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Methyldopa-induced Autoantibodies

Against Red Blood Cells

W. G. Murphy, J. G. Kelton

SUMMA R Y. Methyldopa therapy results in the formation of red cell autoantibodies in lO-20%
of patients taking the drug for longer than 4 months. These red cell antibodies are true
autoantibodies, that is they are directed against an autoantigen on the red blood cell membrane and
not against the drug or against a drug-altered antigen. The target membrane antigen is usually
within the Rhesus system, although often the antibody specificity cannot be defined. Red cell
antibody is usually detectable in the patient’s sera as well as on the red cells. The autoantibody is
usually a warm reacting IgG antibody. Most patients who develop these autoantibodies do not go
on to develop hemolytic anemia in spite of high titres of antihodies on their red cells. In addition,
these patients do not tend to develop hemolysis if methyldopa therapy is continued. Rarely patients
develop hemolytic anemia which can be severe. Differences in antibody characteristics, including
subclass restriction, complement-binding ability, or titre do not explain why some patients with
autoantibody hemolyze while most do not. One group of investigators found that hemolyzing
patients had IgM on their red cells while those who did not had IgG only. But while this
observation could explain why some patients (IgM-sensitized red cells) hemolyze, it does not
explain why most patients with IgG-sensitized red cells do not hemolyze.
Why the autoantibody forms is not known but some investigators have proposed that the drug
may directly affect B or T cells with resulting impairment of immune tolerance. It is also possible
that an impairment of reticuloendothelial ceU function described in some methyldopa patients could
explain the unique combination of immunological disorders induced by this drug.

Three major problems remain to be solved in the (3) why does it take so long (usually 4 months) for the
story of methyldopa-induced red cell autoantibodies. autoantibody to develop after the start of drug
(1) How does the drug induce red cell autoantibody in therapy?
l&20% of those who take the drug for longer than 4 In this review we will present an overview of what is
months?; (2) why do only a small fraction of these known about methyldopa-induced autoimmune he-
patients have hemolysis while most patients have molytic anemia, what theories have been proposed to
normal red cell lifespans in spite of abnormally high answer the questions posed previously, and what
concentrations of IgG on the red cell surface?; experimental evidence has been advanced in support
of these theories.
Alpha-methyldopa (L-cl-methyl-3,4, dihydroxyphe-
nylalanine) (Fig. 1) was introduced as an antihyper-
tensive agent in 1960. It exerts its antihypertensive
W. G. Murphy, Ml3 MRCP, (UK), J. G. Kelton, MD, Depart- effect through a central mechanism.’ With the intro-
ments of Medicine and Pathology, McMaster University Medical
Centre and the Hamilton Centre of the Canadian Red Cross Blood duction of other hypotensive agents its use has de-
Transfusion Service, Hamilton, Ontario, Canada. clined; however, it continues to be widely used. Many

