Autoimmune hemolytic anemia guidelines

(2022 Edition)

Autoimmune Hemolytic Anemia (AIHA) is a condition in which abnormal immune function leads to hyperfunction of B cells producing antibodies to their own red blood cells, and red blood cells adsorbing The group of hemolytic anemias in which the destruction of erythrocytes is accelerated and their life span is shortened is caused by an abnormality in immune function that leads to the hyperfunction of B cells producing antibodies to their own erythrocytes, which adsorb autoantibodies and/or complement. Foreign data show that the annual incidence of AIHA is (0.8-3.0)/100,000. According to the optimal temperature for the reaction between autoantibodies and erythrocytes, AIHA can be classified as warm antibody type (37°C, accounting for 60～).

80 ), cold antibody type (20°C, accounting for 20～30) and mixed warm and cold antibody types

(about 5). AIHA is divided into primary and secondary. About 50 of warm antibody AIHA are secondary to hematopoietic and lymphoproliferative disorders, such as chronic lymphocytic leukemia, non-Hodgkin’s lymphoma, Hodgkin’s lymphoma, Castleman’s disease, myelofibrosis, etc., solid tumors, immune disorders, infections, drugs, primary immunodeficiency disorders, pregnancy, and after allogeneic hematopoietic stem cell transplantation.

II, Diagnostic Criteria and Typing

(A) Diagnostic criteria.

Hemoglobin level up to anemia standard.
Red blood cell autoantibodies were detected.

At least one of the following was met: percentage of reticulocytes>4 or absolute value>120×109/L; conjugated bead protein<100 mg/L; total bilirubin ≥17.1μ

mol/L (predominantly elevated unconjugated bilirubin).

(ii) Fractionation.

Divided into secondary and primary categories based on whether the cause is clear or not.

The optimal temperature required for autoantibodies to bind to red blood cells is divided into warm antibody type, cold antibody type, and cold agglutination type. Antibody type [including cold agglutinin syndrome (CAS) and paroxysmal cold hemoglobinuria (PCH)] and mixed type.

The autoantibody-positive type and autoantibody-negative type are based on the results of autoantibody testing of red blood cells. The autoantibodies are classified as positive and negative. Autoantibody negative AIHA is diagnosed when clinical symptoms are consistent with hemolytic anemia, except for other hemolytic anemias, and immunosuppressive therapy is effective.

(C) Warm antibody-based autoimmune hemolytic anemia.

Clinical and laboratory signs of hemolytic anemia, such as malaise, pallor, jaundice, splenomegaly, and laboratory evidence of increased serum indirect bilirubin, increased serum lactate dehydrogenase, decreased binding bead protein, and increased reticulocyte The results of this study are based on the following laboratory findings

A positive direct anti-human globulin test (Coombs test), usually IgG, IgG+C3, and occasionally IgA.

As in broad-spectrum Coombs test is negative (including IgG, IgM, C3), but the clinical picture is consistent, immunosuppressive therapy such as adrenocorticotropic hormone is effective, and other hemolytic anemias can be considered . span>Coombs test negative for AIHA. 4. Need to exclude systemic lupus erythematosus, rheumatoid arthritis, ulcerative nodules

Autoimmune diseases such as enterocolitis or other diseases such as tumors of the lymphatic system (including slow-onset tumors).

autoimmune diseases such as lymphatic system tumors (including chronic lymphocytic leukemia), lymphoma, etc.; secondary AIHA caused by mycoplasma, cytomegalovirus infection.

(D) Cold agglutinin syndrome.

Clinical and laboratory manifestations consistent with hemolytic anemia: cyanosis of the auricle, nasal tip, and fingers in the cold environment, which disappears with warming. Signs of anemia or jaundice may be present; laboratory tests reveal elevated bilirubin and recurrent episodes of iron-containing hemoglobinuria.
- Positive cold agglutinin test.
- Direct Coombs Coombs < /span>Tests are almost always complement C3 type.
(V) Paroxysmal cold hemoglobinuria.

Clinical and laboratory manifestations consistent with hemolytic anemia: e.g., episodes of hemoglobinuria after exposure to cold, episodes of anemia with rapid progression Rapidly, laboratory tests reveal elevated bilirubin, and recurrent episodes of hemoglobinuria with iron-containing hemoglobinuria.
- Positive cold and heat hemolysis test.
- Direct Coombs Coombs < /span>test is positive for complement C3 type.
III.

