Autoimmune Hemolytic Anemia

What is Autoimmune Hemolytic Anemia?

Under the name hemolytic anemia, a group of acquired and hereditary diseases is combined, characterized by increased intracellular or intravascular destruction of red blood cells.

Autoimmune hemolytic anemia includes forms of the disease associated with the formation of antibodies to red blood cell own antigens.

In the general group of hemolytic anemias, autoimmune hemolytic anemia is more common. Their frequency is 1 case per 75,000-80,000 people.

Causes of Autoimmune Hemolytic Anemia

Immune hemolytic anemia can occur under the influence of anti-erythrocyte iso-and autoantibodies and, accordingly, are divided into isoimmune and autoimmune.

Isoimmune include hemolytic anemia of the newborn, due to the incompatibility of ABO systems and rhesus between the mother and the fetus, post-transfusion hemolytic anemia.

When autoimmune hemolytic anemia occurs, there is a breakdown of immunological tolerance to unchanged antigens of its own erythrocytes, sometimes to antigens that have determinants similar to erythrocytes. Antibodies to such antigens are able to interact with unchanged antigens of their own erythrocytes. Incomplete heat agglutinins are the most common type of antibody capable of causing the development of autoimmune hemolytic anemia. These antibodies belong to IgG, rarely – to IgM, IgA.

Immune hemolytic anemia is divided into isoimmune and autoimmune. The serological principle of differentiation of autoimmune hemolytic anemia makes it possible to isolate forms due to incomplete thermal agglutinins, thermal hemolysins, cold agglutinins, two-phase cold hemolysins (such as Donat – Landshteyner) and erythropsonins. Some authors identify a form of hemolytic anemia with antibodies against bone marrow normoblast antigen.

According to the clinical course, acute and chronic variants are distinguished.

There are symptomatic and idiopathic autoimmune hemolytic anemia. Symptomatic autoimmune anemia occurs against the background of various diseases, accompanied by disorders in the immune system. Most often they are found in chronic lymphocytic leukemia, lymphogranulomatosis, acute leukemia, systemic lupus erythematosus, rheumatoid arthritis, chronic hepatitis and liver cirrhosis. In those cases when the appearance of autoantibodies cannot be associated with any pathological process, they speak of idiopathic autoimmune hemolytic anemia, which accounts for about 50% of all autoimmune anemias.

The formation of autoantibodies occurs as a result of a disruption in the system of immunocompetent cells that perceive the erythrocyte antigen as foreign and begin to produce antibodies to it. After fixation of autoantibodies on erythrocytes, the latter are captured by cells of the reticulohistiocytic system, where they undergo agglutination and disintegration. Hemolysis of erythrocytes occurs mainly in the spleen, liver, bone marrow. Erythrocyte autoantibodies belong to different types.

On a serological basis, autoimmune hemolytic anemia is divided into several forms:

  • anemia with incomplete heat agglutinins
  • anemia with thermal hemolysins
  • anemia with complete cold agglutinins
  • anemia with biphasic hemolysins
  • anemia with agglutinins against bone marrow normoblasts

Each of these forms has some peculiarities in the clinical picture, course and serological diagnosis. The most common anemia with incomplete heat agglutinins, constituting 70 – 80% of all autoimmune hemolytic anemia.

Pathogenesis During Autoimmune Hemolytic Anemia

The essence of autoimmune processes is that as a result of a weakening of the T-suppressor immune system that controls auto-aggression, the B-immune system is activated, which synthesizes antibodies against unchanged antigens of various organs. T-lymphocyte killers are also involved in the implementation of auto-aggression. Antibodies are immunoglobulins (Ig), most often belonging to the class G, less often – M and A; they are specific and directed against a specific antigen. IgM includes, in particular, cold antibodies and biphasic hemolysins. An erythrocyte carrying antibodies is phagocytosed by macrophages and is destroyed in them; possible lysis of red blood cells with the participation of complement. IgM antibodies can cause erythrocyte agglutination directly in the bloodstream, and IgG antibodies can destroy the erythrocyte only in the macrophages of the spleen. In all cases, hemolysis of erythrocytes occurs the more intensely, the more antibodies are on their surface. Hemolytic anemia with antibodies to spectrin is described.

