Pregnancy with autoimmune hemolytic anemia
Introduction
Introduction to pregnancy with autoimmune hemolytic anemia Autoimmunehemolytic anemia (AIHA) is a hemolytic anemia caused by the regulation of immune function disorder in patients, producing autoantibodies and/or complement adsorption on the surface of red blood cells, resulting in the growth of red blood cell destruction. Autoimmune hemolytic anemia is uncommon, and Chaplin (1973) has reported that autoimmune hemolytic anemia is unknown for pregnancy. The cause of abnormal antibody production is still unclear. Anemia may be caused by viable autoantibodies (80% to 90%), inactive antibodies or bound antibodies. This anemia can be divided into primary (idiopathic) immune hemolysis and secondary two categories, the latter including lymphoma, leukemia, connective tissue disease, certain infectious diseases, chronic infectious diseases and drug-induced Factors, in many cases, were initially considered primary, and later found to be caused by underlying disease, patients with direct or indirect anti-human globulin antibodies (Combs) test positive, the antibodies may be anti-erythrocyte IgM and IgG. Mycoplasma pneumonia And infectious prokaryotic cells can cause condensation of antibodies. Women with this disease can be hemolyzed during pregnancy, glucocorticoid treatment is effective, with prednisone 1mg / (kg · d), such as platelets with thrombocytopenia Can also be corrected. basic knowledge The proportion of illness: 0.0002% Susceptible population: pregnant women Mode of infection: non-infectious Complications: shock
Cause
Pregnancy with autoimmune hemolytic anemia
Secondary factors (30%):
Secondary to connective tissue disease (systemic lupus erythematosus, rheumatoid arthritis, scleroderma), hematopoietic tumors (chronic lymphocytic leukemia, lymphoma, myeloma), infection (mycoplasma pneumonia, infectious mononucleosis) Disease), drugs (levus or methyldopa, etc.), ulcerative colitis, etc.
Infection factor (25%):
Because of infection (viruses, bacteria, etc.), drugs, enzymes and other pathogenic factors act on the erythrocyte membrane, causing their antigenic changes, triggering their own immune system, stimulating antibody-producing organs, and producing corresponding anti-erythrocyte autoantibodies.
Disease factors (20%):
Lymphatic tissue infections or tumors, thymic diseases and immunodeficiency factors cause the body to lose its immune surveillance function, unable to recognize its own cells, and mistakenly treat its normal red blood cells as foreign, leading to abnormal autoantibodies.
Body factor (20%):
T cell balance disorder theory test found that patients with autoimmune hemolytic anemia have inhibitory T cell reduction and dysfunction, but also a subset of helper T cell levorotin activation, so that the corresponding B cell overreaction and autoimmune hemolytic anemia .
There are two ways to destroy red blood cells in autoimmune hemolytic anemia:
(1) extravascular hemolysis: mainly seen in warm-antibody autoimmune hemolytic anemia, erythrocyte adsorption is incomplete antibody or complement and sensitized, incomplete antibody sensitized red blood cells are not enough to immediately destroy hemolysis in the blood vessels, but in mononuclear - The phagocytic system is engulfed by macrophages and hemolyzed.
(2) intravascular hemolysis: common in paroxysmal cold hemoglobinuria (cold antibody type), less common in cold agglutinin syndrome, very rare in warm antibody type, the destruction of intravascular red blood cells is mainly due to antibody activation of complement , red blood cell damage caused by traditional methods.
Pathogenesis
The pathogenesis of AIHA mainly includes anti-erythrocyte antibody production and hemolysis.
Antibody production
(1) antigenic variation: when certain viruses, drugs, chemical poisons or radiation act on hematopoietic cells or mature red blood cells, or erythroid hematopoietic gene mutations, and finally cause changes in the membrane antigen components of red blood cells (sometimes full blood cells), and further The immune system that stimulates the body produces autoantibodies that recognize such variant antigens, so-called anti-self red blood cell (or other blood cells) antibodies.
(2) Abnormal antibody production: Some pathological factors (such as pathogenic microbial infections) stimulate the body's immune system to cause dysfunction, or lymphocyte system tumors cause the immune organs to lose their ability to recognize their own blood cell antigens, thereby producing anti-self An antibody to a blood cell antigen.
(3) Cross-immunization: Some pathogenic microorganisms have antigenic components similar to human blood cells. When they invade the human body, they will stimulate the body to produce cross-antibodies. These antibodies will also resist human blood cells while fighting against pathogenic microorganisms. The human body produces antibodies against its own blood cells.
