Warm autoimmune hemolytic anemia (AIHA) in

adults
Authors: Carlo Brugnara, MD, Robert A Brodsky, MD
Section Editor: Robert T Means, Jr, MD, MACP
Deputy Editor: Jennifer S Tirnauer, MD

Contributor Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Feb 2024. | This topic last updated: Feb 21, 2024.

INTRODUCTION

Autoimmune hemolytic anemia (AIHA) is caused by autoantibodies that react with

self red blood cells (RBCs) and cause them to be destroyed. Warm AIHA, due to
antibodies that are active at body temperature, is the most common type of AIHA.

This topic reviews the evaluation and management of warm AIHA in adults.

Separate topic reviews discuss:

● AIHA in children – (See "Autoimmune hemolytic anemia (AIHA) in children:
Classification, clinical features, and diagnosis" and "Autoimmune hemolytic
anemia (AIHA) in children: Treatment and outcome".)
● Drug-induced AIHA – (See "Drug-induced hemolytic anemia".)
● Cold-induced hemolytic anemias – (See "Cold agglutinin disease" and
"Paroxysmal cold hemoglobinuria".)
● General approach to evaluating for hemolytic anemia – (See "Diagnosis of
hemolytic anemia in adults".)

TERMINOLOGY
● Hemolysis – Hemolysis refers to destruction of red blood cells (RBCs). It can
occur intravascularly (within the circulation) or extravascularly (in the
reticuloendothelial system, consisting mostly of splenic and hepatic
 macrophages). Hemolysis usually causes anemia, but the hemoglobin may be
normal if there is sufficient compensation by reticulocytosis.
● Autoimmune hemolytic anemia (AIHA) – Autoimmune hemolysis is
hemolysis caused by autoantibodies. It contrasts with alloimmune hemolysis,
in which the individual produces antibodies against foreign RBC antigens (eg,
those on allogeneic RBCs following a blood transfusion or on fetal RBCs during
a pregnancy).
● Warm AIHA – Warm AIHA is due to an antibody that is active at normal body
temperature. Typically the antibody is an IgG [1]. This contrasts with hemolytic
anemias in which the antibodies are most efficient in the cold (cold agglutinin
disease [CAD; typically due to IgM antibodies] and paroxysmal cold
hemoglobinuria [PCH; typically due to IgG antibodies]).
● Primary versus secondary warm AIHA – Primary warm AIHA (previously
called idiopathic) refers to warm AIHA with no underlying condition or
medication that could be responsible. Secondary warm AIHA refers to warm
AIHA in the setting of an underlying condition. (See 'Associated conditions'
below.)
● Warm agglutinin – Is another name for an anti-RBC antibody that is active at
body temperature. These antibodies can cause agglutination (sticking
together) of RBCs when treated with an antibody-binding reagent in the
laboratory. However, these antibodies rarely cause agglutination of RBCs in
vivo. They are IgG, which only has two valences and cannot bind more than two
RBCs at a time. In contrast, cold agglutinins typically do agglutinate RBCs in
vivo because they are IgM, which is pentameric and binds many RBCs
simultaneously.
● Panagglutinin – An antibody that reacts with all reagent RBCs. Typically found
with warm AIHA. Alloantibodies usually react to specific RBC antigens (eg, Kell,
Kidd). Cold agglutinins often have specificity against i or I. (See "Red blood cell
(RBC) transfusion in individuals with serologic complexity", section on
'Panagglutination'.)
● Antiglobulin test (Coombs test) – A laboratory test for antibodies directed
against RBCs ( figure 1). It is used for evaluating the cause of hemolytic
 anemia as well as in the blood bank for pretransfusion testing and evaluation
of transfusion reactions. (See 'Direct antiglobulin (Coombs) testing' below.)

• Direct – Assays antibodies and/or complement bound to the RBCs by

incubating patient RBCs with anti-human globulin and anti-human C3d.

• Indirect – Assays antibodies in the serum by incubating patient plasma with

test RBCs and anti-human globulin.

PATHOGENESIS

Warm AIHA can arise spontaneously (primary [idiopathic] warm AIHA) or in the
setting of a condition or medication that predisposes to the production of an
autoantibody (secondary warm AIHA).

Antibody and antigen characteristics — The autoantibodies are almost always

IgG, although IgA and warm-acting IgM have been reported [1-4]. The subtype of
IgG likely influences the rate of red blood cell (RBC) destruction, with IgG3 and IgG1
most able to fix complement and thus more destructive than other subtypes [5,6].
(See "IgG subclasses: Physical properties, genetics, and biologic functions", section
on 'Complement activation'.)

The autoantibodies are typically polyclonal panagglutinins directed against

common RBC antigens. This contrasts with alloantibodies, which typically react with
RBC antigens specific to a donor's blood group. Most commonly, warm
autoantibodies are directed against the Rh complex or against glycophorin
antigens.
● Rh complex – The Rh complex consists of several proteins including Rh (which
can express D, Cc, or Ee antigens), glycophorin B, and CD47. (See "Red blood
cell antigens and antibodies", section on 'Rh blood group system'.)
● Glycophorin antigens – Glycophorin antigens are heavily glycosylated
proteins on which blood group antigens are located. Glycophorin A contains
the M and N antigens; glycophorin B contains the S antigen. (See "Red blood
cell antigens and antibodies", section on 'MNS blood group system'.)

These antigens are typically present on RBCs in the majority of individuals, making
it more challenging to find compatible blood for transfusion if needed; however,
transfusion should not be withheld due to this issue. Emergency release blood can
be used if needed. (See 'Stabilization and transfusion for severe anemia' below.)

In one series of individuals with coronavirus disease 2019 (COVID-19) and AIHA, the
antibodies appeared to react to RBCs from other individuals with COVID-19 but not
with reagent RBCs, suggesting that some aspect of the infection is modifying the
RBC membrane to promote antibody binding [7]. (See 'COVID-19' below.)

Anti-RBC autoantibodies with unusual antigen specificity (eg, against Jka, auto-anti-
f, auto-anti-S) have been reported [8].

Red cell destruction — In warm AIHA, RBCs are mostly cleared extravascularly (in
reticuloendothelial macrophages). Intravascular hemolysis may be seen in severe
cases if the reticuloendothelial system becomes overwhelmed or if the complement
membrane attack complex is deposited on the RBC surface.
● Splenic macrophages – Macrophages in the spleen have Fc-gamma receptors
that recognize and phagocytose the IgG heavy chain and a portion of the RBC
membrane, producing a spherocyte [1]. Less commonly, the entire RBC may be
phagocytosed. The slow passage of RBCs through the spleen fosters prolonged
interaction between multiple IgG molecules and multiple Fc receptors in a
patch of membrane of the phagocytic cell, enhancing phagocytic clearance.
Spherocytes are less deformable than normal RBCs and become trapped in
splenic sinusoids, further extending the time during which phagocytosis can
occur.
● Splenic lymphocytes – Cytotoxic T lymphocytes (CTLs) in the spleen also carry
Fc receptors and can cause cell-mediated cytotoxicity of RBCs.
● Hepatic macrophages – Hepatic macrophages have receptors for complement
C3 fragments and can phagocytose RBCs with complement on their surface.

Associated conditions — Approximately 50 to 60 percent of warm AIHA is

associated with an underlying condition, with the remainder classified as primary
(idiopathic) [4,9,10]. The underlying condition generally produces some
combination of immune activation, immune deficiency, or immune dysregulation.

As examples [1]:
● Infection – Includes viral infections such as HIV, Epstein Barr virus (EBV), or
hepatitis C virus (HCV). AIHA has been reported with hepatitis E virus [11].
 Cases of AIHA with SARS-CoV-2 (the virus that causes coronavirus disease 2019
[COVID-19]) have also been reported [12,13]. (See 'COVID-19' below.)
● Autoimmune disorders – Includes autoimmune disorders including systemic
lupus erythematosus (SLE), rheumatoid arthritis, scleroderma, or ulcerative
colitis.
● Lymphoproliferative disorders – Includes autoimmune lymphoproliferative
syndrome (ALPS), chronic lymphocytic leukemia (CLL), lymphoma, and
monoclonal gammopathies (multiple myeloma, monoclonal gammopathy of
undetermined significance [MGUS], Waldenström macroglobulinemia). Therapy
with a purine analog such as fludarabine can increase the risk of AIHA and can
exacerbate the severity of AIHA if already present. (See "Drug-induced
hemolytic anemia", section on 'Immune-mediated'.)

In some cases, a lymphoproliferative disorder may become apparent after the

diagnosis and treatment of primary warm AIHA or warm AIHA associated with
a connective tissue disorder. In a series of 107 patients with primary AIHA, 18
percent developed a lymphoproliferative disorder after a median time of
approximately two years (range, 9 to 76 months) [14].
● Immunodeficiency – Includes inherited immunodeficiencies, hematopoietic
stem cell transplantation, solid organ transplantation, and
hypogammaglobulinemia. The reported incidence of AIHA following allogeneic
hematopoietic stem cell transplantation is 4 to 6 percent [15]. A 2024 report
described 85 patients with recombination-activating gene deficiency (RAG
deficiency) who had AIHA; many had multiple immune cytopenias [16].
● Pregnancy – (See "Immunology of the maternal-fetal interface", section on
'Maternal systemic immune responses'.)

It has been suggested that in these conditions, B-cell clones that normally produce
clinically silent low levels of anti-self IgM autoantibodies are altered or de-repressed
to produce IgG in high and pathogenic titer, or that control of IgG autoreactivity by
autologous IgM becomes deficient [17].

