Autoimmune hemolytic anemias with incomplete heat agglutinins

Autoimmune hemolytic anemia with incomplete thermal agglutinins is the most common form in adults and children, although the latter, according to some reports, paroxysmal cold hemoglobinuria occurs no less frequently, but is less often diagnosed. In children, autoimmune hemolytic anemia with incomplete thermal agglutinins is most often characterized by idiopathic, immunodeficiency syndromes and SLE - the most frequent causes of secondary autoimmune hemolytic anemia. In adults, this form of autoimmune hemolytic anemia often accompanies other autoimmune syndromes, CLL and lymphomas.

Antibodies in autoimmune hemolytic anemia with incomplete thermal agglutinins are classified as IgG, they are not able to bind complement. Accordingly, red blood cells are removed from the bloodstream through their binding and erythrophogocytosis, mainly in the spleen. By specificity, antibodies are often directed against the determinants associated with the Rh-antigen complex.

The clinical picture of autoimmune hemolytic anemia with incomplete thermal agglutinins consists of anemic syndrome (pallor, weakness, palpitation) and hyperbilirubinemia (jaundice, darkening of the urine, occasionally - congestion syndrome: pain in the right hypochondrium, abrupt enlargement of the liver and gallbladder overgrown with thick layered bile ). Less frequent pain in the abdomen and lower back, more characteristic of intravascular hemolysis.

The laboratory characteristics of autoimmune hemolytic anemia include:

• reduction of hemoglobin and hematocrit;
• hyperbilirubinemia;
• increase in the content of reticulocytes.

At the onset of hemolysis and during episodes of its amplification, hyperleukocytosis is common, often up to 20-25x10 ⁹ / l with a left shift. At the onset of autoimmune hemolytic anemia, reticulocytopenia is sometimes recorded due to rapid clearance of reticulocytes by antibodies and delay in hyperplasia and hyperproliferation of the erythroid bone marrow in response to hemolysis. The number of platelets is usually normal or slightly increased. Reducing the concentration of platelets below 100x10 ⁹ / L leads to the need to exclude Fischer-Evans syndrome, in which autoimmune hemolytic anemia is combined with ITP. Fisher-Evans syndrome is much more resistant to therapy than "simple" autoimmune hemolytic anemia. In the debut of autoimmune hemolytic anemia, the bilirubin content is increased both at the expense of the direct and indirect fractions thereof, further indirect protein bilirubin predominates because of an increase in MDR protein expression. A prolonged increase in the concentration of direct bilirubin is characteristic of massive hemolysis and the development of bile condensation syndrome. In young children, due to the sharp relative predominance of the mass of the functional liver parenchyma over the mass of circulating red blood cells, the concentration of bilirubin may not increase, even with severe hemolysis.

Treatment

Aggressiveness of the approach to the treatment of autoimmune hemolytic anemia with incomplete thermal agglutinins depends on the clinical tolerability of anemia and the rate of decrease in hemoglobin concentration. The tolerability of anemia depends more on the severity of the reticulocytosis than on the Hb and Ht values, since the reticulocytes very efficiently give oxygen to the peripheral tissues due to the high level of 2,3-diphosphoglycerate. At the expressed reticulocytosis (> 10%) children well transfer even very low levels of a hemoglobin - 35-45 g / l. If autoimmune hemolytic anemia develops after an infectious disease, the hemoglobin level is not lower than 55-60 g / l, the reticulocytosis is high, the clinical tolerance of anemia is good, and the rate of hemoglobin incidence is not more than 10 g / l per week, then expectant management may be justified. In such cases spontaneous regression of hemolysis within 2-6 months is not uncommon. In other cases, drug treatment is necessary.

