paraneoplastic syndrome due to a malignant tumor will be treated by an oncosurgeon, etc.

Treatment of hemolytic anemia with medications

The basis for the treatment of autoimmune diseases and, in particular, hemolytic anemia are glucocorticoid hormones. They apply long time- first to relieve exacerbation of hemolysis, and then as maintenance treatment. Since glucocorticoids have a number of side effects, then for their prevention, auxiliary treatment with B vitamins and drugs that reduce the acidity of gastric juice is carried out.

In addition to reducing autoimmune activity, great attention should be paid to the prevention of DIC syndrome ( blood clotting disorder), especially with moderate and high intensity of hemolysis. When the effectiveness of glucocorticoid therapy is low, immunosuppressants are the last line of treatment.

Medicine	Mechanism of action	Mode of application
*Prednisolone*	It is a representative of glucocorticoid hormones that have the most pronounced anti-inflammatory and immunosuppressive effects.	1 – 2 mg/kg/day intravenously, drip. In case of severe hemolysis, the dose of the drug is increased to 150 mg/day. After normalization of hemoglobin levels, the dose is slowly reduced to 15–20 mg/day and treatment is continued for another 3–4 months. After this, the dose is reduced by 5 mg every 2 to 3 days until the drug is completely discontinued.
*Heparin*	Is a direct anticoagulant short acting (4 – 6 hours). This drug is prescribed for the prevention of DIC syndrome, which often develops during acute hemolysis. Used in unstable patient conditions for better control of coagulation.	2500 – 5000 IU subcutaneously every 6 hours under the control of a coagulogram.
*Nadroparin*	It is a long-acting direct anticoagulant ( 24 – 48 hours). Prescribed to patients with stable condition for the prevention of thromboembolic complications and disseminated intravascular coagulation.	0.3 ml/day subcutaneously under the control of a coagulogram.
*Pentoxifylline*	Peripheral vasodilator with moderate antiplatelet effect. Increases oxygen supply to peripheral tissues.	400–600 mg/day in 2–3 oral doses for at least 2 weeks. The recommended duration of treatment is 1 – 3 months.
*Folic acid*	Belongs to the group of vitamins. In autoimmune hemolytic anemia, it is used to replenish its reserves in the body.	Treatment begins with a dose of 1 mg/day, and then increases it until a lasting clinical effect appears. Maximum daily dose– 5 mg.
*Vitamin B 12*	With chronic hemolysis, vitamin B 12 reserves are gradually depleted, which leads to an increase in the diameter of the red blood cell and a decrease in its plastic properties. To avoid these complications, additional prescription of this drug is carried out.	100 – 200 mcg/day intramuscularly.
*Ranitidine*	It is prescribed to reduce the aggressive effect of prednisolone on the gastric mucosa by reducing the acidity of gastric juice.	300 mg/day in 1 – 2 doses orally.
*Potassium chloride*	It is an external source of potassium ions, which are washed out of the body during treatment with glucocorticoids.	2 – 3 g per day under daily ionogram monitoring.
*Cyclosporine A*	A drug from the group of immunosuppressants. Used as a last line of treatment when glucocorticoids and splenectomy are ineffective.	3 mg\kg\day intravenously, drip. In case of severe side effects, the drug is discontinued and switched to another immunosuppressant.
*Azathioprine*	Immunosuppressant.
*Cyclophosphamide*	Immunosuppressant.	100 – 200 mg/day for 2 – 3 weeks.
*Vincristine*	Immunosuppressant.	1 – 2 mg/week dropwise for 3 – 4 weeks.

In case of G-6-FDG deficiency, it is recommended to avoid the use of drugs included in the risk group. However, with the development of acute hemolysis against the background of this disease, the drug that caused the destruction of red blood cells is immediately discontinued, and, if urgently necessary, washed donor red blood cells are transfused.

For severe forms of sickle cell anemia or thalassemia that require frequent blood transfusions, Deferoxamine is prescribed, a drug that binds excess iron and removes it from the body. In this way, hemochromatosis is prevented. Another option for patients with severe hemoglobinopathies is a bone marrow transplant from a compatible donor. If this procedure is successful, there is a likelihood of a significant improvement in the patient’s general condition, up to complete recovery.

In the case where hemolysis acts as a complication of a certain systemic disease and is secondary, all therapeutic measures should be aimed at curing the disease that caused the destruction of red blood cells. After recovery primary disease The destruction of red blood cells also stops.

Surgery for hemolytic anemia

For hemolytic anemia, the most commonly practiced operation is splenectomy ( splenectomy). This operation is indicated for the first relapse of hemolysis after treatment with glucocorticoid hormones for autoimmune hemolytic anemia. In addition, splenectomy is the preferred method of treating such hereditary forms of hemolytic anemia as spherocytosis, acanthocytosis, and ovalocytosis. Optimal age, at which it is recommended to remove the spleen in the case of the above diseases, is the age of 4 - 5 years, however, in individual cases, the operation can be performed at more early age.

Thalassemia and sickle cell anemia can be treated for a long time by transfusion of donor washed red blood cells, however, if there are signs of hypersplenism, accompanied by a decrease in the number of other cellular elements of the blood, surgery to remove the spleen is justified.

Prevention of hemolytic anemia

Prevention of hemolytic anemia is divided into primary and secondary. Primary prevention implies measures to prevent the occurrence of hemolytic anemia, and secondary - a decrease clinical manifestations a pre-existing disease.

Primary prevention of idiopathic autoimmune anemia is not carried out due to the absence of such causes.

Primary prevention of secondary autoimmune anemias is:

avoiding concomitant infections;
avoiding being in an environment with a low temperature for anemia with cold antibodies and with a high temperature for anemia with warm antibodies;
avoiding snake bites and being in an environment high in toxins and heavy metal salts;
Avoiding the use of medications from the list below if you have a deficiency of the G-6-FDG enzyme.

In case of G-6-FDG deficiency, hemolysis is caused by the following medications:

antimalarials- primaquine, pamaquine, pentaquine;
painkillers and antipyretics- acetylsalicylic acid ( aspirin);
sulfonamides- sulfapyridine, sulfamethoxazole, sulfacetamide, dapsone;
other antibacterial drugs- chloramphenicol, nalidixic acid, ciprofloxacin, nitrofurans;
antituberculosis drugs- ethambutol, isoniazid, rifampicin;
drugs of other groups- probenecid, methylene blue, ascorbic acid, vitamin K analogues.

Secondary prevention consists of timely diagnosis and appropriate treatment of infectious diseases that can cause exacerbation of hemolytic anemia.

Hemolytic anemia refers to diseases characterized as anemia. The most common hereditary form of the disease, which can even develop in newborns. In general, this blood disease can be found in people of any age (and even in domestic animals, such as dogs) and has both congenital and acquired etiologies. Due to its damaging ability, hemolytic anemia is a very dangerous disease and is difficult to treat, takes a long time and in a hospital setting.

Particularly dangerous is the hemolytic crisis, which causes sharp deterioration the patient's condition and requires adoption urgent measures. Advanced forms of the disease lead to surgical intervention, which indicates the need for timely detection and effective treatment.

The essence of the disease

Hemolytic anemia includes a whole group of anemias with increased hemolysis of erythrocytes, increased levels of erythrocyte destruction products in combination with the presence of reactively enhanced erythropoiesis. The essence of the disease is increased blood destruction due to a significant reduction in the life cycle of red blood cells as a result of the fact that their destruction occurs faster than the formation of new ones.

Erythrocytes (red blood cells) are blood cells responsible for a very important function - transporting oxygen to internal organs. They are formed in the red bone marrow, and after maturation they enter the bloodstream and spread with it throughout the body. The life cycle of these cells is about 100-120 days, their daily death reaches 1% of the total number. It is this quantity that is replaced by a new one, which maintains normal level erythrocytes in the blood.

As a result of pathology in the peripheral vessels or spleen, accelerated destruction of red blood cells occurs, and new cells do not have time to develop - their balance in the blood is disrupted. Reflexively, the body activates the formation of red blood cells in the bone marrow, but they do not have time to mature, and young immature red blood cells - reticulocytes - enter the blood, which causes the process of hemolysis.

Pathogenesis of the disease

The pathogenesis of hemolytic anemia is based on the destruction of red blood cells with the diffusion of hemoglobin and the formation of bilirubin. The process of destruction of red blood cells can occur in two ways: intracellular and intravascular.

