Autoimmune Hemolytic Anemia: Treatment of Common Types

Cold Autoimmune Hemolytic Anemia

In cold AIHA, the hemolysis is mediated by IgM antibodies directed against red cells.³⁵ As discussed earlier, the term “cold” refers to the fact that the antibody binds maximally at temperatures below 37°C. The most efficient temperature for binding is called the “thermal amplitude,” and, in theory, the higher the thermal amplitude, the more virulent the antibody. An antibody titer can be calculated at each reaction temperature from 4°C to 37°C by serial dilutions of the patient’s serum prior to incubating with reagent red cells. Rarely, the IgM can fix complement rapidly, leading to intravascular hemolysis. In most patients, complement is fixed through C3, and the C3-coated red cells are taken up by macrophages in the mononuclear phagocyte system, primarily in the liver.³

The DAT in patients with cold AIHA will show cells coated with C3. The blood smear will often show ag-glutination of the blood, and if the blood cools before being analyzed, the agglutination will interfere with the analysis. Titers of cold agglutinin can range from 1:1000 to over 1 million. The IgM autoantibodies are most often directed against the I/i antigens on the red blood cell membrane, with 90% against I antigen.³⁵ The I antigen specificity is typical with primary cold agglutinin disease and after Mycoplasma infection. The i antigen specificity is most typical of Epstein-Barr virus and cytomegalovirus infections in children. In young patients, cold AIHA often occurs following an infection, including viral and Mycoplasma infections, and the course is self-limited.^35,36 The hemolysis usually starts 2 to 3 weeks after the illness and will last for 4 to 6 weeks. In older patients, the etiology in over 90% of cases is a B-cell lymphoproliferative disorder, usually with monoclonal kappa B-cells.³⁷ The most common disorders are marginal zone lymphoma, small lymphocytic lymphoma, and lymphoplasmacytic lymphoma.³

Therapeutic Options

It is important to diagnose cold AIHA because the standard therapy for warm AIHA (steroids) is ineffective in cold AIHA. Because C3-coated red cells are taken up primarily in the liver, removing the spleen is also an ineffective therapy. Simple measures to help with cold AIHA should be employed.³⁷ Patients should be kept in a warm environment and should try to avoid the cold. If transfusions are needed, they should be infused via blood warmers to prevent hemolysis. In rare patients with severe hemolysis, therapeutic plasma exchange (TPE) can be considered.³⁸ Given that the culprit antibody is IgM—mostly intravascular—use of TPE may slow the hemolysis to give time for other therapies to take effect.

Treatment of cold AIHA remains difficult (Table 3). Because most patients with primary AIHA have underlying lymphoproliferative diseases, chlorambucil has been used in the past to treat cold AIHA. However, responses were rare and the drug could worsen the anemia.³⁸ Currently, the drug of choice is rituximab. Response is seen in 45% to 75% of patients, but is almost always a partial response and retreatment is often necessary.^17,37,39 As with other autoimmune hematologic diseases, there can be a delay in response that ranges from 2 weeks to 4 months (median time, 1.5 months).³⁷ Given the lack of robust response (complete and durable) with rituximab, the Berentsen group has explored adding bendamustine to rituximab.⁴⁰ In a prospective trial, 71% of patients responded with a 40% complete response rate. Therapy was well tolerated, with only 29% of patients needing dose reduction Although more toxic, this combination can be considered in patients with aggressive disease. A small study of the use of bortezomib showed a good response in one-third of patients.⁴¹ There is increasing use of the C5 complement inhibitor eculizumab to halt the hemolysis, but further study of this agent is also required.^36,42,43 Blockers of C1s complement, which block hemolysis by preventing complement activation, are currently being studied in clinical trials.⁴⁴

Since most patients with cold AIHA are older, a frequent issue that must be considered is cardiac surgery. The concern is that the hypothermia involved with most heart bypass procedures will lead to agglutination and hemolysis. The development of normothermic bypass has expanded treatment options. A recommended approach in patients who have known cold agglutinins is to measure the thermal amplitude of the antibody preoperatively. If the thermal amplitude is above 18°C, normothermic bypass should be done, if feasible.⁴⁵ If not feasible, preoperative TPE should be considered.

Paroxysmal Cold Hemoglobinuria

A unique cold AIHA is paroxysmal cold hemoglobinuria (PCH).^3,46 This cold hemolytic syndrome most often occurs in children following a viral infection, but in the past it complicated any stage of syphilis.⁴⁷ The mediating antibody in PCH is an IgG antibody directed against the P antigen on the red blood cell. This antibody binds best at temperatures below 37°C, fixing complement at cold temperatures, but then activates the complement cascade at body temperature.⁴⁸ Because this antibody can fix complement, hemolysis can be rapid and severe, leading to extreme anemia. The DAT is often weakly positive but can be negative. The diagnostic test for PCH is the Donath–Landsteiner test. This complex test is performed by incubating 3 blood samples, 1 at 0° to 4°C, another at 37°C, and a third at 0° to 4°C and then at 37°C. The diagnosis of PCH is made if only the third tube shows hemolysis.³⁵ PCH can persist for 1 to 3 months but is almost always self-limiting. In severe case, steroids may be of benefit.