V.V. Dolgov, S.A. Lugovskaya, V.T.Morozova, M.E.Pochtar Russian Medical Academy postgraduate education
Immune hemolytic anemia(IHA) of isoimmune or autoimmune (AIHA) genesis is a clinical syndrome manifested by uncompensated hemolysis, which develops due to aberration immune reactions, directed against changed and unchanged erythrocyte antigens.
With IHA, foreign antigens appear in the body, to which antibodies are produced by normal cells of the immunological tissue. With AIHA, cells of the immunological system synthesize antibodies to their own unchanged red blood cell antigens. The cause of immunization may be previous infections (viral, bacterial), medications, hypothermia, vaccination and other factors under the influence of which antibodies to cellular elements of the blood are formed. When two diseases are present, IHA is considered symptomatic or secondary.
Immune hemolytic anemia may precede other diseases, however, its presence indicates a generalized, multiple immunological disorder. An immune conflict occurs with antigens located on the surface of cells or with cellular structures, as a result of which red blood cells are destroyed - hemolytic anemia develops. The course of the disease, clinical picture, hematological and laboratory parameters determine the type of antibodies and their functional characteristics.
Acquired hemolytic anemia occurs when agglutinins appear in the blood serum, which, according to their serological properties, represent incomplete and complete cold and warm antibodies. Their distinctive feature is intracellular hemolysis and changes in pigment metabolism. Hemolytic anemia, caused by the presence of hemolysins in the blood, causes the destruction of red blood cells in the bloodstream with mandatory interaction with complement. They are characterized by the presence of intravascular hemolysis, the indicators of which are hemoglobinemia, hemoglobinuria and hemosiderinuria.
The localization of erythrocyte lysis depends on the serological properties of antibodies, their class, concentration on the cell membrane, temperature optimum of antibodies and other factors. Thus, cold antibodies, which belong to IgM, react with red blood cells at low temperatures (below body temperature). Factors of the complement system are usually also involved in this reaction, so intravascular hemolysis predominates, and sequestration of red blood cells in the spleen is limited. Warm antibodies, which belong to the IgG family, cause a reaction at body temperature without the involvement of complement. Sequestration of red blood cells in the spleen is the leading mechanism of cell destruction.
Post-transfusion anemia
The most common extra-erythrocyte factor causing hemolytic anemia is antibodies to erythrocyte antigens. Antibodies in the blood arise when foreign antigens are introduced into the body. The basis of anemia that develops as a result of blood transfusion is, as a rule, intravascular hemolysis of erythrocytes. Numerous reasons that lead to blood transfusion complications are due to non-compliance with the rules during blood transfusion. We can distinguish at least six groups of different factors that contribute to the development of post-transfusion reactions, including anemia.
Causes of complications during blood transfusions
Incompatibility of the blood of the donor and recipient with respect to erythrocyte antigens of the ABO, Rhesus and other systems.
Poor quality of transfused blood (bacterial contamination, overheating, hypothermia, hemolysis of red blood cells, denaturation of proteins due to long-term storage, disorders temperature regime storage, etc.).
Errors in the transfusion technique (air embolism, thromboembolism, circulatory overload, cardiovascular failure, etc.).
Massive doses of transfusion (40-50% of the volume of the bcc). In this case, 50% of the transfused red blood cells are sequestered in the organs, which leads to a violation of blood rheology (homologous blood syndrome).
Contraindications to blood transfusion are not strictly taken into account.
Transfer of pathogens of infectious diseases with transfused blood.
The blood of each person belongs to one of the 4 blood groups of the ABO system, depending on the presence of antigens A and B on red blood cells and the corresponding antibodies in the blood plasma - agglutinins (anti-A and anti-B).
In table 8 shows the characteristics of the main blood groups of the ABO system [show].
Table 8. Characteristics of blood groups of the ABO system
ABO blood group
Red blood cells
Blood serum
presence of antigens
reaction with antibodies
presence of antibodies
reaction with erythrocyte antigens
anti-A (α)
anti-B (β)
anti-A anti-B
A-antigen
B antigen
Оαβ (I)
No
-
-
-
anti-A and anti-B
+
+
Аβ(II)
A
+
-
+
anti-B
-
+
Bα (III)
IN
-
+
+
anti-A
+
-
Avo (IV)
A and B
+
+
+
No
-
-
To avoid incompatibility between the blood of the donor and the recipient in terms of red blood cells, their group and Rh affiliation should be taken into account. Preference is given to blood transfusions of same-group blood compatible with the Rh factor. In emergency cases, it is possible to transfuse red blood cells O (I) to a recipient of any blood group.
The most common cause of post-transfusion complications is non-transfusion compatible blood, the result of which is the development of a reaction of IgM antibodies (ABO incompatibility) or IgG (Rh factor incompatibility) with antigens built into the cell membrane of the recipient’s red blood cells, binding to complement and subsequent hemolysis.
In the clinical picture There are two periods of post-transfusion complications - blood transfusion shock and acute renal failure (ARF). Transfusion shock develops over the next few minutes or hours. The reaction begins with the appearance of pain in the lower back, sternum, and along the veins. Restlessness, chills, shortness of breath, and hyperemia of the skin appear. In severe cases, shock develops. A mandatory sign of transfusion of incompatible blood is acute hemolysis. The nature of hemolysis is determined by the type of antibodies: in the presence of agglutinins, predominantly intracellular hemolysis occurs, hemolysins cause intravascular hemolysis. In case of group incompatibility, intravascular hemolysis is determined by the presence of a high titer of immune or autoimmune anti-A or anti-B antibodies from the donor, whose blood is transfused into the recipient. The first signs of hemolysis are detected immediately after transfusion of incompatible blood. The severity of clinical and hematological symptoms depends on the dose of blood transfused.
Bone marrow hematopoiesis characterized by severe hyperplasia with predominant activation of erythropoiesis. For acute renal failure In the bone marrow, suppression of erythropoiesis is detected according to the hyporegenerative type.
Blood. Anemia, which occurs as a result of increased breakdown of red blood cells, has a hyperregenerative nature, which can be judged by the increase in reticulocytes in the blood, the presence of polychromatophilia, and erythrokaryocytes. Other hematological signs of hemolysis (changes in the osmotic resistance of red blood cells, their volume, diameter, color index) are variable and atypical. Changes in leukopoiesis are also inconsistent; leukocytosis is more often observed with a shift in the leukocyte formula to the left, down to myelocytes.
The concentration of unconjugated bilirubin in the blood serum is increased. Only in the first hours after transfusion of incompatible blood can hemoglobinemia be detected, since free hemoglobin is quickly absorbed by RES cells and excreted by the kidneys (hemoglobinuria). The amount of urine decreases, it becomes brown in color, due to the presence of free hemoglobin (hemoglobinuria) and hemosiderin (hemosiderinuria).
Anemia - persistent symptom OPN. It is characterized as macrocytic, normochromic, hyporegenerative. Anemia is detected from the first days of a blood transfusion complication and does not stop until kidney function is normalized.
Hemolytic disease of the newborn (erythroblastosis fetalis)
Hemolytic anemia of newborns is most often associated with Rh (Rh) incompatibility of parents: an Rh-negative woman during pregnancy with an Rh-positive fetus, which inherited the Rh-positive factor from the father, develops anti-Rh antibodies. Antibodies arising in the mother’s body penetrate into the fetal blood, settle on the surface of cells and cause their agglutination, followed by hemolysis of red blood cells in the fetal body. As a result, the newborn develops hemolytic anemia with erythroblastosis and jaundice in the first hours of life. The development of fetal erythroblastosis is explained by an active reaction of the bone marrow to the breakdown of red blood cells in the fetus.
Anti-Rh antibodies in the blood of an Rh-negative woman can persist for many years. Differentiation of the Rh factor in fetal red blood cells begins at 3-4 months. intrauterine life, and the formation of Rh antibodies in the mother’s body from 4-5 months. pregnancy. Therefore, with early termination of pregnancy, the woman is not immunized. The titer of anti-Rh antibodies in the mother's body accumulates mainly at the end of pregnancy and during childbirth, antibodies settle on the red blood cells of the fetus, causing their hemolysis. The antibody titer increases with each subsequent pregnancy, so the likelihood of an Rh conflict increases with each pregnancy.