Intracellular, or extravascular, hemolysis develops in macrophages of the spleen, less often in the bone marrow and liver. Destructive process caused by pathology of the erythrocyte membrane or limitation of their ability to change shape, which is caused by the congenital morphological and functional inferiority of these cells. In the blood there is a significant increase in the concentration of bilirubin and a decrease in the content of haptoglobin. The main representatives of this variant of pathogenesis are autoimmune hemolytic anemias.

Intravascular hemolysis occurs directly in the blood channels under the influence of external factors, such as mechanical injuries, toxic lesions, transfusion of incompatible blood, etc. The pathology is accompanied by the release of free hemoglobin into the blood plasma and hemoglobinuria. As a result of the formation of methemoglobin, the blood serum turns brown, and the level of haptoglobin sharply decreases. Hemoglobinuria can cause kidney failure.

Both mechanisms of pathogenesis are dangerous due to their extreme manifestation - a hemolytic crisis, when hemolysis of erythrocytes becomes widespread, which leads to a sharp progression of anemia and a deterioration in a person’s condition.

Classification of the disease

Taking into account the etiology of the disease, hemolytic anemia is divided into two main types: acquired and congenital; also in medicine there are rarer specific types. Congenital or hereditary hemolytic anemias include the following main forms of the disease:

Membranopathy: anemia caused by defects in the structure of red blood cells. Microspherocytic, ovalocytic and acanthocytic varieties.
Enzymopenic form: the pathology is caused by a deficiency of various enzymes - the pentose phosphate class, glycolysis, oxidation or reduction of glutathione, ATP, porphyrin synthesis.
Hemoglobinopathies: diseases associated with impaired hemoglobin synthesis, varieties and thalassemia.

Acquired hemolytic anemia has the following characteristic forms:

Immunohemolytic type: isoimmune and hemolytic autoimmune anemia.
Acquired membranopathies: nocturnal paroxysmal hemoglobinuria and spur cell type.
Based on mechanical damage to cells: march hemoglobinuria, microangiopathic type (Moshkovich disease) and anemia as a result of the installation of prosthetic heart valves.
Toxic varieties: the main type is anemia from drugs and exposure to hemolytic poison.

In addition to the two main forms of the disease, specific types of pathology are distinguished.

In particular, hemolytic anemia in children can be expressed as hemolytic jaundice of newborns.

In this case, damage to red blood cells is caused by the destructive effects of maternal antibodies.

A common type of disease is idiopathic anemia, including the secondary form caused by lymphoma.

Causes of hemolytic anemia

The causes of pathology can be divided into external and internal, depending on the influencing factors. Congenital anemia is generated by internal causes at the genetic level: inheritance of an abnormal gene from one or both parents; manifestation of spontaneous gene mutation during the development of the fetus in the womb.

The most dangerous pathology is the homozygous form, when the abnormal gene is present on both chromosomes from the same pair. Such hemolytic anemias in children have an extremely pessimistic prognosis for development.

In the etiology of acquired types of disease, the following main reasons can be distinguished: ingestion of poisons (arsenic, snake venom, poisonous mushrooms, lead, etc.); hypersensitivity to certain chemicals and drugs; infectious lesion(malaria, hepatitis, herpes, food infections, etc.); burns; transfusion of blood incompatible by group and Rh factor; a failure in the immune system, leading to the production of antibodies to one’s own red blood cells; mechanical damage to red blood cells (surgical exposure); lack of vitamin E; excessive intake of certain medications (antibiotics, sulfonamides); systemic connective tissue diseases (lupus erythematosus, rheumatoid arthritis).

Symptoms of the disease

Regardless of the type of disease, there are common characteristic symptoms hemolytic anemia: pallor or yellowness of the skin, oral mucosa, eyes; tachycardia, weakness and shortness of breath, enlarged spleen and liver, signs of jaundice, dizziness, fever, possible clouding of consciousness and convulsions; an increase in blood viscosity, leading to thrombosis and impaired blood supply.

Depending on the mechanism of pathogenesis, specific symptoms are noted.

With intravascular hemolysis, the following signs appear: increased temperature, change in urine color (red, brown or blackened), detection of bilirubin in the blood, color index in the range of 0.8-1.1.

The intracellular mechanism leads to symptoms such as yellowness of the skin and mucous membranes, a decrease in the level of hemoglobin and red blood cells in the blood, the number of reticulocytes exceeds 2%, an increase in the content of indirect bilirubin, a large amount of urobilin in the urine and stercobilin in the feces.

Common clinical forms

In clinical manifestations, several common forms of hemolytic anemia can be distinguished:

HEREDITARY HEMOLYTIC ANEMIA ASSOCIATED WITH DISORDERS IN THE STRUCTURE OF THE RED CELL MEMBRANE
Microspherocytic hemolytic anemia (Minkowski-Choffard disease)
It is inherited in an autosomal dominant manner; the heterozygous form is more common. Distributed almost everywhere, in all racial groups. Most often, the disease manifests itself at the age of 3-15 years, but often clinical signs are detected in the neonatal period. Sporadic forms of microspherocytic anemia may occur.

Pathogenesis. In microspherocytosis, various defects in the composition or function of red blood cell membrane proteins have been described. A hereditary defect in the erythrocyte membrane increases its permeability to sodium and water ions, which ultimately changes the volume of the cell. The most common autosomal dominant form is associated with a disorder in the interaction of spectrin with ankyrin and protein 4.2, or a deficiency of protein 4.2, or a combined deficiency of ankyrin and spectrin.

Weak interaction of transmembrane proteins can lead to membrane fragmentation, a decrease in membrane surface area, an increase in its permeability, and an increase in the content of osmotically active substances in the cell. Thus, hereditary spherocytosis is the result of a defect in any protein involved in the formation of the vertical interaction of the internal cytoskeleton, formed on spectrin, with transmembrane proteins.

Violation of the cytoskeleton leads to partial loss of the membrane, a decrease in the surface area of the erythrocyte, which is accompanied by a decrease in the size of the erythrocyte and transformation of the cell into a microspherocyte. Circulating microspherocytes have a low life expectancy (up to 12-14 days), reduced osmotic and mechanical resistance. After 2-3 passages through the spleen, the spherocyte undergoes phagocytosis by macrophages (intracellular hemolysis). Secondary splenomegaly develops, which aggravates the hemolytic process.

After splenectomy, the residence time of spherocytes in the blood increases significantly.

Clinical picture. The main symptom of the disease is hemolytic syndrome, which is manifested by jaundice, splenomegaly and anemia. Depending on the form of inheritance of the pathology (homo- or heterozygous transmission), the disease can be detected in early childhood or in later periods of life. When the disease occurs in childhood, the normal development of the body is disrupted, as a result, pronounced clinical signs are observed: skeletal deformation (especially of the skull), early enlargement of the spleen, general developmental retardation (splenogenic infantilism). In the heterozygous form of the disease, clinical signs are mild, but characteristic morphological changes in erythrocytes (microspherocytosis) occur. Hemolytic crisis occurs under the influence of provoking factors (infection, hypothermia, overwork, pregnancy, etc.).

Microspherocytic hemolytic anemia has a chronic course, accompanied by periodic hemolytic crises and remissions.

During a crisis, the temperature may rise, jaundice appears, the size of the spleen increases, and anemia increases. During the period of remission, signs of the disease are minor. High hemolysis and frequent hemolytic crises contribute to a rapid increase in the size of the spleen, a constant increase in the concentration of unconjugated bilirubin in the blood, and icterus of the sclera. Conditions are created for stagnation of bile in the liver, which sometimes leads to complications of hemolytic disease: the formation of pigment stones in the gall bladder (cholelithiasis), angiocholecystitis, etc. Sometimes they develop trophic ulcers shins, healing of which is possible only after splenectomy.

Changes in the bone marrow. Bone marrow is hypercellular. Extramedullary foci of hematopoiesis develop in the spleen and other organs. Erythroblasts predominate, the number of which is 60-70% of bone marrow cells, the leukocyte/erythrocyte ratio is 1:3 or more. The maturation of erythroblasts and the release of red blood cells to the periphery proceed at an accelerated pace. With intense hematopoiesis after a severe hemolytic crisis, megaloblasts can be observed in the bone marrow, apparently as a consequence of vitamin B12 deficiency or increased consumption of folic acid. Very rarely, erythroblastopenia is detected in sternal puncture - the so-called aregenerative crisis, which is reversible.

