Etiology and Pathogenesis
Warm autoimmune hemolytic anemia (wAIHA) accounts for approximately 70%–80% of all AIHA cases. The predominant antibody involved is IgG, followed by complement C3, with fewer cases involving IgA and IgM. These antibodies are most active at 37°C, are considered incomplete antibodies, and attach to the surface of red blood cells. Sensitized red blood cells are primarily destroyed within the mononuclear phagocyte system, leading to extravascular hemolysis. The presence of both IgG and C3 results in the most severe hemolysis, while hemolysis is mildest when only C3 is present. Studies have revealed an imbalance of Th1/Th2 cells in AIHA, with abnormalities in Th2 cell functions, such as elevated IL-4, IL-6, and IL-10 levels, as well as abnormalities in Treg cells.
Approximately 50% of warm AIHA cases are idiopathic. Common secondary causes include:
- Lymphoproliferative disorders such as lymphoma.
- Autoimmune diseases such as systemic lupus erythematosus (SLE).
- Infections, especially viral infections.
- Solid tumors.
- Medications.
- Immunodeficiencies, such as those occurring after hematopoietic stem cell or solid organ transplantation.
Clinical Manifestations
Most cases involve chronic extravascular hemolysis with an insidious onset, primarily affecting adult females. The condition is characterized by anemia, jaundice, and splenomegaly. One-third of patients present with both anemia and jaundice, while more than half have mild-to-moderate splenomegaly, and one-third have hepatomegaly. Persistent hyperbilirubinemia may lead to complications such as gallstone formation and liver dysfunction. Thromboembolic diseases, particularly in individuals with positive antiphospholipid antibodies, have also been reported. Triggers like infections may exacerbate hemolysis, resulting in hemolytic or aplastic crises. Between 10% and 20% of patients may have concurrent immune thrombocytopenia, a condition known as Evans syndrome. Secondary warm AIHA cases often present with manifestations of the underlying disease.
Laboratory Tests
Peripheral Blood and Bone Marrow Findings
The severity of anemia varies, with most cases showing normocytic-normochromic anemia. Reticulocyte percentages are markedly elevated, occasionally reaching up to 50% in extreme cases. White blood cell and platelet counts are typically normal, though white blood cells may increase during acute hemolysis. Peripheral blood smears often reveal altered red blood cell morphology, with a notable increase in spherocytes. Rarely, nucleated red blood cells and Howell-Jolly bodies may also be observed. Bone marrow demonstrates hyperplasia, with significant erythroid proliferation and inversion of the myeloid-to-erythroid ratio. During aplastic crises, bone marrow shows decreased activity, pancytopenia, and reduced or even absent reticulocytes.
Direct and Indirect Antiglobulin (Coombs) Tests
The Coombs test is the "gold standard" for diagnosing AIHA. It includes:
- Direct Antiglobulin Test (DAT), which detects incomplete antibodies attached to the surface of red blood cells.
- Indirect Antiglobulin Test (IAT), which identifies free-floating antibodies in plasma.
Other Hemolysis-Related Laboratory Tests
Additional tests are described in related sections.
Diagnosis
The diagnosis is established based on clinical signs of hemolytic anemia, laboratory evidence, a positive DAT for IgG or C3, and a cold agglutinin titer within the normal range. The diagnosis also requires the absence of a recent history (within the previous 4 months) of blood transfusion or use of specific medications. Rare Coombs-negative cases require differentiation from other forms of hemolytic anemia, particularly hereditary spherocytosis. AIHA can be classified as primary or secondary depending on the identification of a specific underlying cause.
Treatment
Etiological Treatment
Identifying the underlying cause and treating the primary disease is emphasized.
Managing Hemolytic Episodes
Glucocorticoids
Glucocorticoids are the first-line treatment, with an efficacy rate exceeding 80%. Prednisone is commonly used at a dose of 1–1.5 mg/(kg·d), and intravenous dexamethasone or methylprednisolone at equivalent doses may be administered as alternatives. Glucocorticoid therapy is generally maintained until the hematocrit exceeds 0.30 or hemoglobin levels stabilize above 100 g/L before tapering. If no improvement is observed after 3 weeks of full-dose glucocorticoid therapy, the treatment is considered ineffective.
Rituximab
Rituximab is a monoclonal antibody targeting the CD20 antigen on B lymphocytes. It is used primarily in AIHA due to its ability to deplete B lymphocytes. Indications include:
- Glucocorticoid resistance;
- Steroid dependence, requiring a prednisone maintenance dose >10 mg/day for efficacy;
- Contraindications to or intolerance of glucocorticoids;
- Recurrence after splenectomy.
A commonly used regimen involves 375 mg/m2 weekly for 4 weeks, with an efficacy rate of approximately 80%. Rituximab is increasingly used as the preferred second-line treatment for AIHA, potentially replacing splenectomy.
Splenectomy
Splenectomy achieves an efficacy rate of approximately 60%. Indications include:
- Ineffectiveness of glucocorticoid therapy;
- Steroid dependence;
- Contraindications to or intolerance of glucocorticoids.
Postoperative relapses may still respond to glucocorticoid therapy.
Other Immunosuppressants
Indications include:
- Ineffectiveness of glucocorticoids and splenectomy;
- Contraindications to splenectomy;
- Steroid dependence with a prednisone maintenance dose >10 mg/day.
Commonly used drugs include cyclophosphamide, azathioprine, mycophenolate mofetil (MMF), or cyclosporine, often in combination with glucocorticoids.
Additional Treatments
Danazol combined with glucocorticoids is effective in some patients. High-dose intravenous immunoglobulin (IVIG) is effective in certain cases of AIHA.
Blood Transfusion
Blood transfusion is minimized or avoided whenever possible. For severe anemia, washed red blood cells may be transfused at a slow rate. Indications for transfusion include:
- Fulminant AIHA;
- Hemolytic crisis;
- Life-threatening severe anemia.