OVERVIEW

What is autoimmune hemolytic anemia?

Autoimmune hemolytic anemia (AIHA) is a general term for a group of immune-mediated acquired hemolytic anemias. The common pathophysiological basis is the production of pathological antibodies against the patient's own red blood cells, leading to their immune destruction. Hyperactive B lymphocyte function produces autoantibodies against red blood cells, increasing their destruction and resulting in anemia.

Clinically, AIHA is classified into primary and secondary types based on etiology. According to the reaction temperature of the autoantibodies, it can be divided into warm antibody type, cold antibody type, and mixed type. Warm antibody-type AIHA (wAIHA) accounts for 75% of all AIHA cases.

Primary or idiopathic wAIHA is an autoimmune disease without an identifiable underlying pathological process, whereas secondary wAIHA may result from various underlying factors. Approximately half of wAIHA cases are secondary.

Cold-reactive AIHA includes cold agglutinin syndrome (CAD) and paroxysmal cold hemoglobinuria (PCH). Cold agglutinin syndrome constitutes the majority of the remaining AIHA cases.

Mixed-type AIHA exhibits characteristics of both warm and cold antibody types.

Is autoimmune hemolytic anemia common?

Foreign reports indicate that this disease accounts for about one-third of all hemolytic disorders. International data show an annual AIHA incidence rate of (0.8–3.0) per 100,000. In China, AIHA is the second most common acquired hemolytic anemia, following paroxysmal nocturnal hemoglobinuria. In recent years, the incidence of AIHA has been increasing annually, reaching (10–20) per 100,000.

Does autoimmune hemolytic anemia have age and gender characteristics?

It is more common in women than men and predominantly affects young and middle-aged adults.

SYMPTOMS

What are the manifestations of autoimmune hemolytic anemia?

Warm antibody-type AIHA: The severity varies greatly, and the degree of hemolysis differs significantly.

• Most cases have an insidious onset, with clinical manifestations such as dizziness, weakness, fatigue, shortness of breath after physical activity, and unexplained fever.
• Elderly patients with impaired cardiac reserve may experience angina.
• Pale skin, mild to moderate splenomegaly in half of the cases, and jaundice with hepatomegaly in one-third.
• In acute cases, viral infections often exacerbate the condition, leading to chills, high fever, back pain, vomiting, and diarrhea. Severe cases may present with shock, renal failure, and neurological symptoms.
• Primary warm antibody-type AIHA is more common in women, while secondary cases often exhibit symptoms of the underlying disease.
• A few patients may have concurrent immune thrombocytopenic purpura, known as Evans syndrome. Evans syndrome can occur at any age and is classified as primary or secondary, with a higher prevalence in women.

Cold antibody-type AIHA:

• Cold agglutinin syndrome: Exposure to cold causes red blood cell agglutination in capillaries, leading to circulatory disturbances and chronic hemolysis. Symptoms include cyanosis of the hands and feet, often accompanied by numbness and pain, which resolve upon warming—known as Raynaud's phenomenon.
• Paroxysmal cold hemoglobinuria: Cold exposure may trigger hemoglobinuria, accompanied by chills, high fever, back pain, weakness, pallor, and jaundice after an episode. Mild hepatosplenomegaly may occur, but patients can be completely asymptomatic after recovery.

What other diseases can autoimmune hemolytic anemia cause?

• Rare cases may involve concurrent immune thrombocytopenia with bleeding symptoms, i.e., Evans syndrome.
• Cases caused by syphilis or viral infections may present with acute hemolysis, including chills, high fever, anemia, jaundice, and hemoglobinuria.

What conditions should autoimmune hemolytic anemia be differentiated from?

• Hereditary spherocytosis: Family history; peripheral blood smears show >10% spherocytes; positive osmotic fragility test; hemolysis >5% in autohemolysis test.
• Paroxysmal nocturnal hemoglobinuria: Positive acid hemolysis test, snake venom factor hemolysis test, and urine hemosiderin test.
• Glucose-6-phosphate dehydrogenase deficiency: Positive methemoglobin reduction test; reduced G6PD activity in fluorescent spot test and nitroblue tetrazolium test.
• Additionally, it should be distinguished from congenital hemolytic diseases and non-immune hemolytic anemias.

CAUSES

What are the causes of autoimmune hemolytic anemia?

