REVIEW RONALD E. DOMEN, MD Director, Bone Marrow and Stem Cell Processing Laboratory, Department of Clinical Pathology, Cleveland Clinic; Associate Professor of Pathology, Ohio State University College of Medicine. An overview of immune hemolytic anemias MMUNE PROCESSES are an often-unrecog- ABSTRACT nized cause of anemia, although in their presentation, the symptoms are consistent Often patients with immune hemolytic anemias with anemia from any cause. For the primary care physician, the key is to be vigilant to the present with symptoms that are common in signs and symptoms of immune hemolytic ane- anemia of any cause. In the different types of mia, especially in patients at high risk, and to initiate treatment promptly when appropriate. immune hemolytic anemia, red blood cells are Although researchers have made remarkable destroyed by processes mediated by antibodies. progress in elucidating the destructive process- es at work in the various types of immune This article reviews the pathophysiology, diagnosis, hemolytic anemia, the many different causes and treatment of this group of diseases. mirror the complexity of the human immune system. This article reviews the etiologies of different forms of immune hemolytic anemias, KEY POINTS the tests that help make the diagnosis, and the Antibody production can be either idiopathic or due to treatments that are available. diseases (eg, leukemia, lymphoma, infections, autoimmune • HOW RED BLOOD CELLS ARE DESTROYED diseases) or a variety of drugs. Autoimmune hemolytic anemia was one of the All age groups can be affected, and clinical signs and first autoimmune diseases to be recognized. In symptoms can be quite variable. one of the earliest experiments in this area, per- formed in 1904, Landsteiner and Donath1.2 The type and amount of antibody or antibodies involved, found that the serum of patients with paroxys- and whether complement fixation occurs, can provide mal cold hemoglobinuria lysed normal red blood valuable information for diagnosis and treatment. cells, a finding that explained the clinical char- acteristics of the disease. However, there was no Corticosteroids, followed by splenectomy, are the mainstays practical way to detect or characterize immune of therapy for non-drug-related hemolysis, and other hemolytic anemia until Coombs, Mourant, and Race developed the direct antiglobulin test (the adjunctive therapies are available for refractory cases. DAT or Coombs' test) in 1945.3 There are several immune hemolytic disor- Corticosteroid therapy has generally not shown clinical ders; in all of them, red blood cells are destroyed efficacy in patients with uncomplicated cold agglutinin in processes mediated by antibodies.4-7 autoimmune hemolytic anemia, paroxysmal cold hemoglobinuria, or drug-induced immune hemolysis. Antibody production: Alioimmune or autoimmune Two types of processes can give rise to anti- bodies against red blood cells: alioimmune and CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 6 5 • NUMBER 2 FEBRUARY 1998 89 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. IMMUNE HEMOLYTIC ANEMIA DOMEN TABLE 1 antibodies are efficient at binding and activat- ing complement, both intravascular and Types of immune hemolytic anemia extravascular hemolysis can occur when these antibodies are involved. Autoimmune hemolysis Warm-antibody autoimmune hemolytic anemia Cold-antibody (agglutinin) autoimmune hemolytic anemia Hemopoiesis increases to compensate Mixed warm and cold autoimmune hemolytic anemia for red blood cell loss Paroxysmal cold hemoglobinuria The normal life span of red blood cells is 100 9 Drug-induced immune hemolysis to 140 days, and under normal, steady-state Immune complex mechanism conditions, the bone marrow produces Drug adsorption (hapten) mechanism approximately 25 mL of mature red cells daily Autoantibody mechanism to replace those that are lost. However, in response to blood loss or increased red blood Alloimmune immune hemolysis cell destruction, the bone marrow can easily Hemolytic disease of the newborn Hemolytic transfusion reaction produce up to 5 times as many red blood cells for sustained periods, and up to 10 times as many for short periods. Therefore, a person can have clinical or laboratory evidence of autoimmune (FIGURE 1). Alloantibodies are pro- increased red cell loss, but as long as the bone duced in response to foreign antigens such as marrow can compensate with increased pro- drugs or allogeneic blood transfusions; autoan- duction, he or she will not have anemia. tibodies react against antigens present on a person's own red cells. Antibodies that react • TYPES OF IMMUNE HEMOLYTIC ANEMIA against antigens common to all red cells are also known as panagglutinins, as