With severe uncompensated hemolysis, the anemia is normochromic. However, anemia for a long time may be absent, but polychromatophilia and reticulocytosis are detected in the peripheral blood - signs of active bone marrow erythropoiesis. Red blood cells (microspherocytes) are characterized by a small diameter (on average 5 microns), increased thickness and normal volume. The average thickness is increased to 2.5-3.0 microns. The spherical index - the ratio of the diameter (d) of an erythrocyte to its thickness (T) - is reduced to an average of 2.7 (with the norm being 3.4-3.9). The hemoglobin content in erythrocytes is within normal limits or slightly higher. The number of microspherocytes during remission and during the latent form of the disease is not high, while during a crisis, hemolysis can be accompanied by an increase of up to 30% or higher. Microspherocytes in blood smears are small, hyperchromatic, without central clearing. The erythrocyte histogram shows a deviation to the left, towards microcytes, RDW is normal or slightly increased. A feature of microspherocytic hemolytic anemia is constantly increased hemolysis, which is accompanied by reticulocytosis. During the period of hemolytic crisis, the number of reticulocytes reaches 50-80% or more, during the period of remission - does not exceed 2-4%. Reticulocytes have a large diameter with normal thickness. Erythrokaryocytes may appear. The hemolytic crisis is accompanied by a slight neutrophilic leukocytosis. The platelet germ, as a rule, is not changed. The erythrocyte sedimentation rate during a crisis is increased.

One of the characteristic signs of the disease is a decrease in the osmotic stability of red blood cells. Among patients with microspherocytic hemolytic anemia, there are patients in whom, despite obvious spherocytosis, the osmotic resistance of erythrocytes is normal. In these cases, it is necessary to study the resistance of erythrocytes to hypotonic saline solutions after preliminary incubation for two days. Splenectomy does not eliminate the reduced osmotic and mechanical stability of red blood cells.

The development of splenomegaly with hypersplenism syndrome is accompanied by leukopenia, neutropenia and often mild thrombocytopenia. There is a decrease in haptoglobin. Consequences of high hemolysis: bilirubinemia with a predominance of unconjugated bilirubin, the content of urobilinogen in the urine is increased, it has a brown-red tint, feces are sharply colored due to the large amount of stercobilinogen.

Ovalocytic hemolytic anemia(oval cell, hereditary ovalocytosis, liptocytosis)
A rare form of the disease, common in Western Africa (2%), inherited in an autosomal dominant manner. Depending on hetero- or homozygous transmission, various clinical and hematological manifestations of the disease are possible.

Pathogenesis. The disease is based on pathology of the erythrocyte membrane. It usually occurs due to a molecular defect in the membrane cytoskeletal proteins. The mechanical basis for the decrease in membrane stability is the weakening of lateral bonds between spectrin molecules (dimerdimer interaction) or a defect in the spectrin-actin-protein 4.1 complex. The most common cause (65% of cases) of hereditary ovalocytosis is a mutation leading to the replacement of amino acids in the amino-terminal part of a-spectrin. Mutations of the genes responsible for the synthesis of b-spectrin occur in approximately 30% of cases; heterozygous carriage of mutations is accompanied by a variety of clinical manifestations. The lifespan of ovalocytes in the body is shortened. The disease is characterized by intracellular hemolysis with predominant destruction of red blood cells in the spleen.

Clinical picture. As an anomaly, ovalocytosis in most cases is an asymptomatic carriage without clinical manifestations, but approximately 10% of patients develop moderate or even severe anemia. In the homozygous form, the clinical signs of ovalocytic anemia are practically no different from microspherocytosis. The disease is characterized by a chronic, mild course with hemolytic crises, accompanied by compensated or decompensated hemolysis, jaundice and anemia, the level of which depends on the compensatory capabilities of erythropoiesis. Patients are characterized by splenomegaly, constitutional changes in the skeleton (skull), possible trophic ulcers of the leg and other symptoms that can be observed with microspherocytic hemolytic anemia.

Changes in the bone marrow. Bone marrow is characterized by a regenerative or hyperregenerative type of hematopoiesis with a predominance of erythroblasts. The leukocyte/erythrocyte ratio is 1:3 or more (thanks to erythroblasts), depending on the activity of hemolysis and bone marrow hematopoiesis.

Changes in peripheral blood. The anemia is normochromic in nature with high reticulocytosis. Ovalocytes have normal average volume and hemoglobin content. The largest diameter of erythrocytes reaches 12 microns, the smallest - 2 microns. Ovalocytosis of erythrocytes can range from 10 to 40-50% of cells in heterozygous carriage and up to 96% of erythrocytes in homozygous carriage of abnormal genes. The osmotic resistance of ovalocytes is reduced, autohemolysis is increased, and the erythrocyte sedimentation rate is increased.

Ovalocytosis as a symptomatic form (with a small number of ovalocytes) can occur in various pathological conditions, mainly in hemolytic anemia, liver diseases, and myelodysplastic syndrome. A combination of ovalocytosis with sickle cell anemia, thalassemia, and pernicious anemia is known. In such cases, ovalocytosis is temporary and disappears with effective treatment of the underlying disease. That is why only those cases in which at least 10% of red blood cells are oval in shape and the pathology is hereditary should be classified as true ovalocytosis.

Dental hemolytic anemia(stomatocytosis)
A rare form of the disease, inherited in an autosomal dominant manner.

Pathogenesis. The disease is based on a violation of the structural proteins of the erythrocyte membrane, leading to disruption of the regulation of cell volume. The deformability of an erythrocyte depends on the ratio of surface area and cell volume. The discoid cell has the ability to change shape and overcome the narrow spaces of capillaries, which also facilitates the exchange of oxygen in the capillaries of the lungs and peripheral tissues. A spherical cell is practically unable to change shape; it has a reduced ability to exchange oxygen with tissues. A normal red blood cell has a surface area of about 140 µm2, a volume of about 90 fl, and a hemoglobin concentration of about 330 g/l. Large membrane proteins play a decisive role in the cationic transmembrane exchange of erythrocytes and thereby regulate cell volume. These proteins include transmembrane Na\K+, Cl1-co-transporters, Na+, Cl- co-transporters, ion exchange protein-3, Na\K+-co-transporters, Na\K+-ATPase, Ca+2-ATPase etc. Impaired functioning of these proteins with the accumulation of cations inside the erythrocyte leads to the accumulation of water in it and the acquisition of cell sphericity. The anomaly of red blood cells is accompanied by increased destruction, mainly in the spleen due to intracellular hemolysis.

Clinical picture. Maybe with various manifestations- from complete compensation in carriers of the pathological gene to severe hemolytic anemia, reminiscent of microspherocytosis. Intracellular hemolysis of red blood cells is accompanied by an enlarged spleen, jaundice, a tendency to form gallstones and skeletal changes.

Changes in the bone marrow. The bone marrow is hypercellular due to the expanded red line. Indicators of bone marrow hematopoiesis depend on the severity of hemolysis and the activity of erythropoiesis. Remission may not be accompanied by anemia; during a crisis, anemia is usually of a regenerative or hyperregenerative nature.

Changes in peripheral blood. Morphological feature disease - stomatocytosis, which is characterized by the presence in the center of the cell of an uncolored area in the form of an elongated light stripe, reminiscent of the shape of a mouth, or a rounded shape. The volume of erythrocytes and the concentration of hemoglobin do not differ from the norm, the resistance of erythrocytes may be reduced. During severe hemolytic crises, low hemoglobin levels and a decrease in the number of red blood cells are observed. Anemia is accompanied increased content reticulocytes and unconjugated bilirubin.

Hereditary hemolytic anemia caused by a violation of the lipid structure of the erythrocyte membrane(acanthocytosis)
A rare disease, inherited in an autosomal recessive manner. Hereditary acanthocytosis is detected in abetalipoproteinemia. A decrease in the content of cholesterol, triglycerides, and phospholipids in the blood is reflected in the lipid composition of the erythrocyte membrane: the concentration of lecithin and phosphatidylcholine is reduced in them, the content of sphingomyelin is increased, the cholesterol level is normal or increased, the phospholipid content is normal or reduced. All these disturbances in the erythrocyte membrane contribute to a decrease in the fluidity of the membrane and a change in their shape. The red blood cells acquire a jagged outline similar to acanthus leaves, which is why they are called acanthocytes. Abnormal red blood cells are destroyed mainly in the spleen by intracellular hemolysis.

