Treatment of Autoimmune Hemolytic Anemia

Karen E. King and Paul M. Ness

The appropriate therapy of autoimmune hemolytic anemia (AIHA) is dependent on the

correct diagnosis and classification of this family of hemolytic disorders. Although the
majority of cases are warm AIHA, there are several distinct types of cold AIHA and a
number of drug-induced etiologies of AIHA, which must be investigated to determine if
stopping a drug will induce a remission. In warm AIHA, corticosteroids are standard,
followed by consideration of splenectomy in recalcitrant cases. If steroids and splenectomy
are insufficient, other forms of immunosuppressive therapy are typically initiated. In cold
AIHA, keeping the patient warm in often sufficient, but therapy directed at an underlying
lympholiferative disorder may be helpful. Brisk hemolysis, inadequate responses to ther-
apy, and worsening anemia require transfusion therapy. Although the pretransfusion
workup is made difficult by the presence of the autoantibody, transfusion services can
usually provide blood safe for transfusion by excluding underlying alloantibodies. When
transfusion is urgently required and compatible blood cannot be located, incompatible
blood may be provided as a life-saving measure. Communication between the transfusion
service and the hematologist is critical to assess the risks in these settings. Hemoglobin-
based oxygen carriers may provide an important bridging therapy in the future. Requests for
least incompatible blood do not enhance transfusion safety and often result in unneces-
sary delays.
Semin Hematol 42:131-136 2005 Elsevier Inc. All rights reserved.

A utoimmune hemolytic anemia (AIHA) can be classified

into two major types on the basis of the in vivo and in
vitro characteristics of the causative autoantibody: those as-
sociated with warm antibodies, reacting optimally at 37C,
and with cold antibodies, reacting optimally at 0 5C. The
AIHAs associated with cold antibodies can be further subdi-
vided into the more common cold agglutinin syndrome and
the rare paroxysmal cold hemoglobinuria (PCH). Both the
warm and cold types of AIHA can be idiopathic, or secondary
to infection or diseases such as leukemia or systemic lupus
erythematosus.
The diagnosis of AIHA is usually made on the basis of both
clinical findings and laboratory results of a peripheral blood
smear, the direct antiglobulin test (DAT), eluate studies, and
indirect antiglobulin tests. A peripheral blood smear reveals
anisocytosis with microspherocytes. Polychromatophilia is
often seen, indicating bone marrow compensation. In cold
agglutinin syndrome, agglutination may be prominent on the
peripheral smear. The DAT using anti-IgG and anti-C3 (C3d)
will detect the presence of IgG and/or complement coating
Transfusion Medicine Division, Johns Hopkins Medical Institutions, Balti-
more, MD.
Address correspondence to Paul M. Ness, MD, Transfusion Medicine Divi-
sion, Johns Hopkins Medical Institutions, Baltimore, MD 21287-6667.
the red blood cells (RBCs). Eluate studies, testing the auto-
antibody dissociated from the patients RBCs against a panel
of RBCs, typically reveal a panagglutinin. In the indirect an-
tiglobulin test, the patients serum is tested against untreated
and enzyme-treated RBCs at 20C and 37C; tests are read for
hemolysis and agglutination. Such a battery of assays will
delineate whether the antibody is an agglutinating and/or
sensitizing antibody and define its hemolytic potential.
Results can be combined with the clinical and hematologic
findings to classify the patient. Sometimes more specific test-
ing must be performed, such as a cold agglutinin titer and
thermal range for cold agglutinin syndrome, a Donath Land-
steiner test for PCH, adsorption procedures to differentiate
alloantibody from autoantibody, serum and eluate studies
investigating the specificity of the autoantibody, and assess-
ment for drug-associated antibodies. These results allow clas-
sification into warm AIHA, cold agglutinin syndrome, or
PCH (Table 1).
