Autoimmune hemolytic anemia (AIHA) is a condition in which binding of autoantibodies and/or complement to red blood cells (RBCs) results in premature clearance of RBCs. Primary AIHA comprises approximately 50% of cases, whereas secondary AIHA is usually associated with diseases or drugs. The classification of the hemolytic anemias is described in Table 1.

AIHA

Autoimmune hemolytic anemia

Cold agglutinin disease

CAHA

Cold hemagglutinin disease

CHAD

CAIHA

Drug-induced hemolytic anemia

Warm autoimmune hemolytic anemia

WAHA

WAIHA

The annual incidence is 1 to 3 cases per 100,000 persons, with 10% mortality; most common in women <50 yr.

• Most common presentation is dyspnea and fatigue.
• Pallor, jaundice may be present.
• Tachycardia with a flow murmur may be present if anemia is pronounced.
• Patients with intravascular hemolysis may present with dark urine and back pain.
• Hepatomegaly and/or lymphadenopathy suggests an underlying lymphoproliferative disorder or malignancy; splenomegaly may indicate hypersplenism as a cause of hemolysis.
• Chronic process with multiple relapses typically seen during the course of the disease.

• Warm antibody mediated: Almost always Immunoglobulin G (IgG) antibodies only (often idiopathic or associated with leukemia, lymphoma [Table 2], thymoma, myeloma, viral infections [Table 3], babesiosis, and collagen-vascular disease). In warm AIHA, antibodies have the highest affinity to the antigen at 37° C
• Cold antibody mediated: IgM and complement in majority of cases (often idiopathic; at times associated with infections, lymphoma, or cold agglutinin disease)
• Interleukin-33 may have a role in promoting increasing RBC autoantibodies in AIHA
• Drug induced (Table 4): Three major mechanisms:
  1. Antibody directed against Rh complex (e.g., methyldopa)
  2. Antibody directed against RBC-drug complex (hapten-induced, e.g., penicillin)
  3. Antibody directed against complex formed by drug and plasma proteins; the drug-plasma protein-antibody complex causes destruction of RBCs (innocent bystander, e.g., quinidine)

• Hemolytic anemia caused by membrane defects (acquired: Paroxysmal nocturnal hemoglobinuria, spur cell anemia, Wilson disease; inherited: Spherocytosis, elliptosis), hemoglobinopathies, and enzyme deficiencies (G6PD, pyruvate kinase)
• Non-immune-mediated (microangiopathic hemolytic anemias, hypersplenism, cardiac valve prosthesis, giant cavernous hemangiomas, march hemoglobinuria, physical agents, infections, heavy metals, certain drugs [nitrofurantoin, sulfonamides, ribavirin])
• Chronic lymphocytic leukemia (CLL) can cause direct antiglobulin test (DAT) positivity (15% of CLL cases) without AIHA. In a series of patients treated with fludarabine and cyclophosphamide, only 30% of patients with DAT+ disease developed AIHA after therapy; conversely, 85% of patients with AIHA were previously positive for DAT

Evaluation consists primarily of laboratory evaluation to confirm hemolysis and exclude other causes of the anemia. Although most cases of AIHA are idiopathic, potential causes should always be sought.

• The basic features of hemolytic anemia are reticulocytosis (rarely reticulocytopenia with concurrent bone marrow suppression), low haptoglobin levels, elevated indirect bilirubin, and elevated lactate dehydrogenase (LDH).
• Initial laboratory tests: Complete blood count (anemia), reticulocyte count (elevated), liver function studies (elevated indirect bilirubin, LDH), evaluation of peripheral smear (Fig. E1).
• A direct antiglobulin test (DAT, Coombs test) is initially performed with a polyspecific antibody to detect IgG or complement C3d bound to RBCs.¹ If the DAT is positive, the diagnosis of autoimmune hemolytic anemia (AIHA) is confirmed. A positive direct Coombs test indicates presence of antibodies or complement on the surface of RBCs. A positive indirect Coombs test indicates presence of freely circulating anti-RBC antibodies in the patient’s serum.
• If the DAT is positive with IgG alone or with IgG + C3d, the AIHA is most likely due to warm antibody (WAIHA), whereas if the DAT is positive with C3d only, it is most likely caused by a cold antibody (CAIHA).
• Positive DAT findings and characteristic features of autoantibody in AIHA are summarized in Table 5. Typical serologic features of the different types of drug-induced hemolytic anemia of immunologic origin are summarized in Table 6.
• Hepatitis A/B/C serology, HIV, antinuclear antibody.
• Urinary tests may reveal hemosiderinuria or hemoglobinuria (documenting intravascular hemolysis).