Clinical picture. There are signs of anemia, hemolysis of red blood cells, symptoms of lipid metabolism disorders: retinitis pigmentosa, eye nystagmus, hand tremor, ataxia.

Changes in the bone marrow. Hyperplasia of cellular elements of erythropoiesis.

Changes in peripheral blood. Normochromic normocytic anemia is observed. The main morphological feature of this form of hemolytic anemia is erythrocytes with a jagged outline (acanthocytes), which can account for up to 40-80% of erythrocytes. Reticulocytosis is noted. The osmotic resistance of red blood cells is normal or reduced. The number of leukocytes and platelets is within normal limits.

HEREDITARY HEMOLYTIC ANEMIA CAUSED BY ERYTHROCYTE ENZYME DEFICIENCY
Hemolytic anemias caused by a deficiency of erythrocyte enzymes (non-spherocytic hemolytic anemias) have a recessive type of inheritance. Clinical and hematological manifestations of the disease depend on the location of the hereditary enzyme defect in erythrocytes. Erythrocyte enzymopathies are associated with deficiency of enzymes of glycolysis (pyruvate kinase, hexokinase, glucose phosphate isomerase, triose phosphate isomerase), pentose phosphate pathway or glutathione metabolism (glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase and glutathione reductase). Most often, enzymopathies are associated with defects in glucose-6-phosphate dehydrogenase, pyruvate kinase or glutathione reductase. Enzymopathies with defects in other metabolic pathways are rare and do not have practical significance in the occurrence of hemolytic anemia. Laboratory confirmation erythrocyte enzymopathies is based on the biochemical determination of enzyme activity in the hemolysate.

Glucose-6-phosphate dehydrogenase deficiency
Glucose-6-phosphate dehydrogenase (G-6-PD) is the only enzyme of the pentose phosphate pathway, the primary deficiency of which leads to hemolytic anemia. This is the most common erythrocyte fermentopathy: about 200 million people in the world have this pathology. It prevails among residents of the Mediterranean basin, Southeast Asia, and India. The gene for G-6-PD synthesis is linked to the X chromosome, so the disease manifests itself much more often in men. Hemolytic anemia associated with G-6-PD deficiency is more often found in residents of Azerbaijan, Dagestan, and less often in Central Asia, among Russians it is about 2%.

Provoking factors for a hemolytic crisis can be infectious diseases (influenza, salmonellosis, viral hepatitis), eating faba beans (favism), inhalation pollen. The latter is usually accompanied by a milder hemolytic crisis, but occurs within a few minutes after contact with pollen. Features of favism are acute hemolysis, which occurs faster than that caused by taking medications, and dyspeptic disorders. A hemolytic crisis can be triggered by taking certain medications, most often antimalarial, sulfonamide, nitrofuran, anthelmintic and other drugs. Clinical symptoms may occur on the 2-3rd day from the start of taking the drug. The first symptoms are usually icteric sclera and dark urine. Stopping the medication prevents the development of a severe hemolytic crisis. Otherwise, on the 4-5th day a hemolytic crisis occurs with the release of black or brown urine as a result of intravascular hemolysis of red blood cells.

In severe cases of the disease, the temperature rises, headache, vomiting, and sometimes diarrhea appear. Shortness of breath and enlarged spleen occur. Intravascular hemolysis provokes activation of blood coagulation, which can lead to blockade of microcirculation in the kidneys and acute renal failure. In the bone marrow there is a sharp stimulation of erythropoiesis. In the blood - anemia, during a crisis the amount of hemoglobin decreases to 20-30 g/l, the number of reticulocytes and leukocytes increases with a shift leukocyte formula to the left to the myelocytes. The platelet count usually does not change. In severe hemolytic crisis, a large number of Heinz-Ehrlich bodies may be detected as a result of precipitation of globin chains and erythrocyte membrane proteins. Anisocytosis, poikilocytosis, polychromatophilia, basophilic punctation, and Jolly bodies are noted. The content of free hemoglobin in the blood serum increases (intravascular hemolysis), the concentration of unconjugated bilirubin often increases, and hypohaptoglobinemia is observed. In the urine - hemoglobinuria, hemosiderinuria. Diagnosis is based on determining the level of the G-6-PD enzyme.

Pyruvate kinase deficiency
Pyruvate kinase at the final stage of glycolysis catalyzes the formation of adenosine triphosphate. Deficiency of pyruvate kinase can lead to a decrease in adenosine triphosphate in red blood cells and the accumulation of intermediate products of glycolysis that are formed at previous stages. Content final products glycolysis (pyruvate and lactate) decreases. A deficiency of adenosine triphosphate is accompanied by dysfunction of the erythrocyte adenosine triphosphatase pump and loss of potassium ions. A decrease in monovalent ions in the erythrocyte leads to dehydration and shrinkage of the cell, which makes it difficult for oxygenation and oxygen release by hemoglobin. At the same time, the accumulation of intermediate products of glycolysis, in particular 2,3-diphospho-glycerate, which reduces the affinity of hemoglobin for oxygen, facilitates the release of oxygen to tissues.

Clinical symptoms of the disease are observed in homozygous carriers. The disease is characterized by moderate to severe hemolytic anemia with intracellular hemolysis. Increased hemolysis is detected from birth, accompanied by frequent and severe hemolytic crises. The appearance of signs of the disease at the age of 17-30 is characterized by scant clinical symptoms in the form of icterus of the sclera and skin. Splenomegaly is observed almost constantly, sometimes in heterozygous carriers, although they usually do not have anemia. Hemolytic crisis is provoked by infection, heavy physical activity, pregnancy, hemolysis intensifies during menstruation.

In the bone marrow punctate there is pronounced erythrokaryocytosis. The most important diagnostic criterion is deficiency of pyruvate kinase activity. Pronounced clinical effects are observed in cases where the residual enzyme activity is below 30% of normal.

In the blood, in most cases, normochromic nonspherocytic anemia with slight anisocytosis and poikilocytosis occurs. The amount of hemoglobin and erythrocytes can be normal, reduced, severe anemia is also possible (Hb - 40-60 g/l), erythrocyte indices are approaching normal. Smears often reveal polychromatophilia and erythrocytes with basophilic punctation, sometimes target-like erythrocytes, erythrokaryocytes. Reticulocytosis during a crisis can reach 70%. The number of white blood cells and platelets is usually normal, although in rare cases there is a combined enzyme defect of red blood cells, white blood cells and platelets. The erythrocyte sedimentation rate during the absence of severe anemia is within normal limits. The osmotic resistance of erythrocytes does not correlate with the form of enzyme deficiency and, even with the same erythrocyte defect, can be different. In the blood serum during a hemolytic crisis, unconjugated (indirect) bilirubin is increased.

HEMOLYTIC ANEMIA ASSOCIATED WITH IMPAIRED GLOBIN SYNTHESIS (HEMOGLOBINOPATHY)
There are quantitative and qualitative hemoglobinopathies. In quantitative hemoglobinopathies, the ratio of normal globin chains is disrupted. Qualitative hemoglobinopathies are diseases in which a genetic abnormality leads to the synthesis of hemoglobin with an altered globin structure. basis laboratory diagnostics qualitative and quantitative hemoglobinopathies is hemoglobin electrophoresis on cellulose acetate.

Thalassemia
A heterogeneous group of hereditary diseases, which are based on a violation of the synthesis of one of the polypeptide chains of globin, which leads to an increase in the production of other chains and the development of an imbalance between them. Thalassemias are classified as quantitative hemoglobinopathies, since the structure of hemoglobin chains is not changed. β-thalassemias are more common. Chains synthesized in excess accumulate and are deposited in bone marrow erythrocytes and peripheral blood erythrocytes, causing damage to the cell membrane and premature cell death. Erythrokaryocytes die in the spleen and bone marrow. Anemia is accompanied by a slight increase in reticulocytes. An imbalance in the synthesis of globin chains causes ineffective erythropoiesis, intracellular hemolysis of peripheral blood erythrocytes - splenomegaly and hypochromic anemia varying degrees gravity.

