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CHAPTER 54 DEFINITION AND HISTORY

HEMOLYTIC ANEMIA The two main features of immune red blood cell (RBC) injury are (1)
shortened RBC survival in vivo and (2) evidence of host antibodies
RESULTING FROM IMMUNE reactive with autologous RBCs, most frequently demonstrated by a
positive direct antiglobulin test (DAT), also known as the Coombs test.
Most cases in adults are mediated by warm-reactive autoantibodies. A
INJURY 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 hemo-
Charles H. Packman lytic anemia, but the distinction between congenital and acquired forms
was imprecise. Some clinicians even doubted the existence of acquired
hemolytic anemia. The sera of some patients with hemolytic ane-
1
mia directly agglutinated saline suspensions of normal or autologous
SUMMARY human RBCs. These serum factors, later shown to be specific antibod-
ies (largely of the immunoglobulin [Ig] M class), were termed direct or
Autoimmune hemolytic anemia (AHA) is characterized by shortened red saline agglutinins. In a smaller proportion of cases, the patients’ sera
blood cell (RBC) survival and the presence of autoantibodies directed against could mediate lysis of the test RBCs in the presence of fresh serum as a
autologous RBCs. Demonstration of antibody and/or complement on RBC complement source. The heat-stable factors (antibodies) necessary for
membranes, usually by a positive direct antiglobulin test (DAT, also referred in vitro complement-mediated lysis were called hemolysins. However, in
to as the Coombs test) is essential for diagnosis. Most patients with AHA the majority of cases of hemolytic anemia, neither direct agglutinins nor
(80 percent) exhibit warm-reactive antibodies of the immunoglobulin (Ig) hemolysins could be demonstrated. In 1945, Coombs and colleagues
2
G isotype on their red cells. Most of the remainder of patients exhibit cold- reported that RBCs coated with nonagglutinating Rh antibodies (now
reactive autoantibodies. Two types of cold-reactive autoantibodies to RBCs are known to be of the IgG isotype) could be agglutinated by rabbit anti-
recognized: cold agglutinins and cold hemolysins. Cold agglutinins are gen- serum to human γ-globulin. That is, the rabbit antiglobulin serum
crosslinked IgG antibody-coated RBCs to produce visible agglutina-
erally of IgM isotype, whereas cold hemolysins usually are of IgG isotype. The tion. Addition of rabbit antiglobulin serum to a suspension of washed
DAT may detect IgG, proteolytic fragments of complement (mainly C3), or both RBCs isolated from patients with suspected acquired hemolytic anemia
on the RBCs of patients with warm-antibody AHA. In cold-antibody AHA, only produced agglutination in many cases, including those patients lacking
complement is detected because the antibody dissociates from the RBCs dur- saline agglutinins or hemolysins. RBCs from patients with congenital
ing washing of the cells. About half of patients with AHA have no underlying hemolytic anemia did not agglutinate. This procedure now is termed
3,4
associated disease; these cases are termed primary or idiopathic. Secondary the direct antiglobulin (Coombs) test. Subsequent studies established that
cases are associated with underlying autoimmune, malignant, or infectious positive direct antiglobulin reactions in autoimmune hemolytic anemia
diseases or with ingestion of certain drugs. (AHA) are attributable to coating of the RBCs with immunoglobulins
Although most patients do not require transfusion of RBCs, transfusion (mainly IgG) and/or complement proteins. When the RBCs are coated
should not be withheld from those with symptomatic anemia. In warm- chiefly with complement proteins, a positive DAT depends upon the
antibody AHA, rituximab and glucocorticoids are effective in slowing the presence of anticomplement (principally anti-C3) in the antiglobulin
reagent. In warm-antibody AHA, the autoantibodies, chiefly of IgG iso-
rate of hemolysis. Splenectomy is indicated for patients who are refractory type, bind optimally to RBCs at 37°C. Warm antibodies may or may not
to medical therapy or who require an unacceptably high maintenance dose activate complement binding to RBCs.
or prolonged administration of glucocorticoids. Intravenous immunoglobulin Cryopathic hemolytic syndromes are caused by autoantibodies
may provide short-term control of hemolysis. Immunosuppressive drugs and that bind RBCs optimally at temperatures less than 37°C and usually
danazol have been used successfully in refractory cases. In cold agglutinin- and less than 31°C. Two major types of “cold antibody” may produce AHA.
cold hemolysin-mediated hemolysis, keeping the patient warm and treating Cold agglutinins, which directly agglutinate RBCs, mediate cold agglu-
underlying lymphoproliferative disorders usually are effective. Rituximab has tinin disease. The Donath-Landsteiner autoantibody, which is not an
been effective in about half of cases of cold AHA. Drug-induced immune hemo- agglutinin but a potent hemolysin, mediates paroxysmal cold hemoglo-
lytic anemia usually is ameliorated by discontinuation of the offending drug. binuria. In both cryopathic syndromes, the complement system plays
a major role in RBC injury (Chap. 19); as such, much greater poten-
tial exists for direct intravascular hemolysis than in warm-antibody–
mediated AHA.
Cold agglutinins were first described by Landsteiner in 1903.
5
However, recognition of the connection among cold agglutinins,
hemolytic anemia, and Raynaud-like peripheral vascular phenomena
evolved slowly. In 1918, Clough and Richter detected cold agglutin-
6
7,8
Acronyms and Abbreviations: AHA, autoimmune hemolytic anemia; CLL, chronic ins in a patient with pneumonia. In 1925 and 1926, Iwai and MeiSai
lymphocytic leukemia; DAF, decay-accelerating factor; DAT, direct antiglobulin test; reported two patients with cold agglutinins and Raynaud phenomenon
HLA, human leukocyte antigen; HRF, homologous restriction factor; HS, hereditary and showed that flow of blood through capillary tubes in vitro or in
spherocytosis; IAT, indirect antiglobulin test; Ig, immunoglobulin; IGHV, immuno- superficial capillaries in vivo was impeded at low temperatures. During
globulin heavy chain variable region; PNH, paroxysmal nocturnal hemoglobinuria; the late 1940s and early 1950s, the observations of many investigators
RBC, red blood cell; SLE, systemic lupus erythematosus. gradually established the pathogenic importance of cold agglutinins in
RBC injury. Schubothe introduced the term cold agglutinin disease in
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