Occasionally, unusual patients may not be classifiable into
one of the three types of AIHA. Some have mixed-type AIHA,
a combination of warm and cold type AIHA1; they may have
the classical serologic features of both: IgG and complement
on RBCs and a high-titer IgM cold antibody together with an
IgG warm autoantibody in the serum, or IgG and C3 on the
RBCs with low-titer IgM cold autoagglutinins of high thermal

0037-1963/05/$-see front matter 2005 Elsevier Inc. All rights reserved. 131
doi:10.1053/j.seminhematol.2005.04.003
132 Treatment of autoimmune hemolytic anemia

Table 1 Classification and Typical Serologic Features of the Autoimmune Hemolytic Anemias
Warm Autoimmune Cold Agglutinin Paroxysmal Cold
Hemolytic Anemia Syndrome Hemoglobinuria
Direct antiglobulin test IgG, IgG and C3 C3 only C3 only
Immunoglobulin class IgG (sometimes IgA) IgM IgG
Eluate IgG Nonreactive Nonreactive
Serum IgG antibody reacting IgM agglutinating IgG biphasic hemolysin
with most, or all, RBCs antibody, often with (Donath-Landsteiner
at the antihuman titers >1,000, reacting antibody)
globulin phase at 30C in albumin
Specificity Rh I, i P

range in the serum. Another group of unusual patients with The basis of the clinical response to corticosteroids is prob-
hemolytic anemia has all the clinical and hematologic fea- ably multifactorial. Steroids have been shown to have an early
tures of warm AIHA present with a negative DAT and no effect on tissue macrophages, so that IgG- and C3-coated
detectable serum antibodies so-called Coombs negative RBCs are not cleared as rapidly by the reticuloendothelial
AIHA.2 More sensitive assays, such as the enzyme-linked an- system (RES); this activity can be demonstrated within the
tiglobulin test or the radiolabeled antiglobulin test, may be early days of therapy.4 Another mechanism by which corti-
necessary to identify RBC-bound IgG in these cases. costeroids act in AIHA is to alter antibody avidity.5 Several
weeks of therapy are usually required before a third mecha-
nism, decrease in antibody production, is observed. Among
Therapeutic adults, permanent remission of AIHA occurs in approxi-
Approaches to AIHA mately 20% to 35% of patients.6 Consequently, additional
therapy is generally required for the initial presentation or the
Corticosteroids relapses that are common in warm AIHA.
For warm AIHA, corticosteroids are the initial therapy of
choice and the mainstay of therapy (Table 2). Many hematol-
ogists use a standard approach in adults, consisting of an
Splenectomy
initial course of prednisone, 60 to 100 mg per day for 1 to 3 Approximately 50% of patients will have a complete initial
weeks. There should be some evidence of clinical improve- response to splenectomy, although patients may continue to
ment within several days to 1 week. Approximately 80% of require low doses of prednisone (15 mg/d) to maintain
patients have a good initial response to corticosteroid thera- adequate hemoglobin levels.7 Late relapses are not uncom-
py.3 After stabilization of hematologic parameters or the mon, presumably due to enhanced antibody synthesis and
elimination of the requirement for transfusion support, the increased hepatic sequestration after the spleen, the primary
dosage of steroids may be gradually tapered. If a relapse oc- location of RES destruction, is removed.8
curs, the dose is often increased to produce another clinical Patients who have had a splenectomy need to be educated
remission. Most clinicians consider a maintenance dose of about the risks of overwhelming postsplenectomy sepsis syn-
prednisone of greater than 15 mg per day to represent a drome. This entity is often due to infections with encapsu-
therapeutic failure. To reduce the side effects of chronic ste- lated bacteria. This is a medical emergency since patients may
roid administration, many clinicians will attempt to treat the rapidly progress from an apparent flu-like illness to bactere-
steroid-dependent patient on an alternate-day schedule. mic shock. The risk of overwhelming postsplenectomy sepsis
syndrome has been quantitated as 3.2% with a mortality rate
of 1.4%.9 The risks of both infection and mortality can be
Table 2 Therapy for Autoimmune Hemolytic Anemia reduced by the use of pneumococcal and meningococcal vac-
cines. Prophylactic antibiotic regimens are controversial;
Warm
however, many advocate the use of penicillin, or tri-
Autoimmune Cold Paroxysmal
methoprim-sulfamethoxazole as an alternative. Febrile ill-
Hemolytic Agglutinin Cold
Anemia Syndrome Hemoglobinuria nesses in these patients must be given prompt attention and
antibiotics should be started rapidly.
