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834 Part VI: The Erythrocyte Chapter 54: Hemolytic Anemia Resulting from Immune Injury 835

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drug sensitivity or cold agglutinins. Studies with concentrated RBC elu- aggregation of band 3 proteins. Such neoantigens are not found on
ates suggest subthreshold quantities of bound IgG antibodies are capa- younger RBCs. An important but unanswered question concerns the
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ble of fixing much larger quantities of C3 to the cell membrane. In possible relationship between naturally occurring and pathologic anti–
cases of low-affinity IgG sensitization, detection of IgG bound to RBCs band 3 autoantibodies.
o
may be accomplished by cold washing (0 to 4 C) or by use of low ionic
strength saline in the wash steps prior to the DAT reaction. Cell Bound Cold-Antibody Hemolytic Anemia
IgA and IgM may be detected by means of antisera to IgA and IgM. Cold agglutinins are distinguished by their ability to directly aggluti-
DAT-negative AHA has been reviewed extensively elsewhere. 257–259 nate saline-suspended human RBCs at low temperature, maximally at
Nature of the Autoantibodies and Red Blood Cell Target Anti- 0 to 5°C. The reaction is reversible by warming. In chronic cold agglu-
gens In any series of warm-antibody AHA patients, the correlation tinin disease, serum titers are commonly 1:1000 or higher and may
11
between the strength of the antiglobulin reaction (IgG molecules per reach 1:512,000 or more. Cold agglutinins are characteristically IgM.
RBC) and the rate of RBC destruction is variable. The IgG subclass of IgA or IgG cold agglutinins have been reported, 11,202,277 sometimes in
warm autoantibodies influences the degree to which these antibodies combination with IgM. In mixed warm- and cold-antibody AHA,
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shorten RBC survival. IgG is the most commonly encountered sub- warm-reactive IgG autoantibodies are found in association with IgM
1
class, either alone or in combination with other IgG subclasses. 245,260 cold agglutinins. 21
IgG and IgG autoantibodies appear to be more effective in decreasing The DAT result is positive with anticomplement reagents. The
1
3
RBC life span than do those of the IgG or IgG subclass. 245,261 antibody itself, however, is not detected by the DAT because the cold
4
2
The difference may result from the greater affinity of macrophage agglutinins readily dissociate from the RBCs both in vivo and during the
Fc receptors for IgG and IgG 3 177,178 and the higher complement-fixing washing steps of the standard antiglobulin procedure. In contrast, C4b
1
activity of IgG or IgG antibodies relative to the activity of IgG or IgG and C3b are covalently bound to target RBCs via thioester linkages. In
4
2
3
1
antibodies. 187 one unusual case, a low-titer IgG cold agglutinin could be detected by
Autoantibodies eluted from patients’ RBCs or present in their washing the patient’s RBCs in ice-cold saline solution and performing
plasma typically bind to all the common types of human RBCs repre- the DAT at 4°C. 277
sented in test panels used by blood banks and thus might appear to be The majority of cold agglutinins are reactive with oligosaccha-
nonspecific. However, the antibodies of any one patient typically recog- ride antigens of the I/i system, which are precursors of the ABH and
nize one or more antigenic determinants (epitopes) that are common Lewis blood group substances. 279–281 The I/i determinants are bound
to almost all human RBCs, that is, “public” antigens. These antibodies to erythrocyte membrane glycoprotein (band 3 anion transporter) or
have been useful for evaluating RBC membrane structures and for iden- to glycolipids. 280,281 Anti-I and anti-i reportedly bind solubilized RBC
tifying rare RBC phenotypes, namely, RBCs that lack a common blood glycoproteins at 37°C, suggesting the temperature dependence of cold
group antigen(s). Nearly half of all AHA patients have autoantibodies agglutination of intact RBCs may be a function of temperature-induced
specific for epitopes on Rh proteins. 10,11,131,262,264 The autoantibodies of conformational effects on the cell surface. 282,283
such patients commonly do not react with human Rh RBCs, which I antigens are expressed strongly on adult RBCs but weakly on
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lack expression of the Rh complex. Occasionally, the anti-Rh autoanti- neonatal (cord) RBCs. The converse is true of i antigens, indicating
