Autoimmune hemolytic anemia (AIHA) is a hemolytic anemia caused by a disturbance in the regulation of the patient’s immune function and the production of autoantibodies and/or complement adsorbed on the surface of red blood cells, leading to an increase in the rate of red blood cell destruction.
The cause of abnormal antibody production is still unclear, and the anemia may be caused by viable autoantibodies (80% to 90%), inactive antibodies or conjugated antibodies. This anemia can be divided into two main categories: primary (idiopathic) immune hemolysis and secondary, the latter including lymphomas, leukemias, connective tissue diseases, certain infectious diseases, chronic infectious diseases, and pharmacogenic factors.
In many cases, initially considered primary, it is later found to be caused by an underlying disease. Patients are positive for direct or indirect anti-human globulin antibodies ((Coombs) test, whose antibodies may be anti-erythrocyte IgM and IgG. mycoplasma pneumonia and infectious prokaryosis can cause condensation set antibodies. Glucocorticoid therapy is effective, with prednisone 1mg/kg/d, if accompanied by thrombocytopenia platelets can also be corrected.
I. Epidemiology
In the 1960s, American scholars reported that the annual incidence of AIHA in the population was 1.25/100,000; in Sweden, it was 2.0/100,000. AIHA can occur at any age, but most patients are older than 40 years old, with the peak age of onset at 70-80 years. There are more women than men. There is no significant difference between races. Family aggregation is not obvious, with isolated reports of several AIHA patients in one family, but they are all secondary to other autoimmune diseases or lymphoproliferative diseases.
Data on the composition of AIHA cases have been published in Shanghai, Tianjin and Beijing, China, and no population incidence has been reported. The disease can occur at any age, with adults being slightly more common in women than in men. Primary cases account for about 45% of cases.
Etiology
The disease can be primary or secondary to connective tissue diseases (systemic lupus erythematosus, rheumatoid arthritis, scleroderma), tumors of the hematopoietic system (chronic lymphocytic leukemia, lymphoma, myeloma), infections (mycoplasma pneumonia, infectious mononucleosis), drugs (levodopa or methyldopa, etc.), ulcerative colitis, etc. The patient’s red blood cells are usually considered normal, but have incomplete antibodies-Igg and/or adsorbed on their surface for a long time. Sensitized erythrocytes are not hemolysed in the blood vessels, but are destroyed by macrophages within the monocyte-macrophage system, or only a portion of the membrane may be dragged in for digestion.
Due to the continuous loss of membranes, they eventually become spherical cells, which are retained and phagocytosed within the splenic cord. The destruction of sensitized red blood cells by the spleen can be accelerated if both IgG and can be present on the membrane. The destruction of sensitized cells by macrophages is determined by both “attachment” and “uptake”. The receptor is associated with “attachment” while “uptake” is dependent on the IgG-Fc receptor. The two receptors have a synergistic effect on each other. If attached alone, hemolysis is not severe because it is not further ingested and does not result in phagocytosis. The adsorbed erythrocytes are mostly retained and destroyed in the liver because of the abundant blood flow in the liver, which has more phagocytic cells.
III. Pathogenesis
The pathogenesis of AIHA mainly includes the production of anti-self-erythrocyte antibodies and the occurrence of hemolysis.
1. Antibody production
(1) Antigen mutation
(2) Abnormal antibody production
(3) Cross-immunity
2.Hemolysis occurrence
(1) Extravascular hemolysis: Antibodies to self-blood cells (mainly warm antibodies) bind to red blood cells (sometimes including white blood cells and platelets), causing a change in the conformation of the Fc end of the antibody and activating a small amount of complement to cause a certain amount of C3b/C4b to adhere to the red blood cell membrane, and the conformation of the changed Fc end and C3b/C4b bind to the Fc receptor and C3b/C4b receptor on monocytes respectively. When the amount of destroyed erythrocytes exceeds the amount of erythrocytes produced by bone marrow, the body becomes anemic; when mononuclear macrophages release more metabolites of erythrocyte destruction ~ indirect bilirubin, it will cause disorders of bilirubin metabolism and hyperbilirubinemia (jaundice, increased serum indirect bilirubin, increased urinary bilirubin or urinary bile) When this type of hemolysis occurs repeatedly and for a long time, the mononuclear macrophage system will proliferate reactively and liver and spleen enlargement will occur.
