Hereditary hemolytic anemia. Depending on the severity of the disease, there are three forms

Hemolytic anemia is a complex of diseases that are combined into one group due to the fact that in all of them the life expectancy of red blood cells is reduced. This promotes hemoglobin loss and leads to hemolysis. These pathologies are similar to each other, but their origin, course and even clinical manifestations differ. Hemolytic anemia in children also has its own characteristics.

Hemolysis is the mass death of blood cells. At its core, this is a pathological process that can occur in two spaces of the body.

1. Extravascular, that is, outside the vessels. Most often, the foci are parenchymal organs - liver, kidneys, spleen, as well as red bone marrow. This type of hemolysis proceeds similar to physiological;
2. Intravascular, when blood cells are destroyed in the lumen blood vessels.

Massive destruction of red blood cells occurs with a typical symptom complex, while the manifestations of intravascular and extravascular hemolysis are different. They are determined when general examination The patient will be helped to establish a diagnosis by a general blood test and other specific tests.

Why does hemolysis occur?

Non-physiological death of red blood cells occurs due to various reasons, among which one of the most important places is occupied by iron deficiency in the body. However, this condition should be differentiated from disorders of the synthesis of red blood cells and hemoglobin, which is helped by lab tests, clinical symptoms.

1. Yellowness of the skin, which is reflected by increased total bilirubin and his free faction.
2. A somewhat distant manifestation is increased viscosity and density of bile with an increased tendency to stone formation. It also changes color as the content of bile pigments increases. This process is due to the fact that liver cells try to neutralize excess bilirubin.
3. The stool also changes its color because bile pigments “reach” it, provoking an increase in the levels of stercobilin and urobilinogen.
4. With extravascular death of blood cells, urobilin levels increase, which is reflected by darkening of the urine.
5. The general blood test reacts with a decrease in red blood cells and a drop in hemoglobin. Young forms of cells – reticulocytes – grow compensatory.

Types of red blood cell hemolysis

The destruction of red blood cells occurs either in the lumen of blood vessels or in parenchymal organs. Since extravascular hemolysis is similar in its pathophysiological mechanism to the normal death of red blood cells in parenchymal organs, the difference lies only in its speed, and it is partially described above.

When red blood cells are destroyed inside the lumen of blood vessels, the following develop:

• an increase in free hemoglobin, the blood acquires a so-called varnish tint;
• change in urine color due to free hemoglobin or hemosiderin;
• hemosiderosis is a condition when iron-containing pigment is deposited in parenchymal organs.

What is hemolytic anemia

At its core, hemolytic anemia is a pathology in which the life expectancy of red blood cells is significantly reduced. This is due to a large number of factors, and they can be external or internal. During the destruction of formed elements, hemoglobin is partially destroyed and partially acquires a free form. A decrease in hemoglobin less than 110 g/l indicates the development of anemia. It is extremely rare that hemolytic anemia is associated with a decrease in the amount of iron.

Internal factors Contributing to the development of the disease are abnormalities in the structure of blood cells, and external factors are immune conflicts, infectious agents, and mechanical damage.

Classification

The disease can be congenital or acquired, and the development of hemolytic anemia after the birth of a child is called acquired.

Congenital is divided into membranopathies, fermentopathy and hemoglobinopathies, and acquired into immune, acquired membranopathy, mechanical damage to the formed elements, due to infectious processes.

To date, doctors do not differentiate the form of hemolytic anemia according to the site of destruction of red blood cells. The most commonly identified is autoimmune. Also, the majority of all fixed pathologies in this group are acquired hemolytic anemias, and they are characteristic of all ages, starting from the first months of life. In children, special caution should be exercised, since these processes can be hereditary. Their development is due to several mechanisms.

1. The appearance of anti-erythrocyte antibodies that come from outside. At hemolytic disease In newborns we are talking about isoimmune processes.
2. Somatic mutations, which serves as one of the triggers of chronic hemolytic anemia. It cannot become a genetic hereditary factor.
3. Mechanical damage to red blood cells occurs as a result of exposure to heavy physical exertion or heart valve replacement.
4. Hypovitaminosis, vitamin E plays a special role.
5. Malarial plasmodium.
6. Exposure to toxic substances.

Autoimmune hemolytic anemia

With autoimmune anemia, the body responds with increased susceptibility to any foreign proteins, and also has an increased tendency to allergic reactions. This is due to an increase in the activity of one’s own immune system. The following indicators may change in the blood: specific immunoglobulins, number of basophils and eosinophils.

Autoimmune anemia is characterized by the production of antibodies to normal blood cells, which leads to impaired recognition of its cells. A subtype of this pathology is transimmune anemia, in which the maternal organism becomes the target of the fetal immune system.

Coombs tests are used to detect the process. They make it possible to identify circulating immune complexes that are not present in in full health. Treatment is carried out by an allergist or immunologist.

Causes

The disease develops for a number of reasons, they can also be congenital or acquired. Approximately 50% of cases of the disease remain without an identified cause, this form is called idiopathic. Among the causes of hemolytic anemia, it is important to highlight those that provoke the process more often than others, namely:

Under the influence of the above triggers and the presence of other triggering mechanisms, formed cells are destroyed, contributing to the appearance of symptoms typical of anemia.

Symptoms

The clinical manifestations of hemolytic anemia are quite extensive, but their nature always depends on the cause that caused the disease, one or another type. Sometimes the pathology manifests itself only when a crisis or exacerbation develops, and remission is asymptomatic, the person does not make any complaints.

All symptoms of the process can be detected only during decompensation of the condition, when there is a pronounced imbalance between healthy, developing and destroyed blood cells, and the bone marrow cannot cope with the load placed on it.

Classic clinical manifestations are represented by three symptom complexes:

• anemic;
• icteric;
• enlargement of the liver and spleen – hepatosplenomegaly.

They usually develop with extravascular destruction of formed elements.

Sickle cell, autoimmune and other hemolytic anemias manifest themselves with such characteristic symptoms.

1. Increased body temperature, dizziness. It occurs when the disease develops rapidly in childhood, and the temperature itself reaches 38C.
2. Jaundice syndrome. The appearance of this symptom is due to the destruction of red blood cells, which leads to an increase in the level of indirect bilirubin, which is processed by the liver. Its high concentration promotes the growth of stercobilin and urobilin in the intestines, due to which feces, skin, and mucous membranes are colored.
3. As jaundice develops, splenomegaly also develops. This syndrome quite often occurs with hepatomegaly, that is, both the liver and spleen enlarge at the same time.
4. Anemia. Accompanied by a decrease in the amount of hemoglobin in the blood.

Other signs of hemolytic anemia include:

• pain in the epigastrium, abdomen, lumbar region, kidneys, bones;
• heart attack-like pain;
• malformations of children, accompanied by signs of disruption of intrauterine fetal formation;
• change in stool character.

Diagnostic methods

Diagnosis of hemolytic anemia is carried out by a hematologist. He makes a diagnosis based on data obtained during examination of the patient. First, anamnestic data is collected and the presence of trigger factors is clarified. The doctor assesses the degree of pallor of the skin and visible mucous membranes, conducts a palpation examination of the abdominal organs, during which an enlargement of the liver and spleen can be determined.

The next stage is laboratory and instrumental examination. A general analysis of urine, blood, and biochemical examination is carried out, during which it is possible to determine the presence of high level indirect bilirubin. An ultrasound of the abdominal organs is also performed.

In especially severe cases, a bone marrow biopsy is prescribed, in which it is possible to determine how red blood cells develop in hemolytic anemia. It is important to carry out correct differential diagnosis in order to exclude pathologies such as viral hepatitis, hematological malignancies, oncological processes, liver cirrhosis, obstructive jaundice.