they aggluti- The immune hemolytic disorders can he clas- nate all red cells in vitro. sified in several ways (TABLE 1). One distinction is the temperature at which the antibody is Complement activation and fixation most active (ie, their thermal range).8'10 60% to 70% Once an antibody attaches to the red cell "Warm" antibodies are most active at 37°C, of immune membrane, the complement system may or while "cold" antibodies are generally most may not become activated, depending on the active at less than 32°C. Occasionally, mix- hemolysis class or subclass of the antibody involved.4-6.8 tures of warm and cold antibody types are seen 8 11 12 cases IgM, IgA, IgG 1, and IgG3 antibodies can acti- in the same patient. - ' The type and vate the complement system and fix comple- amount of antibody or antibodies involved, are warm ment proteins to red blood cells; lgG2 and and whether complement fixation occurs, can autoimmune IgG4 do not. provide valuable information for diagnosis and treatment. hemolytic Hemolysis: anemia Extravascular or intravascular Warm autoimmune hemolytic anemia Two basic mechanisms explain the immune Warm autoimmune hemolytic anemia occurs destruction of red blood cells. in 1 in 50,000 to 80,000 persons, and accounts Extravascular hemolysis. Macrophages for 60% to 70% of cases of immune hemoly- capture and phagocytize red blood cells that sis^-8.^ From 50% to 70% of cases are idio- are coated with antibodies or complement pathic or primary; the remaining 30% to 50% C.3b molecules or both. Red blood cells coat- are associated with underlying diseases present ed with IgG are destroyed primarily in the at the time the patient is first evaluated, such spleen, and IgM-coated cells are destroyed pri- as lymphoproliferative disorders (eg, leukemia, marily in the liver.4.6 lymphoma, multiple myeloma, Waldenstrom's Intravascular hemolysis occurs when macroglobulinemia), autoimmune disorders complement proteins C5 through C9 attach (eg, systemic lupus erythematosus, rheumatoid to red blood cells, forming pores that allow the arthritis, scleroderma, pernicious anemia), cell contents to leak out. Since IgM and IgA and solid tumors. 90 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUM E 65 • NUMBER 2 FEBRUARY 1998 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. How red blood cells are destroyed in immune hemolytic anemia Red blood cells RED BLOOD CELLS carry antigens such as Rh on their surface. ^ -f y IMMUNOGLOBULIN ANTIBODIES y- attach to the antigens. Antigens Antibodies - J a The COMPLEMENT SYSTEM • may become activated and complement molecules may Complement attach to red blood cells if molecules the antibody is an IgM, IgA, IgGI, or lgG3, but not lgG2 or lgG4. / EXTRAVASCULAR HEMOLYSIS LAR HEMOLYSIS begins as macrophages in the occurs if complement proteins C5 liver or spleen capture red through C9 attach to red blood blood cells by attaching to cells and form pores that allow the antibodies or to complement cell contents to leak out. C3b molecules or both, and damage the red blood cell membrane. SPHEROCYTES, red blood cells that have assumed a spherical shape due to loss of membrane, are more rigid than normal red blood cells and therefore more easily damaged and destroyed through normal wear and tear. MACROPHAGES may destroy red blood cells by phagocytosis. CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 6 5 • NUMBER 2 FEBRUARY 1998 32 Downloaded from www.ccjm.org on September 30, 2021. For personal use only. All other uses require permission. IMMUNE HEMOLYTIC ANEMIA DOMEN Cold autoimmune hemolytic anemia Cold autoimmune hemolytic anemia, or cold Partial list agglutinin syndrome, is less common than of drugs associated warm autoimmune hemolytic anemia. with immune hemolysis Classically, this disease occurs after either Immune complex mechanism Mycoplasma pneumoniae pneumonia or infec- Acetaminophen tious mononucleosis, but can also be seen as Antihistamines part of several malignant, nonmalignant, and Cefotaxime infectious disorders.8'10'17-20 Ceftriaxone Usually, the antibody is an IgM autoanti- Cephalosporins body against the I blood group system,8'10'21 or 5-Fluorouracil against the Pr or P systems. Nonpathogenic Hydralazine cold agglutinins, typically polyclonal IgM, Hydrochlorothiazide react only at very low temperatures: 0° to Insulin 4°Q8,io,22 l contrast, pathogenic cold agglu- Isoniazid n Melphalan tinins are almost always a monoclonal IgM Probenecid paraprotein (usually of the kappa light chain Quinidine type), and usually react at 30° to 32°C or high- Quinine er.8,10,22 Such temperatures can occur in the Streptomycin peripheral circulation under normal circum- Sulfonamides stances, allowing pathogenic IgM—and usual- Tetracycline ly