Symptoms of Autoimmune Hemolytic Anemia

With an acute onset of autoimmune hemolytic anemia, patients develop rapidly increasing weakness, shortness of breath and palpitations, pain in the heart area, sometimes in the lower back, fever and vomiting, intense jaundice. In the chronic course of the process, patients feel relatively satisfactory, even with deep anemia, often pronounced jaundice, in most cases an enlarged spleen, and sometimes the liver, alternating periods of exacerbation and remission.

Anemia is normochromic, sometimes hyperchromic, with hemolytic crises usually marked or moderate reticulocytosis. Macrocytosis and erythrocyte microspherocytosis are detected in peripheral blood, normoblasts may appear. ESR in most cases increased. The content of leukocytes in the chronic form is normal, with an acute – leukocytosis, sometimes reaching high numbers with a significant shift of the leukocyte formula to the left. Platelet count is usually normal.
In Fisher-Ivens syndrome, autoimmune hemolytic anemia is combined with autoimmune thrombocytopenia. In the bone marrow, erythropozis is enhanced, megaloblasts are rarely detected. In the majority of patients, the osmotic resistance of erythrocytes is reduced, which is caused by a significant number of microspherocytes in the peripheral blood. The content of bilirubin is increased due to the free fraction, the content of stercobilin in feces is also increased.

Incomplete thermal agglutinins are detected by a direct Coombs test with polyvalent antiglobulin serum. With a positive test with antisera to IgG, IgM, etc., it is specified which class of immunoglobulins are detectable antibodies. If there are less than 500 fixed IgG molecules on the surface of erythrocytes, the Coombs test is negative. A similar phenomenon is usually observed in patients with a chronic form of autoimmune hemolytic anemia or after acute hemolysis. Coombs negative are cases when antibodies belonging to IgA or IgM are fixed on erythrocytes (for which polyvalent antiglobulin serum is less active).
In about 50% of cases of idiopathic autoimmune hemolytic anemia, simultaneously with the appearance of immunoglobulins fixed on the surface of erythrocytes, antibodies to their own lymphocytes are detected.

Hemolytic anemia due to thermal hemolysins is rare. It is characterized by hemoglobinuria with the release of black urine, alternating periods of acute hemolytic crisis and remission. Hemolytic crisis is accompanied by the development of anemia, reticulocytosis (in some cases thrombocytosis) and an enlarged spleen. There is an increase in the level of free fraction of bilirubin, hemosiderinuria. When processing donor erythrocytes with papain, it is possible to detect monophasic hemolysins in patients. Some patients have a positive Coombs test.

Hemolytic anemia due to cold agglutinins (cold hemagglutinin disease) has a chronic course. It develops with a sharp increase in the titer of Cold Hemagglutinins. There are idiopathic and symptomatic forms of the disease. The leading symptom of the disease is excessively sensitive to cold, which manifests itself in the form of blue and whitening of the fingers and toes, ears, and the tip of the nose. Peripheral circulatory disorders lead to the development of Raynaud’s syndrome, thrombophlebitis, thrombosis and trophic changes up to acrogangrene, and sometimes cold urticaria. The occurrence of vasomotor disorders associated with the formation during cooling of large intravascular conglomerates of agglutinated erythrocytes with subsequent spasm of the vascular wall. These changes are combined with enhanced predominantly intracellular hemolysis. In some patients there is an increase in the liver and spleen. Mild normochromic or hyperchromic anemia, reticulocytosis, normal number of leukocytes and platelets, increased ESR, a slight increase in the free bilirubin fraction, a high titer of complete cold agglutinins (detected by agglutination in saline), sometimes signs of hemoglobinuria are observed. A characteristic is the agglutination of erythrocytes in vitro, which occurs at room temperature and disappears when heated. If it is impossible to carry out immunological tests, the provocative test with cooling becomes diagnostic (in the serum obtained from the finger tightened with a harness after lowering it in ice water, the increased content of free hemoglobin is determined).