Corticosteroids Avoidance of Supportive care
cold
Splenectomy Cytotoxic drugs Other Immunosuppressive Therapy
Immunosuppression Rituximab Several immunosuppressive agents have been reported to be
Danazol Plasma exchange successful in the treatment of warm AIHA, but in a literature
IVIg of case reports and small series of patients. The unfortunate
High-dose paucity of randomized therapeutic trials makes it difficult to
cyclophosphamide determine which immunosuppressive drugs and what doses
therapy
should be employed for patients who have failed initial ther-
K.E. King and P.M. Ness
apy with corticosteroids and splenectomy. Immunosuppres-
sive regimens should be considered when conventional ther-
apy has failed or cannot be tolerated as in (1) the patient who
fails to respond to splenectomy or relapses after the spleen
has been removed; (2) when splenectomy represents an un-
acceptable medical risk; and (3) for the patient who cannot
tolerate corticosteroid therapy.
Azathioprine, cyclophosphamide, and other single agents
have been effective in warm AIHA.10 However, their adverse
effects can be limiting, including gastrointestinal intolerance,
hemorrhagic cystitis, and bone marrow suppression.
Several case reports describe the successful use of cyclo-
sporine in warm AIHA,11 but results overall have been mixed.
Cyclosporine has nephrotoxicity and must be used with cau-
tion in patients with renal failure and kidney function should
be closely monitored in all patients.
Mycophenolate mofetil is now frequently used to prevent
kidney allograft rejection and to treat other autoimmune con-
ditions. A few case reports show efficacy of this drug in warm
AIHA, and mycophenolate is worthy of further evaluation in
clinical trials.12
High-dose cyclophosphamide (50 mg/kg/d for 4 days) fol-
lowed by granulocyte colony-stimulating factor has been ef-
fective in patients with refractory AIHA and other chronic
autoimmune diseases that have not responded to less aggres-
sive forms of conventional therapy.13 Early studies have
achieved complete remission in the majority of patients and
partial remission in others, but long-term evaluation will be
required to assess cyclophosphamides role in warm AIHA.
Rituximab is a genetically engineered chimeric murine/
human monoclonal anti-CD20 antibody which targets B-cell
precursors and mature B cells. Plasma cells do not carry the
CD20 antigen. The reported success of rituximab has not
been limited to warm AIHA secondary to B-cell neoplasms.
Rituximab has induced complete remissions in some patients
with idiopathic warm AIHA, including in refractory disease
and in children.14 The typical dosing regimen of rituximab
for this indication is 375 mg/m2, once a week for 2 to 4
weeks. One series of 15 patients showed continuous remis-
sion in 10 patients, relapse after remission in three cases, and
failure to respond in two others.
Warm AIHA is similar in many aspects to the more com-
mon autoimmune thrombocytopenic purpura (ITP), and
there are increasing different immunosuppressive therapies
that are being evaluated for ITP. It is likely that single agents
or therapeutic regimens combining drugs that prove useful in
refractory ITP later will be evaluated in AIHA, but the oppor-
tunities for large evidence-based clinical trials of these agents
will be limited by the lower number of AIHA patients.
Additional Therapies for Warm AIHA
Danazol, an attenuated androgen, has been successful in the
treatment of some cases of warm AIHA.15 In this clinical
setting, its mechanism of action is uncertain.
Because of the experience for intravenous immunoglob-
ulin (IVIg) in ITP, it was predicted to be rewarding in
warm AIHA; however, the literature is discouraging: there
133
are case reports of success and failure. The results are
probably incomplete and potentially misleading because
of the lack of controlled trials, use of IVIg in conjunction
with multiple other agents, and its application to the most
refractory cases.