bodies have anti-e, anti-E, or anti-c (or, more rarely, anti-D) specificity. I/i antigen expression is developmentally regulated. The differences
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Patients who have autoantibodies with selective specificity (e.g., anti-e) between adult and cord blood RBCs allow evaluation of the serologic
nearly always have other autoantibodies reactive with all human RBCs, specificity of cold agglutinins. 10,11,202 I/i antigens, or structurally related
except Rh . Autoantibodies with such specificity are designated collec- analogues, occur in human saliva, milk, amniotic fluid, and hydatid cyst
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tively as Rh related. 136,264 fluid, and are expressed on human lymphocytes, neutrophils, and
202
The remaining patients with warm-antibody AHA have IgG auto- monocytes. 284
antibodies that are fully reactive with Rh RBCs. 10,11,131,262–264 The exact Anti-I is the predominant specificity of cold agglutinins in idio-
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specificity of the autoantibodies for many of these patients is undefined. pathic cold agglutinin disease, in patients with M. pneumoniae, and in
However, in other instances, autoantibody specificity for serologically some cases of lymphoma. Cold agglutinins with anti-i specificity are
defined blood group antigens outside the Rh system has been identi- found in patients with infectious mononucleosis and in some patients
fied (using RBCs of appropriate antigen-deficient phenotype) including with lymphoma. A small percentage of cold agglutinin-containing sera
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anti-Wr , anti-En , anti-LW, anti-U, anti-Ge, 250,268 anti-Sc1, react equally well with adult and neonatal RBCs. These antibodies rec-
a 265
267
b 131
269
or antibodies to Kell blood group antigens. For ease of reference, the ognize antigens outside the I/i system, including Pr antigens, consisting
270
entire group of autoantibodies is designated non-Rh related. 136,264 of carbohydrate epitopes of glycophorins that are inactivated by protease
Immunochemical studies indicate the autoantibodies from almost treatment and, less commonly, the M or P blood group antigens. 285,286
202
any AHA patient react with individual membrane proteins. The major Most cold agglutinins associated with chickenpox exhibit anti-Pr spec-
287
target of Rh-related autoantibodies is a 32- to 34-kDa nonglycosylated ificity. A single case with anti-I specificity has been observed. Hemo-
polypeptide lacking on Rh RBCs. 136,271 This polypeptide is similar, if lysis resulting from a cold agglutinin with anti-Pr specificity occurred
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not identical, to the polypeptide expressing the Rh(e) alloantigen. Many following an allogeneic marrow transplant. 288
α-methyldopa–induced autoantibodies also react with this polypep- In hemolytic anemia associated with infectious mononucleosis,
tide. Autoantibodies with non-Rh serologic specificity react with the the patient’s serum may contain IgM anti-i cold agglutinins or cold-
136
136
band 3 anion transporter 136,272 or with both band 3 and glycophorin A. reactive nonagglutinating IgG anti-i with IgM cold-reactive anti-IgG
The latter autoantibodies may react with an epitope formed through antibodies (“rheumatoid factors”) that may crosslink the IgG-coated
the interaction of these two proteins on the RBC membrane. It is RBCs to produce agglutination. 289
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interesting to note that anti-RBC autoantibodies in NZB mice exhibit In paroxysmal cold hemoglobinuria, the direct antiglobulin reac-
anti–band 3 specificity. Furthermore, naturally occurring anti–band 3 tion usually is positive during and briefly following an acute attack
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IgG autoantibodies are found in almost all humans. 275,276 These autoan- because of the coating of surviving RBCs with complement, primarily
tibodies may play a role in the clearance of senescent RBCs by reacting C3dg fragments. The Donath-Landsteiner antibody is responsible for
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with neoantigens formed on these cells by proteolytic alteration or complement deposition on the cells; it is a nonagglutinating IgG that
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