What Is Autoimmune Hemolytic Anemia?

According to the optimal temperature required for the antibody to act on the red blood cell membrane, it can be divided into warm antibody type (active at 37 ° C, non-agglutinating red blood cells, IgG-type incomplete antibody) and cold antibody type (active below 20 ° C, low temperature). Can directly agglutinate red blood cells, is a complete antibody, the vast majority of IgM). There is also a special IgG-type cold antibody, DL antibody (Donath-Landsteiner antibody), which can bind to the surface of red blood cells at 20 ° C and fix complements. When the temperature rises to 37 ° C, the complements that have been bound to red blood cells are Activation in turn causes red blood cell destruction and triggers "paroxysmal cold hemoglobinuria" (PCH). The target antigen of warm antibody type AIHA is Rh antigen, and the antigen of cold antibody type is mostly Ii. In PCH, P antigen is the main type.

Wang Wensheng

(Chief physician)

Department of Hematology, Peking University First Hospital

Autoimmune hemolytic anemia (AIHA) is a type of hemolytic anemia caused by the disorder of immune function regulation in the body, which produces autoantibodies and / or complements adsorbed on the surface of red blood cells and accelerates the destruction of red blood cells through the antigen-antibody reaction. Autoimmune hemolytic anemia can be divided into warm antibody type and cold antibody type according to the optimal temperature required for the antibody to act on the red blood cell membrane.

Western Medicine Name: Autoimmune hemolytic anemia
English name: Autoimmune hemolytic anemia, AIHA
Affiliated Department: Internal Medicine-Hematology

The main symptoms: Anemia, dizziness, etc.
Main cause: Systemic lupus erythematosus, rheumatoid arthritis, lymphoproliferative disease, infection, tumor
Contagious: Non-contagious

Classification of autoimmune hemolytic anemia diseases

According to the existence of underlying disease, warm and cold antibody hemolysis can be divided into two categories: primary and secondary.

Causes of autoimmune hemolytic anemia

There is no underlying disease in primary warm and cold antibody autoimmune hemolytic anemia.

Common causes of secondary warm antibody autoimmune hemolytic anemia include: Systemic Lupus Erythematosus (SLE), rheumatoid arthritis; Lymphoproliferative diseases: lymphoma, chronic lymphocytic leukemia (CLL), etc. Infection: measles virus, EB virus, cytomegalovirus, etc .; tumor: leukemia, thymoma, colon cancer, etc .; others: MDS, inflammatory bowel disease, thyroid disease, etc.

Common causes of secondary cold antibody-type autoimmune hemolytic anemia include: B-cell lymphoma, Fahrenheit macroglobulinemia, chronic lymphocytic leukemia (CLL), infections such as mycoplasma pneumonia, infectious mononucleosis ).

The common causes of secondary paroxysmal cold hemoglobinuria are: syphilis, viral infection and so on.

Pathogenesis and pathophysiology of autoimmune hemolytic anemia

It has not been clarified that viruses, malignant hematopathy, autoimmune diseases, and other concurrent AIHA or primary AIHA may stimulate genetic production of corresponding anti-erythrocyte autoantibodies through genetic mutations and / or immune dysfunctions, and changes in red blood cell membrane antigens, leading to life span of red blood cells. Shortened, hemolysis occurred.

1) Genetic qualities: New Zealand black rats are animal models of AIHA. They are more prone to produce anti-erythrocyte antibodies and show hemolytic anemia, which is similar to human AIHA. The production of antibodies is related to the increase of CD5 + B cells in the body. Other mice rarely show similar performance, suggesting that the occurrence of this disease may be related to genetic qualities.

2) Immune disorders: Patients have reduced suppressor T cells and / or dysfunction, helper T cells function normally or are hyperactive, and the corresponding B cells produce autoantibodies.

3) Erythrocyte membrane protein composition abnormality: electrophoresis found that the band-protein of erythrocyte membrane of AIHA patients was reduced, suggesting that the modification of erythrocyte protein caused the loss of membrane components.