Blood Reviews (1988) 2, 3-2


Q 1988 Longman Group UK Ltd
BLOOD REVIEWS 37

unwanted effects have been reported. These include to these mechanisms, the antibody of methyldopa-
fever, skin lesions and diarrhea,2 as well as more induced hemolysis is not directed against the drug but
serious side effects such as autoimmune hemolytic against an antigen on the red cell membrane. Other
anemia,3 hepatitis,4 myocarditis,5 thrombocyto- drugs have been reported to give rise to a similar
penia,6 platelet function defects,‘,’ lupus-like syn- autoimmune hemolytic anemia: L-dopa, mefenamic
drome,‘*” central nervous system abnormalities,’ acid, phenacetin, chlorpromazine, ibuprofen,13 and
abnormalities of lipids and glucose” and autoanti- procainamide.’ 3~16 The cell antibodies in methyl-
bodies against factor VIII.” dopa-induced autoimmune hemolytic anemia do not
Methyldopa gives rise to two distinct immunologi- activate complement (described in the next section):
cal abnormalities of red cells. These are (1) methyl- the IgG-coated cells are removed by the Fc receptors
dopa-induced autoimmune hemolytic anemia and (2) of the reticuloendothelial cells, especially those in the
a positive direct antiglobulin test without hemolysis. spleen.
Although these two conditions share many similari-
ties, there is little clinical overlap--patients who do
Characteristics of the Red Cell Autoantibody
not hemolyze at presentation usually do not develop
hemolysis later. In the following sections, these two Methyldopa-induced hemolytic anemia is usually of
disorders will first be considered separately; we will the ‘warm’ type, and almost always of the IgG class.
then discuss the pathophysiological mechanisms that Rarely, exceptions occur: IgM warm-reacting comple-
distinguish between them and the implications of this ment-fixing antibodies have been reported in autoim-
distinction for our understanding of the reticuloendo- mune hemolytic anemia associated with methyldopa
thelial system. in two reports. “J * IgA antibodies were described in
one patient.’ Et
Several studies suggested that the subclass of IgG
Methyldopa-induced Autoimmune Hemolytic
involved in methyldopa-induced autoimmune hemo-
Anemia
lytic anemia was limited to IgG 1 or IgG 1 and
Incidence 3. 19*20,21However, such studies are dependent upon
the quality of the anti-IgG preparations used to detect
Methyldopa is the drug most commonly implicated in
the IgG subclasses. In a more recent report, all four
drug-induced immune hemolytic anemia. l3 The
subclasses of IgG were found on the red cells of
chance of developing hemolytic anemia for patients
patients with the disease.”
taking methyldopa has been estimated to range from
The IgG antibodies in this disease do not deposit
0.02% to o.8%.3.‘4,‘5
complement on the red cell membrane in high concen-
trations.‘4*22 The reasons for this are uncertain. In a
Mechanism of Hemolysis majority of cases, the autoantibody is directed against
an Rh antigen on the red cell membrane (described
Methyldopa induces immune hemolytic anemia via
subsequently). Characteristically, Rh antibodies do
autoimmune red cell antibodies. This is in direct
not activate complement. It is possible that this is due
contrast to other more ‘typical’ drug-induced immune
to the low density of antigenic sites on the red cell
hemolytic anemias. In these disorders an antidrug
membraneZ3 reducing the likelihood of achieving a
antibody forms and the drug-antibody complex binds
sufficiently high concentration of IgG necessary for
directly to the red cell membrane or deposits comple-
complement deposition.
ment on the red cell surface. Quinidine and quinine
result in drug-induced hemolysis via complement
activation. In contrast, penicillin is an example of The Red Cell Membrane Target Antigen in
drug-induced immune hemolysis in which the drug Methyldopa-induced Autoimmune Hemolytic Anemia
binds to the red cell membrane and antidrug IgG in (the SpeciJicity of the Autoantibody)
turn binds to the cell surface. Subsequently, the red
In many cases the specificity of the antibody cannot
cell is cleared through Fc receptors on reticuloendo-
be determined. Since antibody specificity is studied by
thelial cells. These various mechanisms of immune
observing the reactions of test sera with cells lacking
hemolysis have been recently reviewed.13 In contrast
known antigens (e.g. Rh,,ii cells), determination of
antibody specificity depends upon having cells that
y2 lack the target antigen. When the antigen is ‘public’,
that is, present on the cells of almost all donors in a
CH,-y-COOH population, it may be virtually impossible to identify
the target antigen by these ‘negative’ methods.
Where it has been characterized, the most common
CH3 specificity of autoantibody is against the antigens in
the Rhesus system.3*20,24*25 Much less commonly
reported target antigens are Wrb,25 Jk”,26 and U.27
Fig. 1 The structure of a-methyldopa. The proportion of cases in which the antibody is
38 METHYLDOPA-INDUCED AUTOANTIBODIES AGAINST RED BLOOD CELLS