In cold hemagglutinin disease, in contrast to paroxysmal cold hemoglobinuria, hemolytic crisis and vasomotor disturbances arise only from hypothermia of the body and hemoglobinuria, which began in cold conditions, ceases with the patient’s transition to a warm room.

Symptom complex, characteristic of cold hemagglutinin disease, can occur against the background of various acute infections and some forms of hemoblastosis. In idiopathic forms of the disease, complete recovery is not observed, with symptomatic prognosis depends mainly on the severity of the underlying process.

Paroxysmal cold hemoglobinuria is one of the rare forms of hemolytic anemia. People of both sexes, often children, become ill with it.

Patients with paroxysmal cold hemoglobinuria after being in the cold may experience general malaise, headache, body aches and other discomfort. This is followed by chills, fever, nausea and vomiting. Urine becomes black. At the same time sometimes yellowing, spleen enlargement and vasomotor disturbances are detected. On the background of hemolytic crisis, patients show moderate anemia, reticulocytosis, increased levels of the free fraction of bilirubin, hemosiderinuria and proteinuria.

The final diagnosis of paroxysmal cold hemoglobinuria is established on the basis of the detected two-phase hemolysins according to the Donat-Landsteiner method. It is not characterized by autoagglutination of red blood cells, constantly observed during cold hemagglutination of Noah’s disease.

Hemolytic anemia due to erythro-opsonin. The existence of autoopsonin to blood cells is generally recognized. In patients with acquired idiopathic hemolytic anemia, cirrhosis of the liver, hypoplastic anemia with a hemolytic component and leukemia, the phenomenon of autoerythrophrosis has been detected.

Acquired idiopathic hemolytic anemia, accompanied by a positive phenomenon autoeritrofagocytosis, has a chronic course. Periods of remission, sometimes lasting for a considerable time, are replaced by a hemolytic crisis characterized by icteric visibility of the visible mucous membranes, darkening of the urine, anemia, reticulocytosis and an increase in the indirect fraction of bilirubin, sometimes an increase in the spleen and liver.

In case of idiopathic and symptomatic hemolytic anemias, the detection of autoerythritis phagocytosis in the absence of data indicating the presence of other forms of autoimmune hemolytic anemia gives grounds for attributing them to hemolytic anemia due to erythro-opsonins. Diagnostic test autoerythrophilocytosis is carried out in direct and indirect versions.

Immunohemolytic anemia caused by the use of drugs. Various therapeutic drugs (quinine, dopegit, sulfonamides, tetracycline, ceporin, etc.) that can cause hemolysis, form complexes with specific heteroantibodies, then settle on erythrocytes and attach themselves to the complement, which leads to disruption of the erythrocyte membrane. This mechanism of medication due to hemolytic anemia is confirmed by the discovery of complement in erythrocytes of patients in the absence of immunoglobulins. Anemias are characterized by an acute onset with signs of intravascular hemolysis (hemoglobinuria, reticulocytosis, increased content of the free fraction of bilirubin, increased erythropoiesis). Against the background of hemolytic crisis, acute renal failure sometimes develops.

Hemolytic anemia, which develops with penicillin and methyldopa, proceeds in a slightly different way. The introduction per day of 15,000 or more U of penicillin can lead to the development of hemolytic anemia, characterized by intracellular hyperhemolysis. Along with the general clinical and laboratory signs of hemolytic syndrome, a positive direct Coombs test is also detected (detectable antibodies belong to IgG). Penicillin, by binding to the erythrocyte membrane antigen, forms a complex against which antibodies are produced in the body.

With prolonged use of methyldophen, some patients develop hemolytic syndrome, which has the features of the idiopathic form of autoimmune hemolytic anemia. Detected antibodies are identical with heat agglutinins and belong to IgG.

