Autoimmune hemolytic anemia

Autoimmune hemolytic anemia is caused by antibodies that interact with erythrocytes at a temperature of 37 ° C (hemolytic anemia with thermal antibodies) or a temperature of <37 ° C (hemolytic anemia with Cold agglutinins).

Hemolysis, as a rule, is extravascular. A direct antiglobulin test (Coombs) determines the diagnosis and can suggest the cause of hemolysis. Treatment depends on the cause that triggered the development of hemolysis, and includes the use of glucocorticoids, intravenous immunoglobulin, immunosuppressants, splenectomy, avoidance of blood transfusion and / or withdrawal of drugs.

[1], [2], [3]

Causes of autoimmune hemolytic anemia

Hemolytic anemia with thermal antibodies is the most common form of autoimmune hemolytic anemia (AIGA), affecting more often women with this type of anemia. Autoantibodies usually react at a temperature of 37 ° C. They can occur spontaneously or in combination with some other diseases (SLE, lymphoma, chronic lymphocytic leukemia). Certain medications (eg, methyldopa, levodopa) stimulate the production of autoantibodies against Rh antigens (methyldopa type AIGA). Some drugs stimulate the production of autoantibodies against the erythrocyte antibiotic membrane complex as part of the transient hapten mechanism; Hapten may be stable (eg, high doses of penicillin, cephalosporins) or unstable (eg, quinidine, sulfonamides). In hemolytic anemia with thermal antibodies, hemolysis occurs predominantly in the spleen, the process is often intense and can be fatal. Most autoantibodies for this type of haemolysis are IgG, a significant part is panagglutinins and has limited specificity.

Drugs that can cause hemolytic anemia with thermal antibodies

Autoantibodies	Stable	Unstable or unknown mechanism
Cephalosporins Diclofenac Ibuprofen Interferon Levodopa Mefenamic acid Methyldopa Procainamide Teniposide Thioridazine Tolmetin	Cephalosporins Penicillins Tetracycline Tolbutamide	Amphotericin B Antazolin Cephalosporins Chloropropamide Diclofenac Diethylstilbestrol Doxepin Hydrochlorothiazide Isoniazid Beta-aminosalicylic acid Probenecid Quinidine Quinine Rifampicin Sulfonamides Thiopental Tolmetin

Disease of cold agglutinins (Cold Antibody disease) is caused by autoantibodies that react at a temperature of less than 37 ° C. Sometimes it occurs in infections (especially mycoplasmal pneumonia or infectious mononucleosis) and lymphoproliferative diseases; about 1/3 of all cases are idiopathic. Disease of cold agglutinins is the main form of hemolytic anemia in elderly patients. Infections usually cause an acute form of the disease, while idiopathic forms tend to be chronic. Hemolysis occurs mainly in the extravascular mononuclear phagocytic system of the liver. Anemia usually moderately expressed (hemoglobin> 75 g / l). Antibodies for this form of anemia are IgM. The degree of hemolysis is more pronounced, the higher the temperature (closer to normal body temperature), at which these antibodies react with erythrocytes.

Paroxysmal cold hemoglobinuria (UGS, Donat-Landsteiner's syndrome) is a rare type of cold agglutinin disease. Hemolysis is provoked by cooling, which can even be local (for example, with cold water, washing with cold water). Autohaemolysins IgG bind to erythrocytes at low temperature and cause intravascular hemolysis after warming. This occurs most often after a nonspecific viral infection or in healthy people, occurs in patients with congenital or acquired syphilis. The severity and rapidity of the development of anemia varies and may have fulminant course.

Symptoms of autoimmune hemolytic anemia

Symptoms of hemolytic anemia with thermal antibodies are due to the presence of anemia. If the disease is severe, there is an increase in body temperature, chest pain, syncope, signs of heart failure. Moderate splenomegaly is a typical phenomenon.

Disease Cold agglutinin manifests itself in the form of acute or chronic forms. Other cryopathic symptoms may also be present (eg, acrocyanosis, Raynaud phenomenon, occlusive disorders associated with cold). Symptoms of APG can be severe pain in the back and lower limbs, headache, nausea, diarrhea, dark brown urine; may occur splenomegaly.

Diagnosis of autoimmune hemolytic anemia

AIGA is expected in patients with hemolytic anemia, especially with severe symptoms and the presence of other characteristic manifestations. Routine laboratory tests usually confirm the presence of extravascular hemolysis (eg, absence of hemosiderinuria, normal level of haptoglobin), if anemia does not appear suddenly and intensively or its cause is APG. Typical features are spherocytosis and a high ICSU score.

AIGA is diagnosed in the determination of autoantibodies using a direct an-tiglobulin test (Coombs). Anti-globulin serum is added to washed erythrocytes of the patient; the presence of agglutination indicates the presence of an immunolobulin, usually an IgG, or a complement C3 component bound to the erythrocyte surface. The sensitivity of the test for AIGA is about 98%. If the antibody titer is very low or if the antibodies are IgA and IgM, false-negative test results are possible. In general, the intensity of the direct antiglobulin test correlates with the number of molecules of the IgG or C3 complement component bound to the erythrocyte membrane, and roughly with the degree of hemolysis. An indirect antiglobulin test (Coombs) consists in mixing the patient's plasma with normal red blood cells to determine the presence of antibodies in the plasma. A positive indirect antiglobulin test and a negative straight line usually indicates the presence of alloantibodies caused by pregnancy, preliminary transfusions or cross reactivity of lectins, and not by the presence of autoimmune hemolysis. It should be borne in mind that the detection of thermal antibodies by itself does not determine the presence of hemolysis, as 1/10 000 normal blood donors have a positive test for these antibodies.

