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830 Part VI: The Erythrocyte Chapter 54: Hemolytic Anemia Resulting from Immune Injury 831

Fab domain, to a compound neoantigen consisting of loosely bound immune hemolytic anemia resulting from α-methyldopa therapy typ-
drug and a blood group antigen intrinsic to the red cell membrane. ically exhibit strongly positive DAT reactions and serum antibody, evi-
Elegant studies on quinidine- or quinine-induced immune thrombocy- denced by the IAT reaction. Antibodies in the serum or eluted from
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topenia have demonstrated the IgG antibodies implicated in this disor- RBC membranes react optimally at 37°C with unaltered autologous or
der bind through their Fab domains, not by their Fc domains to platelet homologous RBCs in the absence of drug (see Fig. 54–1C). 74,76,224 Fre-
Fcγ receptors. 220,221 quently the autoantibodies are reactive with determinants of the Rh
The data elucidate how one patient with quinidine sensitivity may complex, 74,76,224 and at least some appear to target the same 34-kDa
have selective destruction of platelets and another may have selective Rh-related polypeptide targeted by the autoantibodies in many cases
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destruction of RBCs. This process occurs because the pathogenic anti- of “spontaneously arising” AHA. Thus, distinguishing these drug-in-
body recognizes the drug only in combination with a particular mem- duced antibodies from similar warm-reacting autoantibodies in idio-
brane structure of the RBC (e.g., a known alloantigen) or of the platelet pathic AHA currently is not possible.
(e.g., α domain of the glycoprotein Ib complex). Therefore, at least in The mechanism by which a drug induces formation of an autoan-
these cases, the target cell does not appear to be purely an innocent tibody is unknown. Radiolabeled α-methyldopa does not react directly
bystander. Binding of the drug itself to the target cell membrane is weak with the membranes of intact human RBCs. 76,225 However, both α-meth-
until the attachment of the antibody to both drug and cell membrane yldopa and levodopa reportedly bind to isolated RBC membranes.
is stabilized. Yet the binding of the antibody is drug dependent. Such a Binding of the drug to membranes of intact RBCs is inhibited by RBC
three-reactant interdependent “troika” is unique to this mechanism of superoxide dismutase and probably by hemoglobin. 225,226 Although not
immune cytopenia. formally demonstrated, these drugs probably bind to membrane anti-
The foregoing discussion depicting drugs as creating a “self + gens of cells that are relatively hemoglobin free, for example, cells at the
non-self” neoantigen on the target cell applies to the effector phase early proerythroblast stage or RBC stroma. In any case, the resulting
as opposed to the induction phase of the process. However, the same altered membrane antigens then may induce autoantibodies. The con-
drug-binding membrane protein appears to be involved in forming the cept that a drug–membrane compound neoantigen could lead to pro-
immunogen that induces the antibody, as evidenced by drug-dependent duction of an autoantibody is supported by studies of patients receiving
antibodies exhibiting selective reactivity with defined red cell alloanti- drugs unrelated to α-methyldopa. Patients simultaneously developed a
gens (carrier specificity). 58,84,217–219 How this process is accomplished in drug-dependent antibody and an autoantibody, both of which showed
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the absence of evidence for strong, covalent binding of the drugs in this specificity for the same RBC alloantigen. Another hypothesis is that
group to a host membrane protein remains to be elucidated. α-methyldopa interacts with human T lymphocytes, resulting in loss of
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RBC destruction by this mechanism may occur intravascularly suppressor cell function. Subsequent studies, however, have failed to
after completion of the whole complement sequence, resulting in demonstrate any evidence for such a mechanism. 228
hemoglobinemia and hemoglobinuria. Some destruction of intact C3b- Patients with CLL treated with the purine analogues fludara-
coated RBCs may be mediated by splenic and liver sequestration via the bine 88,229,230 or cladribine may develop AHA. Risk factors for hemolysis
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C3b/C3bi receptors on macrophages. The DAT is positive usually only include previous therapy with a purine analogue, high β -microglobulin,
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with anticomplement reagents, but exceptions occur. Sometimes, how- a positive DAT prior to therapy, and hypogammaglobulinemia. Purine
ever, the drug-dependent antibody itself can be detected on the RBCs analogues are potent suppressors of T lymphocytes. These drugs may
if the offending drug (or its metabolites) is included in all steps of the accelerate the preexisting T-cell immune suppression that normally
antiglobulin test, including washing. 222 occurs during progression of CLL, exacerbating the underlying ten-
Autoantibody Mechanism A variety of drugs induce the forma- dency to autoimmunity in CLL. However, the degree of depletion
tion of autoantibodies reactive with autologous (or homologous) RBCs of T-cell subsets is similar in patients who develop hemolysis and in
in the absence of the instigating drug (see Tables 54–2 and 54–3). The patients who do not.
most studied drug in this category has been α-methyldopa, an antihy- Nonimmunologic Protein Adsorption Less than 5 percent of
pertensive agent that no longer is commonly used. 73–76 Levodopa and patients receiving cephalosporin antibiotics develop positive antiglob-
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several unrelated drugs also have been implicated. 39,46,59,61,68,77–86 Patients ulin reactions as a result of nonspecific adsorption of plasma proteins
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with CLL treated with pentostatin, fludarabine, or cladribine are to their RBC membranes. 93,94,231 This process may occur within 1 to
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particularly predisposed to autoimmune hemolysis, which usually is 2 days after the drug is instituted. Multiple plasma proteins, including
severe and sometimes fatal. immunoglobulins, complement, albumin, fibrinogen, and others, may
Positive DAT reactions (with anti-IgG reagents) in patients taking be detected on RBC membranes in such cases. 231,232 Hemolytic ane-
α-methyldopa vary in frequency from 8 to 36 percent. Patients taking mia resulting from this mechanism has not been reported. The clinical
higher doses of the drug develop positive reactions with greater fre- importance of this phenomenon is its potential to complicate cross-
quency. 73,75,76 A lag period of 3 to 6 months exists between the start of match procedures unless the drug history is considered. Cephalospo-
therapy and development of a positive antiglobulin test. The delay is not rin antibiotics also may induce RBC injury by the hapten mechanism,
shortened when the drug is administered to patients who previously by the ternary complex mechanism, and by the autoantibody mecha-
had positive antiglobulin tests while taking α-methyldopa. 75 nism. The latter reactions are more serious but apparently occur less
In contrast to the frequent observation of positive antiglobu- frequently than nonimmunologic protein adsorption.
lin reactions, less than 1 percent of patients taking α-methyldopa
exhibit hemolytic anemia. Development of hemolytic anemia does CLINICAL FEATURES
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not depend on drug dose. The hemolysis usually is mild to moderate
and occurs chiefly by splenic sequestration of IgG-coated RBCs. α- WARM-ANTIBODY AUTOIMMUNE HEMOLYTIC
Methyldopa has been proposed to suppress splenic macrophage func-
tion in some patients, and normal survival of antibody-coated RBCs in ANEMIA
such patients may be related, in part, to this effect of the drug. 223 Presenting complaints of warm-antibody AHA usually are referable to
The DAT reaction usually is positive only for IgG. Occasionally, the anemia itself, although occasionally jaundice is the immediate cause
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weak anticomplement reactions also are encountered. Patients with for the patient to seek medical advice. Symptom onset usually is slow
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