Plasmapheresis has a temporizing measure and it is not a
practical approach for long-term management of AIHA. Plas-
mapheresis is often less efficient in treating diseases caused
by IgG antibodies such as warm AIHA than for syndromes
due to IgM antibodies because of the extravascular distribu-
tion of IgG antibodies and their rapid reaccumulation in the
blood after mechanical removal.
Treatment of Cold
Autoimmune Hemolytic Anemias
The mainstay of therapy for cold agglutinin syndrome is
avoidance of the cold (Table 2). Acute hemolytic crises can be
prevented if patients maintain a high temperature in their
indoor environment and wear additional clothing outdoors.
By diligent avoidance of the cold, many patients with cold
agglutinin syndrome can be managed without transfusions;
mild, compensated anemia may not require treatment for
prolonged periods of time or only episodic transfusions.
For more severe, partially compensated, idiopathic cold
agglutinin syndrome, medical therapy is generally unsatisfac-
tory, and corticosteroids are not efficacious in most. Splenec-
tomy is not usually effective because the liver is the dominant
site of sequestration of RBCs heavily sensitized with C3.
Chlorambucil has been used with some success but the asso-
ciated hematopoietic suppression can be limiting.16 In pa-
tients without underlying hematologic malignancy, ritux-
imab has been encouraging, but long-term evaluations of
more patients are needed. One study treated 27 patients with
primary chronic cold agglutinin disease with 37 courses of
rituximab and achieved complete remission in one course of
therapy, partial remission in 19, and no remission in 17
courses of therapy.17 These results are consistent with the
pathophysiology of cold agglutinins typically associated with
abnormal lymphocytic clones detected by flow cytometry,
even when bone marrow morphology fails to disclose a lym-
phoproliferative disease.
As with warm AIHA, plasmapheresis may be a temporizing
measure. Plasmapheresis is more likely to be successful in
cold agglutinin disease, since the typical antibody is IgM,
approximately 80% of IgM is in the intravascular space, and
it can be removed efficiently by plasmapheresis. Special at-
tention may be required to maintain the core body tempera-
ture at 37C, as with use of an in-line blood warmer.
PCH is an unusual form of cold AIHA that most commonly
occurs in children following a viral infection; therapy is gen-
erally supportive. Although many children may receive cor-
ticosteroids, they typically are already improving as the ther-
apy is initiated. The efficacy of corticosteroids for these
patients has not been established and their use cannot be
confidently recommended.
134
Table 3 Serologic Problems in AIHA
Alloantibody stimulated by previous transfusion or
pregnancy can be masked by autoantibody
All cross-matches may be incompatible due to
autoantibody
Positive DAT causes phenotyping problems
Transfusion Therapy for AIHA
Serologic Difficulties in AIHA
Transfusion therapy can be complicated in AIHA due to se-
rologic complexities (Table 3). Although AIHA may present
with an ABO and/or Rh typing discrepancy, accurate blood
group identification usually can be determined without spe-
cialized techniques. In an emergency or if ABO results are not
clear, group O donor RBCs are employed. Since the panag-
glutinin in the patients serum typically reacts with all donor
RBCs, cross-matching blood may be a difficult and time-
consuming process.
Patients with AIHA often are candidates for chronic trans-
fusion programs, and knowledge of the patients RBC pheno-
type, including Rh (C, E, c, e), Kell, Duffy, and Kidd blood
group antigens, may be useful. By dissociating autoantibody
from the patients RBCs, phenotyping procedures can be per-
formed. Aliquots of the patients untransfused RBCs can be
frozen for extended phenotyping later. The phenotype can be
used to guide the exclusion of alloantibodies by indicating
which antigen specificities the patient is at risk of developing.
The most important problem in a patient with a history of
previous pregnancies or multiple transfusions is detecting
and identifying an alloantibody that may be hidden by the
autoantibody.18 Sophisticated immunohematology laborato-
ries use a combination of techniques including differential
allogeneic adsorption and autoadsorption, to detect underly-
ing alloantibody.