Unusual associations that deserve special mention include:

● Babesia – Babesiosis appears to be associated with AIHA in individuals who are
asplenic. In a cohort of 86 consecutive individuals treated for babesiosis at a
 single institution, six developed warm AIHA [18]. The typical time course of
AIHA was two to four weeks after diagnosis, when they had exhibited a
response to antimicrobial therapy and had no evidence of parasitemia on their
blood smears. All six had undergone splenectomy, whereas only 12 of the
remaining 80 without AIHA (15 percent) had undergone splenectomy. All cases
of AIHA resolved, although most required therapy with a prolonged course of
glucocorticoids. Post-splenectomy babesiosis has also been associated with
Evans syndrome ( picture 1) [19]. (See 'Evans syndrome' below.)
● Spider bite – Brown recluse spider bites can rarely cause severe intravascular
hemolysis and in some cases AIHA [20]. Management includes antivenom and
transfusion if needed; case reports have described plasma exchange therapy
for concomitant disseminated intravascular coagulation (DIC). (See "Bites of
recluse spiders", section on 'Life-threatening effects' and "Bites of recluse
spiders", section on 'Acute hemolytic anemia'.)
● Organ transplant – Solid organ transplant recipients who receive an ABO-
compatible, but not identical, allograft can develop hemolysis due to passenger
lymphocyte syndrome (donor lymphocytes present in the transplanted organ
that react with recipient RBCs). (See "Pretransfusion testing for red blood cell
transfusion", section on 'Transplant recipients' and "Anemia and the kidney
transplant recipient", section on 'Later (>3 months) posttransplantation'.)
● Sickle cell disease – Individuals with sickle cell disease can develop a condition
called bystander hemolysis, in which a delayed hemolytic transfusion reaction
leads to hemolysis of self RBCs along with transfused RBCs. (See "Overview of
the clinical manifestations of sickle cell disease", section on 'Hyperhemolytic
crisis' and "Transfusion in sickle cell disease: Management of complications
including iron overload", section on 'Alloimmunization and hemolysis'.)

Medications — Medications associated with drug-induced warm AIHA are

summarized in the table ( table 1) and reviewed in more detail separately. (See
"Drug-induced hemolytic anemia", section on 'Immune-mediated'.)

EPIDEMIOLOGY
 ● Incidence – The incidence of AIHA, estimated from national registry studies,
ranges from 17.0 per 100,000 (Denmark) to 2.4 per 100,000 (France) [21,22]. A
2021 review cited an incidence of 5 to 10 per 1 million [10].
● Proportion of all AIHAs – Warm AIHA constitutes approximately 70 to 80
percent of AIHAs, with the remainder due to cold-induced hemolysis or other
less common disorders [1,23].
● Prevalence of secondary warm AIHA – The approximate prevalence of warm
AIHA in selected underlying conditions is as follows [15,24]:

• Chronic lymphocytic leukemia (CLL) – 11 percent

• Systemic lupus erythematosus (SLE) – 10 percent
• Allogeneic hematopoietic stem cell transplantation – 4 to 6 percent
• Non-Hodgkin lymphoma – 2 to 3 percent
The prevalence of secondary AIHA is generally higher in referral centers [25].

CLINICAL MANIFESTATIONS

There is significant heterogeneity in presenting symptoms, ranging from mild to

fulminant, as illustrated in several case series [4,9,26].

Findings include:
● Anemia – Anemia-related symptoms (dyspnea on exertion, fatigue, bounding
pulse or palpitations) are seen in at least three-fourths of individuals.
● Jaundice – Jaundice or dark urine are seen in approximately one-third.
● Splenomegaly – Seen in approximately one-third. In some cases,
splenomegaly is due to an underlying lymphoproliferative disorder.
● Chest pain – Seen in 7 percent.
● Evans syndrome – Seen in 7 percent. (See 'Evans syndrome' below.)

The severity of symptoms depends on the hemoglobin level, its rate of decline,
other comorbidities, and the person's overall level of activity or exertion. Most
adults will become symptomatic when the hemoglobin declines to 8 to 9 g/dL [27].
With severe anemia, an individual may become lethargic, confused, and/or
hemodynamically unstable.
The physical examination may show pallor and/or jaundice. Moderate
splenomegaly may be present. Individuals with severe anemia and/or underlying
cardiac disease may have signs and symptoms of cardiac decompensation
(tachycardia, tachypnea, or signs of heart failure).

EVALUATION AND DIAGNOSIS

Important information from the history — AIHA may be suspected in an

individual with new onset anemia not due to bleeding. They may have an
underlying condition associated with AIHA such as systemic lupus erythematosus
(SLE) or chronic lymphocytic leukemia (CLL), or they may be otherwise well.

This history can focus on:

● Known or suspected underlying conditions and medications associated with
AIHA ( table 1). Systemic symptoms such as new-onset weight loss, night
sweats, or fever may suggest development of a lymphoproliferative disorder,
which is one of the most common underlying conditions. (See 'Associated
conditions' above and "Drug-induced hemolytic anemia".)
● Findings that suggest an especially severe course:

• Hemoglobinuria suggests intravascular hemolysis, which may occur in

severe warm AIHA, cold agglutinin disease (CAD), paroxysmal nocturnal
hemoglobinuria (PNH), or paroxysmal cold hemoglobinuria (PCH). (See
"Clinical manifestations and diagnosis of paroxysmal nocturnal
hemoglobinuria" and "Paroxysmal cold hemoglobinuria".)

• Thromboembolic events including deep vein thrombosis (DVT), pulmonary

embolism (PE), stroke, or myocardial infarction can complicate AIHA. The
absolute increased risk of DVT or PE may be as high as 30 percent.
Symptoms of these complications should be reviewed, both to determine if
they are present and to educate the patient regarding symptoms to report
to their clinician should they occur. (See 'Thromboembolic complications'
below.)

• Severe anemia (or anemia that develops rapidly) can cause lethargy, chest
pain, and/or confusion. Anemia that causes these symptoms or
hemodynamic compromise (or any hemoglobin <6 g/dL if hemodynamically
 stable) is a medical emergency that requires immediate intervention with
transfusions and/or other treatments, regardless of the cause. (See
"Pretransfusion testing for red blood cell transfusion", section on
'Emergency release blood for life-threatening anemia or bleeding'.)
● Elements of the history that suggest a diagnosis other than AIHA:

• Transfusions – For those with a very recent transfusion (prior one to three
days), an acute hemolytic transfusion reaction (AHTR) is possible, and the
transfusion medicine service or blood bank should be contacted
immediately to assist with the evaluation and perform antibody testing.

For those with a transfusion in the prior four weeks (possibly longer), a
delayed hemolytic transfusion reaction (DHTR) is possible and similar
discussions with transfusion medicine or the blood bank should occur.

Serial monitoring of the hemoglobin level and hemolysis indicators following

a transfusion reaction will generally show progressive recovery. (See
"Hemolytic transfusion reactions", section on 'Evaluation and immediate
management of AHTR' and "Hemolytic transfusion reactions", section on
'Evaluation of DHTR and DSTR'.)

• Cold-induced symptoms – Cold-induced symptoms (acrocyanosis, Raynaud

phenomenon) may suggest CAD. Raynaud phenomenon may also occur in
connective tissue disorders. If there is suspicion for one of these conditions
based on clinical features or laboratory findings, specialized testing should
be performed, as discussed separately. (See "Cold agglutinin disease".)

Initial testing (CBC, blood smear, hemolysis labs) — Individuals being evaluated
for warm AIHA will likely have already had a complete blood count (CBC) that shows
anemia and/or reticulocytosis as well as other testing consistent with hemolysis, as
summarized in the table ( table 2) and listed below.

The following testing should be obtained if not available:

● CBC – Anemia is usually present but may be absent if hemolysis is mild and/or
reticulocytosis is brisk. A typical hemoglobin at presentation is between 7 and
10 g/dL, although hemoglobin <7 g/dL is not uncommon (seen in 30 percent of
individuals in one study) [26]. The anemia is usually normocytic or macrocytic
due to reticulocytosis.
 Serial CBCs and reticulocyte counts are often obtained to monitor severity and
response to treatment. (See 'Monitoring and prognosis' below.)

Other findings associated with known associated conditions may include an

increased white blood cell (WBC) count in CLL or reduced platelet count with
concomitant immune thrombocytopenia (ITP).
● Reticulocyte count – The reticulocyte count can be measured as an absolute
count or a percentage of red blood cells (RBCs); the absolute count is preferred
because it is unaffected by the hemoglobin concentration. If the absolute count
is not available, the reticulocyte percentage can be corrected for the
hemoglobin, as discussed separately. (See "Diagnosis of hemolytic anemia in
adults", section on 'High reticulocyte count'.)

The reticulocyte count increases as the bone marrow responds and begins to
produce new RBCs. In one series, the mean reticulocyte percentage was 9
percent at diagnosis (mean corrected reticulocyte count, 7.4 percent; median
corrected reticulocyte count, 5 percent [range, 0.1 to 45 percent]) [26].

In some cases, the reticulocyte response may be less than expected (less than
twofold increase over baseline), due to one or more of the following:

• Delay in bone marrow responsiveness [26,28].

• Concomitant condition that decreases RBC production such as iron
deficiency, hematologic malignancy, or a chemotherapy drug.

• Autoantibody directed against an antigen on RBC precursors, such as certain

Rh antigens.

If the reticulocyte count is low in the setting of AIHA, these possibilities should
be investigated, as discussed in more detail separately. (See "Diagnosis of
hemolytic anemia in adults", section on 'Hemolysis without reticulocytosis'.)
● Haptoglobin – Haptoglobin is typically low or absent/unmeasurable [9]. In a
small predictive modeling study (100 patients), a haptoglobin <25 mg/dL had a
sensitivity of 83 percent, specificity of 96 percent, and predictive value of 87
percent for hemolytic anemia [29].
● Lactate dehydrogenase (LDH) and indirect bilirubin – LDH is typically
increased. In one series, the median LDH was approximately 500 units/L, but
 wide variations up to 5000 units/L have been reported [4,30]. Indirect bilirubin
is in the range of 2 to 3 mg/dL (35 to 51 micromol/L) [30].
● Blood smear – Spherocytes or microspherocytes are often seen ( picture 2
and picture 3). In some cases, spherocytes may represent a small population
or may be difficult to appreciate [9,31].

Reticulocytes may be apparent as larger, purplish RBCs.