B-Thalassemia is a heterogeneous disease. Currently, more than 100 mutations are known to cause p-thalassemia. Typically, the defect consists of the formation of defective b-globin mRNA. The variety of molecular defects leads to the fact that the so-called homozygous p-thalassemia often represents a double heterozygous state for various defects p-globin synthesis. A distinction is made between p-thalassemia, when homozygotes completely lack the synthesis of globin p-chains, and P+-thalassemia, when the synthesis of b-chains is partially preserved. Among p+ thalassemias, there are two main forms: the severe Mediterranean form, in which about 10% of the normal chain is synthesized (thalassemia major, Cooley's anemia), and the lighter, black form, when about 50% of the synthesis of the normal p-chain is preserved. The group of p-thalassemias also includes 8p-thalassemia and Hb Lepore. As a result, there are significant differences in the clinical picture of different forms of thalassemia, but all β-thalassemias have common features: intracellular hemolysis of red blood cells, ineffective erythropoiesis in the bone marrow and splenomegaly.

Thalassemia major (Cooley's anemia, thalassemia major). It is considered a homozygous form of thalassemia, although in many cases the disease is a double heterozygous state for various forms of β-thalassemia. Clinically, the disease manifests itself by the end of 1-2 years of a child’s life with splenomegaly, jaundice, pallor of the skin, bone changes (square skull, flattened bridge of the nose, protruding cheekbones, narrowing of the palpebral fissures). Children are physically poorly developed.

In the bone marrow, hyperplasia of the red line is observed, and a significant number of sideroblasts are detected. In the blood - hypochromic microcytic anemia, severe anisocytosis, there are erythrocytes with basophilic punctation, erythrokaryocytes, poikilocytosis, target-like erythrocytes, schizocytes. Even with severe anemia, the reticulocyte count is not high, since ineffective erythropoiesis is expressed in the bone marrow. There is an increase in the osmotic resistance of erythrocytes. Leukopenia with relative lymphocytosis is characteristic; during a hemolytic crisis - neutrophilic leukocytosis with a shift in the leukocyte formula to the left. There is hyperbilirubinemia in the blood serum due to unconjugated bilirubin, and the serum iron content is increased. Excessive iron deposition leads to organ siderosis. A characteristic feature Thalassemia major is a marked increase in the concentration of fetal hemoglobin. The amount of HbA varies depending on the type of thalassemia. In homozygotes with p-thalassemia, HbA is practically absent. With p+ thalassemia (Mediterranean type), HbA varies from 10 to 25%; with p+ thalassemia of the Negro type, the HbA content is much higher. However, the severity of the disease does not always correlate with the amount of fetal hemoglobin. The HbA2 content may be different, often increased, but the HbA2/HbA ratio is always less than 1:40. The diagnosis is confirmed by hemoglobin electrophoresis (HbF level - up to 70%).

Thalassemia minor is a heterozygous form of p-thalassemia. Clinically, thalassemia minor is characterized by less pronounced symptoms than thalassemia major and can be practically asymptomatic.

In the bone marrow there is hyperplasia of the erythroid lineage, the number of sideroblasts is increased or normal. Moderate hypochromic microcytic anemia is observed in the blood: a moderate decrease in hemoglobin with normal and sometimes increased quantity erythrocytes, decreased MCV, MCH, MSHC indices. Blood smears show anisocytosis, poikilocytosis, target-like erythrocytes, there may be basophilic punctuation of erythrocytes, and reticulocytosis is detected. Unconjugated bilirubin is moderately elevated in the blood serum, and iron levels are usually normal or elevated.

The diagnosis is established based on the results of determining small fractions of hemoglobin HbA2 and HbF. Patients with the heterozygous form of p-thalassemia are characterized by an increase in the content of the HbA2 fraction to 3.5-8% and in approximately half of the patients - HbF to 2.5-7%.

A-Thalassemia occurs when there is a mutation in genes located in the 11th pair of chromosomes, encoding the synthesis of a-chains. With a deficiency of a-chains, tetramers accumulate in the blood of newborns, and HbH (P4) accumulates in the postnatal period (and in adults). There are 4 forms of a-thalassemia.

Homozygous a-thalassemia develops as a result of a complete blockade of the synthesis of a-chains and is characterized by the absence of normal hemoglobins (70-100% is Hb Bart's). Hb Bart's is not able to carry oxygen due to an abnormally increased affinity for it, resulting in anoxia tissues, leading to dropsy and intrauterine fetal death.

H-hemoglobinopathy is caused by a significant inhibition of a-chain production due to the absence of 3 out of 4 genes. Excessive synthesis of b-chains leads to their accumulation and the formation of tetramers. In newborns, 20-40% is accounted for by Hb Bart's, which later changes to HbH. HbH is functionally defective, since it has a very high affinity for oxygen, does not bind to haptoglobin, is unstable, unstable, easily oxidized and precipitated in the cell as it ages.In this disease, there is advanced education MetHb. HbH aggregation changes the elasticity of the erythrocyte membrane, disrupts cell metabolism, which is accompanied by hemolysis.

Clinically, H-hemoglobinopathy occurs in the form of thalassemia intermedia. The disease usually manifests itself towards the end of the first year of life as chronic hemolytic anemia moderate degree severity, occasionally observed asymptomatic. The disease is characterized by a relatively mild clinical course, hepatosplenomegaly, icterus, and anemia. Skeletal changes are minor. In the bone marrow there is moderate hyperplasia of the erythroid germ, slight ineffective erythropoiesis. In the blood - pronounced hypochromia and target-like erythrocytes, slight reticulocytosis. After incubation of blood with cresyl blue at 55 °C, unstable HbH precipitates in the form of many small violet-blue inclusions in the red blood cells, which distinguishes it from other forms of α-thalassemia. After splenectomy, HbH inclusions begin to resemble Heinz-Ehrlich bodies in appearance. However, in chemical structure they differ from Heinz-Ehrlich bodies in that they consist of precipitated b-chains, while Heinz-Ehrlich bodies are precipitated HbA molecules and some other unstable hemoglobins. During electrophoresis of blood serum in an alkaline buffer, an additional fraction is observed moving ahead of HbA (fast-moving fraction). In adults, HbH values are 5-30%, up to 18% may account for Hb Bart's, HbA2 is reduced (1-2%), HbF is normal or slightly increased (0.3-3%).

α-thalassemia minor (a-tht) - heterozygous condition for the α-thr gene. Synthesis of α-chains is moderately reduced. In the peripheral blood, a mild degree of anemia is detected with morphological changes in erythrocytes characteristic of thalassemia. In newborns who are carriers of this gene, the content of Hb Bart's in the umbilical cord blood does not exceed 5-6%. The life expectancy of erythrocytes is at the lower limit of normal.

Sickle cell anemia
Sickle cell anemia (hemoglobinopathy S) is a qualitative hemoglobinopathy. An abnormality in the structure of hemoglobin in sickle cell anemia is the replacement of the b-chain of glutamic acid with valine at position 6, which leads to increased binding of one hemoglobin molecule to another. Hemoglobinopathy S most often develops in people living in countries where malaria is common (Mediterranean, Africa, India, Central Asia). The replacement of one amino acid with another is accompanied by severe physicochemical changes in hemoglobin and leads to depolymerization of HbS. Deoxygenation causes the deposition of abnormal hemoglobin molecules in the form of monofilaments, which aggregate into oblong-shaped crystals, thereby changing the membrane and the sickle shape of red blood cells. Average duration The lifespan of red blood cells in anemia homozygous for hemoglobin S is about 17 days. At the same time, such an anomaly makes these red blood cells unsuitable for the life of plasmodia; carriers of hemoglobin S do not suffer from malaria, which, through natural selection, has led to the spread of this hemoglobinopathy in the countries of the “malarial belt”.