Treatment

Each individual form of the disease requires its own approach to treatment due to the characteristics of its occurrence. It is important to immediately eliminate all hemolyzing factors if we are talking about an acquired process. If treatment of hemolytic anemia occurs during a crisis, then the patient should receive a large volume of blood transfusions - blood plasma, red blood cells, metabolic and vitamin therapy, and compensation for vitamin E deficiency plays a special role.

Sometimes there is a need to prescribe hormones and antibiotics. If a diagnosis of microspherocytosis is made, the only treatment option is splenectomy.

Autoimmune processes involve the use of steroid hormones. Prednisolone is considered the drug of choice. This therapy reduces hemolysis and sometimes stops it completely. Particularly severe cases require the administration of immunosuppressants. If the disease is completely resistant to medications, doctors resort to removing the spleen.

In the toxic form of the disease, there is a need for detoxification intensive therapy - hemodialysis, treatment with antidotes, forced diuresis while maintaining kidney function.

Treatment of hemolytic anemia in children

As mentioned earlier, hemolytic anemia is a group of pathological processes, which in their development mechanism can differ significantly, but all diseases have one common feature - hemolysis. It occurs not only in bloodstream, but also in parenchymal organs.

The first signs of the development of the process often do not cause any suspicion in sick people. If a child develops anemia rapidly, then irritability, fatigue, tearfulness, and pale skin appear. These signs can easily be mistaken for the baby’s character traits. Especially when it comes to children who are often sick. And this is not surprising, since in the presence of this pathology people are susceptible to the development of infectious processes.

The main symptoms of anemia in children are pale skin, which must be differentiated from renal pathologies, tuberculosis, and intoxication of various origins.

The main sign that will allow you to determine the presence of anemia without determining laboratory parameters is that with anemia, the mucous membranes also acquire a pale tint.

Complications and prognosis

The main complications of hemolytic anemia are:

• the worst thing is anemic coma and death;
• decline in performance blood pressure, accompanied by a rapid pulse;
• oliguria;
• formation of stones in the gall bladder and bile ducts.

It should be noted that some patients note an exacerbation of the disease during the cold season. Doctors recommend that such patients not become hypothermic.

Prevention

Preventive measures are primary and secondary.

Immune hemolysis in adults is usually caused by IgG and IgM autoantibodies to self-red blood cell antigens. With the acute onset of autoimmune hemolytic anemia, patients develop weakness, shortness of breath, palpitations, pain in the heart and lower back, the temperature rises, and intense jaundice develops. At chronic course diseases reveal general weakness, jaundice, enlarged spleen, and sometimes liver.

Anemia is normochromic in nature. Macrocytosis and microspherocytosis are detected in the blood, and normoblasts may appear. ESR is increased.

The main method for diagnosing autoimmune hemolytic anemia is the Coombs test, in which antibodies to immunoglobulins (especially IgG) or complement components (C3) agglutinate the patient’s red blood cells (direct Coombs test).

In some cases, it is necessary to detect antibodies in the patient's serum. To do this, the patient's serum is first incubated with normal red blood cells, and then antibodies against them are detected using antiglobulin serum (anti-IgG) - an indirect Coombs test.

IN in rare cases Neither IgG nor complement is detected on the surface of red blood cells (immune hemolytic anemia with a negative Coombs test).

Autoimmune hemolytic anemia with warm antibodies

Autoimmune hemolytic anemia with warm antibodies most often develops in adults, especially women. Warm antibodies refer to IgG that react with protein antigens of red blood cells at body temperature. This anemia can be idiopathic and drug-induced and is observed as a complication of hemoblastosis ( chronic lymphocytic leukemia, lymphogranulomatosis, lymphoma), collagenosis, especially SLE, AIDS.

The clinical picture of the disease is manifested by weakness, jaundice, and splenomegaly. With severe hemolysis, patients develop fever, fainting, chest pain and hemoglobinuria.

Laboratory findings are characteristic of extravascular hemolysis. Anemia is detected with a decrease in hemoglobin level to 60-90 g/l, the content of reticulocytes increases to 15-30%. The direct Coombs test is positive in more than 98% of cases; IgG is detected in combination with or without SZ. Hemoglobin levels are reduced. In a smear peripheral blood microspherocytosis is detected.

Mild hemolysis does not require treatment. For moderate to severe hemolytic anemia, treatment is primarily aimed at the cause of the disease. To quickly stop hemolysis, use normal immunoglobulin G 0.5-1.0 g/kg/day intravenously for 5 days.

Against hemolysis itself, glucocorticoids are prescribed (for example, prednisolone 1 mg/kg/day orally) until hemoglobin levels normalize within 1-2 weeks. After this, the dose of prednisolone is reduced to 20 mg/day, then continued to be reduced for several months and discontinued completely. A positive result is achieved in 80% of patients, but in half of them the disease recurs.

If glucocorticoids are ineffective or intolerant, splenectomy is indicated, which gives positive result in 60% of patients.

In the absence of effect from glucocorticoids and splenectomy, immunosuppressants are prescribed - azathioprine (125 mg/day) or cyclophosphamide (100 mg/day) in combination with or without prednisolone. The effectiveness of this treatment is 40-50%.

In case of severe hemolysis and severe anemia, blood transfusion is performed. Since warm antibodies react with all red blood cells, the usual selection of compatible blood is not applicable. First, the antibodies present in the patient’s serum should be adsorbed using his own red blood cells, from the surface of which the antibodies have been removed. After this, the serum is tested for the presence of alloantibodies to antigens of donor red blood cells. Selected red blood cells are slowly transfused to patients under close supervision. possible occurrence hemolytic reaction.

Autoimmune hemolytic anemia with cold antibodies

This anemia is characterized by the presence of autoantibodies that react at temperatures below 37 °C. There is an idiopathic form of the disease, accounting for about half of all cases, and an acquired form, associated with infections (mycoplasma pneumonia and infectious mononucleosis) and lymphoproliferative conditions.

The main symptom of the disease is increased sensitivity to cold (general hypothermia or ingestion of cold food or drinks), manifested by blueness and whiteness of the fingers and toes, ears, and tip of the nose.

Characteristic disorders peripheral circulation(Raynaud's syndrome, thrombophlebitis, thrombosis, sometimes cold urticaria), resulting from intra- and extravascular hemolysis, leading to the formation of intravascular conglomerates of agglutinated erythrocytes and occlusion of microcirculatory vessels.

Anemia is usually normochromic or hyperchromic. The blood reveals reticulocytosis, a normal number of leukocytes and platelets, a high titer of cold agglutinins, usually IgM and S3 class antibodies. The direct Coombs test reveals only SZ. Agglutination of erythrocytes in vitro at room temperature is often detected, which disappears when heated.

Paroxysmal cold hemoglobinuria

The disease is now rare and can be either idiopathic or caused by viral infections (measles or mumps in children) or tertiary syphilis. In pathogenesis, the formation of biphasic Donath-Landsteiner hemolysins is of primary importance.

Clinical manifestations develop after exposure to cold. During an attack, chills and fever, pain in the back, legs and abdomen, headache and general malaise, hemoglobinemia and hemoglobinuria occur.

The diagnosis is made after the detection of cold Ig antibodies in a two-phase hemolysis test. The direct Coombs test is either negative or reveals SZ on the surface of red blood cells.

The main thing in the treatment of autoimmune hemolytic anemia with cold autoantibodies is to prevent the possibility of hypothermia. In the chronic course of the disease, prednisolone and immunosuppressants (azathioprine, cyclophosphamide) are used. Splenectomy is usually ineffective.

Autoimmune drug-induced hemolytic anemia

Medicines that cause immune hemolytic anemia are divided into three groups according to their pathogenetic mechanism of action.