Other findings may indicate a known associated condition. Examples include

numerous small lymphocytes in CLL and reduced platelets with ITP.

Also important is the absence of findings that raise the possibility of other
causes of anemia, such as schistocytes, target cells, and other abnormal cell
shapes. (See "Evaluation of the peripheral blood smear", section on 'Worrisome
findings'.)

Signs of intravascular hemolysis (hemoglobinemia [red serum], hemoglobinuria

[red urine, positive for hemoglobin but negative for RBCs], and hemosiderinuria)
are not typical of warm AIHA but may be present in severe cases.

Direct antiglobulin (Coombs) testing — Once hemolysis is identified, direct

antiglobulin testing (DAT; Coombs) is used to distinguish immune from non-
immune causes. The principles and mechanics of the tests are illustrated in the
figure ( figure 1).

In the DAT, patient RBCs are washed and reacted with antiserum or monoclonal
antibodies directed against immunoglobulins, particularly IgG and a fragment of
the third component of complement, C3d. The reagent antibodies will only bind
and agglutinate the patient's RBCs if those RBCs already have IgG or C3d on their
surface. When these tests are accurately and specifically performed, 97 to 99
percent of individuals with warm AIHA will have a positive result with anti-IgG, anti-
C3d, or both, compared with less than 1 percent of the general population [32-34].
The strength of the DAT positivity is generally correlated with the severity of
hemolysis. Drug-induced AIHA may have a negative DAT. (See "Drug-induced
hemolytic anemia".)

In contrast to the DAT, the indirect antiglobulin test (IAT; indirect Coombs test) is
not used to evaluate warm AIHA. The IAT detects anti-RBC antibodies in the
patient's serum and is most important for identifying and characterizing
alloantibodies prior to transfusion.

The antigen specificity of the antibody is also important. Warm AIHA

autoantibodies are almost always panagglutinins reacting with all reagent RBCs. In
contrast, alloantibodies virtually always have specificity for individual RBC antigens.
Drug-induced hemolytic anemias generally do not show panagglutinin activity,
although there are exceptions. (See 'Antibody and antigen characteristics' above.)

Patterns of reactivity in different autoimmune hemolytic anemias are summarized

in the table ( table 3). A positive DAT for IgG and/or C3d in a person with
hemolytic anemia who has not had a recent transfusion and does not have a cold
agglutinin or Donath-Landsteiner antibody is considered confirmatory of warm
AIHA. However, it is worth noting that some individuals without hemolysis will have
a positive DAT; thus, this test alone (in the absence of hemolysis) is not sufficient to
make the diagnosis [35]. (See 'Diagnosis' below.)

Although uncommon, some individuals have combined warm-active IgG

autoantibodies and cold-active IgM autoantibodies (so-called mixed autoimmune
hemolytic anemia). In a series of 308 individuals, 24 (8 percent) were in this
category [4].

Also uncommon is DAT-negative warm AIHA, which is thought to be present in <5

percent of individuals with warm AIHA [15]. The negative DAT may be due to
characteristics of the autoantibodies that make them more difficult to detect or due
to a reduced amount of autoantibodies on the surface of RBCs [36,37]. For
individuals suspected to have DAT-negative warm AIHA based on new-onset
hemolytic anemia without evidence of another cause, the following additional
testing is indicated:
● An extended DAT panel can be performed to identify antibodies of the IgA or
IgM isotype, using specific anti-IgA or anti-IgM antisera, respectively [2,38-43].
● Testing using more sensitive methods such as flow cytometry can sometimes
identify IgG bound to RBCs [44]. However, testing such as the "super Coombs"
is rarely needed.
● Testing for cold-reacting antibodies (cold agglutinins or Donath-Landsteiner
antibodies, indicative of CAD or PCH, respectively), if not done already
( table 4).
 ● Flow cytometry for PNH using specialized methods such as fluorescent
aerolysin (FLAER) and antibodies against CD59 and CD55 to detect lack of
glycosylphosphatidylinositol (GPI)-anchored proteins on RBCs and WBCs [45].
● In individuals with spherocytes on the blood smear, the possibility of hereditary
spherocytosis may be considered, especially if spherocytes are abundant
and/or the patient has a positive family history of hemolytic anemia. (See
"Hereditary spherocytosis", section on 'Evaluation'.)

Additional testing — Additional testing may be appropriate in selected cases,

either to confirm the diagnosis, to eliminate other possible diagnoses, to identify
severe disease, and/or to identify associated conditions. The need for added testing
depends on the certainty of the warm AIHA diagnosis; the severity of hemolysis;
and the perceived likelihood of underlying conditions that disrupt immune
homeostasis, which is based on the history, CBC, and physical examination. As
noted below, we have a low threshold for evaluating for underlying
lymphoproliferative disorders.
● Confirmatory testing – Additional testing with an extended DAT panel or more
sensitive assays such as those described above may be reasonable in
individuals for whom the diagnosis of warm AIHA is strongly suspected but
DAT is negative. This is likely to be the case in <5 percent of individuals with
warm AIHA. (See 'Direct antiglobulin (Coombs) testing' above.)
● Testing for alternate diagnoses – In cases where suspicion for other causes
of hemolytic anemia is high, additional testing may be indicated. An important
example is oxidant hemolysis from medications such as dapsone, especially if
findings such as blister cells or bite cells are present on the peripheral blood
smear. Details of the evaluation are individualized according to the clinical
history and findings on laboratory testing. (See "Diagnosis of hemolytic anemia
in adults", section on 'Post-diagnostic testing to determine the cause' and
'Differential diagnosis' below.)

It is important to test for PNH in an individual with AIHA and a negative DAT
before making the diagnosis of DAT-negative warm AIHA. (See "Clinical
manifestations and diagnosis of paroxysmal nocturnal hemoglobinuria".)
● Testing to identify associated conditions – If AIHA is diagnosed or strongly
suspected, additional evaluation for underlying conditions is important.
 We generally review the history for symptoms such as fevers, sweats, or weight
loss; evaluate findings on the physical examination that may suggest an
infection, a hematologic malignancy, or a rheumatologic condition; check the
CBC for abnormalities of WBCs and platelets; and perform additional testing as
indicated. Consultation with infectious disease, hematology, or rheumatology
specialists is appropriate to assist with this testing if needed. (See 'Associated
conditions' above.)

We have a very low threshold for obtaining peripheral blood flow cytometry to
identify a low-grade lymphoproliferative disorder in any adult with warm AIHA
who does not have an obvious other underlying cause of hemolysis or who has
any suggestive features (splenomegaly or lymphocytosis, even if mild).

Some experts do even more extensive testing with additional viral serologies
including HIV and hepatitis, autoantibodies such as anti-nuclear antibody (ANA)
and computed tomography scans [43].
● Evaluation for thromboembolic complications – Up to 30 percent of patients
with warm AIHA will have thromboembolic disease. We ask about leg swelling,
chest pain, and shortness of breath, and we have a low threshold for diagnostic
testing for deep vein thrombosis (DVT), cardiovascular ischemia, and/or
pulmonary embolism (PE) if there are suggestive findings. As noted below, we
check a D-dimer on all patients. We evaluate any patient with a positive D-
dimer for DVT and any patient with dyspnea out of proportion to the degree of
anemia for PE. (See 'Thromboembolic complications' below.)

Diagnosis — Warm AIHA is diagnosed when an individual has antibody-mediated

(DAT [Coombs]-positive) hemolytic anemia not due to another cause such as a
hemolytic transfusion reaction, PNH, or CAD ( algorithm 1).

DAT-negative warm AIHA is diagnosed when other causes of non-immune

hemolysis have been eliminated, including PNH, hereditary spherocytosis, cold-
active antibodies (paroxysmal cold hemoglobinuria or cold agglutinin disease),
hemoglobinopathies, and thrombotic microangiopathies. (See "Diagnosis of
hemolytic anemia in adults", section on 'Post-diagnostic testing to determine the
cause'.)

DIFFERENTIAL DIAGNOSIS
● Cold agglutinin disease (CAD) – CAD is a form of autoimmune hemolytic
anemia in which IgM antibodies recognize red blood cell (RBC) antigens
(typically "I" or "i") at temperatures below normal body temperature. Like warm
AIHA, there is extravascular hemolysis, anemia, and a positive direct
antiglobulin (Coombs) test (DAT). Unlike warm AIHA, CAD is most typical in
individuals over 60 years of age, it is also associated with acrocyanosis, the DAT
is typically positive for complement and negative for IgG ( table 4), and a cold
agglutinin is present with a titer ≥64 at 4°C. The peripheral blood smear in CAD
shows RBC agglutination ( picture 4), whereas in warm AIHA it shows
microspherocytes ( picture 2). Management also differs. (See "Cold agglutinin
disease".)
● Drug-induced hemolytic anemia – Drug-induced hemolytic anemia can be
immune or non-immune. Like warm AIHA, immune drug-induced hemolytic
anemia is characterized by hemolysis and a positive DAT. Unlike warm AIHA, in
drug-induced AIHA there is an implicated drug ( table 1), and the hemolysis
typically abates when exposure to the drug is removed. (See "Drug-induced
hemolytic anemia".)
● Paroxysmal cold hemoglobinuria (PCH) – PCH is a form of autoimmune
hemolytic anemia that typically presents with intravascular hemolysis,
hemoglobinemia, and darkly colored urine (hemoglobinuria), beginning a few
minutes to several hours after exposure to cold along with the presence of an
IgG antibody that reacts with the red cell at reduced temperature but not at
37°C and causes hemolysis on rewarming (ie, a positive Donath-Landsteiner
antibody test). The DAT is positive for the presence of complement, but not
IgG, during the acute hemolytic episode. (See "Paroxysmal cold
hemoglobinuria".)
● Paroxysmal nocturnal hemoglobinuria (PNH) – PNH is a form of hemolytic
anemia caused by an acquired hematopoietic stem cell defect that leads to
complement-mediated hemolysis; there is no autoantibody involved. Like
warm AIHA, it often affects older adults and is associated with markers of
increased hemolysis. Unlike warm AIHA, the DAT is negative for IgG, and PNH-
specific flow cytometry shows absence of glycosylphosphatidylinositol (GPI)-
anchored proteins. (See "Clinical manifestations and diagnosis of paroxysmal
nocturnal hemoglobinuria".)
 ● Hereditary spherocytosis (HS) – HS is a non-immune form of hemolytic
anemia due to inherited pathogenic variants in genes that encode cytoskeletal
proteins. However, HS may be confused with AIHA due to the abundance of
spherocytes and the lack of symptoms due to the chronicity of the disorder.
Like warm AIHA, individuals with HS have hemolysis and anemia, with
spherocytes on the blood smear. Unlike warm AIHA, individuals with HS
generally have lifelong anemia and may have a positive family history of
anemia, and laboratory testing is consistent with a non-immune mechanism of
hemolysis (negative DAT, positive assay for eosin-5’-maleimide [EMA] binding to
RBCs). (See "Hereditary spherocytosis".)