• Primary AIHA: No clear cause. Domestic reports account for 39.7%–58.7%.
• Secondary AIHA: Often secondary to the following causes.
• Autoimmune diseases: Autoimmune liver disease, autoimmune thyroiditis, immune-related pure red cell aplasia, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, and ulcerative colitis.
• Infections or inflammation: Viral infections, mycoplasma infections, tuberculosis, subacute bacterial endocarditis, syphilis, etc.
• Neoplastic diseases: Leukemia, lymphoma, plasma cell disorders, histiocytosis, etc.
• Drug-induced: Caused by methyldopa drugs and penicillin (high doses). Sometimes second- or third-generation cephalosporins such as cefotetan and ceftriaxone sodium may also induce it.

DIAGNOSIS

How to Diagnose Autoimmune Hemolytic Anemia?

Physicians can typically diagnose it without difficulty based on typical medical history, clinical manifestations, physical examination, and laboratory/imaging tests. Diagnostic criteria include:

• Hemoglobin levels meeting anemia standards.
• Detection of red blood cell autoantibodies.
• At least one of the following: Reticulocyte percentage > 4% or absolute count > 120×10⁹/L; Haptoglobin < 100 mg/L; Total bilirubin ≥ 17.1 μmol/L (predominantly unconjugated bilirubin elevation).

What Tests Are Required for Patients with Autoimmune Hemolytic Anemia?

• Blood Tests: Reduced hemoglobin, normocytic normochromic anemia (or macrocytic); elevated reticulocytes, increased spherocytes, and presence of nucleated red blood cells. Normal leukocyte and platelet counts; if platelets are low, Evans syndrome should be considered.
• Bone Marrow Examination: Hypercellularity with prominent erythroid hyperplasia; normal granulocytic and megakaryocytic lineages.
• Blood and Urine Biochemistry: Elevated serum indirect bilirubin, reduced or absent haptoglobin, increased plasma free hemoglobin, negative urine hemosiderin.
• Coombs Test: Positive direct antiglobulin test (DAT), indirect antiglobulin test (IAT). DAT is the classic laboratory test for warm autoimmune hemolytic anemia, with >90% of patients testing positive.
• If moderate splenomegaly is present, CT imaging is needed to rule out masses or other pathologies.

TREATMENT

Which department should I visit for autoimmune hemolytic anemia?

Hematology.

Does autoimmune hemolytic anemia require hospitalization?

Hospitalization is recommended to identify the cause. Patients with infections should be hospitalized promptly for anti-infection treatment, while those with underlying malignancies should receive tumor therapy. Suspected drug-induced cases should discontinue the suspected medication.

How is autoimmune hemolytic anemia treated?

• Etiological treatment: Actively treat the underlying disease. Control infections aggressively; perform tumor resection for solid tumors or chemotherapy for malignant B-cell proliferative disorders. Discontinue suspected medications in drug-induced cases.
• Glucocorticoids: The primary and main treatment for this condition. Prednisone is commonly used. Over 80% of patients respond to glucocorticoid therapy. If no improvement is observed after 3 weeks of full-dose treatment, misdiagnosis or steroid resistance should be considered. Steroid resistance occurs in about 10% of patients. Patients who do not respond to steroids or require maintenance doses exceeding 15 mg daily should consider alternative therapies. Relapse after discontinuation is not uncommon.
• Splenectomy: A second-line treatment. Indications include: glucocorticoid inefficacy; daily maintenance doses exceeding 10 mg; intolerance or contraindications to steroids. The overall efficacy rate of splenectomy is 60%-75%. Recurrent cases post-surgery may still respond to glucocorticoid retreatment.
• Immunosuppressants: Used for refractory patients unresponsive to glucocorticoids and splenectomy. Examples include cyclophosphamide, azathioprine, cyclosporine, and mycophenolate mofetil. Monitor for side effects during treatment, particularly liver/kidney function and bone marrow suppression.
• Rituximab: Reported efficacy rates vary.
• Blood transfusion: Reserved only for aplastic crisis or life-threatening severe anemia.
• Other treatments: High-dose intravenous immunoglobulin therapy and plasma exchange.

DIET & LIFESTYLE

What should patients with autoimmune hemolytic anemia pay attention to in their diet?

There are no special dietary restrictions, a normal diet is sufficient. However, foods that cause allergies should be avoided, as allergic reactions can worsen the patient's condition.

What should patients with autoimmune hemolytic anemia pay attention to in daily life?

• Maintain a regular lifestyle, avoid excessive fatigue, and engage in appropriate exercise and physical activity. Avoid stressful conditions such as infections.
• Patients undergoing immunosuppressive therapy should regularly monitor liver and kidney function as well as blood counts.

PREVENTION

Can Autoimmune Hemolytic Anemia Be Prevented?

• Primary AIHA has no clear cause, and there are currently no effective preventive measures.
• Secondary AIHA can be effectively prevented and its symptoms controlled by preventing infections and managing the underlying disease.