4) The mechanism of hemolysis: erythrocytes sensitized by warm antibody IgG are mainly recognized, bound and further phagocytosed by Fc receptors (FcR) on macrophages; part of the sensitized red blood cells undergo membrane damage when phagocytosed, and part of the cell membrane is lost, and red blood cells Become spherical, reduce deformability, increase permeability, and eventually be destroyed in the spleen or liver; In addition, antibody-dependent cytotoxicity (ADCC) can also cause red blood cell destruction; complement C3 is also adsorbed on red blood cells, and liver Kupffer cells There are C3b receptors, so when IgG and / or C3 are present on red blood cells, the spleen will take up red blood cells adsorbed with IgG, and the liver will seize red blood cells with C3, so this type of hemolysis is the heaviest, followed by those who simply adsorb IgG. , Simple C3 hemolysis is the lightest. If red blood cells coated with C3b are not phagocytosed in the liver, C3b can be gradually degraded to C3d, and the life span of red blood cells adsorbed with C3d is normal.

There are four subtypes of IgG erythrocyte antibodies in AIHA patients: IgG1, IgG2, IgG3, and IgG4.

FcR on spleen monocytes can also be divided into FcRI, FcRII, and RcRIII. These receptors can bind to IgG1 and IgG3 without responding to the remaining two subtypes of IgG. In addition, there are a small amount of IgM and IgA antibodies. Spleen macrophages have no IgM type and IgA type FcR. Therefore, red blood cells adsorbed with IgA antibodies can be destroyed in the spleen, while red blood cells adsorbed with IgM antibodies are destroyed in the liver.

All cold agglutinins in hemolysis caused by cold antibodies are IgM. In most cases, IgM activated complement stays at the C3b stage and is recognized and cleared by the C3b receptor on Kupffer cells when passing through the liver. The hemolysis that occurs is still extravascular hemolysis ; Usually red blood cells can be destroyed only when there is a high concentration of C3b on red blood cells, and many C3b are degraded to C3d and inactivated. Therefore, hemolysis in patients with cold agglutinin syndrome is usually not serious, and it is only possible when the IgM antibody titer is high. Severe hemolysis occurs, but this is rare. ^[1-2]

Clinical manifestations of autoimmune hemolytic anemia

1) Warm antibody type

Most of them have a slow onset, clinical symptoms include dizziness, fatigue, varying degrees of anemia, half have splenomegaly, 1/3 have jaundice and hepatomegaly. Acute onset patients may have chills, high fever, low back pain, vomiting, diarrhea, and severe cases may have shock and nervous system manifestations. Primary warm antibody type is more common in women, secondary often accompanied by clinical manifestations of the primary disease. A small number of patients may be associated with immune thrombocytopenic purpura, called Evans syndrome.

2) Cold antibody type

Cold agglutinin syndrome: Red blood cell agglutination occurs when the capillaries are cold, causing circulation disorders and chronic hemolysis, manifested as cyanosis in the hands and feet, obvious symptoms at the distal limbs, nose tip, earlobe, etc., often accompanied by limb numbness and pain. The return to normal is called Raynaud's phenomenon. Due to the low skin temperature, cold antibody agglutination of red blood cells causes capillary circulation to be blocked. Red blood cells adsorb cold antibodies to activate complement, and intravascular hemolysis can occur. However, in most cases, when the red blood cells circulate to the deep part of the body, the temperature can be restored to about 37 ° C. IgM antibodies fall off from the red blood cells, leaving only C3b. Some C3b red blood cells are phagocytosed by liver Kupffer cells to cause extravascular hemolysis.

Paroxysmal cold hemoglobinuria: The patient developed hemoglobinuria after exposure to a cold environment, with chills, high fever, back pain, weakness, paleness, jaundice, mild hepatosplenomegaly after the attack, and may be completely asymptomatic after recovery.

Autoimmune hemolytic anemia laboratory test

1) Blood image: hemoglobin and red blood cell count are related to the degree of hemolysis. Spherical red blood cells and young red blood cells can be seen in the surrounding blood slices. Occasionally, red blood cells are phagocytosed, and reticulocytes increase.

2) Bone marrow like: Hyperplasia of young red blood cells, occasional mild giant changes of the red blood cell system, which is related to the relative deficiency of vitamin B12 and folic acid during hemolysis.