The homozygous form clinically manifests itself several months after birth. Characterized by severe pain in the joints, swelling of the hands, feet, legs, associated with vascular thrombosis, bone changes (tall, curved spine, tower skull, altered teeth). Aseptic necrosis of the heads of the femur and humerus, pulmonary infarction, and occlusion of cerebral vessels are common. Children develop hepatomegaly and splenomegaly. The disease is characterized by hemolytic crises with intravascular hemolysis, so thrombosis of small and large vessels of various organs is a frequent complication. In the blood - unexpressed normochromic anemia. During a hemolytic crisis - a sharp drop in hemoglobin and hematocrit, reticulocytosis, normoblastosis, Jolly bodies, sickle erythrocytes, basophilic punctation, target erythrocytes, poikilocytosis, leukocytosis, thrombocytosis, increased erythrocyte sedimentation rate, unconjugated bilirubin. Urine is black due to hemoglobinuria, hemosiderin is detected. The addition of infections can be accompanied by aplastic crisis - erythrocytopenia, reticulocytopenia, thrombo- and leukocytopenia. Sickling can be detected in a test with sodium metabisulfite or when a tourniquet is applied to the base of the finger (reduced oxygen availability). The final diagnosis is established after blood electrophoresis, where 90% HbS, 2-10% HbF, and no HbA are observed.

The heterozygous form (carriage of the sickle cell trait) is characterized by a benign course of the disease. In some patients, the only symptom may be spontaneous hematuria associated with small infarctions of the renal vessels.

Severe hypoxia develops at high altitudes. In these cases, there may be thrombotic complications. During a crisis, low levels of hemoglobin, sickle-shaped erythrocytes, and erythrokaryocytes are observed in the blood.
Hemolytic anemia caused by the carriage of abnormal stable hemoglobins C, D, E
Common forms of stable hemoglobins are C, D, E. In HbC, glutamic acid at position 6 is replaced by lysine, which leads to its crystallization; in HbE, glutamic acid at position 26 is replaced by lysine; in HbD, glutamic acid at position 121 is replaced by glutamine. Heterozygous forms occur without clinical manifestations.

In homozygotes, clinical symptoms are caused by anemia: mild hemolytic anemia, jaundice, and splenomegaly are characteristic. The anemia is normocytic in nature; there are many target cells in the blood. There is a tendency for hemoglobin molecules to crystallize. The combination of all 3 types of hemoglobinopathies with thalassemia gives a severe clinical picture.

Hemolytic anemia caused by carriage of abnormal unstable hemoglobins
Substitution of amino acids in HbA in the a- or b-chains causes the appearance of abnormal unstable hemoglobin. Displacement at the heme attachment site causes molecular instability leading to denaturation and precipitation of hemoglobin within the red blood cell. Precipitated hemoglobin attaches to the erythrocyte membrane, which leads to the destruction of the erythrocyte, the appearance of Heinz-Ehrlich bodies, and the elasticity and permeability of the cell membrane is impaired. As red blood cells pass through the spleen, they lose part of their membrane and are then destroyed.

Clinical picture. Hemolytic anemia has been observed since childhood. Crises can be caused medicinal substances or infection. The blood shows low hemoglobin, target-shaped red blood cells, basophilic punctation, polychromasia, reticulocytosis, Heinz-Ehrlich bodies, and an increased content of erythrokaryocytes. The osmotic resistance of red blood cells is normal or slightly increased. The study of the primary structure of pathological hemoglobin allows us to determine the type of unstable hemoglobin. Abnormal hemoglobin accounts for 30-40% of the total hemoglobin.

Subject: Hemolytic anemia - congenital and acquired .

Purpose of study: introduce students to the concept of hemolytic anemia, consider various clinical variants of hemolytic anemia, diagnosis, differential diagnosis, complications. To study changes in the blood picture in various clinical variants of hemolytic anemia.

Key terms:

Hemolytic anemia;

Hemolysis;

Microspherocytosis;

Membrano- and fermentopathy;

Thalassemia;

Sickle cell anemia;

Hemolytic crisis

Topic study plan:

The concept of hemolytic anemia;

Classification of hereditary hemolytic anemias;

Membranopathies;

Minkowski–Choffard disease;

Enzymopathies;

Anemia associated with G-6-PD deficiency of red blood cells;

Hemoglobinopathies;

Thalassemia;

Sickle cell anemia;

Classification of acquired hemolytic anemias;

General principles of diagnosis and treatment of hemolytic anemia.

Presentation of educational material:

Anemia, in which the process of destruction of red blood cells prevails over the process of regeneration, is called hemolytic.

Natural death of an erythrocyte (erythrodierez) occurs 90-120 days after its birth in the vascular spaces of the reticulohistiocytic system, mainly in the sinusoids of the spleen and much less often directly in the bloodstream. With hemolytic anemia, premature destruction (hemolysis) of red blood cells is observed. The resistance of the erythrocyte to various influences of the internal environment is due to both the structural proteins of the cell membrane (spectrin, ankyrin, protein 4.1, etc.) and its enzymatic composition, in addition, normal hemoglobin and the physiological properties of blood and other media in which the red blood cell circulates. When the properties of an erythrocyte are disrupted or its environment changes, it is prematurely destroyed in the bloodstream or in the reticulohistiocytic system of various organs, primarily the spleen.

Classification of hemolytic anemias

Usually, hereditary and acquired hemolytic anemias are distinguished, since they have different mechanisms of development and differ in approach to treatment. Less commonly, hemolytic anemias are classified according to the presence or absence of immunopathology, distinguishing between autoimmune and nonimmune hemolytic anemias, which include congenital hemolytic anemias, acquired hemolytic anemias in patients with liver cirrhosis, as well as in the presence of prosthetic heart valves and the so-called march hemoglobinuria.

Hemolytic anemia They have a number of characteristics that distinguish them from anemias of other origins. First of all, these are hyperregenerative anemias, occurring with hemolytic jaundice and splenomegaly. High reticulocytosis in hemolytic anemia is due to the fact that during the breakdown of red blood cells, all the necessary elements are formed for the construction of a new red blood cell and, as a rule, there is no deficiency of erythropoietin, vitamin B 12, folic acid and iron. The destruction of red blood cells is accompanied by an increase in the content of free bilirubin in the blood; when its level exceeds 25 µmol/l, hysteria of the sclera and skin appears. Enlargement of the spleen (splenomegaly) is the result of hyperplasia of its reticulohistiocytic tissue, caused by increased hemolysis of red blood cells. There is no generally accepted classification of hemolytic anemia.

Hereditary hemolytic anemia.

A. Membranopathies due to disruption of the structure of the erythrocyte membrane:

Violation of erythrocyte membrane proteins: microspherocytosis; elliptocytosis; stomatocytosis; pyropoikilocytosis.

Disorders of erythrocyte membrane lipids: acanthocytosis, deficiency of lecithin-cholesterol acyltransferase (LCAT) activity, increased lecithin content in the erythrocyte membrane, infantile pycnocytosis.

B. Enzymepathies:

Deficiency of pentose phosphate cycle enzymes.

Deficiency of glycolytic enzyme activity.

Deficiency of activity of glutathione metabolism enzymes.

Deficiency in the activity of enzymes involved in the use of ATP.

Deficiency of ribophosphate pyrophosphate kinase activity.

Impaired activity of enzymes involved in the synthesis of porphyrins.

IN. Hemoglobinopathies:

Caused by an anomaly in the primary structure of hemoglobin

Caused by a decrease in the synthesis of polypeptide chains that make up normal hemoglobin

Caused by a double heterozygous state

Hemoglobin abnormalities not accompanied by the development of the disease

Acquired hemolytic anemia

A. Immune hemolytic anemias:

Hemolytic anemias associated with exposure to antibodies: isoimmune, heteroimmune, transimmune.

Autoimmune hemolytic anemia: with incomplete warm agglutinins, with warm hemolysins, with complete cold agglutinins, associated with biphasic cold hemolysins.

Autoimmune hemolytic anemia with antibodies against bone marrow normocyte antigen.

B. Hemolytic anemia associated with membrane changes caused by somatic mutation: PNH.

B. Hemolytic anemia associated with mechanical damage to the membrane of red blood cells.

D. Hemolytic anemia associated with chemical damage to red blood cells (lead, acids, poisons, alcohol).

D. Hemolytic anemia due to deficiency of vitamins E and A.

Hemolytic anemia is a group of diseases that differ in nature, clinical picture and principles of treatment, but are united by a single feature - hemolysis of red blood cells. Among blood diseases, hemolytic anemias account for 5%, and among all anemias, hemolytic anemias account for 11%. The main symptom of hemolytic conditions is hemolysis - a decrease in the life expectancy of red blood cells and their increased breakdown.