INITIAL MANAGEMENT

The management depends on the severity of the anemia. An approach is

summarized in the algorithm ( algorithm 2). As illustrated in the algorithm and
discussed below, individuals with severe anemia may require transfusion and
hemodynamic support. Once the patient is stabilized, the approach to reducing
hemolysis and halting antibody production is similar for most patients. (See
'Stabilization and transfusion for severe anemia' below.)

The autoantibodies have a half-life of two to three weeks; thus, even if therapy
immediately halts production of the autoantibody, hemolysis may continue for two
to three weeks.

Folic acid is generally used for those with persistent hemolysis, and venous
thromboembolism (VTE) prophylaxis is used for those who are hospitalized. (See
'Folic acid' below and 'Thromboembolic complications' below.)

Management of individuals who have a recurrence of autoimmune hemolysis after

recovery are treated similarly to those with a first episode of AIHA, with the
exception that treatments that were effective during the initial episode may be
prioritized for treating subsequent episodes.

Stabilization and transfusion for severe anemia — When a patient first presents,
the blood bank or transfusion service may require some time to perform
pretransfusion testing and identify appropriate units for transfusion. However,
severe anemia (hemoglobin <6 g/dL) and/or hemodynamic compromise from a
rapid decline in hemoglobin is a medical emergency requiring immediate
stabilization and usually transfusion. Delay in transfusion could be fatal. These
patients should be transfused with emergency release blood pending the full blood
bank evaluation. (See "Pretransfusion testing for red blood cell transfusion", section
on 'Emergency release blood for life-threatening anemia or bleeding'.)

Other emergency treatment may also be required for severely anemic or

hemodynamically compromised patients:
● Stabilize the patient with intravenous access and hydration. Provide ventilatory
and circulatory support as needed.
● Contact the blood bank or transfusion medicine liaison immediately and alert
them of the need for transfusion in an individual with AIHA [46,47]. Important
history for the blood bank or transfusion medicine service includes prior
pregnancies and prior transfusions, which may have led to alloantibody
production. If the patient is coming from an outside hospital, it is important to
give them the name of the hospital since that hospital may have already
started the work-up.

Once compatible blood has been identified:

● The transfusion threshold appropriate to that patient should be used. (See
"Indications and hemoglobin thresholds for RBC transfusion in adults".)
● If information about alloantibodies is known (due to previous transfusions or
pregnancy), blood with these antigens should be avoided, as alloimmune
hemolysis is much more likely to cause a significant transfusion reaction than
hemolysis caused by autoantibodies.
● Patients requiring transfusion should receive type-specific blood, even if
crossmatch-compatible blood cannot be identified by the blood bank (which
will be the case for many patients) [1]. For individuals who are at risk of
previous sensitization to RBC alloantigens due to prior transfusions or
pregnancy, blood can be infused slowly (over three to four hours) with close
monitoring; using a slower rate during the first 30 to 60 minutes is most
important.
● If transfusion is not required urgently and there is sufficient time to perform
extended phenotype matching, matching for Rh, Kell, Kidd, and S/s antigens is
 advised [1]. Some guidelines also include matching for Duffy. Genotyping may
be helpful if available [43]. The amount of time involved in extended
phenotyping (or genotyping) varies, and close communication with the blood
bank is advised to share information about the degree of clinical urgency and
the amount of testing that can reasonably be performed. (See "Red blood cell
antigens and antibodies", section on 'Clinically significant (common)' and "Red
blood cell (RBC) transfusion in individuals with serologic complexity", section
on 'Autoantibodies'.)

In one of the largest case series of AIHA (mostly warm type), 115 of 308 patients (37
percent) received transfusions [4]. Historical experience indicates that most
patients will tolerate even serologically incompatible blood [48,49]. One report, for
example, described 53 patients with decompensated AIHA who received blood
transfusions in which none had transfusion-related alloimmunization or a definite
increase in hemolysis [49].

If transfusion-dependent hemolysis continues, we may add intravenous immune

globulin (IVIG). (See 'IVIG' below.)

Treatment of the underlying disorder — Approximately one-half of individuals

with warm AIHA have an associated/underlying disorder that causes immune
dysregulation. (See 'Associated conditions' above.)

Treatment of the underlying disorder is appropriate, although this may not always
lead to resolution of hemolysis, or it may work more slowly than needed [1,43].
Treatment is especially important for infections that may be clinically serious in
their own right.

For some underlying disorders such as chronic lymphocytic leukemia (CLL), it may
be reasonable to treat the AIHA without initiating CLL-specific therapy, especially if
the AIHA rather than CLL is the predominant clinical feature [50].

Details of management for underlying disorders are presented in separate topic

reviews. Examples include the following:
● Drug discontinuation. (See "Drug-induced hemolytic anemia".)
● Systemic lupus erythematosus (SLE). (See "Overview of the management and
prognosis of systemic lupus erythematosus in adults".)
 ● Autoimmune lymphoproliferative syndrome (ALPS). (See "Autoimmune
lymphoproliferative syndrome (ALPS): Management and prognosis".)
● CLL. (See "Overview of the treatment of chronic lymphocytic leukemia".)
● Hodgkin disease. (See "Pretreatment evaluation, staging, and treatment
stratification of classic Hodgkin lymphoma".)
● Non-Hodgkin lymphoma. (See "Initial treatment of limited stage diffuse large B
cell lymphoma" and "Initial treatment of advanced stage diffuse large B cell
lymphoma".)

Decisions about the role of splenectomy are highly dependent on the underlying
disorder, with efficacy in some disorders such as splenic marginal zone lymphoma
and worsening in others such as ALPS. (See 'Splenectomy' below.)

Glucocorticoids with or without rituximab as first-line agents — Once the

patient's hemodynamic status has been addressed, most experts use
glucocorticoids plus rituximab as the initial treatment of warm AIHA, especially for
symptomatic patients [1,10]. This applies to individuals with primary or secondary
AIHA.

If a patient who starts on single agent glucocorticoids has no response by two

weeks, we start rituximab and frequently add mycophenolate mofetil. The
glucocorticoids should be tapered over several weeks to avoid late toxicities. (See
'Rituximab (alone or added to glucocorticoids)' below and 'Other
immunosuppressive and cytotoxic agents' below.)
● Initial dose – Most experts use an initial dose of 1 to 2 mg/kg of prednisone
orally per day or a dose of 60 to 100 mg daily [51]. If parenteral administration
is preferred, an equivalent dose of methylprednisolone (0.8 to 1.6 mg/kg
intravenously per day) can be used.

This is generally continued until the hemoglobin is >10 mg/dL, which occurs in
most patients within two to three weeks.

Most experts add rituximab to initial glucocorticoids, especially for individuals

with severe disease. Two randomized trials (discussed below) have
demonstrated greater efficacy with glucocorticoids plus rituximab compared
with glucocorticoids alone. (See 'Rituximab (alone or added to glucocorticoids)'
below.)
● Taper – Once the hemoglobin level has stabilized and markers of hemolysis are
normal or clearly improving (typically over two to three weeks), a taper can be
initiated.

The general principle of tapering glucocorticoids in AIHA is to use a gradual

taper over two to three months (some experts suggest longer) [1,52]. However,
we may taper more rapidly for individuals at high risk for complications (eg,
diabetes). There is no high-quality evidence to support one specific tapering
protocol over another.

In general, we do the following:

• If the patient is responsive to initial steroid therapy (hemoglobin of 10 g/dL

or more within three weeks) reduce prednisone dose by 10 mg per week
until the dose reaches 20 mg daily.

• Once the dose is 20 mg daily, decrease the dose no faster than 5 mg per
week (often we decrease by 5 mg every other week).

• Relapse is an indication for second-line therapy with or without a boost in

the prednisone dose. (See 'Treatment for persistent disease' below.)

• We also consider lack of a response within three weeks to indicate steroid-

unresponsive disease. We taper glucocorticoids in these individuals by 10
mg per week and initiate a second-line therapy to avoid toxicities of long-
term glucocorticoid use.

During the taper, we monitor the complete blood count (CBC), reticulocyte
count, and lactate dehydrogenase (LDH; more comprehensive hemolysis panel
in some individuals). The frequency depends on the severity of anemia. In
outpatients who continue to require regular transfusions, we obtain this
testing one to two times per week. If the patient is transfusion-independent
and undergoing a taper, once weekly testing is reasonable. Once the
hemoglobin level is stable, the monitoring interval is extended.
● Efficacy – The likelihood of an initial response to glucocorticoids alone ranges
from approximately 70 to 90 percent, based on case series and our experience
[9,53]. However, as many as one-half of individuals who have a response will
experience a relapse within the first year [51]. As noted below, randomized
trials have demonstrated improved response rates when rituximab is added to
 glucocorticoids, without significant increases in adverse events. (See 'Rituximab
(alone or added to glucocorticoids)' below.)