The first group includes drugs causing disease, the clinical signs of which are similar to those of autoimmune hemolytic anemia with warm antibodies. In most patients, the cause of the disease is methyldopa. When taking this drug at a dose of 2 g/day, 20% of patients have a positive Coombs test. In 1% of patients, hemolytic anemia develops; microspherocytosis is detected in the blood. IgG is detected on red blood cells. Hemolysis subsides several weeks after discontinuation of methyldopa.

The second group includes drugs that are adsorbed on the surface of erythrocytes, act as haptens and stimulate the formation of antibodies to the drug-erythrocyte complex. Such drugs are penicillin and other antibiotics similar in structure. Hemolysis develops when the drug is prescribed in high doses(10 million units/day or more), but is usually moderate and quickly stops after discontinuation of the drug. The Coombs test for hemolysis is positive.

The third group includes drugs (quinidine, sulfonamides, sulfonylurea derivatives, phenycytin, etc.) that cause the formation of specific antibodies of the IgM complex. The interaction of antibodies with drugs leads to the formation of immune complexes that settle on the surface of red blood cells.

The direct Coombs test is positive only in relation to SZ. The indirect Coombs test is positive only in the presence medicinal product. Hemolysis is often intravascular and quickly resolves after drug withdrawal.

Mechanical hemolytic anemia

Mechanical damage to red blood cells leading to the development of hemolytic anemia occurs:

• when red blood cells pass through small vessels over bone protrusions, where they are subjected to external compression (marching hemoglobinuria);
• when overcoming a pressure gradient on prosthetic heart valves and blood vessels;
• when passing through small vessels with altered walls (microangiopathic hemolytic anemia).

March hemoglobinuria occurs after prolonged walking or running, karate or weightlifting and is manifested by hemoglobinemia and hemoglobinuria.

Hemolytic anemia in patients with prosthetic heart valves and blood vessels is caused by intravascular destruction of red blood cells. Hemolysis develops in approximately 10% of patients with a prosthetic aortic valve (stellite valves) or its dysfunction (perivalvular regurgitation). Bioprostheses ( pork valves) and artificial mitral valves rarely cause significant hemolysis. Mechanical hemolysis is found in patients with aortofemoral bypass grafts.

Hemoglobin decreases to 60-70 g/l, reticulocytosis and schizocytes (red blood cell fragments) appear, hemoglobin content decreases, hemoglobinemia and hemoglobinuria occur.

Treatment is aimed at reducing oral iron deficiency and limiting physical activity, which reduces the intensity of hemolysis.

Microangiopathic hemolytic anemia

It is a variant of mechanical intravascular hemolysis. The disease occurs with thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, disseminated intravascular coagulation syndrome, pathology of the vascular wall ( hypertensive crises, vasculitis, eclampsia, disseminated malignant tumors).

In the pathogenesis of this anemia, the deposition of fibrin threads on the walls of arterioles, through the interlacing of which red blood cells are destroyed, is of primary importance. Fragmented red blood cells (schizocytes and helmet cells) and thrombocytopenia are detected in the blood. Anemia is usually severe, the hemoglobin level decreases to 40-60 g/l.

The underlying disease is treated, glucocorticoids, fresh frozen plasma, plasmapheresis and hemodialysis are prescribed.

These include congenital forms of the disease associated with the appearance of spherocytes, which undergo rapid destruction (the osmotic resistance of red blood cells is reduced). This same group includes enzymopathic hemolytic anemias.

Anemia can be autoimmune, associated with the appearance of antibodies to blood cells.

All hemolytic anemias are characterized by increased destruction of red blood cells, as a result of which the level of indirect bilirubin increases in the peripheral blood.

In autoimmune hemolytic anemia, an enlarged spleen may be detected; a laboratory test reveals a positive Coombs test.

B12-folate deficiency anemia is associated with a lack of vitamin B12 and folic acid. This type of disease develops due to a lack of intrinsic Castle factor or due to helminthic infestation. The clinical picture is dominated by severe macrocytic anemia. The color index is always increased. The size of the red blood cells is normal or increased in diameter. Often there are symptoms of funicular myelosis (damage to the lateral trunks of the spinal cord), which is manifested by parasthesia lower limbs. Sometimes this symptom is detected before anemia develops. Bone marrow puncture reveals the megalocytic type of hematopoiesis.

Aplastic anemia is characterized by inhibition (aplasia) of all hematopoietic lineages - erythroid, myeloma and platelet. Therefore, such patients are prone to infections and hemorrhages. In bone marrow aspirate, a decrease in cellularity and a decrease in all hematopoietic sprouts are observed.

Epidemiology. In the Mediterranean basin and equatorial Africa, hereditary hemolytic anemia ranks second, accounting for 20-40% of anemia.

Causes of hemolytic anemia

Hemolytic jaundice, or hemolytic anemia, was isolated from other types of jaundice by Minkowski and Shoffar in 1900. The disease is characterized by prolonged, periodically worsening jaundice, associated not with liver damage, but with increased breakdown of less resistant red blood cells in the presence of increased blood-destructive function of the spleen. Often the disease is observed in several family members, in several generations: changes in red blood cells are also characteristic; the latter are reduced in diameter and have the shape of a ball (and not a disk, as is normal), which is why it is proposed to call the disease “microspherocytic anemia” (Rare cases of sickle cell and oval cell anemia have been described, when red blood cells are also less stable and some patients develop hemolytic jaundice.) . In these. characteristics of erythrocytes tended to see a congenital anomaly of erythrocytes. However, in Lately the same microspherocytosis was obtained under the influence of prolonged exposure to small doses of hemolytic poisons. From this we can conclude that with familial hemolytic jaundice it is a question of the long-term action of some kind of poison, formed, perhaps, as a result of persistently impaired metabolism or entering the body of patients from the outside. This allows familial hemolytic jaundice to be placed on a par with hemolytic anemias of a certain symptomatic origin. Due to changes in shape, red blood cells in familial hemolytic anemia are less stable, are more phagocytosed by the active elements of the mesenchyme, especially the spleen, and undergo complete decay. From the hemoglobin of decaying red blood cells, bilirubin is formed, which is contained in the blood of the splenic vein much more than in the splenic artery (as can be seen during the operation to remove the spleen). In the development of the disease, disruption of higher nervous activity is also important, as evidenced by the worsening of the disease or its first detection, often following emotional moments. Activities of one of the most active organs hemorrhage - the spleen, like the hematopoietic organs, is undoubtedly constantly subject to regulation by the nervous system.

Hemolysis is compensated by the increased work of the bone marrow, which releases a large number of young red blood cells (reticulocytes), which prevents the development of severe anemia for many years.

The condition for normal life expectancy of erythrocytes is deformability, the ability to withstand osmotic and mechanical stress, normal restoration potential, as well as adequate energy production. Violation of these properties shortens the lifespan of red blood cells, in some cases down to several days (corpuscular hemolytic anemia). General characteristics of these anemias is an increase in the concentration of erythropoietin, which, under the current conditions, provides compensatory stimulation of erythropoiesis.

Corpuscular hemolytic anemia is usually caused by genetic defects.

One of the forms of diseases in which the membrane is damaged is hereditary spherocytosis (spherocytic anemia). It is caused by a functional abnormality (ankyrin defect) or deficiency of spectrin, which is an essential component of the erythrocyte cytoskeleton and largely determines its stability. The volume of spherocytes is normal, but disruption of the cytoskeleton causes the red blood cells to take on a spherical shape instead of the normal, easily deformable biconcave shape. The osmotic resistance of such cells is reduced, i.e., under continued hypotonic conditions they are hemolyzed. Such red blood cells are prematurely destroyed in the spleen, so splenectomy is effective for this pathology.

