Autoimmune hemolytic anemias with incomplete thermal agglutinins

Autoimmune hemolytic anemia with incomplete warm agglutinins is the most common form in adults and children, although in the latter, according to some data, paroxysmal cold hemoglobinuria is no less common, but is less frequently diagnosed. In children, autoimmune hemolytic anemia with incomplete warm agglutinins is most often idiopathic, immunodeficiency syndromes and SLE are the most common 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 warm agglutinins belong to the IgG class and are not capable of fixing complement. Accordingly, red blood cells are removed from the bloodstream by their binding and erythrophagocytosis, mainly in the spleen. By specificity, antibodies are often directed against determinants associated with the Rh antigen complex.

The clinical picture of autoimmune hemolytic anemia with incomplete warm agglutinins consists of anemic syndrome (paleness, weakness, palpitations) and hyperbilirubinemia (jaundice, darkening of urine, occasionally - bile thickening syndrome: pain in the right hypochondrium, sharp enlargement of the liver and gall bladder, overstretched with thick layered bile). Less common are abdominal and lower back pain, more characteristic of intravascular hemolysis.

Laboratory characteristics of autoimmune hemolytic anemia include:

• decrease in hemoglobin and hematocrit levels;
• hyperbilirubinemia;
• increased reticulocyte count.

At the onset of hemolysis and during episodes of its intensification, hyperleukocytosis is typical, 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 delayed hyperplasia and hyperproliferation of the erythroid lineage of the bone marrow in response to hemolysis. The platelet count is usually normal or slightly increased. A decrease in platelet concentration below 100x10 ⁹ /l leads to the need to exclude Fisher-Evans syndrome, in which autoimmune hemolytic anemia is combined with ITP. Fisher-Evans syndrome is significantly more resistant to therapy than "simple" autoimmune hemolytic anemia. At the onset of autoimmune hemolytic anemia, the bilirubin content is elevated due to both its direct and indirect fractions; later, due to increased expression of the MDR protein, indirect bilirubin dominates. A prolonged increase in the concentration of direct bilirubin is characteristic of massive hemolysis and the development of bile thickening syndrome. In young children, due to the sharp relative predominance of the mass of functional liver parenchyma over the mass of circulating erythrocytes, the bilirubin concentration may not increase even with severe hemolysis.

Treatment

The aggressiveness of the approach to the treatment of autoimmune hemolytic anemia with incomplete warm agglutinins depends on the clinical tolerance of the anemia and the rate of decline in hemoglobin concentration. Tolerability of anemia depends to a greater extent on the severity of reticulocytosis than on the Hb and Ht levels, since reticulocytes very effectively give oxygen to peripheral tissues due to the high level of 2,3-Diphosphoglycerate. With severe reticulocytosis (> 10%), children tolerate even very low hemoglobin levels well - 35-45 g / l. If autoimmune hemolytic anemia developed after an infectious disease, the hemoglobin level is not lower than 55-60 g / l, reticulocytosis is high, clinical tolerance of anemia is good, and the rate of decline in hemoglobin is no more than 10 g / l per week, then a wait-and-see approach may be justified. In such cases, spontaneous regression of hemolysis within 2-6 months is not uncommon. In other cases, drug treatment is necessary.

Drug treatment

Intravenous administration of immunoglobulins in doses of 3-5 g/kg (i.e. two to three times higher than those for ITP!) is quite effective and applicable in small children with mild post-infectious, or "post-vaccination", autoimmune hemolytic anemia with incomplete warm agglutinins. In other cases, glucocorticosteroids are the basis of treatment. The starting dose of prednisolone is 2 mg/kg. This dose is used until the level of Hb, reticulocytosis and bilirubin is normalized, but not less than a month. The effect of initial treatment with prednisolone is never immediate: the Hb concentration begins to increase after 7-10 days. At the same time, in case of relapses of hemolysis, when hyperplasia of the erythroid germ of the bone marrow is extremely pronounced, the rise in the Hb level can begin very quickly. Normalization of reticulocytosis is always delayed in relation to the normalization of the Hb concentration. If the Hb content reaches normal values, but reticulocytosis remains pronounced and the Coombs test is positive, then this is called compensated hemolysis. A complete response is considered to be normalization of the hemoglobin and reticulocyte levels. Complete hematological remission is considered to be normalization of the Hb and reticulocyte levels with a negative Coombs test. After normalization of the hemoglobin and reticulocyte content, which lasts for at least 2 weeks, you can begin to reduce the dose of prednisolone. Autoimmune hemolytic anemia with incomplete warm agglutinins is classified as a steroid-dependent syndrome that tends to relapse starting with a certain dose of the drug. For prednisolone, the minimum threshold dose is usually 10-20 mg per day. Accordingly, the dose can be reduced to 25-30 mg per day fairly quickly: 5-10 mg per week under the control of the degree of reticulocytosis and the concentration of erythrocytes. After this, the dose is reduced by 1.25-2.50 mg per week depending on the child's body weight. The Coombs test often remains positive despite a persistent complete hematological response, which is not considered an obstacle to reducing the dose and completely discontinuing prednisolone, but patients with a persistently positive Coombs test are prone to relapses of hemolysis.

If complete normalization of hemoglobin and reticulocyte levels is not achieved within 2-2.5 months of treatment with prednisolone at a dose of 2 mg/kg, or if remission of the disease depends on unacceptably high doses of prednisolone, it is necessary to consider the issue of alternative treatment. A very effective drug approach to the treatment of refractory or steroid-dependent patients is treatment with cyclophosphamide. Intravenous administration of 400 mg/m2 ^of cyclophosphamide with an appropriate dose per month every 2-3 weeks often leads to surprisingly rapid arrest of hemolysis and normalization of hemoglobin levels. The usual course of treatment consists of 3, maximum 4 administrations and does not cause early complications in the form of neutropenia and hemorrhagic cystitis. At the same time, the risk of late carcinogenic action of cyclophosphamide makes the decision to use it difficult, especially for children. Among other immunosuppressants, azathioprine is used with the greatest success in autoimmune hemolytic anemia.

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

Splenectomy, which used to be a firm second-line treatment for autoimmune hemolytic anemia in children, is used less frequently today for the above-mentioned reasons. However, often, spleen removal is the only method capable of "taming" severe hemolysis. The question of spleen removal is decided for each patient individually. When choosing a solution, the following is taken into account:

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

Paroxysmal cold hemoglobinuria (PCH) is caused by IgG antibodies that bind to red blood cells at low temperatures and activate complement at body temperature. Previously, PCH was most often associated with the late stages of congenital syphilis, a form that is now almost never encountered. Today, the most common form is sporadic, transient PCH. In children, PCH is most often mediated by anti-beta antibodies. Antibodies in PCH react with red blood cells during cooling and cause acute intravascular hemolysis with acute hemoglobinuria and kidney damage up to acute renal failure (ARF). The clinical picture is dominated by abdominal pain, fever, pallor with urine the color of "cherry syrup" (according to mothers) and "pink port" (according to fathers). Black flakes form in urine that has stood in the air. Consumption thrombocytopenia often develops, so at first it is sometimes difficult to differentiate PCH from hemolytic uremic syndrome. PCH is a self-limited syndrome, which resolves spontaneously within a few weeks/months. Since IgM autoantibodies are secreted by B lymphocytes, not controlled by T lymphocytes, GCs are ineffective in the treatment of PCH. Usually, to treat PCH, it is sufficient to prevent the child from becoming cold and to carry out competent infusion therapy during the hemolytic crisis. The transfused red blood cell mass must be warmed to 37 °C.

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