The clinical presentation of AIHA is diverse, with great variability in the speed of onset, degree of hemolysis, and course of disease. The clinical manifestations of anemia and hemolysis are often present, and secondary AIHA is often associated with clinical manifestations of the primary disease.

(A) Typical symptoms.

Signs of hemolysis may be present, such as malaise, anemia, jaundice, change in urine color, splenomegaly, etc. Patients with hemolytic crisis may have low back pain, chills, high fever, syncope, and hemoglobinuria.

pallor and jaundice, seen in about 1/3 of patients.

More than half have splenomegaly, which is usually mild to moderately enlarged, moderately firm, and not painful. In primary AIHA cases, about 1/3 have mild hepatomegaly, moderate stiffness without pain, and marked enlargement is rare.

Lymph node enlargement in patients with primary AIHA is only 23, while patients with AIHA secondary to lymphoreticular system disease counted 37.

(ii) Concomitant symptoms.

1. Warm antibody AIHA: Mostly secondary to other diseases, often with signs of the primary disease on top of the typical signs of hemolysis, and may be accompanied by hepatomegaly, splenomegaly, jaundice, and lymph node enlargement. When the disease starts rapidly, there may be anemia, high fever, chills, back pain, vomiting, diarrhea, headache, irritability and coma when anemia is obvious. 2. Cold antibody type AIHA: cold agglutinin syndrome: aggravated by cold, often manifested

Cyanosis of the terminal extremities, even frostbite and gangrene, may be Raynaud’s phenomenon and improves with warmth.

3. Paroxysmal cold hemoglobinuria: Onset of hemoglobinuria minutes or hours after cold stimulation. Acute attacks may include chills, high fever, generalized weakness, abdominal discomfort, back and lower extremity muscle pain, nausea, and vomiting for several hours or days. It may be accompanied by splenomegaly, hyperbilirubinemia, and repeated attacks of ferritinuria. Patients with syphilis may have Raynaud’s phenomenon and, in some cases, urticaria.

IV.Ancillary Tests

(A) Peripheral blood cell analysis.

Peripheral blood picture shows varying degrees of hemoglobin reduction, and anemia is generally positive

Cellular, orthochromic anemia with a significantly higher percentage and absolute value of reticulocytes, easy to see erythrocyte fragments in blood smears, and spherical and nucleated erythrocytes can be seen. The white blood cell count is normal or mildly elevated, and the platelets are normal or elevated.

(B) Bone marrow cell morphology.

The bone marrow picture is characteristically a juvenile erythropoietic marrow picture with an inverted granulocyte/red ratio and occasional mild erythrocyte megaloblastic changes. In the presence of reoccurrence crisis, the bone marrow is hypoproliferative, and the whole blood cells and reticulocytes are reduced.

(iii) Biochemical tests.

Serum total bilirubin is seen to be elevated, with a predominance of elevated indirect bilirubin, elevated lactate dehydrogenase, and decreased conjugated pearl protein in acute hemolysis, but these indices are nonspecific.

(iv) Specificity check.

Red blood cell autoantibody test.

The direct antiglobulin test (DAT) detects autoantibodies to the covered red blood cell membrane. The optimal binding temperature of warm autoantibodies to erythrocytes is 37 ℃, and the optimal binding temperature of cold autoantibodies to erythrocytes is 0-5 ℃.
The indirect antiglobulin test (IAT) detects free warm antibodies in serum.
The cold agglutinin test detects cold agglutinins in the serum. The cold agglutinin is an IgM-type cold antibody that binds best to red blood cells at 0-5 ℃. CAS is diagnosed with a cold agglutinin potency of >1:32. The DAT result for CAS is positive for complement C3.

The cold-heat hemolysis test detects cold-heat diphasic hemolysin (D-L antibody). （The D-L antibody is an IgG-type cold and heat hemolysin that binds to red blood cells at 0-4°C and adsorbs complement, but does not hemolysis; hemolysis occurs at 30-37°C. The cold and heat hemolysis test for PCH is positive, and the DAT results are positive for complement C3.
- Aetiology.
Primary AIHA was diagnosed in the absence of underlying disease and secondary AIHA in the presence of underlying disease (Table 1).