ETIOLOGY AND PATHOGENESIS. The physiological norm for the lifespan of red blood cells ranges from 100 to 120 days. The red blood cell has a powerful metabolism and carries a colossal functional load. Providing the functions of erythrocytes is determined by the preservation of the structure and shape of cells and processes that ensure hemoglobin metabolism. Functional activity is ensured by the process of glycolysis, which results in the synthesis of ATP, which supplies the red blood cell with energy. The structural integrity and normal metabolism of hemoglobin is ensured by the structural protein tripeptide glutathione. The shape is maintained by lipoproteins in the erythrocyte membrane. An important property of red blood cells is their ability to deform, which ensures the free passage of red blood cells when entering the microcapillaries and when leaving the sinuses of the spleen. The deformability of red blood cells depends on internal and external factors. Internal factors: viscosity (provided by the normal concentration of hemoglobin in the middle part of the erythrocyte) and oncotic pressure inside the erythrocyte (depending on the oncotic pressure of the blood plasma, the presence of magnesium and potassium cations in the erythrocyte). With a high oncotic pressure of the plasma, its elements rush into the erythrocyte, it becomes deformed and bursts. The normal content of magnesium and potassium depends on the operation of the membrane transport mechanism, which, in turn, depends on the correct ratio of protein components and phospholipids in the membrane, i.e. if any part of the genetic program of the erythrocyte is disrupted (synthesis of transport or membrane proteins), then the balance is disturbed internal factors, which leads to the death of the red blood cell.

With the development of hemolytic anemia, the lifespan of red blood cells is reduced to 12-14 days. Pathological hemolysis is divided into intravascular and intracellular. Intravascular hemolysis is characterized by an increased intake of hemoglobin into the plasma and excretion in the urine in the form of hemosiderin or unchanged. Intracellular hemolysis is characterized by the breakdown of red blood cells in the reticulocyte system of the spleen, which is accompanied by an increase in the content of the free bilirubin fraction in the blood serum, the excretion of urobilin in feces and urine, and a tendency to cholelithiasis and choledocholithiasis.

Minkowski-Choffard disease (hereditary microspherocytosis).

Minkowski-Choffard disease is a hereditary disease, inherited in an autosomal dominant manner.

ETIOLOGY AND PATHOGENESIS. In practice, every fourth case is not inherited. Obviously, this type is based on some spontaneously occurring mutation, formed as a result of the action of teratogenic factors. A genetically inherited defect in the erythrocyte membrane protein leads to an excess of sodium ions and water molecules in erythrocytes, resulting in the formation of pathological forms of erythrocytes that have a spherical shape (spherocytes). Unlike normal biconcave red blood cells, they are not able to deform when passing through the narrow vessels of the splenic sinuses. As a result, the progress in the spleen sinuses slows down, some of the red blood cells are split off, and small cells are formed - microspherocytes, which are quickly destroyed. Red blood cell debris is captured by splenic macrophages, which leads to the development of splenomegaly. Increased excretion of bilirubin with bile causes the development of pleiochromia and cholelithiasis. As a result of increased breakdown of red blood cells, the amount of free fraction of bilirubin in the blood serum increases, which is excreted from the intestine with feces in the form of stercobilin and partially in urine. In Minkovsky-Shoffard disease, the amount of stercobilin released exceeds normal levels by 15-20 times.

PATHOLOGICAL-ANATOMICAL PICTURE. Due to the erythroid sprout, the bone marrow in tubular and flat bones is hyperplastic, and erythrophagocytosis is noted. In the spleen, a decrease in the number and size of follicles, hyperplasia of the sinus endothelium, and pronounced blood filling of the pulp are observed. Hemosiderosis can be detected in the lymph nodes, bone marrow and liver.

CLINIC. During the course of the disease, periods of remission and exacerbation alternate (hemolytic crisis). Exacerbation of chronic infection, intercurrent infections, vaccination, mental trauma, overheating and hypothermia predispose to the development of a hemolytic crisis. The disease is usually detected at an early age if a similar disease is present in relatives. The first symptom that should alert you is jaundice that has been prolonged over time. Most often, the first manifestations of the disease are detected in adolescents or adults, as more provoking factors appear. Outside the period of exacerbation, complaints may be absent. The period of exacerbation is characterized by deterioration in well-being, dizziness, weakness, fatigue, palpitations, and increased body temperature. Jaundice (lemon yellow) is the main and may be the only sign of the disease for a long time. The intensity of jaundice depends on the ability of the liver to conjugate free bilirubin with glucuronic acid and on the intensity of hemolysis. Unlike mechanical and parenchymal jaundice of hemolytic origin, it is not characterized by the appearance of discolored feces and beer-colored urine. Bilirubin is not detected in a urine test, since free bilirubin does not pass through the kidneys. The stool turns dark brown due to increased levels of stercobilin. It is possible that cholelithiasis may manifest against the background of a tendency to stone formation with the development of acute cholecystitis. When the common bile duct is blocked by a stone (choledocholithiasis), the clinical picture is accompanied by signs of obstructive jaundice (skin itching, bilirubinemia, the presence of bile pigments in the urine, etc.). A characteristic sign of hereditary microspherocytosis is splenomegaly. The spleen is palpated 2-3 cm below the costal arch. With prolonged hemolysis, splenomegaly is pronounced, which is manifested by heaviness in the left hypochondrium. The liver, in the absence of complications, is usually of normal size; rarely, in some patients with a long course of the disease, it can increase. In addition to jaundice and splenomegaly, one can note an expansion of the boundaries of relative cardiac dullness, systolic murmur, and muffled tones. During examination, bone pathologies may be observed (impaired growth and placement of teeth, high palate, saddle nose, tower skull with narrow eye sockets) and signs of developmental retardation. Hemoglobin levels are usually unchanged or moderately reduced. A sharp increase in anemia is observed during hemolytic crises. In older people, difficult-to-heal trophic ulcers of the leg may be observed, caused by the breakdown and agglutination of red blood cells in the peripheral capillaries of the limb. Hemolytic crises appear against the background of constantly ongoing hemolysis and are characterized by a sharp increase in clinical manifestations. At the same time, due to the massive breakdown of red blood cells, body temperature rises, dyspepsia, abdominal pain appear, and the intensity of jaundice increases. Pregnancy, hypothermia, and intercurrent infections provoke the development of hemolytic crises. In some cases, hemolytic crises do not develop during the course of the disease.

HEMATOLOGICAL PICTURE. The blood smear shows microcytosis and a large number of microspherocytes. The number of reticulocytes is also increased. The number of leukocytes and platelets is within normal limits. During hemolytic crises, neutrophilic leukocytosis with a shift to the left is observed. Hyperplasia of the erythroid lineage is observed in the bone marrow. Bilirubinemia is not expressed. The level of indirect bilirubin averages 50-70 µmol/l. The content of stercobilin in feces and urobilin in urine increases.

DIAGNOSIS. The diagnosis of hereditary microspherocytosis is made on the basis of the clinical picture and laboratory tests. It is mandatory to examine relatives for signs of hemolysis and microspherocytosis without clinical manifestations.

DIFFERENTIAL DIAGNOSTICS. In the newborn period, Minkowski-Choffard disease must be differentiated from intrauterine infection, biliary atresia, congenital hepatitis, and hemolytic disease of the newborn. In infancy - with hemosiderosis, leukemia, viral hepatitis. Acute erythromyelosis is often confused with a hemolytic crisis, accompanied by anemia, leukocytosis with a shift to the left, splenomegaly, and hyperplasia of the erythroid lineage in the bone marrow. Differential diagnosis of hereditary microspherocytosis with autoimmune hemolytic anemia includes performing a Coombs test, which allows the determination of antibodies fixed on erythrocytes, characteristic of autoimmune anemia. It is necessary to distinguish the group of non-spherocytic hemolytic anemias from hereditary microspherocytosis. These diseases are characterized by enzymatic deficiency in erythrocytes, absence of spherocytosis, normal or slightly increased osmotic resistance of erythrocytes, increased autohemolysis, and hyperglycemia that cannot be corrected. Often, for differential diagnosis, the Price-Jones curve (a curve reflecting the size of red blood cells) is used, along which in hereditary microspherocytosis there is a shift towards microspherocytes.