(2) Intravascular hemolysis: Some auto-erythrocyte antibodies (mainly cold-type antibodies) bind to red blood cells in the blood vessels, causing red blood cell agglutination and simultaneous binding and activation of complement; complement directly destroys red blood cells, thus causing intravascular hemolysis. When hemolysis exceeds the compensatory capacity of the bone marrow, the body becomes anemic. Intravascular hemolysis also leads to hyperfree hemoglobinemia: elevated plasma free hemoglobin (FHb), decreased binding pearl protein (HP), elevated methemoglobin albumin, decreased methemoglobin-binding protein, and increased methemoglobin-binding pearl protein- methemoglobin conjugate. Hemoglobinuria and ferric hemoglobinuria occur when the increased FHb exceeds the binding capacity of HP, and positive urine occult blood tests and positive urine Rous tests occur.
Repeated occurrence of hemoglobinuria can also cause iron and zinc deficiency in the body and further aggravate anemia. FHb bound by HP has to be metabolized and broken down in mononuclear macrophages, so it may also cause jaundice and hepatosplenomegaly. Red blood cells agglutinated by antibodies in blood vessels may also affect peripheral circulation and cause Raynaud’s phenomenon in the skin. The type and titer of auto-erythrocyte antibodies affect the degree of intravascular hemolysis. When cold antibodies are cold agglutinins, most activate full complement and lead to intravascular hemolysis, while only a few sensitized red blood cells do not activate complement. When the cold antibody is a D-L (Do-nath-Landsteiner) antibody, it is very easy to fix complement at low temperatures and activate all complement at 37°C, resulting in more severe intravascular hemolysis. Of course, for the same kind of antibody, the hemolysis is generally heavy for those with high titers.
IV. Clinical manifestations
The clinical manifestations of the disease are diverse and vary in severity. Generally, the onset of the disease is slow, often manifesting as general weakness and dizziness, with fever and hemolysis being the rare cases. The acute form is mostly seen in children, but sometimes in adults, often with a history of viral infection. The onset of the disease is rapid, with chills, high fever, lumbago, vomiting, diarrhea, and in severe cases, shock, and neurological manifestations such as headache, irritability, and even coma.
Mild to moderate splenomegaly is seen in more than half of the patients, moderate hepatomegaly is seen in 1/3 of the patients, and lymph node enlargement may be seen in some cases. Some of the less common clinical manifestations are: dyspnea, gastrointestinal discomfort, soy sauce-colored urine, angina pectoris, heart failure, edema, etc.
V. Clinical typing
According to the temperature required for the antibody to act on red blood cells, there are three types: warm antibody type, cold antibody type and mixed warm and cold antibody type.
(1) Warm antibody type AIHA: Warm antibody is generally the most active at 37℃, mainly IgG and a few IgM. Secondary causes include malignancy, connective tissue diseases, viral infections, hypogammaglobulinemia, ulcerative colitis, pregnancy of Rh-positive fetus in Rh-negative women, hyperemesis, ovarian dermatomycosis, etc.
(2) Cold antibody type AIHA: cold antibody is most active at 20℃, mainly IgM, lectin IgM is mostly seen in cold agglutinin syndrome, which can directly occur in the blood circulation for erythrocyte agglutination reaction. Cold agglutinin syndrome can be secondary to mycoplasma pneumonia and infectious mononucleosis, and paroxysmal cold hemoglobinuria can be secondary to viral or syphilis infection.
(3) Mixed warm and cold antibodies AIHA: warm and cold antibodies are present at the same time.
VI. Diagnosis.
Based on the manifestations of anemia, reticulocytosis, and positive direct anti-human globulin test, the diagnosis of the disease is not difficult. However, the primary cause of the disease should be sought.
Laboratory tests.
Laboratory tests for AIHA are often performed in this order.
Determine whether anemia → whether hemolytic anemia → whether AIHA → whether primary or secondary. The main tests include 2 types of general tests and special tests.
1.General tests
The general examination of AIHA is mainly used to determine whether the patient is anemic, hemolytic, has signs of autoimmunity or other primary diseases. If the patient is suffering from AIHA, there are often the following findings.
(1) Blood picture: anemia or with decreased platelet and white blood cell counts and elevated reticulocyte count (may be significantly decreased in the case of remitting crisis).
(2) Bone marrow picture: Mostly proliferative anemia (the red lineage is predominantly medium to young red) bone marrow picture; in remitting crisis, bone marrow changes of aplastic anemia may be seen.
(3) Plasma or serum: hyperhemoglobinemia and/or hyperbilirubinemia.