Defect of glucose metabolism enzymes in erythrocytes:

1. with a defect in pyruvate kinase, the formation of ATP decreases, the activity of Na + /K + -ATPase decreases, the cells swell, which contributes to their early hemolysis;
2. When glucose-6-phosphate dehydrogenase is defective, the pentose phosphate cycle is disrupted so that oxidized glutathione (GSSG) produced by oxidative stress cannot be adequately regenerated to the reduced form (GSH). As a result, free SH groups of enzymes and membrane proteins, as well as phospholipids, are unprotected from oxidation, which leads to premature hemolysis. Consumption of fava beans (Viciafabamajor, which causes favism) or certain drugs (primaquine or sulfonamides) increases the severity of oxidative stress, thereby exacerbating the situation;
3. a defect in hexokinase results in a deficiency of both ATP and GSH.

Sickle cell anemia and thalassemias also have a hemolytic component.

In (acquired) paroxysmal nocturnal hemoglobinuria, some red blood cells (derived from stem cells with somatic mutations) have increased sensitivity to the action of the complement system. It is caused by a defect in the membrane portion of the anchor (glycosylphosphatidylinositol) protein that protects red blood cells from the action of the complement system (especially decay accelerating factor CD55 or membrane reactive lysis inhibitor). These disorders lead to activation of the complement system with subsequent possible perforation of the erythrocyte membrane.

Extracorpuscular hemolytic anemia can be caused by the following reasons:

• mechanical, such as damage to red blood cells when they hit artificial heart valves or vascular prostheses, especially when cardiac output increases;
• immune, for example, during transfusion of ABO-incompatible blood, or during an Rh conflict between mother and fetus;
• the influence of toxins, such as some snake venoms.

In most hemolytic anemias, red blood cells, as in normal conditions, are phagocytosed and digested in the bone marrow, spleen and liver (extravascular hemolysis), and the released iron is utilized. Small amounts of iron released into the vascular bed bind to haptoglobin. However, with massive acute intravascular hemolysis, the level of haptoglobin increases and is filtered by the kidneys as free hemoglobin. This leads not only to hemoglobinuria (dark urine appears), but also due to tubular occlusion to acute renal failure. In addition, chronic hemoglobinuria is accompanied by the development of iron deficiency anemia, an increase in cardiac output and a further increase in mechanical hemolysis, leading to a vicious circle. Finally, fragments of erythrocytes formed during intravascular hemolysis can cause the formation of blood clots and emboli with subsequent development of ischemia of the brain, myocardium, kidneys and other organs.

Symptoms and signs of hemolytic anemia

Patients complain of weakness, decreased performance, periodic attacks of fever with chills, pain in the spleen and liver, increased weakness and the appearance of obvious jaundice. For years, sometimes from the first years of life, they have mild yellowness of the skin and sclera, usually also an enlarged spleen and anemia.

Upon examination, the integument is slightly lemon-yellow in color; in contrast to hepatic jaundice, there is no scratching or itching; Developmental anomalies can often be found - a tower skull, a saddle nose, widely spaced eye sockets, a high palate, and sometimes six-fingered teeth.

On the part of the internal organs, the most constant sign is an enlarged spleen, usually of a moderate degree, less often significant splenomegaly; the spleen is painful during crises, when, due to muscular protection, palpation may be difficult and respiratory excursions may be limited chest left. The liver is often not enlarged, although with a long course of the disease, the passage of bile saturated with bilirubin causes loss of pigment stones, sharp pain in the liver area (pigmentary colic) and an enlargement of the organ itself.

Laboratory data. Port wine-colored urine due to increased urobilin content does not contain bilirubin and bile acids. The stools are more colored than usual (hypercholic stools), the release of urobilin (stercobilin) ​​reaches 0.5-1.0 per day instead of the normal 0.1-0.3. Blood serum is golden in color; the content of hemolytic (indirect) bilirubin was increased to 1-2-3 mg% (instead of 0.4 mg% normally, according to the diazoreagent method), the cholesterol content was slightly reduced.

Characteristic hematological changes in erythrocytes come down primarily to the following triad:

1. decreased osmotic stability of red blood cells;
2. persistent significant reticulocytosis;
3. decrease in red blood cell diameter.

Decreased osmotic resistance of red blood cells. While normal red blood cells are preserved not only in physiological salt solution (0.9%), but also in slightly less concentrated solutions and begin to hemolyze only with a 0.5% solution, with hemolytic jaundice hemolysis begins already at 0.7-0 .8% solution. Therefore, if, for example, a drop of healthy blood is added to a precisely prepared 0.6% sodium chloride solution, then after centrifugation all the red blood cells will be precipitated, and the solution will remain colorless; with hemolytic jaundice, the red blood cells in a 0.6% solution are partially hemolyzed, and the liquid turns pink.

To accurately establish the boundaries of hemolysis, take a series of test tubes with solutions table salt, for example, 0.8-0.78-0.76-0.74%, etc. up to 0.26-0.24-0.22-0.2% and mark the first tube with the onset of hemolysis (“ minimal resistance") and that test tube in which all the red blood cells were hemolyzed, and if the solution is drained, only a whitish precipitate of leukocytes and shadows of red blood cells will remain ("maximum resistance"). The normal limits of hemolysis are approximately 0.5 and 0.3% sodium chloride, with hemolytic jaundice usually 0.8-0.6% (onset) and 0.4-0.3% (complete hemolysis).

Reticulocytes are normally no more than 0.5-1.0%, but with hemolytic jaundice - up to 5-10% or more, with fluctuations only within relatively small limits during repeated studies over a number of years. Reticulocytes are counted in a fresh, unfixed smear made on glass with a thin layer of brilliant cresyl blue paint and briefly placed in a humid chamber.

The average diameter of erythrocytes instead of normal 7.5 μ in hemolytic jaundice is reduced to 6-6.5 μ; erythrocytes in the dative preparation do not give, as normally, the phenomenon of coin columns, and do not show retractions when viewed in profile.

The amount of hemoglobin is often reduced to 60-50%, red blood cells - to 4,000,000-3,000,000; the color index fluctuates around 1.0. However, the numbers of red blood, due to enhanced regeneration, despite the increased breakdown of blood, can be almost normal; The white blood cell count is normal or slightly elevated.

Course, complications and prognosis of hemolytic anemia

The onset of the disease is usually gradual during puberty, sometimes the disease is detected already from the first days of life. Often the disease is detected for the first time after an accidental infection, overexertion, injury or surgery, anxiety, which in the future often serves as an impetus for the worsening of the disease, for a hemolytic crisis. Once it occurs, the disease lasts a lifetime. True, in favorable cases there may be long periods of mild or latent disease.

The crisis is accompanied sharp pain in the area of ​​the spleen, then the liver, fever, often with chills (from the breakdown of the blood), a sharp increase in jaundice, severe weakness that confines the patient to bed, a drop in hemoglobin to 30-20% or lower and, accordingly, low numbers of red blood cells.

In case of pigmentary colic with blockage of the common bile duct by a stone, mechanical jaundice may be associated with discolored feces, itchy skin, the presence in the blood, in addition to hemolytic, also of hepatic (direct) bilirubin, icteric urine containing bilirubin, etc., which does not exclude hemolytic jaundice as the main disease. Severe damage to the liver parenchyma, in particular liver cirrhosis, does not develop even with a long-term course of the disease, just as depletion of bone marrow hematopoiesis does not occur.

The spleen may develop infarctions, perisplenitis, for a long time constituting the main complaint of patients or combined with great anemia and general weakness of patients.
Sometimes trophic ulcers develop on the legs, stubbornly resistant to local treatment and pathogenetically associated with increased hemolysis, because these ulcers quickly heal after the removal of the spleen and the cessation of abnormally increased breakdown of blood.

In mild cases, the disease can have the effect of almost only a cosmetic defect (as they say, such “patients are more jaundiced than sick”), in moderate cases the disease leads to loss of ability to work, especially since physical fatigue undoubtedly increases the breakdown of blood in these patients; in rare cases, hemolytic jaundice is the direct cause of death - from severe anemia, consequences of splenic infarction, halemia with obstructive jaundice, etc.