TREATMENT. Splenectomy is the only 100% effective treatment method for patients with hereditary microspherocytosis. Despite the fact that the decrease in osmotic resistance and microspherocytosis in erythrocytes persists, the phenomena of hemolysis are stopped, since as a result of splenectomy the main springboard for the destruction of microspherocytes is removed, and all manifestations of the disease disappear. Indications for splenectomy are frequent hemolytic crises, severe anemia in patients, and splenic infarction. Often, if a patient has cholelithiasis, cholecystectomy is performed simultaneously. In adult patients with mild flow disease and compensation process, indications for splenectomy are relative. Preoperative preparation includes transfusion of red blood cells, especially in cases of severe anemia, and vitamin therapy. The use of glucocorticoid drugs in the treatment of hereditary microspherocytosis is not effective.

FORECAST. The course of hereditary microspherocytosis is rarely severe, and the prognosis is relatively favorable. Many patients live to an old age. Spouses, one of whom has hereditary microspherocytosis, should be aware that the likelihood of microspherocytosis occurring in their children is slightly less than 50%.

Hereditary hemolytic anemia associated with enzyme deficiency (enzymopathies).

The group of hereditary non-spherocytic hemolytic anemias is inherited in a recessive manner. They are characterized by a normal shape of erythrocytes, normal or increased osmotic resistance of erythrocytes, and no effect from splenectomy. A deficiency of enzymatic activity leads to increased sensitivity of red blood cells to the effects of drugs and substances of plant origin.

Acute hemolytic anemia associated with deficiency of glucose-6-phosphate dehydrogenase (G-6-PDG).

It occurs most often; according to WHO, about 100 million people in the world have a deficiency of glucose-6-phosphate dehydrogenase. G-6-FDG deficiency affects ATP synthesis, glutathione metabolism, and the state of thiol protection. It is most widespread among residents of the Mediterranean countries of Europe (Italy, Greece), Africa and Latin America.

PATHOGENESIS. In erythrocytes with reduced G-6-PD activity, the formation of NADP and the binding of oxygen decreases, as well as the rate of methemoglobin reduction decreases and the resistance to the effects of various potential oxidants decreases. Oxidizing agents, including drugs, in such an erythrocyte reduce reduced glutathione, which in turn creates conditions for oxidative denaturation of enzymes, hemoglobin, and constituent components of the erythrocyte membrane and entails intravascular hemolysis or phagocytosis. More than 40 medications, not counting vaccines and viruses, are known to have the potential to cause acute intravascular hemolysis in individuals with insufficient G6PD activity. Hemolysis of such red blood cells can also be caused by endogenous intoxications and a number of plant products.

Examples of drugs and products that can potentially cause hemolysis: quinine, delagil, streptocide, bactrim, promizol, furatsilin, furazolidone, furagin, isoniazid, chloramphenicol, aspirin, ascorbic acid, colchicine, levodopa, nevigramon, methylene blue, herbal products (faba beans , field peas, male fern, blueberries, blueberries).

PATHOLOGICAL-ANATOMICAL PICTURE. Icterus of the skin and internal organs, spleno- and hepatomegaly, moderate swelling and enlargement of the kidneys are observed. Microscopy reveals hemoglobin-containing casts in the kidney tubules. In the spleen and liver, a macrophage reaction is detected with the presence of hemosiderin in macrophages.

CLINIC. G6PD deficiency is observed predominantly in males who have a single X chromosome. In girls, clinical manifestations are observed mainly in cases of homozygosity.

Select 5 clinical forms insufficiency of G-6-PD in erythrocytes:

acute intravascular hemolysis is a classic form of G-6-PD deficiency. Found everywhere. Develops as a result of taking medications, vaccinations, diabetic acidosis, in connection with a viral infection;

favism associated with eating or inhaling pollen from certain legumes;

hemolytic disease of newborns, not associated with hemoglobinopathy, with group and Rh incompatibility;

hereditary chronic hemolytic anemia (non-spherocytic);

asymptomatic form.

A hemolytic crisis can be triggered by analgesics, some antibiotics, sulfonamides, antimalarials, non-steroidal anti-inflammatory drugs, chemotherapy drugs (PASK, furadonin), herbal products (pods, legumes) and vitamin K, as well as hypothermia and infections. Manifestations of hemolysis depend on the dose of hemolytic agents and the degree of G-6-FDG deficiency. 2-3 days after taking the drugs, body temperature rises, vomiting, weakness, back and abdominal pain, palpitations, shortness of breath, and collapse often develops. The urine becomes dark in color (even black), which is due to intravascular hemolysis and the presence of hemosiderin in the urine. A characteristic sign of intravascular hemolysis is hyperhemoglobinemia; when standing, the blood serum becomes brown due to the formation of methemoglobin. Hyperbilirubinemia is also observed at the same time. The content of bile pigments in duodenal contents and in feces increases. IN severe cases renal tubules become clogged with hemoglobin breakdown products, glomerular filtration decreases and acute renal failure develops. On physical examination, icterus of the skin and mucous membranes, splenomegaly, and, less commonly, liver enlargement are noted. After 6-7 days, hemolysis ends regardless of whether the medication continues or not.

HEMATOLOGICAL PICTURE. During the first 2-3 days of a hemolytic crisis, severe normochromic anemia is detected in the blood. The hemoglobin level decreases to 30 g/l and below, reticulocytosis and normocytosis are observed. Microscopy of red blood cells reveals the presence of Heinz bodies (lumps of denatured hemoglobin). With a pronounced crisis, there is a pronounced shift in the leukocyte formula to the left, up to juvenile forms. In the bone marrow, a hyperplastic erythroid germ with symptoms of erythrophagocytosis is detected.

DIAGNOSIS. The diagnosis is made on the basis of the characteristic clinical and hematological picture of acute intravascular hemolysis, laboratory data revealing a decrease in the enzymatic activity of G-6-FDG, and the identification of a connection between the disease and the use of hemolytic agents.

TREATMENT. First of all, the drug that caused hemolysis should be discontinued. In case of a mild hemolytic crisis, antioxidants are prescribed and agents that help increase glutathione in erythrocytes (xylitol, riboflavin) are used. At the same time, phenobarbital is given for 10 days.

In severe cases with pronounced signs of hemolysis, prevention of acute renal failure is necessary: infusion therapy and blood transfusion are carried out. Drugs that improve renal blood flow (aminophylline IV) and diuretics (mannitol) are used. In the case of DIC syndrome, heparinized cryoplasma is prescribed. Splenectomy is not used for this type of hemolytic anemia.

Hemoglobinopathies

Hemoglobinopathies are hereditary abnormalities in the synthesis of human hemoglobins: they are manifested either by a change in the primary structure or by a violation of the ratio of normal polypeptide chains in the hemoglobin molecule. In this case, red blood cell damage always occurs, most often occurring with congenital hemolytic anemia syndrome (sickle cell anemia, thalassemia). At the same time, there are numerous cases of latent carriage of abnormal hemoglobin. Hemoglobinopathies are the most common monogenic hereditary diseases in children. According to WHO (1983), there are about 240 million people around the globe suffering from both structural (qualitative) and quantitative (thalassemia) hemoglobinopathies. Every year 200 thousand sick people are born and die in the world. Significant prevalence of hemoglobinopathies in Transcaucasia, Central Asia, Dagestan, Moldova, Bashkiria. It is known that normally the hemoglobin of an adult consists of several fractions: hemoglobin A, which forms the bulk, hemoglobin F, which makes up 0.1-2%, hemoglobin A 2-2.5%.

Thalassemia.

This is a heterogeneous group of hereditarily caused hypochromic anemias with varying severity, which are based on a violation of the structure of globin chains. In some patients, the main genetic defect is that abnormal tRNA functions in the cells, while in other patients there is a deletion of genetic material. In all cases, there is a decrease in the synthesis of hemoglobin polypeptide chains. Various types of thalassemias with different clinical and biochemical manifestations are associated with a defect in any polypeptide chain. Unlike hemoglobinopathy, in thalassemia there are no disturbances in the chemical structure of hemoglobin, but there are distortions in the quantitative ratios of hemoglobin A and hemoglobin F. Changes in the structure of hemoglobin interfere with the normal course of metabolic processes in the erythrocyte, the latter turns out to be functionally defective and is destroyed in the cells of the reticuloendothelial system. In thalassemia, the HLA content in erythrocytes decreases. Depending on the degree of reduction in the synthesis of a particular polypeptide chain of the hemoglobin molecule, two main types of thalassemia are distinguished: a and b.