2. Hemolysis occurs
(1) Extravascular hemolysis: autologous blood cell antibodies (mainly warm antibodies) bind to red blood cells (sometimes including white blood cells and platelets), which changes the Fc end configuration of the antibody, and simultaneously activates a small amount of complement to adhere a certain amount to the erythrocyte membrane. C3b/C4b, the Fc-terminal and C3b/C4b, which are altered in conformation, bind to Fc receptors and C3b/C4b receptors on monocyte macrophages, respectively, and finally cause erythrocytes to be phagocytized, dissolved, and destroyed by mononuclear macrophages. When the amount of damaged red blood cells exceeds the amount of red blood cells produced by the bone marrow, the body develops anemia; when mononuclear macrophages release more metabolites that damage red blood cells - indirect bilirubin, it causes bilirubin metabolism disorder. Hyperbilirubinemia occurs (jaundice, serum indirect bilirubin increased, urinary bilirubin or urinary bilirubin increased, gallstones or cholecystitis, and even "nuclear jaundice" may occur in severe cases; when this type of hemolysis is repeated, When it occurs for a long time, the mononuclear macrophage system will proliferate reactively, and the liver and spleen will appear. The extravascular hemolysis is affected by the following three factors:
1 types of autoantibodies: autoantibodies are classified into IgG, IgA and IgM3, and IgG is divided into four subtypes of IgG1, IgG2, IgG3 and IgG4. The incidence of extravascular hemolysis is highest in IgG, lower in IgA and IgM; In addition, IgG1 is the most, followed by IgG3, IgG2 and IgG4 are rare, and the degree of hemolysis is heavier than IgM and IgG3; the main sites of hemolysis occur, IgG and IgA are in the spleen, and IgM is in the liver.
2 The number of antibodies adsorbed on the erythrocyte membrane: For the same type of autoantibody, the more antibodies adsorbed on the erythrocyte membrane, the more easily the red blood cells are swallowed by the mononuclear macrophages, and the hemolysis becomes heavier.
3 Whether the erythrocyte membrane is "sensitized" by both antibody and C3: Since the mononuclear macrophage membrane has both Fc receptor and C3b/C4b receptor, when the red blood cells are simultaneously "sensitized" by the antibody and C3, When swallowed, the probability of destruction is large, and the degree of hemolysis occurs.
(2) Intravascular hemolysis: Some autologous erythrocyte antibodies (mainly cold-type antibodies) bind to red blood cells in the blood vessels, causing red blood cells to aggregate and simultaneously bind to activate complement; complement directly destroys red blood cells, which causes intravascular hemolysis, when hemolysis exceeds When the bone marrow is compensatory, anemia occurs in the body, and intravascular hemolysis leads to high free hemoglobinemia: elevated plasma free hemoglobin (FHb), decreased haptoglobin (HP), elevated hemoglobin, high iron Heme binding protein is reduced, methemoglobin binding globin-hemin conjugate is increased, increased FHb exceeds HP binding ability, hemoglobinuria, hemosiderinuria, urinary occult blood test positive and urine Rous test Positive, repeated hemoglobinuria can cause iron deficiency, zinc deficiency, and further anemia. HP-bound FHb is metabolized and decomposed in mononuclear macrophages, so it may cause jaundice and hepatosplenomegaly in the blood vessels. The red blood cells agglomerated by the antibody also affect the peripheral circulation, causing the skin to exhibit a Raynaud phenomenon.
The type and titer of autologous erythrocyte antibodies affect the degree of intravascular hemolysis. When the cold antibody is a cold agglutinin, most of them activate full complement and cause intravascular hemolysis. Only a few sensitized red blood cells do not activate complement, when the cold antibody is DL (Do -nath-Landsteiner) antibody, it is easy to fix complement at low temperature, activate full complement at 37 °C, and cause more severe intravascular hemolysis. Of course, for the same antibody, hemolysis is generally heavy.
Prevention
Pregnancy with autoimmune hemolytic anemia prevention
There are two main aspects of preventive measures:
(1) The clinical manifestations of this disease are not specific. The diagnosis mainly depends on laboratory tests. Since most of the diseases are secondary to other diseases, it is necessary to continue to search for the presence or absence of primary diseases such as tumors and connective tissue diseases after a clear diagnosis. In order to achieve the goal of treating the symptoms, the disease can be truly cured. Therefore, we must actively treat the primary disease. During the treatment period, regular medication should be followed. Patients who take hormones for a long time should not stop or reduce the dose at their own discretion. Otherwise, the disease will be aggravated and serious complications will occur.
