Autoimmune hemolytic anemia with complete Cold agglutinins

Autoimmune hemolytic anemia with complete cold agglutinins (cold agglutinin disease) is much less common in children than other forms. In adults, this disease is often detected: this form is either secondary to lymphoproliferative syndromes, hepatitis C, infectious mononucleosis, or idiopathic. In the idiopathic form of anemia, however, the presence of clonal expansion of the population of morphologically normal lymphocytes producing monoclonal IgM is also shown. In the overwhelming majority of cases, antibodies are directed against carbohydrate determinants of the I/i complex on the surface of erythrocytes. In 90% of cases, antibodies are specific for I, and in 10%, antibodies are formed against i. Although in this form of autoimmune hemolytic anemia antibodies react with red blood cells at low temperatures and bind complement, overt intravascular thrombosis is rare, and clearance of "sensitized" red blood cells is mediated by C3c1 receptors of liver macrophages and, to a lesser extent, the spleen. Hemolytic crisis is often provoked by hypothermia: during walks in cold weather and wind, when swimming, etc. Hemolysis in cold agglutinin disease is often subacute, without catastrophic drops in hemoglobin concentration. The Coombs test in this form is negative in reaction with anti-IgG, but positive in reaction with anti-C3e. Bright spontaneous agglutination of red blood cells on glass is typical. Treatment with glucocorticosteroids, cyclophosphamide and interferon, as well as splenectomy, are not effective enough in autoimmune hemolytic anemia with complete Cold agglutinins, and complete remissions are rare. In this regard, there is a need to search for and implement new methods of drug treatment, primarily immunosuppressive treatment of autoimmune hemolytic anemia.

Treatment with rituximab (monoclonal antibodies to the CD20 molecule), which has been used for several years in the treatment of oncohematological and autoimmune diseases, has become another effective method of conservative treatment of autoimmune hemolytic anemia, although the question of its place has not yet been finally resolved. Naturally, rituximab is not considered a first-line drug for now, but its place in subsequent lines is obvious. On the other hand, the good efficacy of rituximab in Cold agglutinin disease, which is usually resistant to standard immunosuppressive therapy, may soon move it to the first line. Indications for rituximab in autoimmune hemolytic anemia:

• autoimmune hemolytic anemias caused by warm or cold antibodies;
• Fisher-Evans syndrome:
  • in case of refractoriness to first (glucocorticosteroids) and second (splenectomy, cyclophosphamide, high doses of immunoglobulins) line therapy;
  • in case of dependence on high (>0.5 mg/kg per day) doses of glucocorticosteroids.

The usual course of rituximab therapy consists of 4 administrations at a single dose of 375 mg/ ^m2 with a weekly interval. According to the available data, 50-80% of patients with autoimmune hemolytic anemia respond to rituximab. As a rule, in parallel with rituximab treatment, it is recommended to use glucocorticosteroids at the previous dose, if it does not exceed 1 mg/kg per day. Other immunosuppressive therapy (for example, azathioprine, cyclosporine) is recommended to be discontinued. However, in case of catastrophic hemolysis, directly threatening the patient's life, rituximab can be combined with any other methods of therapy (ultra-high doses of glucocorticosteroids, cyclophosphamide, high doses of intravenous immunoglobulin). As a rule, the rate of hemolysis decreases and the hemoglobin level begins to increase after 2-3 weeks of therapy, but the quality of the response can vary significantly - from complete cessation of hemolysis to its more or less complete compensation. Patients who do not need blood transfusions and who have increased the Hb level by at least 15 g/l are considered to be responders. Approximately 25% of patients experience a relapse after achieving remission, usually within the first year, with a high probability of a repeated response to rituximab. Cases have been described where patients successfully received 3 or even 4 courses of rituximab.

Transfusion therapy for autoimmune hemolysis

Indications for red blood cell transfusion depend not on the current Hb level, but on the clinical tolerance of anemia and the rate of decline in hemoglobin content. Each transfusion can cause intravascular hemolysis, but refusal of transfusion can lead to the death of the patient. It is important to remember: the more massive the transfusion, the more massive the hemolysis, so the goal of transfusion in autoimmune hemolytic anemia is not to normalize the hemoglobin concentration, but to maintain it at a clinically sufficient level. Minimal blood typing for transfusions in autoimmune hemolytic anemia includes:

• determination of ABO affiliation;
• determination of the complete Rh phenotype (D, Cc, Ee);
• typing according to Kell antigens and the Duffy system.

Transfusions of red blood cells in autoimmune hemolytic anemias are associated with certain difficulties. Firstly, all blood samples of the same group agglutinate, and therefore, according to classical canons, are incompatible. Secondly, in clinics it is impossible to differentiate alloantibodies that have developed as a result of previous blood transfusions and are capable of causing severe intravascular hemolysis from autoantibodies that cause intracellular hemolysis. This is why transfusions are recommended to be treated as conservatively as possible. To prevent febrile non-hemolytic reactions, leukofiltration of red blood cells with III-IV generation filters or, in extreme cases, washing them is recommended. Washing red blood cells does not reduce hemolysis and does not reduce the risk of alloantibody formation.

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