directed against an antigen within the Rhesus system occur. Possible explanations for why some patients
varies from 6 out of 6” to 10 out of 33.25 In some hemolyze and others do not will be discussed later in
cases the antibody has specificity for more than one this report.
antigen.22’28
Clinical Course
Clinical Course of Methyldopa-induced
Those patients who have a positive antiglobulin test
Autoimmune Hemolytic Anemia
without hemolysis usually do not develop hemolysis if
Hemolysis due to methyldopa is always autoantibody the drug is continued. In fact, the autoantibody can
mediated, and is always extravascular in type. This spontaneously disappear. 11*33
condition is relatively uncommon and it arises in less
than 1% of patients taking the drug.3 It can occur in
Treatment
those taking less than 1 gm/day, but there appears to
be an increasing frequency of autoantibody formation For most patients who have methyldopa-induced
with increasing drug dosage.22p2g The onset is slow. It autoantibodies, but who are not hemolyzing, no
can occur by 3 months after starting the drug2’ and treatment is required. Usually it is acceptable to
has arisen as late as 4 years after therapy began.14 continue the drug. However, deciding to continue
The hemolysis can be severe and deaths have occur- methyldopa therapy in a patient with positive direct
red.30 antiglobulin test who is not hemolyzing requires that
the following be considered: the positive indirect
antiglobulin test will interfere with crossmatching,
Treatment of Methyldopa-induced Hemolytic Anemia
should the patient require blood transfusions. This
Stopping of methyldopa therapy usually results in a could add to the risk of the transfusion. The autoanti-
rapid resolution of the hemolysis;‘3 however, it can body will not shorten the life of the transfused red
take many months before the direct antiglobulin test cells (provided it does not hemolyze the patient’s own
(DAT) becomes negative. Corticosteroids may speed cellist), but it could obscure clinically relevant allo-
the recovery,3*10*14 but controlled trials are lacking antibodies in the crossmatch. However, the use of
and it is not possible to know if this therapy is additional techniques such as autoabsorption of the
beneficial. On rare occasions blood transfusions may autoantibody allows accurate crossmatching to be
be required. Although no evidence is available at performed in almost all cases.
present, high dose intravenous IgG should be con-
sidered in patients with severe hemolysis since the
Pathophysiology of the Immunological
hemolysis is mediated via the Fc receptors on macro-
Abnormalities Associated with Methyldopa
phages. Consequently, blocking these receptors with
intravenous IgG could diminish red cell destruc- The clearance from the circulation of a particle or cell
tion.31 The re-introduction of methyldopa is con- foreign to the body can be effected by three mechan-
traindicated, since the autoantibody may redevelop.2g isms. (1) The particle is coated with immunoglobulin,
especially IgG, with or without C3b. These red cell-
bound proteins bind to specific receptors on the
reticuloendothelial cells, particularly those in the
Methyldopa-induced Positive Direct spleen and liver; (2) the complement cascade is com-
Antiglobulin Test Without Hemolysis pleted through either the classical or the alternate
Incidence pathways, resulting in the intravascular destruction of
the cells; (3) circulating reticuloendothelial cells with
Although less than 1% of patients receiving methyl- receptors for the Fc portion of IgG, or cells with
dopa therapy develop hemolysis, lO-20% of those natural killer activity, destroy the sensitized cells
taking the drug for longer than 3-6 months will intravascularly. Only the first of these three pathways
develop a positive direct antiglobulin test, indicating causes the red cell destruction in patients with methyl-
abnormally high concentrations of IgG bound to the dopa-induced autoimmune hemolytic anemia.
surface of their red cells. Of these, 60% will also have In general, complement is not activated by the
a positive indirect antiglobulin test,32 indicating that methyldopa-induced autoantibody, and the red cells
red cell autoantibodies are present in their serum. are destroyed by the tissue reticuloendothelial cells
following the binding of the opsonized red cells to the
Fc receptors of the reticuloendothelial cells. Thus
Characteristics of the Red Cell Autoantibody
there are two major steps in this system of immune
The IgG red cell autoantibody in those patients destruction. (1) The production of specific antibody
without hemolysis is the same as the autoantibody in and, (2) the destruction of the antibody-sensitized red
those patients with hemolysis. In particular (a) all cells by the reticuloendothelial cells. Abnormalities of
four subclasses of IgG are represented; (b) the specifi- both of these components have been described in
city is the same; (c) complement binding does not patients with methyldopa-induced autoantibodies. In
BLOOD REVIEWS 39