Glucocorticoids may be less effective in certain populations such as individuals

who develop AIHA following hematopoietic stem cell transplant, although this
is very rare [15,54].
● Addition of rituximab and other agents – As noted above, we typically use
glucocorticoids plus rituximab as initial therapy. For individuals who did not
receive rituximab as initial therapy and who do not have a response to
glucocorticoids in the first two to three weeks, rituximab and mycophenolate
mofetil can be added and the glucocorticoid taper initiated. (See 'Rituximab
(alone or added to glucocorticoids)' below and 'Other immunosuppressive and
cytotoxic agents' below.)
● Adverse effects – Glucocorticoids are generally well-tolerated over the short
term but have numerous adverse effects when given for prolonged periods,
including weight gain, diabetes, hypertension and cardiovascular disease,
neuropsychiatric changes, osteoporosis and osteoporotic fractures,
immunosuppression, and cataracts ( table 5). These effects are thought by
some to be lower when glucocorticoids are given at very low doses or on an
every-other-day schedule, but there is unlikely to be a dose at which side
effects are eliminated. (See "Major adverse effects of systemic
glucocorticoids".)

Patients who are on glucocorticoids for more than three months should be treated
with calcium (intake of 1000 to 1200 mg daily) and vitamin D (intake of 600 to 800
international units daily), through diet and/or supplements. (See "Prevention and
treatment of glucocorticoid-induced osteoporosis".)

We use prophylaxis for pneumocystis infection in individuals receiving long-term

glucocorticoids plus rituximab, but not those receiving long-term glucocorticoids
alone. Supporting evidence and details of administration are presented separately.
(See "Treatment and prevention of Pneumocystis pneumonia in patients without
HIV".)

Rituximab (alone or added to glucocorticoids)

● Indications – Rituximab may be used as follows:
 • As initial therapy in combination with glucocorticoids (our usual practice).
• Added to glucocorticoids if the hemoglobin does not improve with
glucocorticoids alone.
• As a single agent for initial therapy.
• As a single agent for refractory disease.
● Dosing – The optimal dose, schedule, and duration of rituximab is unknown.
Many experts use 375 mg per square meter of body surface area intravenously
(375 mg/m2) weekly for four weeks, based on the schedule used in
hematologic malignancies. Other doses and schedules may also be reasonable.
● Supporting evidence – Two randomized trials and a prospective non-
randomized study have shown better response rates for rituximab plus
glucocorticoids than for glucocorticoids alone:

• A trial from 2013 randomly assigned 64 adults with newly diagnosed warm
AIHA to receive prednisolone (1.5 mg/kg daily for two weeks followed by a
taper) with or without rituximab (375 mg/m2 weekly for four weeks) [30].
Compared with prednisolone monotherapy, combined therapy was
associated with a better response rate at 12 months (36 versus 75 percent),
with responses continuing to occur over the first six months, even after
therapy had been completed. The benefit persisted for at least 36 months,
with remission rates of 45 versus 70 percent. Relapse-free survival was also
better in the combined therapy group (hazard ratio [HR] 0.33, 95% CI 0.12-
0.88). Adverse events were similar in both groups.

• A trial from 2017 randomly assigned 32 adults with warm AIHA to receive
prednisolone (1 mg/kg daily for two weeks followed by a taper) with or
without rituximab (two infusions of fixed dose 1000 mg two weeks apart)
[55]. Results were remarkably similar to the 2013 trial, with response rates at
12 months of 31 versus 75 percent, and at 24 months of 19 versus 63
percent. Adverse effects were lower in the rituximab group (fewer severe
infections, likely due to chance). There were six deaths in the monotherapy
group and no deaths with combination therapy.

• A prospective single arm study from 2012 treated 18 adults with warm AIHA
using a short course of oral prednisone and low-dose rituximab (100 mg
 fixed dose weekly for four weeks) and noted responses in all 18 that lasted
for at least 36 months [56,57]. Therapy was well tolerated.
● Adverse effects – Rituximab can cause infusion reactions and long-term
immunosuppression. (See "Rituximab: Principles of use and adverse effects in
rheumatoid arthritis", section on 'Adverse effects'.)

Clinicians should be aware of Boxed Warnings in the rituximab prescribing

information regarding infusion-related reactions, reactivation of hepatitis B
infection, severe mucocutaneous reactions, as well as progressive multifocal
leukoencephalopathy, any one of which may be fatal. (See "Infusion-related
reactions to therapeutic monoclonal antibodies used for cancer therapy",
section on 'Rituximab'.)
● Mechanisms of action – The mechanism by which rituximab induces long-
term responses is incompletely understood. It is thought to eliminate B cells
via apoptosis, antibody-dependent cytotoxicity, and complement-mediated
cytotoxicity [58]. Plasma cells responsible for long-term antibody production do
not express CD20 and are not eliminated by rituximab.

Folic acid — Chronic hemolysis can lead to folate deficiency due to increased folate
requirements for compensatory red blood cell (RBC) production.

Administration of folic acid (1 mg per day orally) is reasonable as long as hemolysis

persists. This may not be necessary given routine folate supplementation of grains
and other foods in most countries, but it is unlikely to be harmful. (See "Causes and
pathophysiology of vitamin B12 and folate deficiencies", section on 'Increased
requirements'.)

IVIG — Intravenous immune globulin (IVIG) has limited efficacy as a single agent in
AIHA, but it is often helpful as an adjunct to other therapies. In patients who are
improving but still transfusion dependent two weeks after starting prednisone and
rituximab, we sometimes use IVIG (500 mg/kg daily for four days) to improve RBC
survival and decrease the need for blood transfusions.

Case reports have described use in individuals with very severe disease (doses in
the range of 1 gram/kg daily for five days), with efficacy in small series of 30 to 40
percent [59-62].
Details of administration and adverse effects are presented separately. (See
"Overview of intravenous immune globulin (IVIG) therapy" and "Intravenous
immune globulin: Adverse effects".)

As noted above, the autoantibodies have a half-life of two to three weeks (see
'Initial management' above). IVIG may help during this time by blocking
macrophage Fc receptors and preventing RBC destruction in the spleen and liver.

VTE prophylaxis and D-dimer testing — For individuals with brisk hemolysis (eg,
severe enough to require hospital admission or to cause a significant decline in
hemoglobin level), venous thromboembolism (VTE) prophylaxis should be used, as
individuals with hemolysis are at increased risk for thromboembolic complications.
(See "Prevention of venous thromboembolic disease in acutely ill hospitalized
medical adults".)

VTE prophylaxis may be used in other selected cases, such as in outpatients,

especially during episodes of active or severe hemolysis, due to this increased risk.

We also check a D-dimer in all new cases and perform bilateral lower extremity
compression ultrasonography with Doppler in all individuals with an elevated D-
dimer. (See 'Thromboembolic complications' below.)

TREATMENT FOR PERSISTENT DISEASE

It is common for patients to require additional treatment beyond glucocorticoids

and rituximab (approximately one-half of patients in two of the larger series) [4,9].
This generally applies to those with a hemoglobin <10 g/dL despite therapy and/or
inability to taper prednisone to ≤10 mg daily to maintain a higher hemoglobin level.

If glucocorticoids were used alone (without rituximab) for initial therapy, we add
rituximab. The major treatment options for persistent disease that does not
respond to glucocorticoids and/or rituximab include a variety of other
immunosuppressive and cytotoxic agents and splenectomy.

Small case series have shown good responses with rituximab for
persistent/refractory disease and for Evans syndrome:
● Responses in refractory disease as high as 77 to 92 percent have been
reported, with a significant portion of individuals having persistent response
for over a year [63-69].
 ● Responses have been seen in some Evans syndrome case reports but not
others [70-75]. (See 'Evans syndrome' below.)

These approaches have not been compared in randomized trials. We typically try at
least one or two other immunosuppressive agents before splenectomy. (See 'Other
immunosuppressive and cytotoxic agents' below.)

Other immunosuppressive and cytotoxic agents — Various other

immunosuppressive and cytotoxic agents have been reported to be effective in
AIHA and can be used for individuals who do not have a good response to
glucocorticoids and rituximab.

None of these have been compared with each other in a randomized trial, and the
choice among them may be individualized. We often use mycophenolate mofetil
(MMF) starting at a dose of 500 mg every 12 hours and escalating the dose every 2
weeks up to 1000 mg every 12 hours if necessary. Our preference for MMF is based
on our clinical experience and familiarity with this agent rather than on high-quality
clinical studies.

Children and young adults with coexisting autoimmune lymphoproliferative

syndrome (ALPS) often have a response to sirolimus. Individuals with severe
intravascular hemolysis are often treated with intravenous cyclophosphamide. We
generally defer splenectomy until we have tried at least one or two other
immunosuppressive agents.

Individuals who do not have a response to one agent may have success with
another [76]. Responses may take several weeks to occur. The decision regarding
when to switch from one agent to another (ie, deciding that an agent is ineffective)
is also individualized, as responses may occur over different time frames. Generally,
it is reasonable to switch if there is no response within three to four weeks (or if an
agent is not well-tolerated). These therapies are stopped when a stable remission is
documented.

In a series of 54 patients with severe refractory AIHA from 2019, the two most
commonly used agents were azathioprine (79 percent response rate) and
cyclophosphamide (59 percent response rate) [77]. Other small series have
reported similar or even better response rates, but these are likely subject to
reporting bias, and actual response rates may be lower [51].
● Cyclophosphamide – Cyclophosphamide is the most rapidly acting therapy
and may be used for severe anemia due to refractory AIHA. For mild anemia
due to refractory AIHA, we use one of the therapies mentioned below.

When using cyclophosphamide, we often give a single dose of 600 to 750 mg

per square meter intravenously (600 to 750 mg/m2) to an inpatient with severe
anemia who requires more than two units of RBCs per week despite
glucocorticoids or rituximab. This dose is based on personal experience; high
quality studies to guide dosing are lacking. High-dose cyclophosphamide (eg,
50 mg per kg daily for four days, based on ideal body weight) has also been
used [78]. We generally do not use this approach unless the 600 to 750 mg/m2
dose has been tried twice and is ineffective.