Hemolytic anemia due to mechanical factors is associated with the destruction of red blood cells as they pass through altered vessels or through artificial valves. Vascular endothelium changes with vasculitis, malignant hypertension; at the same time, adhesion and platelet aggregation are activated, as is the coagulation system and the formation of thrombin. Common blood stasis and thrombosis of small blood vessels (DIC) develop with the trauma of red blood cells, resulting in their fragmentation; numerous fragments of erythrocytes (schistocytes) are found in the blood smear. Red blood cells are also destroyed as they pass through artificial valves (more often – with multi-valve correction); hemolytic anemia is described against a senile calcined aortic valve. The diagnosis is based on signs of anemia, an increase in the concentration of free bilirubin in the blood serum, the presence of schistocytes in a peripheral blood smear and the symptoms of the underlying disease that caused mechanical hemolysis.

Less common in clinical practice is hemolytic anemia caused by exposure to lead, poisoning with acids, snake venoms or vitamin E deficiency, as well as intracellular parasites. Hemolytic anemia develops, for example, after a snake bite, accidental or intentional (suicide) taking acetic acid, in contact with lead vapors, against the background of malaria. Anemia is normocytic, normochromic, regenerative in nature; in the serum increased the free fraction of bilirubin and iron.

Hemolytic uremic syndrome (Moshkovich’s disease, Gasser syndrome) may complicate the course of autoimmune hemolytic anemia. The autoimmune disease is characterized by hemolytic anemia, thrombocytopenia, and kidney damage. Disseminated vascular and capillary damage with the involvement of almost all organs and systems, marked changes in coagulogram characteristic of DIC are noted.

Diagnosis of Autoimmune Hemolytic Anemia

The diagnosis of autoimmune hemolytic anemia is based on the presence of clinical and hematological signs of hemolysis and autoantibodies detected on the surface of erythrocytes using a Coombs test (positive in almost 60% of autoimmune hemolysis). Differentiate the disease from hereditary microspherocytosis, hemolytic anemia, associated with an enzyme deficiency.

In the blood – normochromic or moderately hyperchromic anemia of varying severity, reticulocytosis, normoblasts. In some cases, microspherocytes are detected in blood smears. The number of leukocytes may increase with hemolytic crisis. The number of platelets is usually in the normal range, but thrombocytopenia can occur. ESR significantly increased. In the bone marrow there is marked hyperplasia of the erythroid germ. The content of bilirubin in the blood, as a rule, increased by indirect.

Treatment of Autoimmune Hemolytic Anemia

In acute forms of acquired autoimmune hemolytic anemia, prednisone is prescribed in a daily dose of 60-80 mg. With inefficiency, it can be increased to 150 mg or more. The daily dose of the drug is divided into 3 parts in a ratio of 3: 2: 1. As the hemolytic crisis subsides, the dose of prednisone is gradually reduced (2.5-5 mg per day) to half the initial dose. A further dose reduction of the drug in order to avoid the recurrence of hemolytic crisis is carried out on 2.5 mg for 4-5 days, then in smaller doses and with longer intervals until the drug is completely discontinued. In chronic autoimmune hemolytic anemia, it is sufficient to prescribe 20–25 mg of prednisone, and as the patient’s general condition and erythropoiesis indicators improve, switch to a maintenance dose (5–10 mg). With cold hemagglutinin disease, similar therapy with prednisone is indicated.

Splenectomy in autoimmune hemolytic anemia associated with heat agglutinins and autoerythroopsins, can be recommended only to patients who have corticosteroid therapy accompanied by short-term remissions (up to 6-7 months) or have resistance to it. In patients with hemolytic anemia due to hemolysins, splenectomy does not prevent hemolytic crises. However, they are observed less frequently than before surgery, and are more easily controlled with corticosteroid hormones.

When refractory autoimmune hemolytic anemia in combination with prednisone can be used immunosuppressive drugs (6-mercaptopurine, imuran, hlorbutin, methotrexate, cyclophosphamide, etc.).

In the stage of deep hemolytic crisis, erythrocyte mass transfusions are used, selected using an indirect Coombs test; To reduce severe endogenous intoxication, hemodez, polydez, and other detoxification agents are prescribed.

Treatment of hemolytic-uremic syndrome, which can complicate the course of autoimmune hemolytic anemia, includes corticosteroid hormones, fresh frozen plasma, plasmapheresis, hemodialysis, washed or cryopreserved red blood cell transfusion. Despite the use of a complex of modern therapeutic agents, the prognosis is often poor.