Diagnosis and differential diagnosis of hemolytic anemia

You should think more often about familial hemolytic jaundice, since many cases have long been incorrectly interpreted as persistent malaria, malignant anemia, etc.

In malaria, increased blood breakdown accompanies only periods of active infection, when plasmodia are easily detected in the blood, and there is leukopenia with neutropenia; reticulocytosis is also observed periodically, only after febrile paroxysms; osmotic resistance and erythrocyte size are not reduced.

With malignant anemia, the increase in blood bilirubin generally lags behind the degree of anemia, the enlargement of the spleen is less constant, patients are usually elderly, there is glossitis, achylia, diarrhea, paresthesia and other signs of funicular myelosis.

Sometimes physiological deposition of fat on the conjunctiva (pinguecula) or individual yellowish skin color in healthy individuals, etc. are mistaken for hemolytic jaundice.

Treatment of hemolytic anemia

Acute hemolytic crisis - discontinuation of the “provoking” medication; forced diuresis; hemodialysis (for acute renal failure).

Therapy for AIHA with warm antibodies is carried out with prednisolone orally for 10-14 days with gradual withdrawal over 3 months. Splenectomy - in case of insufficient effect of prednisolone therapy, relapse of hemolysis. If prednisolone therapy and splenectomy are ineffective, cytostatic therapy is used.

When treating AIHA with cold antibodies, hypothermia should be avoided and immunosuppressive therapy is used.

Of great importance is a gentle regimen with the correct alternation of work and rest, staying in a warm climate, and preventing accidental, even mild infections. Treatment with iron and liver is ineffective. Blood transfusions sometimes lead to severe reactions, but when used with carefully selected single-group fresh blood, they can be usefully used in patients with significant anemia.

In cases with a progressive increase in anemia, significant weakness, frequent hemolytic crises, making patients incapacitated and often bed sick, an operation to remove the spleen is indicated, which quickly leads to the disappearance of jaundice that has lasted for years, an improvement in blood composition, and a clear increase in performance. The operation of splenectomy is, of course, a serious intervention in itself, so the indications for it should be seriously weighed. The operation is complicated by the presence of a large spleen, with extensive adhesions to the diaphragm and other organs.

Only as an exception, after removal of the spleen, increased breakdown of the blood may again occur, and a leukemoid reaction may be observed in the white blood. Reduced osmotic resistance of erythrocytes and microspherocytosis usually remain in splenectomized patients.

Other forms of hemolytic anemia

Hemolytic anemias are observed as a symptom of a number of blood diseases or infections (for example, with malignant anemia, malaria, which are mentioned above in the section differential diagnosis familial hemolytic jaundice).

Serious clinical significance has rapidly advancing hemolysis, leading to the same clinical picture of hemoglobinemia, hemoglobinuria and renal complications, with various painful forms. Hemoglobinuria is observed, as an exception, periodically "and with classic familial hemolytic jaundice, and also sometimes with a special form of chronic hemolytic anemia with attacks of nocturnal hemoglobinuria and with severe atypical acute hemolytic anemia accompanied by fever (the so-called acute hemolytic anemia) without microcytosis, with fibrosis spleen and reticulocytosis up to 90-95%.

It is believed that in general, if at least 1/50 of all blood quickly breaks down, then the reticuloendothelium does not have time to completely process hemoglobin and bilirubin and hemoglobinemia and hemoglobinuria occur, along with hemolytic jaundice developing simultaneously.

Acute hemolytic anemia with hemoglobinuria and anuria after transfusion of incompatible blood (due to hemolysis of donor red blood cells) develops as follows.
Already in the process of blood transfusion, the patient complains of pain in the lower back, in the head, with a feeling of swelling, “fullness” of the head, shortness of breath, and tightness in the chest. Nausea, vomiting, stunning chills with increased temperature occur, the face is hyperemic, with a cyanotic tint, bradycardia, followed by a frequent, thread-like pulse with other signs of vascular collapse. Already the first portions of urine are the color of black coffee (hemoglobinuria); anuria soon sets in; By the end of the day, jaundice develops.

In the coming days, up to a week, a period of latent or symptomatic improvement begins: the temperature drops, appetite returns, restful sleep; the jaundice disappears in the coming days. However, little urine is excreted or complete anuria continues.

In the second week, fatal uremia develops with high levels of nitrogenous waste in the blood, sometimes even with restored diuresis with impaired renal function.
Such phenomena are observed when transfusion is usually 300-500 ml of incompatible blood; in the most severe cases, death occurs already in the early shock period; with transfusion of less than 300 ml of blood, recovery occurs more often.

Treatment. Repeated transfusion of 200-300 ml of obviously compatible, better than the same group, fresh blood (which is believed to eliminate the destructive spasm of the renal arteries), administration of alkalis and large amounts of fluid to prevent blockage of the renal tubules with hemoglobin detritus, novocaine blockade of the perirenal tissue, diathermy of the renal area , liver preparations, calcium salts, symptomatic remedies, general body warming.

Other forms of hemoglobinuria are also known, usually occurring in separate paroxysms (attacks):

• malarial hemoglobinuric fever, occurring in patients with malaria after taking quinine in rare cases acquired hypersensitivity to him;
• paroxysmal hemoglobinuria, occurring under the influence of cooling - from special “Cold” autohemolysins; with this disease, blood cooled in a test tube to 5° for 10 minutes and again heated to body temperature undergoes hemolysis, and this is especially easy when adding fresh complement from a guinea pig; earlier illness associated with syphilitic infection, which is not justified for most cases of the disease;
• March hemoglobinuria after long treks;
• myohemoglobinuria due to the excretion of myohemoglobin in the urine during traumatic crushing of muscles, for example, limbs;
• toxic hemoglobinuria in case of poisoning with Berthollet salt, sulfonamide and other chemotherapy drugs, morels, snake venom etc.

In milder cases, the matter does not reach hemoglobinuria, only toxic anemia and hemolytic jaundice develop.

Treatment carried out according to the above principles, taking into account the characteristics of each painful form and individual characteristics sick.

1

1. Hematology / O.A. Rukavitsyn, A.D. Pavlov, E.F. Morshakova [etc.] /ed. O.A. Rukavitsina. – St. Petersburg: LLC “DP”, 2007. – 912 p.

2. Cardiology. Hematology / ed. ON THE. Buna, N.R. College and others - M.: Reed Elsiver LLC, 2009. - 288 p.

3. Visual hematology / Translation from English. Edited by prof. IN AND. Ershova. – 2nd ed. – M.: GEOTAR-Media, 2008. – 116 p.: ill.

4. Papayan A.V., Zhukova L.Yu. Anemia in children: a guide for doctors. – SPb.: PETER. – 2001 – 384 p.

5. Pathophysiology: textbook: in 2 volumes/ed. V.V. Novitsky, E.D. Goldberg, O.I. Urazova. – 4th ed. – GEOTAR-Media, 2010. – T.2. – 848 p.: ill.

6. Pathophysiology: textbook, 3 volumes: [A.I. Volozhin and others]; edited by A.I. Volozhina, G.V. Poryadina. – M.: Publishing Center “Academy”, 2006.- T.2 – 256 pp.: ill.

8. Guide to hematology / Ed. A.I. Vorobyova. - M.: Newdiamed, 2007. - 1275 p.

9. Shiffman F.J. Pathophysiology of blood. – M.: Publishing house BINOM, 2009. – 448 p.

Hemolytic anemia is a group of diseases characterized by pathologically intense destruction of red blood cells, increased formation of their breakdown products, as well as a reactive increase in erythropoiesis. Currently, all hemolytic anemias are usually divided into two main groups: hereditary and acquired.