Although cyclophosphamide may be more effective than azathioprine, it has

numerous side effects including hair loss, gonadal toxicity, bone marrow
suppression, bladder irritation with hematuria, and leukemogenesis. Bladder
irritation can be minimized by giving the medication as a single dose in the
morning, increasing urinary output during the day, and voiding before retiring
to bed at night, or by intravenous pulse therapy. (See "General toxicity of
cyclophosphamide in rheumatic diseases".)
● Mycophenolate mofetil (MMF) – MMF often takes weeks to months before a
response occurs. Thus, we often use MMF for individuals with more stable
hemolysis who can be managed in the outpatient setting. A small series of
individuals treated with MMF reported many responses, including one
individual with Evans syndrome [79]. Another series that included four patients
with AIHA reported responses in all four [80]. A starting dose is 500 to 1000 mg
orally per day in two divided doses, increasing to 1000 to 2000 mg daily.
● Azathioprine – Azathioprine has been reported to result in responses, and
toxicity may be less than with prolonged courses of cyclophosphamide
[72,81,82]. It is given in an initial oral dose of 100 to 150 mg orally per day.
● Danazol – Case reports have described successful treatment with danazol
[76,83-85]. Dosing is started at 200 mg orally per day, increased to 600 to 800
mg per day, and reduced to 200 mg per day following response. One series of
16 individuals, including three with Evans syndrome, reported responses in 100
percent [86].
 ● Cyclosporin A – A series of 44 patients with AIHA and/or Evans syndrome
reported responses to cyclosporin A in 89 percent [87]. Smaller series have
reported similar response rates [88,89]. A starting dose is 5 to 10 mg/kg orally
per day in two divided doses, with subsequent dose adjustment depending on
hematologic response and renal function.
● Fostamatinib – A trial that randomly assigned 90 individuals with refractory
warm AIHA to receive fostamatinib or placebo found responses in 36 percent
with fostamatinib and 27 percent with placebo [90]. Post-hoc analysis that
removed individuals treated with glucocorticoids showed a more dramatic
difference in responses (33 percent with fostamatinib versus 14 percent with
placebo). Non-life-threatening adverse events were common (diarrhea,
hypertension, fatigue).
● Sirolimus – Children and young adults with coexisting ALPS often have a
response to sirolimus. (See "Autoimmune lymphoproliferative syndrome (ALPS):
Management and prognosis", section on 'Autoimmune manifestations'.)
● Plasma exchange – Case reports have described use of plasma exchange in
severe refractory AIHA, but in many cases, this was used in combination with
immunosuppression [91]. Plasma exchange for AIHA is considered a category
III indication by the American Society for Apheresis (ASFA); category III
indicates disorders for which the optimum role of apheresis therapy is not
established. (See "Therapeutic apheresis (plasma exchange or cytapheresis):
Indications and technology", section on 'ASFA therapeutic categories'.)
● Other agents – Case reports have described use of these agents, but these
therapies are unproven for warm AIHA, and we do not use them for warm
AIHA in our practice:

• Alemtuzumab, alone or in combination with low-dose rituximab [92-94].

• Vinca alkaloids (vincristine, vinblastine).
• Bortezomib [95,96].
• Daratumumab [97].
• Eculizumab [98-100].
• Venetoclax (in individuals with chronic lymphocytic leukemia [CLL]) [101].
Splenectomy
● Indications – Splenectomy may be used if glucocorticoids and rituximab are
ineffective, although its efficacy has never been compared with other
approaches in randomized trials. Splenectomy and medical therapies listed
above differ significantly in their risks and burdens, making shared decision-
making especially important in the decision between them.

Patients should have the opportunity to understand the permanence of

splenectomy, the likely efficacy, and the possible adverse effects. Some experts
reserve splenectomy for individuals who have not had a good response to
glucocorticoids and rituximab (or who cannot tolerate these therapies),
whereas others may prefer splenectomy to rituximab.

Individuals are especially likely to benefit from splenectomy if they have splenic
marginal zone lymphoma. (See "Splenic marginal zone lymphoma", section on
'Management'.)
● Efficacy – The efficacy of splenectomy in individuals with AIHA is similar to
glucocorticoids. In 32 individuals from the GIMEMA cohort treated with
splenectomy, the response rate was 75 percent [4].
● Contraindications – Splenectomy is not used in individuals if they have:

• Autoimmune lymphoproliferative syndrome (ALPS). (See "Autoimmune

lymphoproliferative syndrome (ALPS): Management and prognosis".)

• Cold-active antibodies. (See "Cold agglutinin disease" and "Paroxysmal cold

hemoglobinuria".)

The rationale for avoiding splenectomy and other contraindications is

discussed separately. (See "Elective (diagnostic or therapeutic) splenectomy",
section on 'Conditions in which splenectomy is generally contraindicated'.)
● Surgical planning – Preoperative and postoperative concerns are similar to
those for individuals with immune thrombocytopenia (ITP).

• Preoperative vaccinations should be provided against pneumococci,

meningococci, and haemophilus, preferably at least two to three weeks
before the procedure. (See "Prevention of infection in patients with impaired
splenic function".)

• Postoperative thromboprophylaxis is especially important as surgery,

splenectomy, and AIHA all independently increase venous
 thromboembolism (VTE) risk. (See 'Thromboembolic complications' below.)

• Patients should be educated about post-splenectomy immunosuppression

and the need to address fever or other infectious symptoms promptly. (See
"Clinical features, evaluation, and management of fever in patients with
impaired splenic function".)

These and other considerations such the role of laparoscopic versus open
procedures are discussed separately. (See "Elective (diagnostic or therapeutic)
splenectomy" and "Second-line and subsequent therapies for immune
thrombocytopenia (ITP) in adults", section on 'Splenectomy'.)
● Mechanism – The mechanism by which splenectomy reduces hemolysis may
include removal of a substantial portion of reticuloendothelial macrophages,
and in some cases, removal of the lymphocytes or plasma cells that produce
the autoantibodies.

MONITORING AND PROGNOSIS

Most adults with AIHA have an initial response to therapy within two to three
weeks. However, waxing and waning disease is common, and many individuals live
with chronic disease [1]. Patients should be educated about the possibility of
relapses and to seek medical attention for recurrent symptoms or other concerns.

A reasonable approach to monitoring during and after recovery is as follows:

● For individuals undergoing a glucocorticoid taper, we generally check the
complete blood count (CBC) every two to four weeks, although this is highly
variable depending on the patient's circumstances.
● For individuals receiving chronic immunosuppressive therapy, we individualize
the monitoring interval depending on the hemoglobin level (eg, more
frequently for those with hemoglobin of 8 to 9 g/dL than for someone with a
hemoglobin of 11 to 12 g/dL).
● For individuals who have had a complete response (return of their hemoglobin
to baseline and no evidence of hemolysis), we generally check the CBC every
three to four months during the first year and then yearly (or less frequently)
unless new signs or symptoms occur.
Relapses are treated similarly to the first episode of hemolysis, incorporating
information about which agents were most effective for that individual. Individuals
who did not receive rituximab for the initial episode might benefit from receiving it
if they have one or more relapses. (See 'Initial management' above.)

Prognosis depends on the underlying condition and other factors. In the GIMEMA
cohort of 308 individuals with AIHA followed for a median of approximately three
years, 63 had died, 11 (3.6 percent of the entire cohort) due to their disease [4].
Causes of death included infection, myocardial infarction, pulmonary embolism,
and multi-organ failure. Evans syndrome was associated with a higher mortality
(hazard ratio [HR] 6.8, 95% CI 1.99-23.63). Other series have reported survival of
approximately 90 percent at three years [102].

THROMBOEMBOLIC COMPLICATIONS

AIHA is associated with a significantly increased risk of venous thromboembolism

(VTE), which is further increased following splenectomy and with certain associated
conditions.

In one study, for example, of nine patients with warm AIHA who underwent
splenectomy, four developed postoperative portal vein thrombosis and a fifth
developed pulmonary embolism (PE) [9]. This high rate of VTE factors into our
preference for rituximab over splenectomy in most cases.
● We check D-dimer on all patients, and if positive, we perform bilateral lower
extremity compression ultrasound to evaluate for deep vein thrombosis (DVT).
● For individuals with dyspnea out of proportion to the degree of anemia, we
perform chest computed tomography to evaluate for PE.

Other implications include the need to adhere to thromboprophylaxis during

hospitalizations and other high-risk settings (eg, pregnancy), to have a low
threshold for evaluating symptoms of VTE, and to avoid other prothrombotic
stimuli when possible (eg, estrogen-containing contraceptives). (See "Prevention of
venous thromboembolic disease in acutely ill hospitalized medical adults".)

For individuals who develop a VTE, we generally consider them high-risk for
recurrence, and we often treat them with indefinite anticoagulation. If they are in a
stable remission (eg, hemoglobin >10 g/dL and lactate dehydrogenase [LDH] <1.5
times the upper limit of normal for the laboratory) and are receiving no therapy or
minimal therapy (eg, less than 10 mg daily of prednisone), we often discontinue
anticoagulation as long as there are no other major VTE risk factors. There are no
data comparing different anticoagulants in this setting, and AIHA does not
influence the choice of anticoagulant in individuals with VTE associated with AIHA.

SPECIAL CONSIDERATIONS

COVID-19 — Coronavirus disease 2019 (COVID-19) has been associated with AIHA,
although the prevalence in different patient groups has not been well-established
[10].

In a series of 103 consecutive individuals who were admitted to the hospital with
COVID-19 and had a sample sent to the laboratory for ABO and Rh typing or pre-
transfusion testing, nearly one-half (46 percent) had a positive direct antiglobulin
(Coombs) test (DAT), most of which were positive for IgG alone (without
complement) [7]. The DAT-positive individuals were more likely to be anemic
(median hemoglobin, 9.8, versus 12.2 in DAT-negative patients) and to require
transfusions, with a trend towards increased bilirubin and lactate dehydrogenase
(LDH) that was not statistically significant, suggesting an association between the
autoantibodies and clinically significant anemia. The mechanism is unknown but
appeared to involve autoantibodies directed against RBCs that are in some way
modified by the infection rather than directly bound by virus.