When using the Coombs test to diagnose autoimmune hemolytic anemia, differential diagnosis should be made between hemolytic anemia with thermal antibodies and the disease with Cold agglutinins, as well as determining the mechanism responsible for hemolytic anemia with thermal antibodies. This diagnosis can often be performed with a direct antiglobulin reaction. There are three options:

1. The reaction is positive with anti-IgG and negative with anti-C3. This model is typical for idiopathic autoimmune hemolytic anemia, as well as for drug or methyldopa type autoimmune hemolytic anemia, usually with hemolytic anemia with thermal antibodies;
2. the reaction is positive with anti-IgG and anti-C3. This model is typical in cases of SLE or idiopathic autoimmune hemolytic anemia with thermal antibodies and less often in drug-associated cases;
3. the reaction is positive with anti-C3 and negative with anti-IgG. This is manifested in idiopathic autoimmune hemolytic anemia with thermal antibodies, when IgG of low affinity is present, in isolated drug-associated cases, in the case of cold agglutinins, paroxysmal cold hemoglobinuria.

Other diagnostic studies used in autoimmune hemolytic anemia usually do not produce a definite result. With the disease Cold agglutinins, erythrocytes agglutinate in blood smears, and automatic analyzers often determine an increase in the MCV index and falsely low levels of hemoglobin. After warming the hands and then recalculating the results, the indicators change toward their normalization. Differential diagnosis between hemolytic anemia with thermal antibodies and Cold agglutinin disease can be made by determining the temperature at which a direct antiglobulin test is positive. If the test is positive at a temperature of> 37 ° C, this indicates a hemolytic anemia with thermal antibodies, whereas a positive test at low temperature indicates a disease of Cold agglutinins.

If UGS is suspected, a Donat-Landsteiner test, which is specific for UGS, should be performed. It is recommended to conduct laboratory tests for syphilis.

[4], [5], [6], [7], [8]

Treatment of autoimmune hemolytic anemia

With drug-induced hemolytic anemia with thermal antibodies, the abolition of preparations reduces the intensity of hemolysis. With methyldopa, the type of autoimmune hemolytic anemia, hemolysis usually stops within 3 weeks, however, a positive Coombs test may persist for more than 1 year. In hapten-associated autoimmune hemolytic anemia, hemolysis ceases after purification of blood plasma from the drug. The intake of glucocorticoids leads to a moderately pronounced effect on drug-induced hemolysis, lg infusions have a more significant effect.

Glucocorticoids (eg, prednisolone 1 mg / kg orally 2 times a day) is a therapy of choice in idiopathic autoimmune hemolytic anemia with thermal antibodies. At very expressed hemolysis the recommended initial dose is from 100 to 200 mg. Most patients have a good response to therapy, which in 1/3 of the cases persists after 12-20 weeks of therapy. When the stabilization of the level of erythrocytes in the blood is achieved, a slow decrease in the dose of glucocorticoids is necessary. Patients with a recurrence of hemolysis after the withdrawal of glucocorticoids or with the initial ineffectiveness of this method of treatment is performed splenectomy. After splenectomy, a good response is observed from 1/3 to 1/2 patients. In the case of fulminant hemolysis, the use of plasmapheresis is effective. With less expressed, but uncontrolled hemolysis, infusions of the immunoglobulin provide a temporary control. Long-term therapy with immunosuppressants (including cyclosporine) may be effective in regaining the disease after therapy with glucocorticoids and splenectomy.

The presence of panagglutinating antibodies in hemolytic anemia with thermal antibodies makes cross-matching of donor blood difficult. In addition, transfusions often lead to a summation of the activity of alloantibodies and autoantibodies, stimulating hemolysis. Thus, blood transfusions should be avoided whenever possible. If necessary, blood transfusions should be produced in small amounts (100-200 ml per 1 -2 hours) under the control of hemolysis.

In acute cases of cold agglutinins, only maintenance therapy is carried out, since the course of anemia is self-limiting. In chronic cases, treatment of the underlying disease often controls anemia. However, in chronic idiopathic cases, moderate anemia (hemoglobin from 90 to 100 g / l) can continue throughout life. It is necessary to avoid cooling. Splenectomy does not have a positive effect. The effectiveness of immunosuppressants is limited. The use of blood transfusion requires caution, if necessary blood transfusion blood should be heated in thermostatic heaters. The effectiveness of transfusions is low, since the lifespan of allogeneic erythrocytes is much lower than that of autologous ones.

With UGS treatment is a strict restriction of stay in the cold. Splenectomy is not effective. The effectiveness of immunosuppressants has been shown, but their use should be limited to cases of progression of the process or idiopathic variants. Therapy of available syphilis can cure UGS.