Hemolytic disease of newborns may also depend on incompatibility between the blood of mother and fetus according to the ABO group system, when maternal anti-A or anti-B agglutinins pass through the placenta into the fetal blood. Typically, group incompatibility according to the ABO system of the blood of the mother and fetus is observed during the first pregnancy. In hemolytic disease, intracellular hemolysis occurs.
Clinic and laboratory parameters. Newborns experience severe jaundice, enlarged spleen and liver, skin hemorrhages, anemia with a significant number of erythroblasts, reaching 100-150 thousand in 1 μl and high reticulocytosis. Neutrophilic leukocytosis with a shift to myelocytes, unconjugated hyperbilirubinemia, increased content stercobilin in feces and urobilin in urine.
Autoimmune hemolytic anemia occurs mainly after 40 years of age and in children under 10 years of age as a result of sensitization of the body and the appearance in the blood of antibodies that have the ability to destroy cellular elements of the blood in the RES or vascular bed. A complex of factors plays a role in the pathogenesis of hemolysis: the class, subclass and titer of anti-erythrocyte antibodies, the temperature optimum of their action, the antigenic characteristics of the erythrocyte membrane and the orientation of immunoglobulins to certain antigens, the complement system and the activity of cells of the mononuclear phagocyte system. Autoimmune hemolytic anemia is diagnosed by the presence of autoantibodies fixed on erythrocytes using the Coombs test, in which antiglobulin antibodies interact with erythrocyte immunoglobulins (direct Coombs reaction) and cause agglutination of erythrocytes. It is possible to detect circulating antibodies in blood serum using an indirect Coombs test, mixing the serum with donor red blood cells. As a rule, the severity of the direct Coombs reaction closely correlates with the amount of IgG fixed on erythrocytes. A negative Coombs test does not exclude AIHA. It can occur with intense hemolysis, massive hormonal therapy, and low antibody titers.
Autoimmune hemolytic anemia caused by incomplete heat agglutinins
This is the most common form of autoimmune anemia. The disease can be either idiopathic, that is, without obvious reason, and symptomatic. Symptomatic or secondary AIHA develops against the background of lymphoproliferative diseases and other malignant tumors, diseases connective tissue, infections, autoimmune diseases (thyroiditis, ulcerative colitis, diabetes Type I, sarcoidosis, etc.). Warm agglutinins can appear during treatment with large doses of penicillin or cephalosporins, and they are directed against the complex of the antibiotic with erythrocyte membrane antigens. Canceling the antibiotic leads to the cessation of hemolysis of red blood cells.
Incomplete thermal agglutinins belong to the class IgG, IgA. In most cases, antibodies are directed to antigens of the Rh system. The course of the disease can be acute, chronic and subacute. Typically, hemolysis develops gradually, rarely acutely. Acute onset is more typical for childhood and always in association with infectious process. The destruction of red blood cells occurs in the spleen (intracellular hemolysis). Therefore, in the clinic there are signs characteristic of anemia (pallor, palpitations, dizziness) and intracellular hemolysis (jaundice varying intensity, splenomegaly).
In the bone marrow hyperplasia of the erythroid germ is noted, cells with a megaloblastoid structure of nuclear chromatin are found. Anemia is normo- or hyperchromic in nature and is usually accompanied by moderate, less often high, reticulocytosis. The decrease in hemoglobin concentration depends on the degree of hemolytic crisis and reaches 50 g/l. Blood smears show anisocytosis, polychromatophilia; microcytes, microspherocytes, macrocytes, and erythrokaryocytes may be present. When automatically counting cells, a high rate of anisocytosis (RDW) and average hemoglobin content in erythrocytes (MCH) are noted (Fig. 49).
The number of leukocytes depends on the activity of the bone marrow and the underlying disease that underlies hemolysis: it can be normal, in the acute form - leukocytosis with a shift to the left, sometimes leukopenia.
Decisive diagnostic sign This type of AIHA is a positive direct Coombs test. According to a number of researchers, there is no parallelism between the severity of the direct Coombs test and the intensity of hemolysis. A negative Coombs test does not exclude the diagnosis of AIHA. Its minimum resolution is 100-500 IgG molecules per red blood cell; at a lower antibody concentration, the reaction will be negative. In addition, insufficient washing of erythrocytes during the reaction leads to the fact that unwashed serum immunoglobulins remain on the surface of erythrocytes, which neutralize the antiglobulin serum. A negative test may be a consequence of the loss of low-affinity antibodies from the surface of the erythrocyte during the washing process.
The hemagglutination test unit, developed in 1976, has greatly increased the sensitivity of the Coombs reaction, but due to its complexity it is not widely used. clinical practice. Usage enzyme immunoassay allows you to quantitatively assess the content of immunoglobulins on the surface of one red blood cell, as well as determine their class and type. The significance of these studies is due to the fact that different classes and types of immunoglobulins have different physiological activities in vivo. An increase in the severity of hemolysis has been shown with the simultaneous participation of several classes of immunoglobulins in the process. In addition, the subclass of immunoglobulins largely determines the severity of hemolysis and the site of predominant destruction of red blood cells.
Currently, a gel test is used (Diamed, Switzerland), similar to the Coombs test, but more sensitive. The test does not require washing of erythrocytes, with which part of the IG is lost, since the gel separates erythrocytes and plasma.
Idiopathic forms have been described, but most often the process is secondary. At a young age, cold hemagglutinin disease (CHAD) usually complicates the course of acute mycoplasma infection and resolves as the latter resolves. In elderly patients, cold hemolysis accompanies chronic lymphoproliferative diseases that occur with the secretion of the IgM paraprotein, which plays a leading role in the hemolytic process. Most often, CHAB accompanies Waldenström's macroglobulinemia and chronic lymphocytic leukemia with the secretion of IgM, as well as systemic diseases connective tissue. This type of anemia is characterized primarily by intracellular hemolysis.
Macroglobulin, which has the properties of cold agglutinins, due to its high molecular weight, causes hyperviscose syndrome. The disease is manifested by Raynaud's syndrome, the development of acrocyanosis, thrombophlebitis, thrombosis, trophic changes, up to acrogangrene. IgM functions at low temperatures; the optimal temperature for macroglobulin action is +4 °C. Therefore, the entire symptom complex of the disease occurs in the cold, with hypothermia of exposed parts of the body. When moving to a warm room, hemolysis stops.
In blood Normochromic anemia (Hb > 75 g/l), reticulocytosis, and erythrocyte agglutination are noted. Agglutination often results in increased mean red blood cell volume and falsely low hemoglobin values when tested on hematology analyzers. The number of leukocytes and platelets is within normal values, accelerated ESR. In the blood serum there is a slight increase in unconjugated bilirubin.
The presence of cold agglutinins makes it difficult to determine the number of red blood cells, group affiliation erythrocytes and ESR. Therefore, the determination is carried out either with heated saline solution, or in a thermostat at a temperature of 37 °C (blood is taken into a test tube previously immersed in hot water). In the blood serum of such patients, a diagnostically significant increase in the titer of cold antibodies is detected, and on the surface of erythrocytes - IgM. When using polyvalent antiglobulin serum, the direct Coombs test is positive in some cases. Complete cold agglutinins have specificity for the Ii antigen system (PP) on the surface of erythrocytes.
Autoimmune hemolytic anemia caused by warm hemolysins
This variant of AIHA is much less common. In the pathogenesis of this form of anemia, the main role is played by warm hemolysins, the optimal action of which is manifested at 37 °C. The disease has chronic course and is characterized by signs of intravascular hemolysis. The dominant diagnostic criterion is hemoglobinuria and hemosideronuria, which usually color the urine black (brown). The intensity of the color depends on the degree of hemolysis. With severe hemolysis, there is slight splenomegaly and slight increase unconjugated bilirubin.