• Chest x-ray examination
• Computed tomography scans of chest, abdomen, and pelvis if underlying lymphoproliferative disorder is suspected

• Discontinuation of any potentially offending drugs
• Plasmapheresis and exchange transfusion for severe life-threatening cases only
• Avoid cold exposure in patients with cold antibody AIHA

• Warm AIHA:
  1. Initially, prednisone 1 to 2 mg/kg/day in divided doses is used. A sustained response is achieved in 80% to 90% cases after which tapering is initiated (after 2 to 3 wk) and completed over 3 to 6 mo.
  2. Based on the results of two clinical trials that demonstrated improved outcomes and longer duration of response, the combined upfront use of steroids and rituximab is another option for up-front clinical use.²
  3. For patients relapsing or refractory to initial steroid therapy alone, rituximab is used instead of splenectomy in most cases with response rates of 80%, which are achieved in 2 to 3 wk and are persistent in up to 60% of cases at 3 yr.^2,3
  4. Splenectomy is nowadays typically used in patients refractory to both corticosteroids and rituximab.
  5. Immunosuppressive drugs (mycophenolate, cyclosporine, cyclophosphamide) and/or immunoglobulins are recommended after failure of the above approaches to produce an adequate remission.
  6. Danazol, used in conjunction with corticosteroids, may be useful in some cases of warm AIHA.
• Cold AIHA:
  1. Corticosteroids are generally ineffective, and response rates are much lower than those seen with warm AIHA, and they should not be used to treat cold agglutinin disease.
  2. Therapy of underlying lymphoproliferative disorder or infection is recommended.
  3. In primary cold agglutinin disease, the use of bendamustine and rituximab chemotherapy is the standard approach in fit patients; rituximab alone is used in elderly patients.²
  4. In severe cases, intravenous immunoglobulin therapy or plasmapheresis can be used as a temporary bridge until more effective therapies achieve durable responses.
  5. Complement-directed therapy with eculizumab can also be considered in severe cases.
  6. Sutimlimab, a humanized monoclonal antibody, selectively targets the C1s protein in the complement pathway, which is a complex serine protease responsible for activating this pathway.⁴ Patients who received sutimlimab show rapidly halted hemolysis, increased hemoglobin levels, and reduced fatigue.
  7. Splenectomy is not effective as the sensitized RBCs are mainly removed in the liver.
• Table 7 summarizes treatment options for primary and secondary warm autoimmune hemolytic anemia and cold autoimmune hemolytic anemia. Second-line treatment options after steroids are described in Table 8.

Prognosis is generally good unless anemia is associated with underlying disorder with a poor prognosis (e.g., leukemia, myeloma).

• Hematology referral in all cases of AIHA
• Surgical referral for splenectomy in refractory cases of warm AIHA

• The direct antiglobulin test demonstrates the presence of antibodies or complement on the surface of RBCs and is the hallmark of autoimmune hemolysis.
• Warm AIHA is often associated with autoimmune diseases, whereas cold AIHA often follows viral infections (e.g., mononucleosis) and Mycoplasma pneumoniae infections.
• HIV can induce both warm and cold AIHA.
• Hemolytic anemia is a common autoimmune complication of hematopoietic stem cell transplantation occurring in up to 6% of patients as a late complication (median 202 days); it presents as either warm or cold AIHA.