Hereditary hemolytic anemias, depending on the etiology and pathogenesis, are divided into:

I. Membranopathy of erythrocytes:

a) “protein-dependent”: microspherocytosis; ovalocytosis; stomatocytosis; pyropoikilocytosis; "Rh-zero" disease;

b) “lipid-dependent”: acanthocytosis.

II. Enzymopathies of erythrocytes caused by deficiency:

a) enzymes of the pentose phosphate cycle;

b) glycolysis enzymes;

c) glutathione;

d) enzymes involved in the use of ATP;

e) enzymes involved in the synthesis of porphyrins.

III. Hemoglobinopathies:

a) associated with a violation of the primary structure of globin chains;

b) thalassemia.

Acquired hemolytic anemia:

I. Immunohemolytic anemia:

a) autoimmune;

b) heteroimmune;

c) isoimmune;

d) transimmune.

II. Acquired membranopathies:

a) paroxysmal nocturnal hemoglobinuria(Marchiafava-Micheli disease);

b) spur cell anemia.

III. Anemia associated with mechanical damage to red blood cells:

a) march hemoglobinuria;

b) arising from prosthetics of blood vessels or heart valves;

c) Moshkovich disease (microangiopathic hemolytic anemia).

IV. Toxic hemolytic anemia of various etiologies.

Mechanisms of development and hematological characteristics of congenital hemolytic anemias

The above classification of hemolytic anemia convincingly indicates that the most important etiopathogenetic factors in the development of erythrocyte hemolysis are disturbances in the structure and function of erythrocyte membranes, their metabolism, the intensity of glycolytic reactions, pentose phosphate oxidation of glucose, as well as qualitative and quantitative changes in the structure of hemoglobin.

I. Features separate forms erythrocyte membranopathies

As already indicated, pathology can be associated either with a change in the structure of the protein or with a change in the structure of the lipids of the erythrocyte membrane.

The most common protein-dependent membranopathies include the following hemolytic anemias: microspherocytosis (Minkowski-Choffard disease), ovalocytosis, stomatocytosis, more rare forms - piropoikilocytosis, Rh-null disease. Lipid-dependent membranopathies occur in a small percentage among other membranopathies. An example of such hemolytic anemia is acanthocytosis.

Microspherocytic hemolytic anemia (Minkowski-Choffard disease). The disease is inherited in an autosomal dominant manner. The basis for disturbances in microspherocytosis is a reduced content of the actomyosin-like protein spectrin in the erythrocyte membrane, a change in its structure and a disruption of the connection with actin microfilaments and lipids of the inner surface of the erythrocyte membrane.

At the same time, there is a decrease in the amount of cholesterol and phospholipids, as well as a change in their ratio in the erythrocyte membrane.

These disorders make the cytoplasmic membrane highly permeable to sodium ions. A compensatory increase in the activity of Na, K-ATPase does not ensure sufficient removal of sodium ions from the cell. The latter leads to overhydration of red blood cells and contributes to a change in their shape. Red blood cells become spherocytes, lose their plastic properties and, passing through the sinuses and intersinus spaces of the spleen, are injured, lose part of their membrane and turn into microspherocytes.

The lifespan of microspherocytes is approximately 10 times shorter than that of normal erythrocytes, mechanical resistance is 4-8 times lower, and the osmotic resistance of microspherocytes is also impaired.

Despite the congenital nature of microspherocytic hemolytic anemia, its first manifestations are usually observed in older childhood, adolescence and adulthood, rarely in infants and the elderly.

In patients with microspherocytic anemia, yellowness of the skin and mucous membranes occurs, an enlargement of the spleen, in 50% of patients the liver becomes enlarged, and there is a tendency to form stones in the gall bladder. Some patients may have congenital anomalies of the skeleton and internal organs: tower skull, gothic palate, brady- or polydactyly, strabismus, malformations of the heart and blood vessels (the so-called hemolytic constitution).

Picture of blood. Anemia of varying severity. Reduced number of red blood cells in peripheral blood. The hemoglobin content during hemolytic crises decreases to 40-50 g/l, during the inter-crisis period it is approximately 90-110 g/l. The color index may be normal or slightly reduced.

The number of microspherocytes in peripheral blood varies - from a small percentage to a significant increase in the total number of red blood cells. The content of reticulocytes is persistently increased and ranges from 2-5% during the inter-crisis period to 20% or more (50-60%) after a hemolytic crisis. During a crisis, single erythrokaryocytes may be detected in the peripheral blood.

The number of leukocytes during the inter-crisis period is within the normal range, and against the background of a hemolytic crisis - leukocytosis with a neutrophilic shift to the left. The platelet count is usually normal.

Bone marrow puncture reveals pronounced hyperplasia of the erythroblastic lineage with an increased number of mitoses and signs of accelerated maturation.

With microspherocytic anemia, as with other hemolytic anemias, there is an increase in the level of bilirubin in the blood serum, mainly due to the unconjugated fraction.

Ovalocytic hemolytic anemia (hereditary elliptocytosis). Ovalocytes are a phylogenetically more ancient form of red blood cells. In the blood of healthy people they are detected in a small percentage - from 8 to 10. In patients with hereditary elliptocytosis, their number can reach 25-75%.

The disease is inherited in an autosomal dominant manner. The pathogenesis is caused by a defect in the erythrocyte membrane, which lacks several fractions of membrane proteins, including spectrin. This is accompanied by a decrease in the osmotic resistance of ovalocytes, an increase in autohemolysis and a shortening of the life span of ovalocytes.

The destruction of ovalocytes occurs in the spleen, so most patients experience its enlargement.

Picture of blood. Anemia of varying severity, most often normochromic. The presence of ovalocytes in the peripheral blood is more than 10-15%, moderate reticulocytosis. Increase in indirect bilirubin in blood serum. Ovalocytosis is often combined with other forms of hemolytic anemia, for example, sickle cell anemia, thalassemia.

Hereditary stomatocytosis. The type of inheritance is autosomal dominant. This is a rare pathology. The diagnosis is based on the detection of a peculiar appearance of red blood cells in a blood smear: an unstained area in the center of the red blood cell is surrounded by colored areas connected at the sides, which resembles an open mouth (Greek stoma). Changes in the shape of red blood cells are associated with genetic defects the structure of membrane proteins, which causes increased membrane permeability for Na + and K + ions (the passive penetration of sodium into the cell increases approximately 50 times and the release of potassium from erythrocytes increases by 5 times). In most carriers of the anomaly, the disease is not clinically manifested.

Picture of blood. Patients develop anemia, often normochromic. During the hemolytic crisis there is a sharp decline hemoglobin, high reticulocytosis. The level of indirect bilirubin increases in the blood serum.

The osmotic resistance and lifespan of defective red blood cells are reduced.

Determination of an increased amount of sodium ions in altered red blood cells and a decrease in potassium ions is of diagnostic importance.

Acanthocytic hemolytic anemia. The disease belongs to lipid-dependent membranopathies, is inherited in an autosomal recessive manner and manifests itself in early childhood. With this pathology, peculiar red blood cells are found in the blood of patients - acanthocytes (Greek akanta - thorn, thorn). on the surface of such red blood cells there are from 5 to 10 long spike-like projections.

It is believed that in the membranes of acanthocytes there are disturbances in the phospholipid fraction - an increase in the level of sphingomyelin and a decrease in phosphatidylcholine. These changes lead to the formation of defective red blood cells.

At the same time, the amount of cholesterol, phospholipids, triglycerides in the blood serum of such patients is reduced, and β-protein is absent. The disease is also called hereditary abetalipoproteinemia.

Picture of blood. Anemia, often normochromic, reticulocytosis, the presence of red blood cells with characteristic spike-like projections.

The content of indirect bilirubin in the blood serum is increased.