In the bone marrow active erythropoiesis is noted. IN peripheral blood- anemia of normo- or hypochromic type, as a result of gradual loss of iron by the body, reticulocytosis. The number of leukocytes can be increased, often with a shift to myelocytes. Sometimes thrombocytosis develops, complicated by thrombosis of peripheral veins. There may be a positive Coombs test.
Paroxysmal cold hemoglobinuria with biphasic hemolysins (Donath-Landsteiner anemia)
In the pathogenesis of the disease, hypothermia of the body and a viral infection, in particular influenza, measles, and mumps, play a role; syphilis cannot be completely excluded. Biphasic hemolysins belong to class IgO. Fixation of hemolysins on erythrocytes occurs at a temperature of 0-15 °C (first phase), and intravascular hemolysis, which occurs with the participation of complement, at a temperature of 37 °C (second phase). The hemolytic effect occurs when a person moves into a warm room.
The disease is manifested by attacks of chills, fever, abdominal pain, vomiting, nausea, vasomotor disturbances, and the appearance of black urine several hours after hypothermia. Icterus of the sclera and splenomegaly may appear.
In the bone marrow hyperplasia of the red sprout is noted. In peripheral blood, the hemoglobin content outside a crisis is normal. During the crisis, anemia, reticulocytosis, leukopenia, and, less commonly, thrombocytopenia develop. In the blood serum, there is an increase in the level of free plasma hemoglobin and a decrease in the concentration of haptoglobin. A positive Hem test (lysis of the test red blood cells with donor serum containing proteins of the complement system) and a direct sucrose test are registered. In the urine - hemoglobinuria, hemosiderinuria.
Hereditary anemia and hemoglobinopathies / Ed. Yu.N. Tokareva, S.R. Hollan, F. Corral-Almonte. - M.: Medicine, 1983.
Troitskaya O.V., Yushkova N.M., Volkova N.V. Hemoglobinopathies. - M.: Publishing house of the Russian Peoples' Friendship University, 1996.
Shiffman F.J. Pathophysiology of blood. - M.-SPb., 2000.
Baynes J., Dominiczak M.H. Medical Biochemistry. - L.: Mosby, 1999.
Source: V.V. Dolgov, S.A. Lugovskaya, V.T. Morozova, M.E. Pochtar. Laboratory diagnosis of anemia: A manual for doctors. - Tver: "Provincial Medicine", 2001
pathogens of malaria are present, barto-
nellese and clostridial infections. In some patients, hemolysis was also caused by other microorganisms, including many gram-positive and gram-negative bacteria and even tuberculosis pathogens. Hemolytic disorders can be caused by viruses and mycoplasmas, but, apparently, indirectly through immunological mechanisms.
Immune hemolytic anemia
Immune hemolytic anemia caused by warm antibodies
Warm antibodies causing hemolytic anemia may occur primarily (idiopathically) or as a secondary phenomenon in various diseases(Table 24). This anemia is more common in women, and the frequency of secondary forms increases with age. Autoimmune hemolytic anemia appears to occur in the presence of a genetic predisposition and a disorder of immunological regulation. When searching for the causes of autoimmune hemolytic anemia in the elderly, one should first think about secondary phorygia or drug etiology.
Table 24. Immune hemolytic anemia
Associated with heat antibodies
a) idiopathic autoimmune hemolytic anemia
b) secondary when:
systemic lupus erythematosus and other collagenoses chronic lymphocytic leukemia and other malignant lymphoreticular diseases, including multiple myeloma other tumors and malignant neoplasms
viral infections immunodeficiency syndromes
Associated with cold antibodies
a) primary - idiopathic “cold agglutinin disease”
b) secondary when:
infections, especially mycoplasma pneumonia, chronic lymphocytic leukemia, lymphomas
c) paroxysmal cold hemoglobinuria
idiopathic secondary to syphilis and viral infections
Drug-induced immune hemolytic anemia
a) penicillin type
b) stibofen type ("innocent bystander" type)
c) type conditioned by a-methyldopa
d) streptomycin type
Autoimmune hemolytic anemia due to warm antibodies is caused by for various reasons and proceeds differently. Forms of anemia secondary to malignant neoplasms usually develop gradually, and their course corresponds to the course of the underlying disease. Primary forms of anemia are very variable in their manifestations - from mild, almost asymptomatic to fulminant and ending fatal. Symptoms are usually those of anemia and include weakness and dizziness. TO
Typical signs include hepatomegaly, lymphadenopathy and especially splenomegaly, but jaundice is not usually observed.
Yes.
Diagnosis of autoimmune hemolytic anemia is based primarily on laboratory data. Typically, normocytic normochromic anemia is found, but sometimes it is macrocytic, depending on the degree of reticulocytosis. The reticulocyte count is usually elevated, but associated disorders - anemia accompanying chronic diseases, deficit state or myelophthisis can significantly reduce the severity of reticulocytosis.
In approximately 25% of cases, reticulocytopenia is observed, apparently due to antibodies to reticulocytes. Peripheral blood smears classically show microspherocytosis, poikilocytosis, polychromatophilia, anisocytosis, and polychromatophilic macrocytes. Nucleated red blood cells are common. The white blood cell count may be low, normal, or increased (with acute development anemia); The platelet count is usually within normal limits. The simultaneous presence of autoimmune hemolytic anemia and autoimmune thrombocytopenia is characteristic of Evans syndrome, which can
may accompany lymphoma.
Serum bilirubin levels are usually slightly elevated, and hemolysis is usually extravascular.
Coombs tests. Positive results Direct antiglobulin test indicates the presence of antibodies on the surface of red blood cells, which is typical for almost all patients with autoimmune hemolytic anemia.
This test can be modified to provide information about immunoglobulin class and subclass, as well as the presence of complement components. An indirect antiglobulin test can be used to detect antibodies in serum. Theoretically, the only drawback of the Coombs test is its relatively low sensitivity. Commercial reagents commonly used in blood bank laboratories give positive reactions if there are 100-500 antibody molecules on the surface of each red blood cell. It should be remembered that since 10 molecules of antibodies to the Rh factor are sufficient to reduce the half-life of red blood cells to 3 days, severe hemolytic anemia can occur in patients with negative anemia.
tiglobulin test, however, this situation is rare. Currently using
or polybrene into a suspension of red blood cells in order to reduce the distance between them. In particular, the use of polybrene in automatic analyzers with flow systems has significantly increased the sensitivity of the method. Much more sensitive and widely used methods involve treating erythrocytes proteolytically.
mi enzymes.
With autoimmune hemolytic anemia caused by warm antibodies, in 30-40% of patients only IgG antibodies are found on red blood cells, in 40-50% - IgG and complement, and in 10% - only complement (usually in patients with systemic lupus erythematosus). Many antibodies are directed against Rh antigenic determinants, making it difficult to determine blood grouping and compatibility. IgG antibodies are usually polyclonal
cash.
Therapy for autoimmune hemolytic anemia caused by warm antibodies must include
treatment of the underlying disease. If the underlying disease is lymphoma and especially chronic lymphocytic leukemia or a tumor, its treatment in many cases leads to remission of hemolytic anemia. In emergency situations lightning-fast development hemolysis may require a blood transfusion. At the same time, however, we must remember the problems associated with determining group affiliation and blood compatibility. In these cases, the “most compatible” red blood cells are used for transfusion. Transfusion of insufficiently compatible blood must be carried out slowly, constantly monitoring the patient's condition. Adrenergic corticosteroids should be administered at the same time.
These hormones are the drugs of choice at the beginning of treatment. Typically, prednisolone is started at a dose of 40 mg/m2 of body surface area per day, but higher doses may be required. Improvement in hematological parameters usually occurs on the 3-7th day and in subsequent weeks the level of hematological
can be gradually reduced. As a rule, the dose should be halved over 4-6 weeks and then the prednisone should be slowly withdrawn.
Zolon in the next 3-4 months. At-
In approximately 15-20% of patients, corticosteroids do not have an effect, which is why it is necessary to resort to splenectomy or the prescription of cytotoxic drugs. In approximately a quarter of cases, the corticosteroid can be completely discontinued, but in the remaining cases, maintenance doses of steroids must be used, despite the risk of associated complications in the elderly.