Another difficult issue is transfusion of patients whose au-
toantibody demonstrates a specificity. Some cases of warm
AIHA can be shown to have Rh specificity, most often auto
anti-e, but is is unclear if e negative blood transfusions are
advantageous and result in improved erythrocyte survival, as
compared to antigen-positive blood.19 In cases of cold agglu-
tinin syndrome, the autoantibody often demonstrates speci-
ficity against I or i antigens, and auto anti-P is commonly
associated with PCH.
When compatible units cannot be located, many clinicians
request least incompatible blood with the hopes that addi-
tional safety will be provided. Such requests only serve to
delay needed blood transfusions and offer no additional pro-
tection to the patient.20 Of critical importance is that the
clinician and the transfusion medicine physician cooperate in
assessing and managing the transfusion needs in AIHA when
anemia is severe and progressing.
Many patients with AIHA require chronic transfusion sup-
port, but they may present occasionally with urgent transfu-
sion needs when a complete serologic evaluation can not be
performed. A recent study by Shirey et al21 evaluated an
algorithm of providing antigen-matched donor blood for pa-
Treatment of autoimmune hemolytic anemia
tients with warm autoantibodies: by determining the pa-
tients red cell phenotype, extensive serologic evaluation to
exclude underlying alloantibodies can be circumvented, al-
lowing blood to be safely and expeditiously provided.
Issues Complicating Transfusion Therapy
Blood transfusion may be required when AIHA presents with
fulminant hemolysis or for chronic hemolysis that becomes
symptomatic before a response occurs to primary therapy.
The presence of RBC autoantibody coating the patients RBCs
or appearing as a panagglutinin in the serum contributes to
the general risks of a blood transfusion (allergic and febrile
nonhemolytic transfusion reactions and transfusion-trans-
mitted infectious diseases). The autoantibody can make it
difficult to detect coexisting RBC alloantibodies, which can
cause severe hemolytic transfusion reactions; in addition, the
RBC autoantibody itself can increase destruction of donor
RBCs. Despite these concerns, transfusion may be required in
AIHA and it can be life-saving (Table 4). Conley et al docu-
mented a series of patients with AIHA and reticulocytopenia
despite intense erythroid hyperplasia in the bone marrow22:
in all five cases, transfusions were required as a life-sustaining
measure for profound anemia in patients transferred from
other hospitals, where transfusions had been withheld be-
cause of serologic incompatibilities. Reticulocytopenia per-
sisted from 4 to 160 days before the onset of adequate eryth-
ropoiesis or control of the hemolytic process with
corticosteroids or splenectomy. This experience emphasizes
that transfusion should not be withheld in AIHA, despite old
dogma to the contrary, and in many cases transfusion re-
quirements should be regarded as a medical emergency.22
The transfusion management of patients with AIHA re-
quires careful communication between the clinician and the
transfusion service. It is important to know the capabilities of
the transfusion service for performing specialized immuno-
hematologic procedures or where these procedures may be
available on a referral basis. It is also critical to assess the
history of pregnancies and previous transfusions with great
care; it is unlikely, for example, that a previously untrans-
fused male will have masked alloantibodies.
Table 4 Transfusion Therapy in AIHA
If patient is clinically stable and responding to therapy,
transfusions may not be required.
Reticulocytopenia indicates high likelihood of early need
for transfusion support.
Incompatible blood may be required; least
incompatible blood is not useful and may cause
significant delay in the provision of urgently needed
RBCs.
Neurologic signs such as confusion suggest transfusion
is urgently required.
Leukocyte reduced donor RBCs are recommended to
avoid febrile nonhemolytic transfusion reactions that
may mimic a hemolytic reaction.
K.E. King and P.M. Ness
Clinical Issues With Transfusion
Occasionally a transfusion may be required before serologic
evaluation is completed; even after thorough serologic eval-
uation, the optimal blood for transfusion may be incompat-
ible. The clinician must understand that in some circum-
stances, serologically incompatible blood is safe for
transfusion and can be expected to have in vivo survival
comparable to the patients own RBCs. Reluctance to trans-
fuse patients due to serologic incompatibility or an incom-
plete evaluation can be devastating. Patients with severe ane-
mia may appear to be hemodynamically stable, but they have
life-threatening anemia and should be transfused immedi-
ately regardless of the serologic evaluation or compatibility.
