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INTRODUCTION

SUMMARY

Autoimmune hemolytic anemia (AHA) is characterized by shortened red blood cell (RBC) survival and the presence of autoantibodies directed against autologous RBCs. Demonstration of antibody or complement on RBC membranes, usually by a positive direct antiglobulin test (DAT) result, is essential for diagnosis. Most patients (80%) with AHA exhibit warm-reactive antibodies of the immunoglobulin (Ig) G isotype on their red cells. Most of the remainder of patients exhibit cold-reactive autoantibodies. Two types of cold-reactive autoantibodies to RBCs are recognized: cold agglutinins and cold hemolysins. Cold agglutinins are generally of IgM isotype, whereas cold hemolysins usually are of IgG isotype. The DAT may detect IgG, proteolytic fragments of complement (mainly C3), or both on the RBCs of patients with warm-antibody AHA. In cold-antibody AHA, only complement is detected because the antibody dissociates from the RBCs during washing of the cells. About half of patients with AHA have no underlying associated disease; these cases are termed primary or idiopathic. Secondary cases are associated with underlying autoimmune, malignant, or infectious diseases or with administration of certain drugs.

Although most patients do not require transfusion of RBCs, transfusion should not be withheld from those with symptomatic anemia. In warm-antibody AHA, rituximab and glucocorticoids are effective in slowing the rate of hemolysis. Splenectomy is indicated for patients who are refractory to medical therapy or who require an unacceptably high maintenance dose or prolonged administration of glucocorticoids. IV immunoglobulin may provide short-term control of hemolysis. Immunosuppressive drugs and danazol have been used successfully in refractory cases. In cold agglutinin– and cold hemolysin–mediated hemolysis, keeping the patient warm and treating underlying lymphoproliferative disorders usually are effective. Rituximab alone or in combination with bendamustine has been effective in more than half of cases of cold AHA. Drug-induced immune hemolytic anemia usually is ameliorated by discontinuation of the offending drug. Glucocorticoids are effective in AHA induced by immune checkpoint inhibitors.

DEFINITION AND HISTORY

The two main features of immune red blood cell (RBC) injury are (a) shortened RBC survival in vivo and (b) evidence of host antibodies reactive with autologous RBCs, most frequently demonstrated by a positive direct antiglobulin test (DAT) result, also known as the Coombs test. Most cases in adults are mediated by warm-reactive autoantibodies. A smaller proportion of patients exhibit cold-reactive autoantibodies or drug-related antibodies.

By the early 20th century, reticulocytes, spherocytes, and osmotic fragility of RBCs had been described. Clinicians could diagnose hemolytic anemia, but the distinction between congenital and acquired forms was imprecise. Some clinicians even doubted the existence of acquired hemolytic anemia.1 The sera of some patients with hemolytic anemia directly agglutinated saline suspensions of normal or autologous human RBCs. These serum factors, later shown to be specific antibodies (largely of the immunoglobulin [Ig] M class), were termed direct or saline agglutinins. In a smaller proportion of cases, the patients’ sera could mediate lysis of the test RBCs in the presence of ...

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