Splenectomy is indicated in cases where anemia does not respond to treatment with steroids, if long-term use is necessary high doses steroids, as well as when serious complications steroid therapy. The effectiveness of splenectomy increases when selecting for surgery those patients in whose spleen 51Cr-labeled erythrocytes are intensively retained. The question of the advisability of splenectomy in a given elderly patient should always be decided taking into account all the diseases he has. Before the opera
tion, the patient should be given a pneumococcal vaccine to reduce the risk of postoperative pneumococcal sepsis.
Cytotoxic drugs are prescribed to elderly people only in cases where there is no effect from treatment with corticosteroids or splenectomy, as well as in cases of relapse of hemolytic anemia after splenectomy or in the presence of contraindications to this operation. The most commonly used drugs are cyclophosphamide and azathioprine (both drugs in combination with prednisone).
Immune hemolytic anemia caused by cold antibodies
Autoantibodies that react with red blood cells at temperatures below 32 ° C are called cold antibodies. They cause the development of two clinical syndromes: the “cold agglutinin” syndrome and paroxysmal cold hemoglobinuria (Table 24). The latter condition is very rare, usually with syphilis.
Cold
agglutinins, like
relate
IgM class. These
antibodies
be both polyclonal and monoclonal (Table 25),
and almost all of them bind complement. Pain-
Most antibodies are specific to one of the erythro-
cytic antigens Ii. II-antigens are also present on other
cells, so
cold anti-II agglutinins can
Table 25.
Diseases leading to cold
commercial agglutinins
Polyclonal cold agglutinins
Monoclonal cold agglutinins
Chronic cold agglutination disease
Pneumonia caused by mycoplasmas
Waldenström's macroglobulinemia
Angioimmunoblastic lymphadenopathy
Collagenoses and immune complex diseases
Chronic lymphocytic leukemia
Subacute bacterial endocarditis
Kaposi's sarcoma
Other infections
Multiple myeloma
Mycoplasma pneumonia (rare)
Polyclonal variant of the disease “cold agglutination”
new" most often
caused by Mycoplasma pneumoniae infection
and is observed
mostly among young people
sick, but can also occur in the elderly. Other diseases in which polyclonal cold agglutinins are produced are rare. However, hemolytic anemia caused by monoclonal cold agglutinins is observed mainly in the elderly, and its frequency reaches a maximum in the age group 60-80 years
Cold agglutinins, related
associated with malignant lymphoreticular neoplasms, also occur almost exclusively in elderly individuals
Clinical manifestations are due to intravascular cell agglutination or hemolysis. As blood passes through the capillaries of the skin and subcutaneous tissue, its temperature can drop to 28 ° C or even lower. If cold antibodies are active at this temperature, they agglutinate cells and fix complement. Agglutination leads to blockage of blood vessels, and complement activation can cause
intravascular hemolysis and sequestration of cells in the liver
Acrocyanosis or a pronounced change in skin color - from pale to bluish - is caused by intracapillary agglutination of red blood cells in those parts of the body that are cooled.
or pain and are most often observed in the distal parts of the co-
Chronic hemolytic anemia in idiopathic cold agglutinin disease is usually moderate and is characterized by extravascular hemolysis. Hemoglobin concentration is usually maintained above 70 g/L. In many cases, the condition of patients worsens in cold weather. The C3 b inactivator system may be functionally insufficient under cold stress, high antibody titres, or high thermoresponsiveness. The development of acute intravascular hemolysis caused by cooling may be accompanied by hemoglobinuria, chills and even acute renal failure. The Ehrlich finger test can be used to detect hemolysis during cooling. The finger is tightened with a rubber cuff so as to block the venous outflow, and immersed in cold water (20 ° C) for 15 minutes. To control, another finger is immersed in water having a temperature of 37 ° C. After centrifuging a blood sample from the finger that was in cold water, revealing
hemolysis occurs; blood taken from a finger that was in warm water, does not hemolyze.
The patient usually exhibits acrocyanosis, pallor and sometimes mild jaundice. Occasionally, the spleen is difficult to palpate, and the liver may also be slightly enlarged.
Blood tests reveal signs of anemia, mild reticulocytosis and sometimes mild hyperbilirubinemia, as well as specific manifestations of intravascular hemolysis. Blood cells may agglutinate at room temperature, and the first clue to a possible diagnosis arises from difficulties in counting the number of red blood cells or in preparing a peripheral blood smear. The diagnosis is confirmed by the detection of elevated titers of Cold agglutinins. The antiglobulin test is positive, but specific only for complement components, while the reaction with antigammaglobulin serum is negative. With severe hemolysis, complement levels are reduced.
Treatment this state consists mainly of giving the patient advice on how to maintain body temperature above that at which antibodies show their activity. There is usually no need for blood transfusions; they can even be dangerous due to possible increased hemolysis. If it is still necessary to transfuse blood, then the compatibility test should be carried out at 37 ° C, and donor blood should not be used before transfusion.
bypassed
warm up . The effectiveness of corticosteroids and splenectomy has not been proven. Application experience cytotoxic drugs limited; Chlorbutin in low doses (2-4 mg per day) may be beneficial. Currently, the best treatment is to avoid cooling the body.
Drug-induced immune hemolytic anemia
The number of reported cases of drug-induced immune hemolytic anemia is small. Meanwhile, most experts believe that this disease occurs much more often than it is diagnosed. In particular, in an elderly patient suffering from one or another chronic disease, usual signs hemolysis may go unnoticed and the diagnosis will not be made. In addition, it should be noted that elucidating the type of hemolysis induced by drugs allows us to better understand the mechanisms of development of the autoimmune process as a whole. The types of hemolysis induced by drugs are listed in Table. 26.
In penicillin-type hemolysis, the drug acts as a hapten and binds tightly to the red blood cell membrane. The antibodies produced react with the drug itself, and not with any component of the red blood cell membrane. The reaction of this type of meeting is
is rare and occurs only when used relatively
usually of the IgG class, they are warm and do not fix complement, although there are anecdotal reports of complement activation. This reaction was also observed during therapy with cephalosporins, but less frequently than with
understanding of penicillin.
Penicillin-induced hemolysis usually occurs extravascularly and most red blood cells are destroyed in the spleen. The direct antiglobulin test is strongly positive, and the eluted antibodies react with penicillin derivatives and not with components of the erythrocyte membrane. Treatment
consists of discontinuing penicillin, after which hemolysis is usually
stops within a few days or weeks. Sometimes it occurs
necessity
in blood transfusion
or administration of corticosteroids.
Stibophen type hemolysis, when red blood cells play
the role of the “innocent bystander” can be induced by a large
rue with a complex of medicinal substances and soluble
macromolecules,
large antigen-antibody aggregate.
Such a complex
settles on
cellular
surfaces.
Here the erythrocyte is an “innocent bystander”, since
its components do not form antibodies, and it itself does not form
does not interact with the herbal drug.
Antibodies to a drug are classified as
IgG class
or IgM or both classes and, as a rule, are capable of binding
give complement. Therefore, developing hemolytic anemia
myia is usually intravascular.
Table 26. Types of drugs
immune hemolytic
ski anemia
Prototype medicine
The role of medicine
Attachment of antibodies to red blood cells
Antiglobuli-
Place of destruction
new test
Hapten associated with
Joins the drug
Penicillin
vein substance associated
Outside the vessels
erythrocyte
mu with cage
stibofen
Antigen as part of the com-
Immune complex
Complement
Inside the vessels
plexa antigen - anti-
a-Methyldopa
Suppresses suppressor
Rh receptors on red blood cells
Outside the vessels
Hapten associated with
Joins the drug
Streptomycin
vein substance associated
Inside the vessels
erythrocyte
mu with cage
Cephalosporins
Whey proteins ab-
are sorbed on erythro-
(“pseudohemo-
Absent
No hemolysis
quote; not immunological
The dose of a drug that causes immunoge-
molytic anemia of this type is usually mild, and for different
development of hemolysis
presence required
drug in the organization
meh. Hemolytic anemia can be very severe and
Since hemolysis is intravascular in nature, it is accompanied by
Hemoglobinemia and hemoglobinuria occur. Often occurs due to
renal failure. Leukopenia and
thrombocytopenia, as well as diffuse
intravascular
Liz. Direct antiglobulin test
positive, however
its production should use reagents containing complement. The reaction may remain positive for two months after discontinuation of the drug.