The onset of confusion in a patient with worsening anemia is
a particular clinical indicator of an imminent transfusion re-
quirement (Table 4). While it is difficult to generalize as to
the appropriate transfusion trigger for a patient with severe
AIHA, factors such as the rate of onset, presence or absence of
accompanying hypovolemia, and, most important, the un-
derlying health status and cardiorespiratory reserve must be
considered. If the heart and lungs are healthy and there is no
significant hypoperfusion, good tissue oxygenation can be
maintained at subnormal hemoglobin levels.
Experiments in acute, normovolemic anemia in rats,23
dog,24 and baboon25 have focused on the whole-body oxygen
extraction ratio (ER): the heart is the major organ at risk.
With progressive hemodilution, healthy animals with normal
coronary vasculature maintained normal levels of oxygen
consumption through a moderate increased cardiac output,
coronary blood flow, and in the ER up to a ratio of 50%. As
the hematocrit fell below 10%, however, oxygen consump-
tion declined, and the animals were no longer able to increase
the ER sufficiently to compensate for the low oxygen blood
tension. An ER of 50% represents the critical point at which
the myocardium converts from aerobic to anaerobic metab-
olism, as reflected in net lactate production. At this point
metabolic acidosis ensues, resulting in hemodynamic insta-
bility. Some illustrative studies compared the response to
acute normovolemic anemia in healthy dogs to the response
in dogs with a critical coronary stenosis; both groups con-
verted to anaerobic metabolism and developed congestive
heart failure at an ER greater than 50%. Dogs with a critical
coronary stenosis experienced an ER greater than 50% at a
hematocrit of 17%, in contrast to the healthy dogs who ex-
perienced an ER greater than 50% at a hematocrit of 8.6%.26
Thus transfusions are indicated at a higher hematocrit in
patients with AIHA who are elderly and likely to have under-
lying, undiagnosed cardiovascular disease.
When the decision has been reached to transfuse, several
additional steps can enhance patient safety. In some cases,
transfusions of small aliquots of blood may be sufficient to
provide relief of symptoms while avoiding the complications
of fluid overload. Leukocyte-reduced RBCs are recom-
mended to avoid febrile, nonhemolytic transfusion reactions,
in which the initial presentation may mimic a hemolytic re-
action with more severe consequences.
135
Transfusion in Cold Agglutinin Syndrome
Similar to warm AIHA, cold agglutinin syndrome may have
complex serology that complicates transfusion management.
ABO discrepancies can make it difficult to determine the
ABO group. Washing the patients RBCs with warm (37C)
normal saline to remove the IgM autoantibody can facilitate
determination of an accurate ABO group. If the ABO typing is
not clear from the serologic testing, group O RBCs can be
administered. If transfusion is required for patients with cold
agglutinin syndrome, blood warmers are often suggested de-
spite limited data to support this recommendation.
Alternatives to Red Blood Cell Transfusion
In recent years, numerous biotechnology products have been
developed as alternatives to blood transfusion and progress
in the development of blood substitutes as artificial oxygen
carriers has accelerated. Although there have been substan-
tial efforts to develop chemicals such as perfluorocarbons
into clinically useful blood substitutes, hemoglobin based
oxygen carriers (HBOC) appear more likely to provide an
alternative to blood transfusion.
Currently, the most promising HBOC preparations consist
of extracted hemoglobin from lysed RBCs recovered from
outdated human or bovine blood. These materials are chem-
ically manipulated by polymerization or binding to macro-
molecules to increase in vivo survival and to decrease the
potential for adverse reactions due to vasoconstriction. Case
reports have demonstrated their successful use in AIHA and
sickle cell anemia for patients refusing blood therapy.27 These
products will have an important role in transfusion practice
in the future. For patients with AIHA without available com-
patible blood, HBOC may become a lifesaving therapeutic
bridge until compatible blood can be found.27
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