(2) Prevent infection, avoid or reduce the use of drugs such as levorotatory or methyldopa.
Complication
Pregnancy with complications of autoimmune hemolytic anemia Complications
When the condition is serious, it can be caused by shock and heart failure.
Symptom
Pregnancy with autoimmune hemolytic anemia symptoms Common symptoms Dizziness immune hemolysis high fever jaundice coma dyspnea cold diarrhea shock syphilis infection
1. The clinical manifestations of the disease are diversified, varying in severity, generally slow onset, often manifested as general weakness, dizziness, less common in patients with fever and hemolysis, acute type is more common in children, but sometimes also in adults, There is often a history of viral infection, rapid onset, chills, high fever, low back pain, vomiting, diarrhea, severe shock, neurological manifestations of headache, irritability and even coma.
Skin mucous membrane pale and jaundice can be seen in 1/3 patients, more than half of patients have mild to moderate splenomegaly, 1/3 of patients have moderate hepatic enlargement, and some cases may have lymphadenopathy. Some rare clinical manifestations are: Difficulty breathing, gastrointestinal discomfort, soy sauce urine, angina pectoris, heart failure, edema, etc.
2. Classification According to the temperature required for the antibody to act on red blood cells, it can be divided into two types: warm antibody type and cold antibody type.
(1) Warm antibody type AIHA: warm antibodies are generally most active at 37 ° C, mainly IgG, a small number of IgM, according to the cause can be divided into two types of idiopathic and secondary, secondary causes include malignant tumors, Connective tissue disease, viral infection, hypogammaglobulinemia, ulcerative colitis, Rh-negative women with Rh-positive fetuses, pregnancy-induced hypertension, ovarian dermoid cysts, etc.
(2) cold antibody type AIHA: cold antibody is most active at 20 °C, mainly IgM, lectin IgM is more common in cold agglutinin syndrome, can directly erythrocyte agglutination reaction in blood circulation, cold agglutinin syndrome can be secondary For mycoplasmal pneumonia and infectious mononucleosis, paroxysmal cold hemoglobinuria can be secondary to viral or syphilis infection.
Examine
Examination of pregnancy with autoimmune hemolytic anemia
Laboratory tests for AIHA are often performed in this order:
Determine whether anemia hemolytic anemia whether AIHA is primary or secondary, the main examination includes general examination and special examination 2 categories.
1. General inspection
The general examination of AIHA is mainly used to determine whether the subject is anemia, whether it is hemolyzed, with or without autoimmune signs or other primary diseases. If the person being examined is suffering from AIHA, the following findings are often found:
(1) Blood picture: anemia or accompanied by platelets, the number of white blood cells decreased, and the reticulocyte count increased (significantly reduced in the case of aplastic anemia).
(2) Bone marrow: Most of the bone marrow is a proliferative anemia (the red is mainly medium and young red); the bone marrow changes of aplastic anemia can be seen in the aplastic crisis.
(3) Plasma or serum: hyperhemoglobinemia and/or hyperbilirubinemia.
(4) Urine: high urinary biliary or high free Hb or high hemosiderin.
(5) Immune index: the amount of gamma globulin can be increased, the level of C3 can be decreased, and abnormalities such as anti-O, erythrocyte sedimentation rate, rheumatoid factor, anti-nuclear antibody, anti-DNA antibody and the like can occur.
(6) Others: including cardiopulmonary, liver and kidney function tests, different primary diseases may have different manifestations in different organs.
2. Specific inspection
The specific examination is used to determine whether the examinee has its own red blood cell antibody, what type of antibody, and how many antibody titers. There are several special tests that are often performed:
(1) Direct Coombs test: for detecting incomplete thermophilic antibodies bound to erythrocyte membranes, the principle is to use anti-human globulin antibody to bind to incomplete thermophilic antibodies on sensitized erythrocyte membrane to cause agglutination of sensitized red blood cells; The type and subtype of warm antibodies can be identified by changing the anti-human globulin antibody species [anti-IgG (IgG1, IgG2, IgG3, IgG4), anti-C3, anti-IgA, anti-IgM], direct Coombs test when: Can be false negative:
1 The number of warm antibody IgG molecules bound to the erythrocyte membrane is <500.
2 The red blood cells are not sufficiently washed, and the suspension is mixed with serum-free non-warming antibody globulin (neutralizing anti-human globulin.