Treatment consists of discontinuing the drug. The use of steroids is pointless, since hemolysis is intravascular in nature. A blood transfusion may be necessary, but injected red blood cells are destroyed as quickly as the patient's own cells. Kidney failure poses a real threat to the patient's life and requires intensive treatment.
Table 27. Drugs that can cause immune hemolytic anemia of the stibophen type or the “innocent bystander” type
Hemolytic anemia caused by taking a-methyldopa is the most common type of drug-induced immunohemolytic anemia. The direct antiglobulin test is positive in 15% of patients taking this drug, but hemolytic anemia occurs in less than 1% of patients. It is known that a-methyldopa suppresses
rarely leads to T-cell impairment. In some individuals, this reduction in T-suppressor activity is thought to result in unregulated production of autoantibodies by a subset of B cells. The highest risk group is probably
but, people who have HLA-B7. In those patients taking a - methyldopa in whom the antiglobulin test gives a positive result, the general content T cells.
A positive antiglobulin test result is probably not due to any reaction between the drug and the red blood cell membrane. Some of the antibodies formed are directed against the Rh antigens of the erythrocyte. In addition, other autoantibodies are found in patients taking a-methyldopa - antinuclear factor, rheumatoid factor and antibodies to gastric mucosal cells. This drug should be used with caution in elderly people, who often develop similar autoimmune phenomena
The antibodies produced are IgG, warm, and appear to be identical to the warm antibodies described in autoimmune hemolytic anemia. Indeed, many researchers suggest that this medicinal product may be a prototype large number other substances that cause autoimmune phenomena as a result of damage immune system, but are not directly involved in the immune response. It is now installed
that this type of hemolytic anemia is also caused by other drugs, namely mefenamic acid and levodopa.
Clinical manifestations of hemolytic anemia usually occur 18 weeks to 4 years after the start of treatmenta - methyldopa. The disease is usually mild or moderate and is similar in course to autoimmune hemolytic anemia caused by warm antibodies. Most patients do not require any therapy other than drug discontinuation. However cardiopulmonary failure In some cases, it poses a real threat to the lives of patients and may require blood transfusions.
Cases of immune hemolytic anemia and renal failure have been reported in patients treated with streptomycin. It is assumed that in these cases the drug acts as a hapten, binding to the red blood cell membrane. Hemolysis is caused by complement-fixing antibodies of the IgG class, specific for
streptomycin. Intravascular hemolysis occurs as a result of complement fixation. Consequently clinical picture very similar to that observed in hemolytic anemia of the stibofen type (type of “innocent bystander”); treatment is also similar, consisting in the abolition of pre-
paratha
Positive
antiglobulin
be the result of nonspecific and nonimmune absorption of serum
collar proteins on red blood cells. This phenomenon is often observed
cephalothin and does not lead
hemolysis
(“pseudohemolysis”). This type of reaction is apparently possible.
drugs. Except
Moreover, it is observed in severe megaloblastic anemia.
Red blood cells exposed to intense physical impact in the bloodstream, may prematurely frag-
1967]. In such cases, hemolysis is intravascular, and its sign is the appearance of schizocytes. Schizocytes are fragments of red blood cells formed as a result of membrane rupture. They are quickly eliminated from the bloodstream by the reticuloendothelial system. Schizocytes are shaped like caps, microspherocytes, triangles and crescents
also by direct injury to red blood cells as a result of their collision with natural or artificial abnormal vascular structures.
Hemolysis increases with increasing activity of the patient and increasing cardiac output. A vicious circle arises: hemolysis increases, anemia becomes more severe, heart function increases, and anemia progresses.
synthetic valve prostheses, valve homografts, autoplasty of valves, rupture of chordae tendineae
elimination of intracardiac septal defects, valve defects (unoperated) arteriovenous fistulas, coarctation of the aorta
Microangiopathic hemolytic anemia
disseminated intravascular coagulation
microangiopathy caused by immune mechanisms -
hemangiomas disseminated cancer malignant hypertension pulmonary hypertension
others (rarely observed in older people)
The severity of anemia is variable. Peripheral blood smear shows erythrocyte fragmentation and reticulocytosis. There are signs of intravascular hemolysis, the patient
iron and folic acid. If anemia progresses and cardiovascular complications are observed, it is necessary to resort to surgical intervention.
Microangiopathic hemolytic anemia is usually associated with fibrin deposition in small vessels[Vi11 et al., 1968; Rubenberg et al., 1968], severe systemic hypertension or vascular spasm. IN
Under these conditions, fragmentation of red blood cells occurs during their passage under pressure through the fibrin network, as well as during direct damage to the vessel. With inflammation, disturbances in the structure and proliferation of the endothelium, fragmentation of erythrocytes occurs when a powerful flow arterial blood passes by red blood cells adhering to the damaged endothelium. In this case, the diagnosis is also made based on the detection of schizocytes and signs of intravascular hemolysis. However, anemia in such patients is usually not the main problem, and treatment consists mainly of addressing the underlying disease.
In older adults, microangiopathic hemolytic anemia is probably most commonly seen with disseminated intravascular coagulation. The latter condition can develop secondary to sepsis, malignant neoplasms
Heat stroke, suturing of thrombosed vascular grafts
Fulminant purpura, as well as with immune damage to small cells
ships
Spur cell anemia in liver disease
Spur cells, or acanthocytes, can occur when the liver parenchyma is severely damaged. A spur cell is a dense, compressed erythrocyte with several spur-shaped processes unevenly distributed on its surface. The number of such processes is less than that of the "styloid" cells observed in uremia, and, in addition, the processes vary in length and width. In liver diseases, the appearance of spur-shaped cells is due to an increase in cholesterol content and the cholesterol/phospholipid ratio in erythrocyte membranes. Hemolysis, according to
apparently, is the result of the capture of altered cells by macrophages.
Paroxysmal nocturnal hemoglobinuria
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease caused by
hemoglobinuria and hemosiderinuria, phenomena, thrombosis and bone marrow hypoplasia. This disease is usually first diagnosed in people in the 20-40 age group, but can also occur in older people.
It is assumed that PNH occurs due to the proliferation of a defective clone of bone marrow stem cells; such a clone gives rise to at least three populations of erythrocytes, differing in sensitivity to activated complement components. Increased sensitivity to complement in the greatest degree
The clinical course is very variable - from mild
benign to severe aggressive. In the classical form, hemolysis occurs
diseases and acute myeloid leukemia. Detection of splenomegaly in
sick
aplastic
serve as a basis
for examination to identify PNH
Anemia is often severe, with hemoglobin levels of 60 g/L or lower. Leukopenia and thrombocytopenia are common. In a peripheral blood smear, as a rule, a picture of normocytosis is observed, however, with prolonged hemosiderinuria, iron deficiency occurs, manifested by signs of anisocytosis and the presence of microcytic hypochromic erythrocytes. The reticulocyte count is elevated unless there is bone marrow failure. The bone marrow at the onset of the disease is usually hyperplastic, but later hypoplasia and even aplasia may develop.
alkaline
phosphatases
neutrophils
sometimes up to
until it's full
absence. All signs of intravascular
hemolysis,
however usually
severe hemosiderin is observed
ria, which leads to iron deficiency. In addition, chronic
Chinese hemosiderinuria causes iron deposition in the kidneys
tubules
violation
proximal
Antiglobulin test is usually
negative
PNH should be suspected in any patient with hemolytic anemia unknown etiology in the presence of iron deficiency, combined iron and folic acid deficiency, pancytopenia, splenomegaly and episodic thrombus formation. For diagnostic purposes, the Ham test is used. These tests are used to determine the resistance of red blood cells to small doses of complement.