Medication

Intravenous administration of immunoglobulins in doses of 3-5 g / kg (ie, twice or three times that of ITP!) Is quite effective and is useful in young children with a mildly flowing postinfection, or "postvaccinal", autoimmune hemolytic anemia with incomplete thermal agglutinins. In other cases, the basis of treatment is glucocorticosteroids. The starting dose of prednisolone is 2 mg / kg. This dose is used before the normalization of the level of Hb, reticulocytosis and bilirubin, but not less than a month. The effect of initial treatment with prednisolone is never instant: the concentration of Hb begins to rise after 7-10 days. At the same time, with recurrences of hemolysis, when the hyperplasia of the erythroid bone marrow is extremely pronounced, the rise in the Hb level can begin very quickly. The normalization of reticulocytosis is always late in relation to the normalization of the concentration of Hb. If the Hb content reaches normal values, but the reticulocytosis remains pronounced and the Coombs test is positive, then we speak of compensated hemolysis. A complete response is the normalization of hemoglobin and reticulocyte levels. Complete hematologic remission is considered normalization of the level of Hb and reticulocytes with a negative Coombs test. After normalization of the hemoglobin and reticulocyte content, which lasts for at least 2 weeks, it is possible to start reducing the dose of prednisolone. Autoimmune hemolytic anemia with incomplete thermal agglutinins is classified as steroid-dependent syndromes with a tendency to relapse beginning with a certain dose of the drug. For prednisolone, the minimum threshold dose is usually 10-20 mg per day. Accordingly, up to 25-30 mg per day the dose can be reduced quite quickly: 5-10 mg per week under the control of the degree of reticulocytosis and the concentration of red blood cells. After that, the dose is reduced by 1.25-2.50 mg per week, depending on the weight of the child's body. The Coombs test is often positive, despite a persistent full hematologic response that is not considered an obstacle to lowering the dose and completely eliminating prednisolone, but patients with a persistent positive Coombs test are prone to recurrence of hemolysis.

If the complete normalization of hemoglobin and reticulocyte levels is not achieved within 2-2.5 months of prednisolone treatment at a dose of 2 mg / kg, or if the remission of the disease depends on unacceptably high doses of prednisolone, alternative treatment should be considered. A very effective medication approach to the treatment of refractory or steroid-dependent patients is treatment with cyclophosphamide. Intravenous injection of 400 mg / m ^{2 of} cyclophosphamide with a suitable dose of mos every 2-3 weeks often leads to surprisingly rapid arrest of hemolysis and normalization of hemoglobin level. The usual course of treatment consists of 3, a maximum of 4 injections and does not cause early complications in the form of neutropenia and hemorrhagic cystitis. At the same time, the risk of late carcinogenic effects of cyclophosphamide makes the decision of its use difficult, especially for children. Among other immunosuppressants in autoimmune hemolytic anemia, azathioprine is most commonly used.

Plasmapheresis and immunoadsorption on columns with staphylococcal protein A can have a pronounced temporary effect, but they must be accompanied by aggressive immunosuppressive therapy, as these methods are fraught with ricochet syndrome.

A splenectomy, previously firmly established in the second line of therapy for autoimmune hemolytic anemia in children, is less commonly used today for the aforementioned reasons. Nevertheless, removal of the spleen is often the only method capable of "curbing" severe hemolysis. The question of removing the spleen is decided for each patient individually. When choosing a solution, take into account:

• age of the patient;
• severity of hemolysis;
• availability, cost and side effects of drug treatment needed to maintain a partial or complete response.

Paroxysmal cold hemoglobinuria (UGS) causes IgG antibodies that bind to erythrocytes at low temperature and activate complement at body temperature. Previously, UGS was most often associated with late stages of congenital syphilis - a form that is now almost non-existent. Today, the most common is the sporadic, transient form of UGS. In children, UGS is most often mediated by antibodies of anti-beta specificity. Antibodies in UGS react with erythrocytes upon cooling and cause acute intravascular hemolysis with acute hemoglobinuria and renal damage up to acute renal failure (ARF). The clinical picture is dominated by abdominal pains, fever, pallor with the discharge of urine in the color of "cherry syrup" (according to moms) and "pink port wine" (according to the fathers). In the urine, standing in the air, black flakes are formed. Quite often thrombocytopenia of consumption develops, therefore at first it is sometimes difficult to differentiate UGS with hemolytic-uremic syndrome. UGS is self-limited syndrome, self-resolving for several weeks / months. Since autoantibodies of IgM class are secreted by B-lymphocytes not controlled by T-lymphocytes, in the treatment of UGS UGCs are ineffective. Usually, for treating UGS, it is sufficient not to allow the child to cool down and perform competent infusion therapy during the hemolytic crisis. Transfused erythrocytic mass must be heated to 37 ° C.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]