Autoimmune Hemolytic Anemia
GENERAL PRINCIPLES
Definition
Autoimmune hemolytic anemia (AIHA) results from autoantibodies targeted to antigens on the patient's RBCs, resulting in either extravascular hemolysis (removal of RBC by tissue macrophages in the liver or spleen) or complement-mediated intravascular hemolysis.
Classification
There are two main types of AIHA: warm and cold AIHA. Warm AIHA antibodies interact best with RBCs at 37°C, whereas cold antibodies (or cold agglutinins) are most active at temperatures below 37°C and almost always fix complement.
Etiology
• Warm AIHA is usually caused by an IgG autoantibody. It may be idiopathic or secondary to an underlying process (i.e., lymphoma, chronic lymphocytic leukemia [CLL], collagen vascular disorder, or drugs).
• Cold AIHA (or cold agglutinin disease [CAD]) is typically caused by an IgM autoantibody.
î The acute form of CAD is often secondary to an infection (Mycoplasma, Epstein-Barr virus).
î The chronic form is associated with an IgM paraprotein or lymphoproliferative disorder in approximately one-half of cases and is primary (idiopathic) in the others.
DIAGNOSIS
• Laboratory data usually identify hemolysis with anemia, reticulocytosis, elevated LDH, decreased haptoglobin, indirect hyperbilirubinemia, and hemoglobinuria (if intravascular hemolysis is present).
• Peripheral blood smear may show spherocytes, occasional fragmented RBCs in warm AIHA, and RBC agglutination in CAD. Polychromasia and nucleated RBCs may be seen in either form.
• The hallmark of diagnosis is by a positive DAT (also known as a direct Coombs test). The DAT detects the presence of IgG or complement in the form of C3 bound to the RBC surface. The typical results for the DAT are shown here:
° Warm AIHA: IgG positive and C3 positive or negative
î Cold AIHA: IgG negative and C3 positive
• The indirect antiglobulin test (indirect Coombs) detects the presence of autoantibodies in the serum but also detects alloantibodies in the serum from alternate causes, including from transfusion or maternal- fetal incompatibility.
• An elevated cold agglutinin titer is seen with cold AIHA.
• If secondary AIHA is suspected, a workup for the underlying cause should be performed.
TREATMENT
• Initial therapy should be aimed at correcting complications from the hemolytic anemia. Definitive therapy should include identification and treatment of any underlying cause.
• RBC transfusions may result in the hemolysis of transfused cells, but they are still indicated in severe or life-threatening anemia.
• If a complete crossmatch cannot be completed in a timely manner, transfusion of universal donor (O-negative) or type-matched blood is appropriate.
• Warm AIHA.
î First-line treatment involves glucocorticoids, such as oral prednisone 1-2 mg/kg/d, which is effective in 80%-90% of patients. Response is typically seen in 7-25 days. When hemolysis has abated, glucocorticoids can be tapered over 4-6 months. Rapid steroid taper can result in relapse.
î Second-line treatments include rituximab, a monoclonal antibody directed against CD20 antigen expressed on B cells. Rituximab 375 mg/m2 weekly for four doses has been shown to be effective in 80% of cases with median response time of 3-6 weeks, and responses to treatment are observed with monotherapy or in combination with corticosteroids. Low-dose rituximab, 100 mg weekly for four doses, has also demonstrated efficacy in AIHA.20 Splenectomy is as effective as rituximab with median response of 7-10 days but its use has declined due to increased risk of serious infections and thrombosis.
î Treatment for relapsed/refractory cases is not well defined and includes azathioprine, cyclophosphamide, cyclosporine, and mycophenolate mofetil.
• Primary CAD
î Avoidance of cold exposure can minimize exacerbations. RBC transfusions at 37°C (blood warmer) and keeping the room warm can prevent exacerbation of hemolysis.
î Glucocorticoids and splenectomy are not effective and should not be used.
î Plasma exchange removes 60%-70% of IgM, thus offering effective, temporary control of the disease in severe hemolysis.
î Rituximab as a single agent or in combination with other agents (i.e., bendamustine) has shown to be effective in some cases and may be used as first-line therapy.