II. Hereditary hemolytic anemia associated with impaired activity of erythrocyte enzymes

Hemolytic anemia associated with deficiency of pentose phosphate cycle enzymes. Insufficiency of glucose-6-phosphate dehydrogenase of erythrocytes is inherited in a sex-linked type (X-chromosomal type). In accordance with this, clinical manifestations of the disease are observed mainly in men who inherited this pathology from their mother with her X chromosome, and in women who are homozygous for the abnormal chromosome. In heterozygous women, clinical manifestations will depend on the ratio of normal red blood cells and red blood cells with glucose-6-phosphate dehydrogenase deficiency.

Currently, more than 250 variants of glucose-6-phosphate dehydrogenase deficiency have been described, of which 23 variants were discovered in the USSR.

The key role of G-6-FDG is its participation in the reduction of NADP and NADPH2, which ensure the regeneration of glutathione in erythrocytes. Reduced glutathione protects red blood cells from decay upon contact with oxidants. In individuals with glucose-6-phosphate dehydrogenase deficiency, oxidants of exogenous and endogenous origin activate lipid peroxidation of erythrocyte membranes, increase the permeability of the erythrocyte membrane, disrupt the ionic balance in cells and reduce the osmotic resistance of erythrocytes. Acute intravascular hemolysis occurs.

More than 40 different types of medicinal substances are known that are oxidizing agents and provoke hemolysis of red blood cells. These include antimalarials, many sulfa drugs and antibiotics, anti-tuberculosis drugs, nitroglycerin, analgesics, antipyretics, vitamins C and K, etc.

Hemolysis can be induced by endogenous intoxications, for example, diabetic acidosis, acidosis in renal failure. Hemolysis occurs during toxicosis of pregnant women.

Picture of blood. A hemolytic crisis provoked by taking a drug is accompanied by the development of normochromic anemia, reticulocytosis, neutrophilic leukocytosis, and sometimes the development of a leukemoid reaction. Reactive erythroblastosis is noted in the bone marrow.

In newborns with a severe deficiency of glucose-6-phosphate dehydrogenase activity, hemolytic crises occur immediately after birth. This is a hemolytic disease of newborns, not associated with an immunological conflict. The disease occurs with severe neurological symptoms. The pathogenesis of these crises has not been sufficiently studied; it is assumed that hemolysis is provoked by the pregnant or nursing mother taking medications with a hemolytic effect.

Hereditary hemolytic anemia caused by deficiency of erythrocyte pyruvate kinase activity. Congenital hemolytic anemia occurs in individuals homozygous for an autosomal recessive gene. Heterozygous carriers are practically healthy. The enzyme pyruvate kinase is one of the concluding enzymes of glycolysis that ensures the formation of ATP. In patients with pyruvate kinase deficiency, the amount of ATP in erythrocytes decreases and the products of glycolysis of previous stages - phosphophenolpyruvate, 3-phosphoglycerate, 2,3-diphosphoglycerate - accumulate, and the content of pyruvate and lactate decreases.

As a result of a decrease in ATP levels, all energy-dependent processes are disrupted, and primarily the work of Na+, K+-ATPase of the erythrocyte membrane. A decrease in the activity of Na+, K+-ATPase leads to the loss of potassium ions by the cell, a decrease in the content of monovalent ions and dehydration of red blood cells.

Dehydration of red blood cells makes it difficult to oxygenate hemoglobin and release oxygen from hemoglobin to tissues. An increase in 2,3-diphosphoglycerate in erythrocytes partially compensates for this defect, since the affinity of hemoglobin for oxygen decreases when it interacts with 2,3-diphosphoglycerate, and, consequently, the release of oxygen to tissues is facilitated.

Clinical manifestations of the disease are heterogeneous and can manifest as hemolytic and aplastic crises, and in some patients - in the form of mild anemia or even asymptomatic.

Picture of blood. Moderate anemia, often normochromic. Sometimes macrocytosis is detected; the osmotic resistance of erythrocytes is reduced or unchanged; during crises, the content of indirect bilirubin in the plasma increases. The number of reticulocytes in the peripheral blood increases sharply during a crisis, and in some patients erythrokaryocytes appear in the blood.

III. Hemoglobinopathies

This is a group of hemolytic anemias associated with a violation of the structure or synthesis of hemoglobin.

There are hemoglobinopathies caused by an anomaly in the primary structure of hemoglobin, qualitative (sickle cell anemia), and caused by a violation of the synthesis of hemoglobin chains, or quantitative (thalassemia).

Sickle cell anemia. The disease was first described in 1910 by Herrick. In 1956, Itano and Ingram established that the disease is a consequence gene mutation, as a result of which an amino acid substitution occurs in position VI of the β-polypeptide chain of glutamic acid hemoglobin with neutral valine and abnormal hemoglobin S begins to be synthesized, which is accompanied by the development of pronounced poikilocytosis and the appearance of sickle cell forms of erythrocytes.

The reason for the appearance of sickle-shaped red blood cells is that hemoglobin S in the deoxygenated state has 100 times less solubility than hemoglobin A, as well as a high ability to polymerize. As a result, oblong crystals form inside the red blood cell, which give the red blood cell a sickle shape. Such red blood cells become rigid, lose their plastic properties and are easily hemolyzed.

In the case of homozygous carriage we speak of sickle cell anemia, and in heterozygous carriage we speak of sickle cell anomaly. The disease is common in the countries of the “malarial belt” of the globe (countries of the Mediterranean, the Near and Middle East, North and West Africa, India, Georgia, Azerbaijan, etc.). The presence of hemoglobin S in heterozygous carriers provides them with protection against tropical malaria. In residents of these countries, hemoglobin S occurs in up to 40% of the population.

The homozygous form of the disease is characterized by moderate normochromic anemia, the total hemoglobin content is 60-80 g/l. The number of reticulocytes is increased - 10% or more. The average lifespan of red blood cells is about 17 days. A characteristic feature is the presence of sickle-shaped red blood cells and red blood cells with basophilic punctation in the stained smear.

Hemolysis of red blood cells contributes to the development of thrombotic complications. Multiple thromboses of the vessels of the spleen, lungs, joints, liver, and meninges may occur, followed by the development of infarction in these tissues. Depending on the localization of thrombosis in sickle cell anemia, several syndromes are distinguished - thoracic, musculoskeletal, abdominal, cerebral, etc. Worsening of anemia may be associated with a hypoplastic crisis, which most often occurs in children against the background of an infection. In this case, inhibition of bone marrow hematopoiesis is noted and reticulocytes disappear in the peripheral blood, the number of red blood cells, neutrophils and platelets decreases.

A hemolytic crisis can be provoked in patients with sickle cell anemia by infectious diseases, stress, and hypoxia. During these periods, the number of red blood cells sharply decreases, the level of hemoglobin drops, black urine appears, icteric discoloration of the skin and mucous membranes appears, and indirect bilirubin in the blood increases.

In addition to aplastic and hemolytic crises in sickle cell anemia, sequestration crises are observed, in which a significant part of the red blood cells is deposited in internal organs, in particular in the spleen. When red blood cells are deposited in internal organs, they may be destroyed at the deposit sites, although in some cases red blood cells are not destroyed during deposit.

The heterozygous form of hemoglobinopathy S (sickle cell anomaly) is asymptomatic in most patients, since the content pathological hemoglobin in erythrocytes is small. A small percentage of heterozygous carriers of abnormal hemoglobin during hypoxic conditions (pneumonia, rise to altitude) may have dark urine and various thrombotic complications.

Thalassemia. This is a group of diseases with a hereditary disorder of the synthesis of one of the globin chains, hemolysis, hypochromia and ineffective erythrocytopoiesis.

Thalassemia is common in Mediterranean countries, Central Asia, Transcaucasia, etc. Environmental and ethnic factors, consanguineous marriages, and the incidence of malaria in a given area play a significant role in its spread.

The disease was first described by American pediatricians Cooley and Lee in 1925 (probably a homozygous form of α-thalassemia).