(4) Urine: high urobilinogen or high free Hb or high iron-containing hemoglobin.
(5) Immune indicators: gammaglobulin may be elevated, C3 levels may be decreased, and abnormalities of anti-O, sedimentation, rheumatoid factor, anti-nuclear antibodies, anti-DNA antibodies, etc. may be present.
(6) Other: including heart, lung, liver and kidney function tests, different primary diseases may have different manifestations in different organs.
2.Specific tests
Specific tests are used to determine whether the patient has auto-erythrocyte antibodies, what type of antibodies, and how much antibody titers are present.
(1) Direct Coombs test
(2) Indirect Coombs test
(3) Cold agglutinin test
(4) Dang-lan test
(5) Enzyme-treated RBC agglutination test
(6) Blood group antigen specific identification of auto-erythrocyte antibodies
In addition to the above tests, there are still more sensitive experimental methods for determining antibodies using 125I-staphylococcal protein A, radioimmunoassay and enzyme-linked immunoassay. These methods are not yet popular, but they play an important role in reducing the number of so-called “Coombs test-negative AIHA”.
Other auxiliary examinations: Ultrasound and electrocardiogram should be done according to the clinical manifestations, symptoms and signs of the disease.
VII. Treatment.
1.Etiology treatment actively search for the primary cause and treat the primary disease.
2. Glucocorticoids are the first choice for the treatment of this disease. The mechanism of action is to inhibit lymphocyte production of auto-erythrocyte antibodies, reduce the affinity between antibodies and red blood cells, and inhibit the role of macrophages to remove the attached antibody red blood cells. It is equally effective during pregnancy as during non-pregnancy. Most scholars believe that it is best not to use it in early pregnancy, and to use it cautiously in the middle of pregnancy, with less effect on the fetus in the last three months of pregnancy. The starting dose should be sufficient, the reduction should not be too fast, and the maintenance time should be long. Take prednisone as an example, the dosage is 1~1.5mg/(kg?d), divided into 3~4 oral doses, the clinical symptoms will be relieved first, and the red blood cells will rise rapidly after about 1 week. If the treatment is ineffective for 3 weeks, other treatment methods need to be changed promptly.
If effective, after hemolysis stops and red blood cells return to normal, gradually and slowly reduce the dose. The daily dose should be reduced by 10-15mg per week, and after the daily dose reaches 30mg, the daily dose should be reduced by 5mg per week or every 2 weeks, and after the daily dose reaches 15mg, the daily dose should be reduced by 2.5mg every 2 weeks. Long-term remission after hormone discontinuation. If at least 15 mg of prednisone is used daily to maintain blood picture remission, a switch to other therapies should be considered.
3. Splenectomy is the organ that produces antibodies and is the main destruction site of allergic red blood cells. Even though red blood cells are still sensitized after splenectomy, the impact of antibodies on the lifespan of red blood cells is greatly reduced. Some count 316 splenectomized patients with a postoperative efficiency of 60%. The literature describes that splenectomy may be more effective in those with a negative indirect anti-human globulin test or antibody IgG. Splenectomy during pregnancy is preferable to surgery in the middle of pregnancy. The application of hormones is still effective in cases of postoperative recurrence.
Immunosuppressive drugs are not recommended during pregnancy, but can be used after delivery. Commonly used drugs are: azathioprine, cyclophosphamide, methotrexate, etc. They are mainly used for: those who cannot be relieved by hormone therapy and splenectomy; those who have contraindications to splenectomy; those who need more than 10mg of prednisone per day to maintain.
5, other therapies anti-lymphocyte globulin, anti-thymocyte globulin, cyclosporine, etc., are still in the practice stage. High-dose human gammaglobulin intravenous injection or plasma exchange have certain efficacy, but the effect is not long-lasting.
If anemia is not serious, blood transfusion is generally not recommended; in case of emergency, saline-washed red blood cells can be considered for severe anemia.
VIII. Prognosis
Most patients with primary treatment respond well to the drug, and the blood picture can return to normal in a month or several months, but maintenance treatment is required. Recurrent patients have poor outcome and the duration of the disease varies from several months to several years, with a mortality rate of about 50%. The prognosis of secondary disease varies with the original disease, those with infection will be cured after controlling the infection; those with collagen system disease or tumor have a poor prognosis, Evans syndrome is also difficult to cure and can die from bleeding.CAS has a long course and can be recurrent, not easy to cure.Some patients with PCH can disappear after 2 to 3 months of onset of the disease, but there are a few patients who do not recover.