Treatment is symptomatic, since there is no specific therapy. If there is a need to re-
Even better are frozen red blood cells, which are thawed and washed from glycerol before administration. Iron supplements given after blood transfusion suppress erythropoiesis
It has been reported that some patients good effect were given corticosteroids in high doses; The use of androgens may be helpful. Anticoagulants are indicated after
The content of the article
Hemolytic anemia - pathological process caused by accelerated hemolysis of red blood cells.
Etiology and pathogenesis of hemolytic anemia
The causes of increased hemolysis of erythrocytes in the vast majority of cases are hereditary defects in the enzyme systems of erythrocytes, mainly glycolytic enzymes, membrane structure, and disturbances in the amino acid composition of hemoglobin. All these reasons cause less resistance of red blood cells and increased destruction. The direct cause of hemolysis can be infectious, drug and toxic effects, realizing increased hemolysis of erythrocytes with their functional and sometimes morphological inferiority. In a number of cases (diffuse connective tissue diseases, acute immune processes arising from infectious disease or after prophylactic vaccination), an autoimmune process occurs with the formation of antibodies to red blood cells that agglutinate red blood cells.
Classification of hemolytic anemia
The classification of hemolytic anemia has not been fully developed. The following can be used as a working classification. 1. Hereditary hemolytic anemia associated with a defect in the erythrocyte membrane. 2. Hereditary hemolytic anemia associated with impaired activity of erythrocyte enzymes. 3. Hereditary hemolytic anemia associated with a violation of the structure or synthesis of hemoglobin. 4. Acquired hemolytic anemia (immune, infectious, toxic). Hemolytic anemia is characterized by the following clinical and laboratory signs. Due to increased destruction of red blood cells, varying degrees severity of anemia and jaundice. As a rule, jaundice develops against the background of pronounced pallor of the skin (pale jaundice). With significant hemolysis, stool and sometimes urine may be intensely colored. Due to the increased excretion of bilirubin conversion products, the liver may become enlarged, and the spleen, which is the site of breakdown of red blood cells, is enlarged. Hematologically, anemia of the normochromic type with a pronounced regenerative reaction (reticulocytosis, sometimes significant - up to 8 - 10% or more) is revealed; in some cases, single normoblasts appear in the peripheral blood. Changes in the size, shape and osmotic resistance of red blood cells depend on the form of the disease. There is an increase in blood levels indirect bilirubin, in urine - an increased amount of urobilin, in feces - stercobilin. When examining bone marrow punctate, there was a pronounced erythronormoblastic reaction.
Hereditary hemolytic anemia associated with a defect in the red blood cell membrane
Hereditary familial microspherocytic anemia of Minkowski-Shoffard is usually observed in several family members. The type of inheritance is autosomal dominant. The probability of the disease in offspring is 50%. The disease is based on the loss of lipids by red blood cells, as a result of which the surface of the membrane is reduced. Red blood cells take the form of a microspherocyte (the diameter of red blood cells decreases to 5 - 6 microns, normally 7 - 7.5 microns, their life expectancy is significantly reduced and rapid hemolysis occurs. The disease occurs in the form of severe hemolytic crises; sometimes hemolysis can be constant or wave-like, somewhat accelerated. Appearance patients are sometimes typical for hereditary diseases - square skull, deformed ears, “Gothic” palate, strabismus, dentition, extra fingers, etc. With this form of anemia, a significant enlargement of the spleen is observed. When examining blood, a decrease in the number of red blood cells, reticulocytosis, and a decrease in the osmotic resistance of red blood cells are noted. The amount of indirect bilirubin is increased and amounts to 26 - 43 µmol/l in mild forms and 85 - 171 µmol/l in severe forms. Hereditary ovalocytosis- hemolytic anemia of moderate severity, occurring without hemolytic crises (children in the first months of life may have hemolytic crises), with moderate pallor and icterus of the skin and mucous membranes. In some cases, the family nature of the disease is established. In hematological examination - 80 - 90% of ovalocytes (erythrocytes) oval shape), moderate anemia (3.5 - 3.8 T/l of red blood cells) with good regenerative capacity of the bone marrow (reticulocytes up to 5% or more). Hereditary stomatocytosis- a rare form of morphological immaturity of erythrocytes. Clinically, the disease occurs in the form of moderate anemia, followed by jaundice and splenomegaly. The osmotic resistance of erythrocytes is increased. Pediatric pycnocytosis, apparently, is not hereditary, but a transient inferiority of red blood cells in children in the first months of life, causing their increased destruction. Pycnocytes are red blood cells with jagged edges (numerous sharp branches). Clinically, the disease manifests itself when the number of pycnocytes is 40 - 50% or more. The disease usually occurs in the first weeks of life.
Hereditary hemolytic anemia associated with impaired activity of red blood cell enzymes
The process is based on a violation of various enzyme systems of the erythrocyte - glucose-6-phosphate dehydrogenase (G-6-PD), pyruvate kinase, glutathione-dependent enzymes. The disease is often familial in nature with a dominant transmission of the trait. Sometimes family character is not established. Hemolysis occurs as a chronic type, without pronounced hemolytic crises. With G-6-PD deficiency, hemolysis may first occur in children under the influence of intercurrent diseases and after taking medications (sulfonamides, salicylates, nitrofurans). There is pallor, yellowness of the skin and mucous membranes, an “anemic” noise over the heart area, and moderate hepatosplenomegaly. Blood tests reveal a decrease in the number of red blood cells, high reticulocytosis, and an increase in the level of indirect bilirubin. There is no microspherocytosis, erythrocytes are of normal size and shape or slightly changed (such as macrocytes of a round or somewhat oval shape). The osmotic resistance of erythrocytes is normal.
Hereditary hemolytic anemia associated with a violation of the structure or synthesis of hemoglobin
The protein part of hemoglobin - globin has a complex structure and includes 574 amino acids. Currently, about 50 variants of hemoglobin are known, depending on its physical and chemical properties and amino acid composition. IN normal conditions from 6 to 8 months of age, hemoglobin consists of three fractions: HbA (adultus - adult) makes up the main part, HBF (foetus - fetus) - 0.1 - 0.2%, HbA - 2 - 2.5%. At birth, the majority is HBF - 70 - 90%. Other types of hemoglobin are pathological. Under the influence of a number of environmental factors fixed hereditarily, it can change amino acid composition hemoglobin. In this case, pathological varieties of hemoglobin arise - hemoglobin C, D, E, G, H, K, L, M, O, S, etc. Currently, symptom complexes associated with the presence of normal, but characteristic of the fetus, HBF, as well as diseases associated with HBS, HBC, HBE, HBD AND a combination of various pathological forms of hemoglobin. It should be noted that hemoglobinopathy is widespread in a number of places around the world, especially in Africa, on the coast Mediterranean Sea, as well as in tropical areas of Southeast Asia and among certain populations in North and Central America. Thalassemia(congenital leptocytosis, target cell anemia, Mediterranean anemia, Cooley's anemia). The disease was first described by Cooley and Lee in 1925 in the population of the coastal areas of the Mediterranean Sea, from which it received its name (from the Greek thalassa - sea). The process is based on increased synthesis of fetal hemoglobin in quantities not characteristic of the body a child over a year old and an adult (up to 80 - 90%). Thalassemia is hereditary disorder hemoglobin formation. Clinically, the disease is characterized by severe progressive hemolysis in thalassemia major or milder hemolysis in thalassemia minor, with the development of anemia and hepatosplenomegaly. A pronounced picture of the disease develops between the ages of 2 and 8 years. Developmental anomalies are often observed. Hematological examination reveals typical target cell erythrocytes. Sickle cell anemia(drepanocytosis) refers to diseases in which, instead of normal HbA, pathological HBS is synthesized, which differs from HbA in that the glutamic acid molecule in globin is replaced by a valine molecule. As a result, the electrical charge of hemoglobin changes, which determines its colloidal state, the possibility of changing shapes, gluing and hemolysis of red blood cells. These properties are most clearly manifested under hypoxic conditions. Specific feature This disease is the formation of sickle-shaped red blood cells when the tension (partial pressure) of oxygen in the environment, which leads to hemolysis. The course of the disease is with frequent hemolytic crises. Characteristic symptoms: jaundice, splenomegaly, delayed physical development.