3 Some warm antibodies have low affinity with red blood cells and fall into the plasma.
The Coombs test can be positive in the following cases:
1 Some normal people sensitize red blood cells to C3 due to infection.
2 Certain diseases (such as nephritis, PNH, etc.) increase the level of C3 in the body.
3 Red blood cell C3 receptor binds to circulating immune complexes.
4 Certain antibiotics (such as cephalosporins) cause red blood cells to non-specifically adsorb plasma globulin.
(2) Indirect Coombs test: used to detect free-temperature antibodies in serum. The principle is to first incubate the patient's serum and red blood cells at 37 ° C, bind the antibodies in the serum to the red blood cells, and then add anti-human globulin. Red blood cells combined with warm antibodies are agglutinated by binding to anti-human globulin.
(3) Cold agglutinin test: used to determine the cold agglutinin in the serum of patients with cold antibodies. At normal body temperature, the cold agglutinin is mostly in a free state, so the serum containing the cold agglutinin needs to be the same as the patient's red blood cell or ABO blood type. The red blood cells are "cooled" together at 4 ° C (generally more than 2 h), at which time the cold agglutinin in the serum binds to the I antigen on the erythrocyte membrane, causing red blood cell agglutination; followed by re-warming the agglutinated red blood cells to 37 ° C At this time, because the cold agglutinin is dissociated from the red blood cells, the agglutinated red blood cells are deagglomerated, but not hemolyzed, except for the cold agglutinin type AIHA patients can detect and collect agglutination, some virus infection, plasma cell disease patients The serum may also be positive for the cold agglutinin test.
(4) Donat-Landsteinertest: DL test is used to detect DL antibody, DL antibody is also present in the patient's serum. When the patient's serum is "cooled" with self-red blood cells and complement at 4 ° C for 30 min, The erythrocyte-antibody-complement complex is formed, and when it is rewarmed to 37 ° C, the antibody activates complement, which leads to significant hemolysis.
(5) Enzyme treatment RBC agglutination test: Sometimes the free antibody in the serum (which may be a warm antibody or a cold antibody) is not high, and can not be measured by the general indirect Coombs test and the cold antibody test (lectin test and DL test). At this time, it is necessary to do enzyme treatment of red blood cell agglutination test. The basic procedure of the test is to first hydrolyze the surface of erythrocyte sialic acid with proteolytic enzyme (trypsin, papain, bromelain) reduce the Q potential of red blood cells shorten the distance between red blood cells. Then do an indirect Coombs test or a cold antibody test, which increases the sensitivity by a factor of two.
(6) Specific identification of autologous erythrocyte antibody blood group antigen: In order to increase the safety of AIHA patients who have to transfuse blood, it is necessary to know the blood group antigen specificity of their own erythrocyte antibodies. When the antibody is a warm antibody, the antibody can be heated or the like. Isolation from red blood cells (not required for cold antibodies), then combining red blood cells with different known blood group antigens with free antibodies (thermal incubation or cooling), using direct Coombs test to determine if warm antibodies bind to red blood cells, or directly observing whether cold antibodies "condense Pyrolysis" / "condensation hot solution", and finally determine the blood group antigen specificity of the antibody based on the red blood cell blood antigen reacting with the antibody, and the method is as follows: the main blood group antigen targeted by the warm antibody is Rh antigen, and the cold collectin is mainly I or i antigen, DL antibody is mainly P antigen. When AIHA patients must transfuse blood, blood donors lacking corresponding specific antigens on red blood cells should be used.
In addition to the above tests, 125I-Staphylococcal protein A, radioimmunoassay and enzyme-linked immunosorbent assays are more sensitive methods for measuring antibodies. These methods are not yet widely available, but they are important for reducing the so-called "Coombs test-negative AIHA". effect.
According to the clinical manifestations, symptoms and signs of the disease, choose B-ultrasound, electrocardiogram and other tests.
Diagnosis
Diagnosis and differentiation of pregnancy complicated with autoimmune hemolytic anemia
According to anemia, reticulocyte increase, direct anti-human globulin test positive performance, the diagnosis of the disease is not difficult, but should look for the primary disease causing the disease.
Identification with other hemolytic anemia, such as hereditary spherocytosis, can be identified according to the direct anti-human globulin test.