The etiological factor in thalassemia is mutations of regulatory genes, the synthesis of abnormally unstable or non-functioning messenger RNA, which leads to disruption of the formation of the α-, β-, γ-, and δ-chain of hemoglobin. It is possible that the development of thalassemia is based on hard mutations of structural genes such as deletions, which can also be accompanied by a decrease in the synthesis of the corresponding globin polypeptide chains. Depending on the disturbance in the synthesis of certain polypeptide chains of hemoglobin, α-, β-, δ- and βδ-thalassemia is distinguished, however, each form is based on a deficiency of the main fraction of hemoglobin - HbA.

Normally, the synthesis of various polypeptide chains of hemoglobin is balanced. In pathology, in the case of a deficiency in the synthesis of one of the globin chains, excess production of other polypeptide chains occurs, which leads to the formation excessive concentrations unstable abnormal hemoglobins of various types. The latter have the ability to precipitate and fall out in the erythrocyte in the form of “inclusion bodies”, giving them the shape of targets.

Classification of thalassemias:

1. Thalassemia caused by impaired synthesis of the α-globin chain (α-thalassemia and diseases caused by the synthesis of hemoglobins H and Brats).

2. Thalassemia caused by impaired synthesis of β- and δ-chains of globin (β-thalassemia and β-, δ-thalassemia).

3. Hereditary persistence of fetal hemoglobin, i.e. a genetically determined increase in hemoglobin F in adults.

4. Mixed group - double heterozygous states for the thalassemia gene and the gene for one of the “qualitative” hemoglobinapathies.

α-thalassemia. The gene responsible for the synthesis of the α chain is encoded by two pairs of genes located on the 11th chromosome. One of the pairs is manifest, the other is secondary. In the case of development of α-thalassemia, gene deletion occurs. With homozygous dysfunction of all 4 genes, the globin α-chain is completely absent. Hemoglobin Brats is synthesized, which consists of four γ-chains that are unable to carry oxygen.

Carriers of homozygous α-thalassemia are not viable - the fetus dies in utero due to dropsy.

One of the forms of α-thalassemia is hemoglobinopathy H. With this pathology, there is a deletion of three genes encoding the synthesis of hemoglobin α-chains. Due to a deficiency of α-chains, abnormal hemoglobin H is synthesized, consisting of 4 β-chains. The disease is characterized by a decrease in the number of erythrocytes, hemoglobin (70-80 g/l), severe hypochromia of erythrocytes, their target appearance and basophilic punctation. The number of reticulocytes is moderately increased.

Deletion in one or two genes encoding the α chain causes a slight deficiency of hemoglobin A and is manifested by mild hypochromic anemia, the presence of basophilic puncta and target red blood cells, and a slight increase in reticulocyte counts. As with other forms of hemolytic anemia, with heterozygous α-thalassemia, icteric discoloration of the skin and mucous membranes and an increase in indirect bilirubin in the blood are noted.

β-thalassemia. It is more common than α-thalassemia and can be found in homozygous and heterozygous forms. The gene encoding the synthesis of the β chain is located on chromosome 16. Nearby are the genes responsible for the synthesis of globin γ- and δ-chains. In the pathogenesis of β-thalassemia, in addition to gene deletion, there is a violation of splicing, leading to a decrease in mRNA stability.

Homozygous β-thalassemia (Cooley's disease). The disease is most often detected in children aged 2 to 8 years. Jaundice discoloration of the skin and mucous membranes, enlarged spleen, deformations of the skull and skeleton, and stunted growth appear. In severe forms of homozygous β-thalassemia, these symptoms appear already in the first year of a child’s life. The prognosis is unfavorable.

From the blood side, signs of severe hypochromic anemia are detected (CP about 0.5), a decrease in hemoglobin to 20-50 g/l, the number of red blood cells in the peripheral blood is 1-2 million per day.

Heterozygous β-thalassemia. Characterized by a more benign course, signs of the disease appear in more advanced late age and are less pronounced. Anemia is moderate. The content of red blood cells is about 3 million in 1 micron, hemoglobin is 70-100 g/l. The content of reticulocins is 2-5% in peripheral blood. Aniso- and poikilocytosis, target-like erythrocytes are often detected; basophilic punctured erythrocytes are typical. The iron content in serum is usually normal, less often - slightly increased. In some patients, indirect serum bilirubin may be slightly increased.

Unlike the homozygous form, with heterozygous β-thalassemia there are no skeletal deformities and no growth retardation.

The diagnosis of β-thalassemia (homo- and heterozygous forms) is confirmed by an increase in the content of fetal hemoglobin (HbF) and HbA2 in erythrocytes.

Bibliographic link

Chesnokova N.P., Morrison V.V., Nevvazhay T.A. LECTURE 5. HEMOLYTIC ANEMIA, CLASSIFICATION. DEVELOPMENTAL MECHANISMS AND HEMATOLOGICAL CHARACTERISTICS OF CONGENITAL AND HEREDITARY HEMOLYTIC ANEMIA // International Journal of Applied and basic research. – 2015. – No. 6-1. – pp. 162-167;
URL: https://applied-research.ru/ru/article/view?id=6867 (access date: 03/20/2019). We bring to your attention magazines published by the publishing house "Academy of Natural Sciences"

The erythrocyte membrane consists of a double lipid layer, permeated with various proteins that act as pumps for various microelements. Cytoskeletal elements are attached to the inner surface of the membrane. On the outer surface of the red blood cell there are 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 new era in medicine, since 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 There shouldn’t be any anaphylactic reactions from one patient to another; they do happen periodically. 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 when physiological process aging of the erythrocyte, but also with many congenital and acquired pathologies, such as hereditary membranopathies, fermentopathy 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– 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 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 total number 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 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 erythrocytes are various anomalies in the structure of erythrocyte enzymes, heme or cell membrane. External factors that can lead to the destruction of red blood cells are various kinds 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.


The following types of congenital hemolytic anemias are distinguished:

• 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 form corresponds to the correct protein composition 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 erythrocytes, on the one hand, allows them to perform their main function as efficiently as possible - the exchange of gases between the internal environment of the body and 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 liver damage with high blood fat levels ( 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. Birth defects 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 systems of the cell. 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 targets of the immune system, even if Rh incompatibility is not detected, as in hemolytic disease of the newborn.

Acquired membranopathies

A representative of this group is paroxysmal nocturnal hemoglobinuria or Marchiafava-Micheli disease. The basis of this disease is the 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 immune defense body). 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, lightning-fast platelet aggregation occurs throughout the entire circulatory system, 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, sharp increase or decreased blood pressure and increased 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 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 certain 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 studies are carried out to determine the cause of the destruction of red blood cells.

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 - if in various ways staining and fixation of the smear determines the majority of anomalies in the structure of the erythrocyte.

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-PDG), pyruvate kinase, etc.);
• hemoglobin electrophoresis;
• test for sickling of red blood cells;
• Heinz body test;
• bacteriological blood culture;
• 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 hidden 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 the causative agents of malaria, life cycle 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 makes it possible to identify pathologies such as malignant blood diseases, which, through a cross-immune attack in paraneoplastic syndrome, also 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 in malignant tumor will be treated by an oncologist, etc.

Treatment of hemolytic anemia with medications

The basis for the treatment of autoimmune diseases and, in particular, hemolytic anemia are glucocorticoid hormones. They are used for a 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	It is a short-acting direct anticoagulant ( 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. The maximum daily dose is 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. With pronounced side effects the drug is discontinued with a transition 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 significant improvement general condition patient until 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 the primary disease is cured, 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 an earlier age.

Thalassemia and sickle cell anemia can be treated for a long time by transfusion of donor washed red blood cells, however, in the presence of signs of hypersplenism, accompanied by a decrease in the number of other cellular elements 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 with high content toxins and salts of heavy metals;
• 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.