Table 1 Common causes of secondary autoimmune hemolytic anemia

Lymphoproliferative disorders

Solid tumors/ovarian dermatomal cysts autoimmune diseases

Infection

Immunodeficiency

Drugs

Chronic lymphocytic leukemia other non-Hodgkin’s lymphoma

Significant unnamed monoclonal IgM gammaglobulinemia Hodgkin’s lymphoma

Autoimmune lymphoproliferative syndrome

Systemic lupus erythematosus Hashimoto’s thyroiditis Ulcerative colitis

Mycoplasma infection EBV infection

Cytomegalovirus infection microviral infection

Human Immunodeficiency Virus Infection Hepatitis Virus Infection

Rotovirus and other enterovirus infectionsAdenovirus infections

Respiratory Syncytial Virus and Influenza Virus Infections

Common variant immunodeficiency disease primary combined immunodeficiency disease

Purine analogs: fludarabine, cladribine cephalosporins: cefotetan, ceftriaxone piperacillin

β-lactamase inhibitors: tazobactam, sulbactam

Blood type does not contract for seed immunization

Chronic hemolysis after allogeneic hematopoietic stem cell transplantation/solid organ transplantation transfusion in blood group incompatibility

V. Differential Diagnosis

(A) Paroxysmal sleep hemoglobinuria.

Anemia as well as hematuria may also occur, similar to paroxysmal cold hemoglobinuria, but the former occurs more often after sleep and is not associated with cold stimuli, and can be distinguished from the latter by a negative cold hemolysis test and positive acid hemolysis test and sugar water test.

(II) Thrombotic thrombocytopenic purpura.

A microangiopathic hemolysis with a negative anti-human globulin test and a blood smear with a large number of lytic cells in addition to small irregularly circumscribed spherical cells, which can be differentiated from warm antibody AIHA.

It is a form of hemolytic anemia with congenital defects in the red blood cell membrane, mainly manifesting as anemia, jaundice, and splenomegaly, similar to AIHA, but with a negative anti-human globulin test and an enhanced autohemolytic test that is markedly corrected by the addition of glucose, whereas AIHA is mostly not The combination of this with the response to glucocorticoid therapy helps to differentiate between the two.

(iv) Other diseases that can cause Raynaud’s phenomenon.

Similarities with AIHA include cyanosis of the terminal extremities, but the former is not associated with cold and has a negative condensation set test.

VI, Treatment

(i) Supportive therapy.

Transfusion should be avoided or reduced as much as possible. It increases the risk of hemolytic transfusion reactions caused by homologous antibodies.
The timing of transfusion should be determined by the degree of anemia, the presence of significant symptoms, and the speed of onset. For patients with acute hemolytic anemia, those who can exclude homologous antibodies when serious symptoms appear must be transfused with red blood cells immediately. In patients with chronic anemia, transfusion is not necessary if the hemoglobin is above 70 g/L; if the hemoglobin is between 50 and 70 g/L, transfusion is appropriate if there are intolerable symptoms; if the hemoglobin is below 50-70 g/L, transfusion should be given.
Test for autoantibody anti-ABO, Rh blood type specificity, donor selection and cross-matching. Cross-matching test. In case of incomplete cross-matching, the least reactive of the multiple specimens will be used for transfusion. Slow titration and close observation for transfusion reactions.
- Do not emphasize the use of washed red blood cells during resuscitation.
  - Plasmapheresis or immunosuppressive therapy is indicated if conventional therapy is not effective.

Therapy.

Adding glucocorticoids before transfusion can reduce and mitigate the onset of transfusion reactions.

Glucocorticoids are used to reduce the incidence of transfusion reactions.

In addition, attention should be paid to alkalinization diuresis, biliary de-yellowing, and electrolyte balance.

(B) Glucocorticoids.

Recommended in the absence of contraindications to glucocorticoid use. Recommended starting

Dose is 1 mg/(kg-d) based on prednisone, which can be converted to intravenous infusion of dexamethasone, methylprednisolone, etc. as appropriate. Glucocorticoids are used until the red fine

Cellular specific volume > 30or a stable hemoglobin level of 100 g/L or more before taking the test

Consider dose reduction. If these results are not achieved after 4 weeks of treatment with the recommended dose, it is recommended that second-line dosing be considered. Acute heavy AIHA may require 100 to 200 mg/d methylprednisolone for 10 to 14 days to control the disease.