3) Examination of hemolysis: serum bilirubin is elevated, mainly indirect bilirubin; fresh urine examination shows increased urobilinogen; serum bound globin is reduced or disappeared; hemoglobinuria and Rous test may be positive.

4) Anti-human globulin (Coombs) test: divided into direct anti-human globulin test (DAT, detection of incomplete antibodies on red blood cells) and indirect anti-human globulin test (IAT, detection of free antibodies in serum), warm antibodies Type DAT is positive, and IAT is also positive in some patients. DAT can be negative when the number of antibodies is below the test threshold. The intensity of DAT has nothing to do with the severity of hemolysis. Sometimes the test is weakly positive, but severe hemolysis occurs; on the contrary, sometimes the test is strongly positive without significant hemolysis.

5) Cold agglutinin test: The time titer of cold agglutinin syndrome increased.

6) Cold hemolysis test: Also known as Donath-Landsteiner (DL) test. DL-type autoantibodies are IgG-type immunoglobulins. With the participation of complement, they can be detected by two hemolysis tests at 4 ° C and 37 ° C. The test was positive in patients with paroxysmal cold hemoglobinuria. ^[3]

Diagnosis and differential diagnosis of autoimmune hemolytic anemia

Diagnosis of autoimmune hemolytic anemia

Has clinical manifestations of hemolytic anemia, DAT positive, except for other types of hemolysis, can be diagnosed as warm antibody type AIHA; If the DAT is negative, but the clinical manifestations are more consistent, adrenocortical hormone or spleen cutting is effective, except for other hemolytic Anemia can be diagnosed as DAT negative AIHA.

If there is Raynaud phenomenon, the agglutinin titer is significantly increased, or DAT C3 positive, anti-IgG negative, can be diagnosed as agglutinin syndrome.

Hemoglobinuria or Rous test positive, DL antibody positive can be diagnosed as paroxysmal cold hemoglobinuria.

Differential diagnosis of autoimmune hemolytic anemia

Disease name	Inherited or acquired	Hemolytic site	The flaw	Laboratory Features	treatment
Hereditary spherocytosis	Hereditary	Extravascular	Red blood cell membrane	Spherical red blood cells and osmotic fragility are significantly increased	Splenectomy
Thalassemia	Hereditary	Extravascular	Globin peptide chain Reduced synthesis	Small cells, low pigmented red blood cells, increased iron	Symptomatic, Bone marrow transplant
Paroxysmal nocturnal hemoglobinuria	Acquired	Intravascular	Red blood cell membrane defects, Sensitive to complement	Sucrose hemolysis test (+), acid hemolysis test (+), Rous test (+), CD59-cells> 10%	Symptomatic, Androgens, Bone marrow transplant
Autoimmune hemolytic anemia	Acquired	Extravascular (main)	Produce autoantibodies	Coombs test (+)	Corticosteroids, splenectomy, immunosuppressants

Treatment of autoimmune hemolytic anemia

Etiology of autoimmune hemolytic anemia

The most important treatment is the primary disease.

Autoimmune hemolytic anemia

As the main drug for the treatment of warm antibody type AIHA, prednisone 1 ~ 1.5mg / (kg · d), after the red blood cell count returns to normal, it is reduced by 5-10mg per week, and the decrease is slowed down to 30mg / d, 1 ~ 2 Decrease 5mg weekly, and finally hope to maintain it with 5 ~ 10mg / d or 10mg every other day. Those who are not effective after 3 weeks of treatment or need more than 15 mg / d of prednisone to maintain, should be switched to other therapies.

Autoimmune hemolytic anemia danazol

It is a weakly androsteroid protein-promoting preparation, which can reduce the number of FcRs in macrophages. This drug has a slow onset of action. It should be used in combination with prednisone. After the effect is taken, the hormone drugs can be gradually reduced. Finally, it can be used alone. Danazol was maintained at 50-100 mg / d. Side effects include liver injury, hairiness, fatigue, etc., which can be improved after stopping treatment.