Acquired hemolytic anemia of immune origin
Sometimes it can be observed with diffuse connective tissue diseases, most often with systemic lupus erythematosus ( autoimmune form). In the neonatal period, isoimmune hemolytic anemia occurs due to Rh conflict or incompatibility of the blood of mother and fetus in the main groups of the ABO system. Diagnosis established on the basis of clinical data, laboratory tests, as well as the study of family history. Treatment. In case of hemolytic crisis it is prescribed intravenous administration liquids (5% glucose solution, Rpnger solution), blood plasma, vitamins, as indicated steroid hormones, antibiotics. Drugs that have a beneficial effect on carbohydrate (cocarboxylase, ATP, thiamine) and protein (anabolic hormones, etc.) metabolism are indicated. For microspherocytosis, splenectomy is a highly effective measure. Indications: the presence of constant or in the form of crises of anemia, significant hyperbilirubinemia, developmental delay. Blood transfusions are carried out only for health reasons during periods of severe crises, with deep anemia. Steroid therapy is recommended for the development of aplastic crises. The prognosis is favorable. Hereditary forms associated with an abnormality of red blood cells do not require special treatment. For thalassemia, it is advisable to prescribe folic acid, which is necessary bone marrow V large quantities due to ineffective erythropoiesis. The use of blood transfusions gives a temporary effect. The use of desferal is recommended. At sickle cell anemia During a crisis, the patient must be placed in a warm room, since at low temperatures the degree of sickle cell increases. It is recommended to use drugs aimed at preventing thrombus formation (magnesium sulfate, acetylsalicylic acid).
II. Immune hemolytic anemias
A. Damage to red blood cells is manifested by hemolysis. Normally, the lifespan of red blood cells is about 120 days. With hemolysis it shortens. The causes of hemolysis can be both red blood cell defects and external influences. Immune hemolysis is caused by the production of antibodies to erythrocyte antigens with subsequent destruction of erythrocytes due to phagocytosis or complement activation. Immune hemolysis can be caused by both allo- and autoantibodies. Other causes of hemolysis that need to be considered include: differential diagnosis immune hemolytic anemia, it should be noted: 1) congenital defects of the erythrocyte membrane; 2) mechanical damage red blood cells, for example in microangiopathy; 3) infection; 4) congenital deficiency of erythrocyte enzymes; 5) splenomegaly; 6) hemoglobinopathies. There are extravascular and intravascular immune hemolysis. The effectors of extravascular immune hemolysis are macrophages, and the effectors of intravascular immune hemolysis are antibodies. Macrophages carry receptors for the Fc fragment of IgG 1 and IgG 3, so red blood cells coated with these antibodies bind to macrophages and are destroyed. Partial phagocytosis of erythrocytes leads to the appearance of microspherocytes - distinctive feature extravascular hemolysis. Because macrophages also carry a receptor for C3b, C3b-coated red blood cells also undergo extravascular hemolysis. The most pronounced destruction of red blood cells is observed when both IgG and C3b are simultaneously present on their membranes. Antibodies that cause extravascular hemolysis are called heat antibodies because they bind most effectively to erythrocyte antigens (usually Rh, less commonly MNSs) at 37°C. The effectors of intravascular hemolysis in most cases are IgM. The complement binding sites located on the Fc fragments of the IgM molecule are located at a short distance from each other, which facilitates the fixation of the components of the membrane attack complex (see Chapter 1, paragraph IV.D.3) on the surface of erythrocytes. The formation of the membrane attack complex leads to swelling and destruction of red blood cells. Antibodies that cause intravascular hemolysis are called cold antibodies because they bind most effectively to erythrocyte antigens at 4°C. IN in rare cases intravascular hemolysis is caused by IgG. Comparative characteristics extra- and intravascular immune hemolysis is given in table. 16.1. The production of autoantibodies to red blood cells may be due to the following reasons.
1.
Fixation of a hapten, such as a drug, or high molecular weight antigens, such as bacterial ones, on the surface of red blood cells.
2.
Impaired T-suppressor function.
3.
Changes in the structure of erythrocyte antigens.
4.
Cross-reactions between bacterial and erythrocyte antigens.
5.
Impaired function of B-lymphocytes, usually with hematological malignancies and collagenoses.
B. Severe transfusion reactions. These reactions occur when transfusion of red blood cells that are incompatible according to the ABO system. Severe transfusion reactions are caused by IgM antibodies to erythrocyte antigens A and B. The interaction of antibodies with erythrocytes causes complement activation and intravascular hemolysis, which is accompanied by the release of free hemoglobin into the plasma, the formation of methemalbumin (brown pigment) and hemoglobinuria.
1. Clinical picture. Immediately after transfusion of incompatible red blood cells, fever, chills, and back and chest pain occur. These symptoms can occur when even a small amount of red blood cells is transfused. Most severe transfusion reactions occur as a result of errors made in determining blood type. To avoid these errors, it is necessary to carefully label vials of donated blood and determine the blood type of the donor and recipient. In severe cases, acute renal failure, disseminated intravascular coagulation syndrome and shock develop. The prognosis depends on the titer of antibodies to red blood cell antigens A and B in the recipient's serum and the volume of red blood cells transfused.
Treatment
A. If signs of a transfusion reaction appear, red blood cell transfusion is stopped immediately.
b. Samples of the recipient's red blood cells and blood are collected for microscopy and culture.
V. The vial with red blood cells is not thrown away. It is sent to the blood transfusion center along with a sample of the recipient's blood for a direct Coombs test, repeated determination of antigens of the ABO and Rh systems and individual compatibility.
G. A biochemical blood test is performed.
d. Active infusion therapy is started. After determining the blood group and conducting an individual compatibility test, the patient is transfused with another dose of red blood cells.
e. In acute intravascular hemolysis, it is first necessary to maintain diuresis. To accelerate the excretion of hemoglobin, urine is alkalinized, and mannitol is administered to maintain renal blood flow and glomerular filtration.
and. If bacterial contamination of the transfused packed red blood cells is suspected, antimicrobial therapy is started immediately.
h. For urticaria, diphenhydramine is prescribed IV or IM. For bronchospasm, laryngospasm or arterial hypotension carry out the same treatment as for anaphylactic reactions (see Chapter 10, paragraph VI and Chapter 11, paragraph V).
B. Mild transfusion reactions. These reactions are caused by antibodies to weak erythrocyte antigens that are not related to the ABO system. Because they are usually caused by IgG, extravascular hemolysis is common. It develops 3-10 days after red blood cell transfusion. Common symptoms include fatigue, mild shortness of breath, anemia, microspherocytosis, increased indirect bilirubin levels, and decreased serum haptoglobin levels.
1. Diagnostics. Since mild transfusion reactions develop several days after red blood cell transfusion, it is impossible to determine the donor's red blood cell antigens. An indirect Coombs test is performed to detect antibodies to erythrocyte antigens in the patient's serum.
2. Treatment usually not required. Subsequently, red blood cells that do not contain the antigens that caused the transfusion reaction are used for transfusion.
D. Autoimmune hemolytic anemia caused by extravascular hemolysis, can be primary (55%) and secondary: with hemoblastosis (20%), drug use (20%), collagenosis and viral infections (5%). This form of hemolytic anemia can be very severe. The mortality rate of primary autoimmune hemolytic anemia is no more than 4%. The prognosis for secondary autoimmune hemolytic anemia depends on the underlying disease.
1. Clinical picture. Anemia often develops unnoticed. In severe cases, fever, chills, nausea, vomiting, and abdominal, back and chest pain are observed. Possible weakness and drowsiness. Sometimes heart failure develops. 24 hours after the onset of acute massive hemolysis, jaundice appears. Physical examination may reveal splenomegaly.