the next sections we first consider the question: why Why Do Most Patients Who Develop Methyldopa-
do some patients taking methyldopa develop red induced Red Cell Autoantibodies not Hemolyze?
blood cell antibodies? Next, we discuss theoretical
It is far more likely for a patient taking methyldopa to
reasons why some patients hemolyze and others do
form red cell autoantibodies and not to hemolyze,
not. Last, the function of the reticuloendothelial
than to form the autoantibodies and to hemolyze.
system in patients treated with methyldopa will be
Approximately 1@20% of patients who receive me-
discussed.
thyldopa for longer than 3-6 months will develop a
positive direct antiglobulin test. But, as noted pre-
Why Do Some Patients Taking Methyldopa Develop
viously, less than 1% of these patients will have
Red Cell Autoantibodies?
clinical or laboratory evidence of increased red cell
Several theories have been proposed to explain the destruction. This issue is not just of biological in-
formation of methyldopa-induced red blood cell terest: the understanding of why some patients have
autoantibodies. These include the following: antibody sensitizing their red cells but do not destroy
these red cells could have therapeutic implications in
Altered Red Cell Membrane. It has been suggested the management of patients with autoimmune dis-
that methyldopa alters the red cell membrane, result- orders. We will briefly list possible reasons why
ing in the formation of a neoantigen on the cell patients with autoantibodies on their red cells might
surface. These antigens are the targets of the autoan- not have hemolysis and summarize some of the
tibody. 3,20 Such a mechanism would imply that me- studies addressing these various issues.
thyldopa initially binds to and subsequently alters
the red cell membrane. Although one group of inves-
tigators did report binding of methyldopa to red Characteristics Of The Autoantibody
cells,35 others were unable to demonstrate this phe- DiJerences in antibody class. The direct antiglobulin
nomenon.20 Another group of investigators reported test gives an approximate estimate of the amount of
that the drugs glafenine and latamoxef induced auto- IgG or complement on the surface of red cells.
antibody formation which developed in conjunction However, this measure is very inexact and it is
with drug antibodies and that the autoantibodies possible that the precise amount of autoantibody on
were directed against the drug-binding sites on the red cells is not strictly comparable in patients with
red cell membrane.36 These observations were inter- methyldopa-induced IgG autoantibodies that are as-
preted to support a hypothesis that drug-membrane sociated with hemolysis and those that are not associ-
binding was the initial event for some drug-induced ated with hemolysis. Furthermore, IgM is far more
immune hemolytic disorders. This theory does not efficient than IgG at complement activation. Conse-
explain why the autoantibody persists long after quently, if patients had IgG plus small amounts of
the drug has been stopped and presumably cleared IgM on their red cells, one would anticipate a much
from the body. It also fails to explain why sera or more rapid red cell destruction than if the patient had
the IgG fraction alone reacts with normal red cells IgG alone on the red cells. To address this issue,
without the presence of the drug. Finally, this theory Lalezari and associates used an auto-analyzer to
does not explain the more general autoimmune phe- estimate semi-quantitatively the amount of IgG and
nomena associated with methyldopa where many IgM on red cells from patients with positive DAT
other cells or proteins become the target of autoanti- tests associated with methyldopa therapy.’ 7 These
bodies. investigators found that 8 of 11 patients with positive
DAT tests had both IgM and IgG autoantibodies on
Spontaneous Formation of Autoantibodies. Methyl-
their red cells. All of these patients had evidence of
dopa could directly affect B-lymphocytes allowing the
hemolysis. The three patients with IgG only on their
proliferation of autoantibody-producing cell lines.37
red cells did not have hemolysis. These investigators
Kirtland and coworkers demonstrated that methyl-
postulated that these findings explained why only this
dopa caused a sustained elevation in cyclic-AMP
subset of patients with methyldopa-induced autoanti-
concentrations in lymphocytes3’ This effect induced
bodies had hemolysis, i.e. these patients with both
an inhibition of T-cell proliferation with diminished
IgG and IgM autoantibodies had two mechanisms of
suppressor cell maturation and activation. They pro-
cell destruction making hemolysis more likely to
posed that the resultant loss of suppressor function
occur. However, this study does not answer why those
allowed unregulated autoantibody production by
patients with ZgG only on their red cells did not
B-cells. These theories could explain many of the
hemolyze. The results of this study await confirma-
serological observations. Unfortunately, other groups
tion by other investigators.
of investigators were unable to confirm these
studies.39*40 Thus this most important issue remains Differences in the subclass of the autoantibody. The
unresolved. direct antiglobulin test provides a relative estimate of
As yet no satisfactory explanation has been pro- the amount of IgG on red cells. However, it does not
posed to explain why it takes over 3 months for the give information about the spatial orientation of the
autoantibody to appear. antibody: whether it is clustered on certain membrane
40 METHYLDOPA-INDUCED AUTOANTIBODIES AGAINST RED BLOOD CELLS