We would not intervene for a positive DAT without clear evidence of hemolysis.
Membrane-bound IgG can complicate pre-transfusion testing, although this should
not delay transfusion in individuals with life-threatening anemia. (See 'Stabilization
and transfusion for severe anemia' above.)

Drug-induced — (See "Drug-induced hemolytic anemia".)

Pregnancy — Warm AIHA may be exacerbated during pregnancy, and in rare

instances, the maternal autoantibody may cross the placenta and affect the fetus or
newborn [103-105].

In some cases, the newborn may only show a positive direct antiglobulin (Coombs)
test, while some may develop severe anemia and require treatment for
alloantibody-induced hemolytic anemia. (See "Management of non-RhD red blood
cell alloantibodies during pregnancy", section on 'Warm autoimmune hemolytic
anemia'.)

Evans syndrome — Evans syndrome refers to the co-occurrence of two or more

immune cytopenias, most often AIHA and immune thrombocytopenia (ITP) [106].
Less commonly, some patients will also have autoimmune neutropenia (15 percent
in one series) [72].

Evans syndrome is considered more difficult to treat (less responsive to standard

therapies, with more frequent relapses and higher mortality) than isolated warm
AIHA. In a series of 68 patients with Evans syndrome, short-term responses were
seen in over 80 percent, but only 22 (32 percent) were in remission off treatment at
a median follow-up of 4.8 years, and 16 (24 percent) had died [72].

We generally use glucocorticoids, rituximab, and mycophenolate mofetil in

combination, and we often add intravenous immune globulin (IVIG) if the platelet
count is <20,000/microL, although supporting data are lacking.

In addition to the therapies described above, case reports have described

responses to hematopoietic stem cell transplantation and IVIG [107-109]. In the
series of 68 patients, responses were most likely with glucocorticoids, rituximab,
and splenectomy [72]. (See 'Glucocorticoids with or without rituximab as first-line
agents' above and 'Rituximab (alone or added to glucocorticoids)' above and
'Splenectomy' above and 'Other immunosuppressive and cytotoxic agents' above.)

Resource-limited settings — Management of AIHA in communities with limited

access to resources is an important consideration given the costs of extensive
resources discussed above. Not surprisingly, there are a paucity of publications on
this issue. As examples:
● A report from South India showed reasonably good results using oral
prednisolone as initial therapy (1.5 mg/kg daily for three weeks, followed by a
gradual taper), with azathioprine as a second-line therapy if glucocorticoids
were ineffective [110]. Responses were seen in 26 of 29 (90 percent) of the
glucocorticoid-treated patients and 11 of 14 (79 percent) of the azathioprine-
treated patients.
● A single referral center in Mexico City used glucocorticoids as first-line therapy
with splenectomy as second-line therapy if glucocorticoids were ineffective
[111]. Responses were seen in 75 of 89 (84 percent) of the glucocorticoid-
 treated patients and in 34 of 36 (94 percent) of the patients who underwent
splenectomy. Due to financial constraints, rituximab could only be considered
as third-line therapy in only 2 of 89 patients.

SOCIETY GUIDELINE LINKS

Links to society and government-sponsored guidelines from selected countries and

regions around the world are provided separately. (See "Society guideline links:
Anemia in adults".)

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and
"Beyond the Basics." The Basics patient education pieces are written in plain
language, at the 5th to 6th grade reading level, and they answer the four or five key
questions a patient might have about a given condition. These articles are best for
patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and
more detailed. These articles are written at the 10th to 12th grade reading level and
are best for patients who want in-depth information and are comfortable with
some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage
you to print or e-mail these topics to your patients. (You can also locate patient
education articles on a variety of subjects by searching on "patient info" and the
keyword(s) of interest.)
● Basics topic (see "Patient education: Autoimmune hemolytic anemia (The
Basics)")

SUMMARY AND RECOMMENDATIONS

● Definition – Warm autoimmune hemolytic anemia (AIHA) is caused by
autoantibodies that react with self red blood cells (RBCs) at body temperature.
(See 'Terminology' above.)
● Pathogenesis – Warm AIHA can arise spontaneously (primary) or associated
with an autoimmune, infectious, lymphoproliferative, or immunodeficiency
syndrome or medication (secondary). Approximately 50 to 60 percent of cases
are secondary. Hemolysis is mostly extravascular. (See 'Pathogenesis' above.)
● Prevalence – Warm AIHA affects approximately 10 per million and accounts for
70 to 80 percent of AIHA. (See 'Epidemiology' above.)
● Presentation – Presenting symptoms related to anemia range from mild to
fulminant. Mild splenomegaly may be present. (See 'Clinical manifestations'
above.)
● Evaluation – The history focuses on underlying conditions and medications
( table 1) and possible alternate diagnoses (cold-induced symptoms,
transfusion history). Laboratory evaluation includes complete blood count
(CBC), reticulocyte count, hemolysis testing ( table 2), and blood smear
review. Direct antiglobulin (Coombs) testing distinguishes immune from
nonimmune hemolysis ( table 3). Warm AIHA is DAT-positive hemolytic
anemia not due to another cause ( algorithm 1). (See 'Evaluation and
diagnosis' above.)
● Differential – The differential diagnosis includes drug-induced hemolysis, cold
agglutinin disease (CAD), paroxysmal cold hemoglobinuria (PCH), paroxysmal
nocturnal hemoglobinuria (PNH), and hereditary spherocytosis. (See
'Differential diagnosis' above.)
● Management

• Transfusions – Severe anemia (hemoglobin <7 g/dL) and hemodynamic

compromise are medical emergencies. Contact the blood bank or
transfusion medicine liaison immediately and alert them of the need for
transfusion in an individual with AIHA ( algorithm 2). Emergency release
blood may be used if needed. In less urgent situations, extended phenotype
matching is advised to identify the most compatible blood. (See 'Stabilization
and transfusion for severe anemia' above.)

• Underlying disorder – Treatment of the underlying condition is appropriate

but may not always halt hemolysis rapidly ( algorithm 2). (See 'Treatment
of the underlying disorder' above.)
 • Immunosuppression – For symptomatic patients, we suggest a
glucocorticoid (prednisone 1 to 2 mg/kg daily for two to three weeks
followed by a very slow taper) plus rituximab (four weekly treatments) rather
than a glucocorticoid alone ( algorithm 2) (Grade 2B). A glucocorticoid
alone is reasonable if hemolysis is mild and/or rituximab would create an
unacceptable burden toxicity. (See 'Glucocorticoids with or without rituximab
as first-line agents' above and 'Rituximab (alone or added to
glucocorticoids)' above.)

• Second-line treatments – For individuals lacking an initial response, we add

rituximab if not given previously. Therapy for those who lack a response to
glucocorticoids and rituximab is individualized; we often use mycophenolate
mofetil. Children and young adults with coexisting autoimmune
lymphoproliferative syndrome often have a response to sirolimus.
Individuals with severe intravascular hemolysis are often treated with
intravenous cyclophosphamide. We generally defer splenectomy until one or
two other immunosuppressive agents have been tried. (See 'Treatment for
persistent disease' above.)

• Folic acid – We suggest daily folic acid (1 mg) as long as hemolysis continues
(Grade 2C). (See 'Folic acid' above.)
● Monitoring – Monitoring includes CBC, reticulocyte count, and lactate
dehydrogenase (LDH). The interval depends on severity and disease course.
Initial responses are common, but many individuals require retreatment
periodically. (See 'Monitoring and prognosis' above.)
● Complications – Up to 30 percent of patients have thromboembolic
complications. We check a D-dimer in all patients and evaluate for deep vein
thrombosis (DVT) if the D-dimer is high. We evaluate for pulmonary embolism
in any patient with dyspnea out of proportion to the degree of anemia. (See
'Thromboembolic complications' above.)

ACKNOWLEDGMENTS

The UpToDate editorial staff acknowledges Wendell F Rosse, MD, who contributed
to earlier versions of this topic review.
UpToDate gratefully acknowledges Stanley L Schrier, MD (deceased), who
contributed as Section Editor on earlier versions of this topic and was a founding
Editor-in-Chief for UpToDate in Hematology.

The UpToDate editorial staff also acknowledges the extensive contributions of

William C Mentzer, MD, to earlier versions of this and many other topic reviews.
REFERENCES

