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826 Part VI: The Erythrocyte Chapter 54: Hemolytic Anemia Resulting from Immune Injury 827

M. pneumoniae infections or infectious mononucleosis and, rarely, in autoantibodies of any one patient often are specific for only a single
children with chickenpox. The term also has been used to describe a RBC membrane protein (see “Serologic Features” below). The narrow
chronic disorder occurring in older patients with known malignant spectrum of autoreactivity suggests the mechanism underlying AHA
lymphoproliferative diseases. On the other hand, idiopathic (primary) development in such patients is not secondary to a generalized defect in
chronic cold agglutinin disease has its peak incidence after age 50 years. immune regulation. Rather, these patients may develop warm-antibody
This disorder, with its characteristic monoclonal IgM cold agglutinins, AHA through an aberrant immune response to a self-antigen or to an
may be considered a special form of monoclonal gammopathy (Chap. immunogen that mimics a self-antigen.
106). Nearly all of these patients exhibit clonal B lymphocyte prolifer- In patients with secondary AHA, the disease may be associated
ation. As with other “essential” or idiopathic monoclonal gammopa- with a fundamental disturbance in the immune system, for example,
24
thies, some patients in this group gradually develop features of a B-cell when in the setting of lymphoma, CLL, SLE, primary agammaglobu-
lymphoproliferative disorder resembling Waldenström macroglobuline- linemia (common variable immunodeficiency), or hyper-IgM immu-
mia, CLL, or a B-cell lymphoma. Thus, the distinction between primary nodeficiency syndrome. In these settings, warm-antibody AHA most
and secondary types of chronic cold agglutinin disease is not absolute. likely arises through an underlying defect in immune regulation,
Although the majority of patients with mycoplasma pneumonia although the contribution of an aberrant immune response to self-
have significant cold agglutinin titers, they only infrequently develop antigen cannot be excluded. AHA seems especially frequent in patients
clinical hemolytic anemia. 124–126 However, subclinical RBC injury may with low-grade lymphoma or CLL treated with fludarabine 88,89
90
occur. In M. pneumoniae infections, weakly positive direct antiglobulin or 2-chlorodeoxyadenosine (cladribine). The T-lymphocytopenia
reactions and/or mild reticulocytosis are often noted in the absence of induced by these drugs may exacerbate the preexisting tendency of
124
anemia in a substantial number of cases. Cold agglutinins occur in patients to form autoantibodies.
more than 60 percent of patients with infectious mononucleosis, but A long-recognized but poorly understood phenomenon, the
again, hemolytic anemia is rare. 127–129 development of AHA or a positive DAT following RBC transfusion, has
Medical centers that receive many referrals report that parox- received renewed interest lately. 132,133 Although generally transient, the
ysmal cold hemoglobinuria constitutes 2 to 5 percent of all cases of positive DAT may persist for up to 300 days in some transfusion recip-
AHA. 10,11 Among children, however, Donath-Landsteiner hemolytic ients, long after any transfused RBCs have disappeared. 134,135 It is not
anemia accounted for 32.4 percent of 68 immune hemolytic syn- clear whether this represents true autoimmunity or some other mecha-
dromes diagnosed over a 4-year period. Commonly, the diagnosis is nism, for example, microchimerism resulting from temporary engraft-
15
missed because of lack of physician awareness or failure to perform the ment of passenger memory lymphocytes from the RBC donor. 132
proper serologic studies (see “Serologic Features” below). 12,15 Thus, the A still unexplained observation is that certain drugs, such as
true incidence may be higher. Although familial occurrence has been α-methyldopa, can induce warm-reacting IgG anti-RBC autoantibod-
10
reported, no racial or genetic risk factors are known. As noted, most ies in otherwise normal persons. The autoantibodies induced by α-
childhood cases follow either specific viral infections or upper respira- methyldopa have Rh-related serologic and immunochemical spec-
136
tory infections of undefined etiology. 10–15 ificity similar to that of autoantibodies arising in many patients with
Older series report that drug-induced immune hemolytic ane- “spontaneous” AHA. A critical difference is that the drug-associated
mia accounts for 12 to 18 percent of immune hemolytic anemias. The autoantibodies subside when the drug is discontinued, suggesting that
11
disorder is much less common now that α-methyldopa and megaunit (1) the latent potential to form this type of anti-RBC autoantibody is
doses of penicillin rarely are used. The current incidence of drug- present in many immunologically normal individuals, and (2) the
induced immune hemolytic anemia is estimated at 1 per 1 million steps required to generate such autoantibodies do not necessarily cre-
population, approximately 88 percent of which result from the second- ate a sustained autoimmune state. On the other hand, maintenance of
and third-generation cephalosporins, cefotetan, and ceftriaxone. 89,130 chronic idiopathic AHA may be either secondary to a continuing (but
Fludarabine has replaced α-methyldopa as the most common cause of unknown) stimulus or induced by a short stimulus to which the patient
drug-induced autoantibodies. 89 continues to respond.
Normal subjects sometimes have a positive DAT when they vol-
ETIOLOGY AND PATHOGENESIS unteer to donate blood. 137,138 The positive DAT in these normal donors
often results from warm-reacting IgG autoantibodies, similar in sero-
131
137
ETIOLOGY logic specificity and in IgG subclass to the autoantibodies occurring
in AHA. Although many of these donors remain DAT-positive without
Warm-Antibody Autoimmune Hemolytic Anemia developing overt hemolytic anemia, a few have been documented to
The etiology of AHA is unknown. In warm-antibody AHA, the auto- develop AHA. 137,138 The prevalence of positive DATs in normal blood
antibodies that mediate RBC destruction are predominantly (but not donors is approximately 1 in 10,000 donors. 137,139 Because blood dona-
exclusively) IgG globulins possessing relatively high binding affinity for tion per se likely does not contribute to an increased risk of developing
human RBCs at 37°C. As a result, the major share of plasma autoanti- autoantibodies, the 1 in 10,000 proportion likely is the approximate
body is bound to the patient’s circulating RBCs. Eluates prepared from frequency of positive DATs in the entire population. A proportion of
the patient’s washed, autoantibody-coated RBCs constitute an impor- patients who present with clinically overt primary AHA may come from
tant source of purified autoantibody for investigation of specificity, a subset of asymptomatic individuals who are DAT-positive, but this
immunoglobulin structure, or other properties. In addition, sera from notion is not established.
patients with warm AHA often are used in blood banks for crossmatch- Several concepts have been developed to explain immunologic
ing and for general screening of antibody specificity. The quantity of tolerance to self-antigens. 140–143 Relevant to warm-antibody AHA,
such autoantibody in serum may be low and in some cases may not membrane-bound antigens expressed in a multivalent array at high
reflect the full spectrum of anti-RBC specificity revealed in concur- concentration may induce tolerance by effecting clonal deletion of auto-
144
rently prepared RBC eluates. 124 reactive B cells. Both the Rh-related and the non-Rh types of RBC
In patients with primary AHA, erythrocyte autoantibodies are antigens targeted by AHA autoantibodies (see “Serologic Features”
the only recognizable immunologic aberration. Furthermore, the below) are expressed normally by human fetal erythrocytes, as early as

Kaushansky_chapter 54_p0823-0846.indd 827 9/19/15 12:27 AM