Maintain the original dose for 1 month after hemoglobin normalization, then taper. The rate of dose reduction was determined at the discretion of the patient, and hemoglobin levels and absolute reticulocyte values were closely monitored during this period. Consider discontinuing glucocorticoids when the prednisone dose is reduced to 5 mg/d and remission continues for 2 to 3 months.

Cold antibody AIHA is mostly secondary and is treated differently than warm antibody AIHA, as described in the treatment of secondary AIHA.

(iii) Second-line therapy.

Second-line therapy is recommended for (1) glucocorticoid resistance or maintenance doses greater than 15 mg/d (based on prednisone); (2) other contraindications or intolerance to glucocorticoid therapy; (3) AIHA relapse; and (4) refractory/severe AIHA. severe AIHA.

Second-line treatments include splenectomy, rituximab, cyclosporine A, and cytotoxic immunosuppressants.

Splenectomy.

Splenectomy may be considered for refractory warm antibody AIHA, and there are no indicators to predict the efficacy of splenectomy. The incidence of infection is increased after splenectomy, but an association with immunosuppression cannot be excluded. Other complications include venous thrombosis, pulmonary embolism, and pulmonary hypertension.

Rituximab.

The rituximab dose was 375 mg/(m2-d) for 4 doses on days 1, 8, 15, and 22. Low-dose rituximab (100 mg/d) has also been reported to reduce the financial burden on patients and reduce adverse effects without reducing efficacy. Monitoring B-lymphocyte levels can guide the management of complications of rituximab including infections and progressive multifocal leukoencephalopathy. Patients with hepatitis B virus infection should be administered rituximab with effective antiviral control and continued dosing.

Cytotoxic immunosuppressants.

The most commonly used drugs are cyclophosphamide, azathioprine, and vincristine, with a general efficacy rate of 40 to 60 , most often still in combination with glucocorticoids.

Cyclosporine A has been widely used for the treatment of AIHA, mostly at a starting dose of 3 mg/(kg-d) with a maintenance blood level (trough concentration) of no less than 150-200 μg/L. Adverse effects of cyclosporine A include gingival hyperplasia, hair growth, hypertension, increased bilirubin, and impaired renal function. The adverse effects of cyclosporine A include gingival hyperplasia, hair growth, hypertension, increased bilirubin and renal impairment. Because cyclosporine A requires an effective blood concentration to be effective, it is recommended that it be used initially in combination with glucocorticoids. Tacrolimus and mycophenolate have also been reported for refractory AIHA.

(iv) Secondary AIHA treatment.

Secondary AIHA requires aggressive treatment of the primary disease, and the rest of the treatment is the same as primary AIHA.

Most cold-antibody AIHA is secondary, and it is important to treat AIHA with concomitant insulation.

(E) Other medications and treatments.

Intravenous immunoglobulin is effective in some patients with AIHA. Plasma exchange is effective for IgM-type cold antibodies (80 at 37°C
IgM-type antibodies are free).

But not effective against other warm antibodies adsorbed on erythrocytes, and replacement brings in large amounts of complement.

VII.

(a) Cured.

In those with secondary infection, AIHA is cured after the primary disease is cured. Patients with CAS have normal cold agglutinin potency. patients with PCH have negative cold and heat hemolysis tests.

(ii) Complete remission.

Disappearance of clinical symptoms, normal red blood cell count, hemoglobin level and reticulocyte percentage, normal serum bilirubin level. negative for DAT and IAT.

(iii) Partial remission.

Basic resolution of clinical symptoms, hemoglobin>80g/L, reticulocyte percentage<4 , serum total bilirubin<34.2 μmol/L. DAT negative, or still positive but significantly lower potency than before.

(iv) Ineffective.

There are still varying degrees of anemia and hemolytic symptoms, and laboratory tests do not meet the criteria for partial remission.

Attachment.

The Autoimmune Hemolytic Anemia Treatment Guidelines ( 2022 Edition)

Writing Validation Expert Group

(sorted by surname stroke)

Team leader: Huang Xiaojun

Members: Jing Wang, Haixia Fu, Lanping Xu, Qian Jiang, Hao Jiang, Xiaohui Zhang, Shenmiao Yang, Yuanyuan Zhang, Jin Song Jia, Xiaojun Huang, Jin Lu