proteins, or whether the antigen-antibody complexes likely to clear IgG-sensitized cells than are patients
are mobile within the red cell membrane. Neither does with a less active reticuloendothelial system. This
it provide information on the subclass of the anti- concept is illustrated schematically in Figure 2. The
body. All of these factors could affect the rate of functional activity of the reticuloendothelial cell sys-
clearance of IgG sensitized red cells. Indeed, there is tem can be studied either in vitro or in vivo. In vitro
evidence that IgG subclasses 2 and 4 interact weakly studies are performed by separating reticuloendothe-
with the Fc receptors on the reticuloendothelial cells; lial cells (usually monocytes) from peripheral blood
therefore, if certain methyldopa-induced autoanti- and then studying their function. Such studies have
bodies were primarily subclasses 2 and 4, then been criticized because the cells that are collected, the
hemolysis would not occur. In contrast, those autoan- circulating reticuloendothelial cells, are probably less
tibodies mostly comprised of IgG subclasses 1 and 3 important than the tissue-bound cells of the reticulo-
would cause hemolysis. This issue has been investi- endothelial system for the clearance of anti-
gated by a number of investigators and although body-sensitized cells and particles. Furthermore, the
some have proposed that patients who did not have isolation and processing of these cells may alter their
hemolysis were more likely to have IgG subclasses 2 function. Nonetheless, some in vitro reticuloendothe-
and 4 1g*20*21recent studies have shown that the lial studies have provided new and useful informa-
autoantibody consists of all subclasses of 1gG.l’ tion. Branch and associates42 studied monocytes and
macrophages collected from the peripheral blood of
The amount of autoantibody. Because the direct
patients receiving methyldopa and found that the
antiglobulin test is semi-quantitative at best, investi-
circulating monocytes of the hemolyzing patients, but
gators have suggested that those patients who have
not of the non-hemolyzing patients, phagocytosed the
methyldopa-induced autoimmune hemolysis have
DAT positive red cells in vitro. Other investigators
more IgG on their red cells compared to those
have reported similar findings.‘g,43
patients who have autoantibody but no hemo-
Reticuloendothelial function can also be studied in
lysis. 3~1g*33,41However, there do not appear to be
vivo. This is accomplished by measuring the rate of
major quantitative differences in the amount of auto-
clearance of radiolabelled autologous red cells which
antibody on the red cells from these two groups of
have been heat damaged (to measure the sieving
patients, making this an unlikely explanation.
capacity of the reticuloendothelial system) or sensi-
tized by alloantibodies. This latter manoeuvre allows
Reticuloendothelial Function in Patients with one to study the Fc component of the reticuloendothe-
Methyldopa-induced Red Cell Immunological lial system, i.e., the ability of monocytes and macro-
Abnormalities phages to remove IgG sensitized cells. One group of
investigators performed this type of study in patients
It is important to remember that the type and amount
treated with methyldopa. 44 The reticuloendothelial
of autoantibody, its subclass and its membrane mo-
clearance studies from these studies demonstrated the
bility represent only one-half of the cell clearance
following: (a) in one patient with methyldopa-induced
equation: the other being the functional integrity of
autoantibodies who had hemolysis, the reticuloendo-
the reticuloendothelial system. For example, patients
thelial system was normal; (b) in several patients who
with a very active reticuloendothelial system are more
had methyldopa-induced red cell autoantibodies, but
who did not have hemolysis, the activity of the
tXTERMlNANK OF CELL CLEARANCE
reticuloendothelial system was markedly impaired; (c)
in several patients treated with methyldopa, who did
not have red cell autoantibodies, the reticuloendothe-
Sasitimtii
lial system also was impaired. These studies suggest
that in patients with methyldopa-induced red cell
autoantibodies, the absence of hemolysis is caused by
drug-induced impaired Fc-dependent reticuloendo-
thelial function. The demonstration of impaired reti-
culoendothelial function in several patients who did
not have autoantibodies suggests that the drug itself is
responsible for the impaired reticuloendothelial func-
tion. Indirectly, this supports the concept that drug-
RE Cdl Fuxtim induced autoantibody production is independent of
Easily Mcasvsd DMkllltteMaarc drug-induced impaired reticuloendothelial function.
Consequently, one can propose a number of different
Fig. 2 A schematic representation of some of the determinants
of red cell clearance. The amount of immunoglobulin (usually
scenarios. In most patients, methyldopa does not
IgG) or complement on a cell is easily measured and produce autoantibodies nor does it impair reticuloen-
consequently most biological models of cell clearance focus on dothelial function: such patients would not have
these cell-specific factors. Reticuloend~helial function probably
is just as important in cell clearance, but because it usually has
hematological consequences. In other patients, the
not been assessed, its contribution tends to be overlooked. drug impairs reticuloendothelial function but does
BLOOD REVIEWS 41

not initiate autoantibody formation, again a clinically alphamethyldopa-induced hemolytic anemia: correlation
undetectable event. In some patients, autoantibodies between cell-bound IgM and hemolysis. Blood 59: 61-68
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42 METHYLDOPA-INDUCED AUTOANTIBODIES AGAINST RED BLOOD CELLS

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