Autoimmune hemolytic anemia immunosuppressant

Cyclophosphamide, azathioprine, vincristine, etc. can inhibit the synthesis of autoantibodies at doses of 200 mg / d, 100 mg / d and 2 mg per week. Cyclosporine A (CsA) inhibits T-cell proliferation and T-cell-dependent B-cell function, suppresses immune response, and blocks lymphocyte effects related to cellular immunity, without bone marrow suppression, the dosage is 3 ~ 6mg / kg / d . You can also choose the enzyme phenolate (Xiaoxi) 500mg twice daily. In recent years, it has been discovered that the macrolide antibiotic rapamycin (rapaming, sirolimus, RAPA) has the effect of inhibiting autoimmunity by increasing CD4 + / CD25 + / Foxp3 + regulatory T cells (Treg), without kidney Toxicity and myelosuppression, the dosage is 1.5mg or 3mg or 6mg on the first day, and the maintenance amount is started on the second day, 0.5mg or 1mg or 2mg per day, for 3 months in a row, and gradually reduced to withdrawal according to the situation , Can also treat immune thrombocytopenia.

IVIG Autoimmune hemolytic anemia with high-dose IV gamma globulin (IVIG)

If rapid relief is needed, a large dose of IVIG can be applied, 0.4 ~ 1.0g // (kg · d), for 3 to 5 days.

Autoimmune hemolytic anemia splenectomy

For those who are ineffective with glucocorticoid therapy or need large doses to maintain remission, splenectomy can be considered. The effective rate is 60 ~ 70%, and the secondary AIHA effect is poor. For cold agglutinin syndrome and paroxysmal cold hemoglobinuria, cutting the spleen is not effective.

Autoimmune hemolytic anemia plasma exchange

The blood cell separator was used to remove the patient's IgG antibody-rich plasma. Replace 200 ~ 300ml of plasma every week. Can reduce autoantibody titers by more than 50%.

Autoimmune hemolytic anemia blood transfusion

It is only used for patients with cardiopulmonary dysfunction due to hemolytic crisis or fulminant AIHA. Transfusion can also be performed when chronic anemia is not improved. Before transfusion, check for the specificity of allotype antibodies, autoantibody blood group antigens, and cross-matching tests. Because AIHA may worsen hemolysis after transfusion, the indications for transfusion should be strictly controlled.

Autoimmune hemolytic anemia other

In recent years, domestic and foreign scholars have used CD20 monoclonal antibody Rituximab (Meluhua), CD52 monoclonal antibody Cammpath-1H, complement C5 monoclonal antibody Eculizumab and other drugs for the treatment of refractory / recurrent AIHA. CD20 monoclonal antibody (rituximab) 375mg / , once a week, 2 to 4 times, effective in 2/3 cases. Recently, it has been discovered that histone deacetylase inhibitors can also increase the number and function of CD4 + / CD25 + / Foxp3 + regulatory T cells. Try sodium valproate at 5-10mg / kg / d. ^[4-5]

Prognosis of autoimmune hemolytic anemia disease

Warm antibody type AIHA: Most of the patients with primary treatment respond well after taking the drug, and the hemogram can return to normal in the months to months, but maintenance treatment is required. Anti-relapse authors have poor efficacy. The prognosis of secondary patients varies with the primary disease, and it will heal after infection control of infected persons; the prognosis of patients with systemic connective tissue disease or tumor is relatively poor. The prognosis of cold agglutinin syndrome is better than that of warm antibody type. Most patients can tolerate mild anemia, have a small effect on labor and physical activity, and most survive long-term. Paroxysmal cold hemoglobinuria does not cause chronic severe anemia or death. Although the symptoms are severe during an acute attack, they resolve spontaneously after a few days or weeks. But DL antibodies can last for years. ^[6]

Prevention of autoimmune hemolytic anemia

For patients secondary to infection, prevention of related pathogens (virus, mycoplasma, Treponema pallidum) is very important. For patients with cold agglutinin syndrome and paroxysmal cold hemoglobinuria, heat preservation, avoiding cold, even if the body's ambient temperature exceeds the maximum temperature of the cold antibody response are the main preventive measures.