Diagnostics
A. General analysis blood. Characterized by normochromic, normocytic anemia, polychromasia, nucleated erythrocyte precursors, an increase in the number of reticulocytes, spherocytes, and sometimes fragmented erythrocytes.
b. When examining urine, urobilinogen and hemoglobin are determined.
V. The diagnosis is made based on the results of the direct Coombs test. In 2-4% of patients with clinical manifestations of autoimmune hemolytic anemia, the direct Coombs test is negative. The indirect Coombs test is positive in 60% of patients with autoimmune hemolytic anemia. There is no connection between the severity of hemagglutination during the Coombs test and the severity of hemolysis. Red blood cells can be coated only with immunoglobulins (in 20-40% of cases), immunoglobulins and complement components (in 30-50% of cases) and only complement components (in 30-50% of cases). Determining the type of molecules fixed on the surface of red blood cells sometimes makes it possible to clarify the diagnosis. Thus, the diagnosis of SLE is unlikely if the red blood cells are coated only with IgG.
G. It is important to determine the class of antibodies fixed on the surface of red blood cells. If only IgG is detected, it is most likely directed against Rh system antigens. If antibodies are detected different classes, then the patient is likely sensitized against several erythrocyte antigens, which makes donor selection very difficult.
3. Treatment(see Table 16.2). In case of secondary autoimmune hemolytic anemia, the underlying disease is treated first. In children, this form of the disease is usually caused by viral infection and passes quickly. In other cases, anemia occurs in waves. During exacerbations, a significant decrease in hemoglobin levels is possible and emergency care is often required.
A. Drug of choice - prednisone, 1-2 mg/kg/day orally in several doses. In 70% of patients, remission occurs after using the drug for 3 weeks. In severe cases, prednisone is prescribed at a dose of 4-6 mg/kg/day orally for 3-5 days. After the condition improves, the dose of the drug is slowly, over 6-8 weeks, reduced to maintenance. The maintenance dose of prednisone is on average 10-20 mg orally every other day.
b. If corticosteroids are ineffective or high doses of prednisone (more than 20-40 mg/day orally) are required to maintain remission, splenectomy is indicated. The effectiveness of splenectomy does not depend on which erythrocyte antigens the autoantibodies are directed to. Positive results of splenectomy are observed in 70% of patients in whom corticosteroids were ineffective. After surgery, the dose of prednisone can be reduced to 5-10 mg/day orally or even discontinued.
V. If splenectomy does not lead to improvement, immunosuppressants are prescribed: cyclophosphamide, 2-3 mg/kg/day orally, or azathioprine, 2.0-2.5 mg/kg/day orally. These drugs can be combined with corticosteroids. During treatment with cyclophosphamide, the number of leukocytes in the blood is regularly determined.
G. Red blood cell transfusion is performed only in acute hemolysis accompanied by severe anemia. Because transfused red blood cells are rapidly destroyed, corticosteroids are given at the same time as the red blood cell transfusion. It can be difficult to select a red blood cell mass for a patient with autoimmune hemolysis, especially if he has already received multiple blood transfusions, since with autoimmune hemolytic anemia, along with autoantibodies, alloantibodies are also produced. In the presence of autoantibodies, it is often impossible to determine the antigens against which alloantibodies are directed.
d. Folic acid. In chronic hemolysis, there is often a deficiency of folic acid, which plays an important role in erythropoiesis. Folic acid is prescribed at a dose of 1 mg/day orally. If hemolysis has stopped, this dose is sufficient to compensate for the deficiency of folic acid in the body.
e. Danazol causes improvement in 70% of patients in whom corticosteroids were ineffective. The mechanism of action is unknown. Average dose- 200 mg orally 3 times a day. Improvement occurs 2-24 months after the start of treatment.
and. Autoimmune hemolytic anemia caused by extravascular hemolysis is characterized by periodic exacerbations. During them, the following treatment is carried out.
1)
Increase the dose or re-prescribe corticosteroids. This usually stops hemolysis.
2)
Red blood cell transfusion is performed only in cases of severe anemia.
3)
Normal immunoglobulin is prescribed for intravenous administration, 400-500 mg/kg/day for 4-5 days. The effectiveness of high doses of normal immunoglobulin in hemolytic anemia is probably based on its ability to prevent phagocytosis of red blood cells. In addition, the drug may contain anti-idiotypic antibodies that block antibodies to erythrocyte antigens.
4)
Plasmapheresis is performed. Its effectiveness in autoimmune hemolytic anemia is attributed to the removal of autoantibodies from the plasma. However, it is possible that plasmapheresis has an immunomodulatory effect. The procedures are carried out every other day. The removed plasma (60-80 ml/kg) is replaced with a 5% albumin solution. With this treatment regimen, extravascular IgG gradually passes into the plasma and is removed. Instead of plasmapheresis, plasma immunosorption is sometimes used using protein A (a component of the cell wall of staphylococci), which selectively removes IgG. Among the complications of immunosorption, anaphylactic and anaphylactoid reactions should be noted. The latter usually occurs in patients taking AChE inhibitors.
In children over 1 year of age, acquired hemolytic anemia can be immunopathological, autoimmune or heteroimmune.
In older children and adults, it often occurs as a result of a breakdown of immunological tolerance to the antigen as a result of various chronic diseases(lymphocytic leukemia, nonspecific ulcerative colitis and other diseases).
This is often a symptomatic form.
Antibodies can damage red blood cells in peripheral blood or bone marrow.
Due to the different types of antibodies, autoimmune hemolytic anemias are divided into:
Autoimmune hemolytic anemia (AIHA) with incomplete cold agglutinins;
AIHA with complete cold agglutinins;
AIHA with thermal hemolysins;
AIGAs with biphasic hemolysins.
Cold agglutinins (complete and incomplete) cause agglutination of red blood cells in the body (test tube) when the temperature decreases.
In these cases, red blood cells stick together and their membranes are damaged. Incomplete antibodies attach to red blood cells, causing them to stick together.
In autoimmune hemolytic anemia, the bone marrow is in the stage of irritation of the bone growth with high megacoriocytosis, and reticulocytosis is common.
In this case, during the study of blood serum, an increase in the content of gamma globulins is determined; in addition to hyperbilirubinemia, erythrocytes do not change morphologically, the level of reticulocytes is high, erythrokaryocytes can be detected. Blood smears show red blood cells with “eaten” edges.
Main clinical symptoms
Reduces to the appearance of signs of anemic syndrome. In the case of the phonic course of the disease, along with anemia, slightly pronounced jaundice occurs. When hemolysis occurs in other cases, anemia and jaundice rapidly increase, which is often accompanied by an increase in temperature.
An enlarged spleen appears.
In the variant with the phenomena of intravascular coagulation and autoimmune hemolytic anemia, red blood cells damaged by autoantibodies are absorbed by macrophage cells. With this form, dark urine is discharged.
Autoimmune anemia can occur in old age. If this is associated with the occurrence of cold agglutinins, the disease develops against the background of “full health”: shortness of breath, pain in the heart and lower back suddenly occur, the temperature rises, and jaundice appears. In other cases, the disease manifests itself as pain in the abdomen, joints, and low-grade fever.
The chronic course often takes the form of intracellular hemolysis caused by cold agglutinins, which is a consequence of sudden cooling.
In such cases, patients do not tolerate cold well, and gangrene of the fingers may develop.
Patients often experience intolerance to cold; when exposed to cold, fingers, ears, and the tip of the nose turn blue, pain in the extremities occurs, and the spleen and liver become enlarged.
Diagnostics
It is based on signs of hemolysis, staging serological reactions, straight and indirect sample Coombs, incubation of erythrocytes and serum under different temperature conditions.
Glucocorticoids are prescribed. If steroid therapy is ineffective, the issue of splenectomy is resolved. In cases of autoimmune hemolytic anemia with complete cold agglutinins, immunosuppressants (cyclophosphamide, methotrexate, etc.) are prescribed along with corticosteroids. In severe cases, blood or “washed” (frozen) red blood cells are transfused.