1. Brodsky RA. Warm Autoimmune Hemolytic Anemia. N Engl J Med 2019; 381:647.
2. Reusser P, Osterwalder B, Burri H, Speck B. Autoimmune hemolytic anemia
associated with IgA--diagnostic and therapeutic aspects in a case with long-
term follow-up. Acta Haematol 1987; 77:53.
3. Sokol RJ, Booker DJ, Stamps R, et al. IgA red cell autoantibodies and
autoimmune hemolysis. Transfusion 1997; 37:175.
4. Barcellini W, Fattizzo B, Zaninoni A, et al. Clinical heterogeneity and predictors
of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308
patients. Blood 2014; 124:2930.
5. Engelfriet CP, Borne AE, Beckers D, Van Loghem JJ. Autoimmune haemolytic
anaemia: serological and immunochemical characteristics of the
autoantibodies; mechanisms of cell destruction. Ser Haematol 1974; 7:328.
6. Schur PH. IgG subclasses--a review. Ann Allergy 1987; 58:89.
7. Berzuini A, Bianco C, Paccapelo C, et al. Red cell-bound antibodies and
transfusion requirements in hospitalized patients with COVID-19. Blood 2020;
136:766.
8. Jacobs JW, Binns TC, Abels E, et al. Warm autoantibodies mimicking
alloantibodies: Three cases of autoantibodies with unusual antigenic specificity.
Am J Clin Pathol 2023; 160:561.
9. Roumier M, Loustau V, Guillaud C, et al. Characteristics and outcome of warm
autoimmune hemolytic anemia in adults: New insights based on a single-center
experience with 60 patients. Am J Hematol 2014; 89:E150.
10. Berentsen S, Barcellini W. Autoimmune Hemolytic Anemias. N Engl J Med 2021;
385:1407.
11. Leaf RK, O'Brien KL, Leaf DE, Drews RE. Autoimmune hemolytic anemia in a
young man with acute hepatitis E infection. Am J Hematol 2017; 92:E77.
12. Lazarian G, Quinquenel A, Bellal M, et al. Autoimmune haemolytic anaemia
associated with COVID-19 infection. Br J Haematol 2020; 190:29.
13. Lopez C, Kim J, Pandey A, et al. Simultaneous onset of COVID-19 and
autoimmune haemolytic anaemia. Br J Haematol 2020; 190:31.
14. Sallah S, Wan JY, Hanrahan LR. Future development of lymphoproliferative
disorders in patients with autoimmune hemolytic anemia. Clin Cancer Res 2001;
7:791.
15. Barcellini W, Fattizzo B, Zaninoni A. Management of refractory autoimmune
hemolytic anemia after allogeneic hematopoietic stem cell transplantation:
current perspectives. J Blood Med 2019; 10:265.
16. Wang C, Sun B, Wu K, et al. Clinical, immunological features, treatments, and
outcomes of autoimmune hemolytic anemia in patients with RAG deficiency.
Blood Adv 2024; 8:603.
17. Stahl D, Lacroix-Desmazes S, Heudes D, et al. Altered control of self-reactive IgG
by autologous IgM in patients with warm autoimmune hemolytic anemia. Blood
2000; 95:328.
18. Woolley AE, Montgomery MW, Savage WJ, et al. Post-Babesiosis Warm
Autoimmune Hemolytic Anemia. N Engl J Med 2017; 376:939.
19. Shatzel JJ, Donohoe K, Chu NQ, et al. Profound autoimmune hemolysis and
Evans syndrome in two asplenic patients with babesiosis. Transfusion 2015;
55:661.
20. Eichner ER. Spider bite hemolytic anemia: positive Coombs' test,
erythrophagocytosis, and leukoerythroblastic smear. Am J Clin Pathol 1984;
81:683.
21. Hansen DL, Möller S, Andersen K, et al. Increasing Incidence and Prevalence of
Acquired Hemolytic Anemias in Denmark, 1980-2016. Clin Epidemiol 2020;
12:497.
22. Maquet J, Lafaurie M, Walter O, et al. Epidemiology of autoimmune hemolytic
anemia: A nationwide population-based study in France. Am J Hematol 2021;
96:E291.
23. Barcellini W. Immune Hemolysis: Diagnosis and Treatment Recommendations.
Semin Hematol 2015; 52:304.
24. Giannouli S, Voulgarelis M, Ziakas PD, Tzioufas AG. Anaemia in systemic lupus
erythematosus: from pathophysiology to clinical assessment. Ann Rheum Dis
2006; 65:144.
25. Tranekær S, Hansen DL, Frederiksen H. Epidemiology of Secondary Warm
Autoimmune Haemolytic Anaemia-A Systematic Review and Meta-Analysis. J
Clin Med 2021; 10.
26. Liesveld JL, Rowe JM, Lichtman MA. Variability of the erythropoietic response in
autoimmune hemolytic anemia: analysis of 109 cases. Blood 1987; 69:820.
27. Jones J. Transfusion in oligemia. In: Blood Transfusion in Clinical Medicine, 8th e
d, Mollison PL, Engelfriet CP, Contreras M (Eds), Blackwell, Oxford 1987. p.41.
28. Conley CL, Lippman SM, Ness P. Autoimmune hemolytic anemia with
reticulocytopenia. A medical emergency. JAMA 1980; 244:1688.
29. Marchand A, Galen RS, Van Lente F. The predictive value of serum haptoglobin
in hemolytic disease. JAMA 1980; 243:1909.
30. Birgens H, Frederiksen H, Hasselbalch HC, et al. A phase III randomized trial
comparing glucocorticoid monotherapy versus glucocorticoid and rituximab in
patients with autoimmune haemolytic anaemia. Br J Haematol 2013; 163:393.
31. Mantripragada K, Quesenberry PJ. Doublet spherocytes. Blood 2014; 124:12.
32. Chaplin H Jr. Clinical usefulness of specific antiglobulin reagents in autoimmune
hemolytic anemias. Prog Hematol 1973; 8:25.
33. Wheeler CA, Calhoun L, Blackall DP. Warm reactive autoantibodies: clinical and
serologic correlations. Am J Clin Pathol 2004; 122:680.
34. Sachs UJ, Röder L, Santoso S, Bein G. Does a negative direct antiglobulin test
exclude warm autoimmune haemolytic anaemia? A prospective study of 504
cases. Br J Haematol 2006; 132:655.
35. Meulenbroek EM, Wouters D, Zeerleder SS. Lyse or not to lyse: Clinical
significance of red blood cell autoantibodies. Blood Rev 2015; 29:369.
36. Podberezin M, Levina A, Romanova L, et al. Quantitation of red cell-bound
immunoglobulins and complement in lymphoma patients. Immunohematology
2000; 16:147.
37. Bencomo AA, Diaz M, Alfonso Y, et al. Quantitation of red cell-bound IgG, IgA,
and IgM in patients with autoimmune hemolytic anemia and blood donors by
enzyme-linked immunosorbent assay. Immunohematology 2003; 19:47.
38. Garratty G, Arndt P, Domen R, et al. Severe autoimmune hemolytic anemia
associated with IgM warm autoantibodies directed against determinants on or
associated with glycophorin A. Vox Sang 1997; 72:124.
39. Janvier D, Sellami F, Missud F, et al. Severe autoimmune hemolytic anemia
caused by a warm IgA autoantibody directed against the third loop of band 3
(RBC anion-exchange protein 1). Transfusion 2002; 42:1547.
40. Bardill B, Mengis C, Tschopp M, Wuillemin WA. Severe IgA-mediated auto-
immune haemolytic anaemia in a 48-yr-old woman. Eur J Haematol 2003; 70:60.
41. Arndt PA, Leger RM, Garratty G. Serologic findings in autoimmune hemolytic
anemia associated with immunoglobulin M warm autoantibodies. Transfusion
2009; 49:235.
42. Bartolmäs T, Salama A. A dual antiglobulin test for the detection of weak or
nonagglutinating immunoglobulin M warm autoantibodies. Transfusion 2010;
50:1131.
43. Hill A, Hill QA. Autoimmune hemolytic anemia. Hematology Am Soc Hematol
Educ Program 2018; 2018:382.
44. Thedsawad A, Taka O, Wanachiwanawin W. Significances of red cell bound
immunoglobulin G as detected by flow cytometry in patients with Coombs-
negative immune hemolysis. Transfus Med 2016; 26:130.
45. Brodsky RA, Mukhina GL, Li S, et al. Improved detection and characterization of
paroxysmal nocturnal hemoglobinuria using fluorescent aerolysin. Am J Clin
Pathol 2000; 114:459.
46. Petz LD. A physician's guide to transfusion in autoimmune haemolytic anaemia.
Br J Haematol 2004; 124:712.
47. Ness PM. How do I encourage clinicians to transfuse mismatched blood to
patients with autoimmune hemolytic anemia in urgent situations? Transfusion
2006; 46:1859.
48. Sokol RJ, Hewitt S, Booker DJ, Morris BM. Patients with red cell autoantibodies:
selection of blood for transfusion. Clin Lab Haematol 1988; 10:257.
49. Salama A, Berghöfer H, Mueller-Eckhardt C. Red blood cell transfusion in warm-
type autoimmune haemolytic anaemia. Lancet 1992; 340:1515.
50. Schuh AH, Parry-Jones N, Appleby N, et al. Guideline for the treatment of
chronic lymphocytic leukaemia: A British Society for Haematology Guideline. Br
J Haematol 2018; 182:344.
51. Go RS, Winters JL, Kay NE. How I treat autoimmune hemolytic anemia. Blood
2017; 129:2971.
52. Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias.
Haematologica 2014; 99:1547.
53. Zupańska B, Sylwestrowicz T, Pawelski S. The results of prolonged treatment of
autoimmune haemolytic anaemia. Haematologia (Budap) 1981; 14:425.
54. Hosoba S, Jaye DL, Cohen C, et al. Successful treatment of severe immune
hemolytic anemia after allogeneic stem cell transplantation with bortezomib:
report of a case and review of literature. Transfusion 2015; 55.
55. Michel M, Terriou L, Roudot-Thoraval F, et al. A randomized and double-blind
controlled trial evaluating the safety and efficacy of rituximab for warm auto-
immune hemolytic anemia in adults (the RAIHA study). Am J Hematol 2017;
92:23.
56. Barcellini W, Zaja F, Zaninoni A, et al. Low-dose rituximab in adult patients with
idiopathic autoimmune hemolytic anemia: clinical efficacy and biologic studies.
Blood 2012; 119:3691.
57. Barcellini W, Zaja F, Zaninoni A, et al. Sustained response to low-dose rituximab
in idiopathic autoimmune hemolytic anemia. Eur J Haematol 2013; 91:546.
58. Cragg MS, Walshe CA, Ivanov AO, Glennie MJ. The biology of CD20 and its
potential as a target for mAb therapy. Curr Dir Autoimmun 2005; 8:140.
59. Flores G, Cunningham-Rundles C, Newland AC, Bussel JB. Efficacy of intravenous
immunoglobulin in the treatment of autoimmune hemolytic anemia: results in
73 patients. Am J Hematol 1993; 44:237.
60. Macintyre EA, Linch DC, Macey MG, Newland AC. Successful response to
intravenous immunoglobulin in autoimmune haemolytic anaemia. Br J
Haematol 1985; 60:387.
61. Bussel JB, Cunningham-Rundles C, Abraham C. Intravenous treatment of
autoimmune hemolytic anemia with very high dose gammaglobulin. Vox Sang
1986; 51:264.
62. Majer RV, Hyde RD. High-dose intravenous immunoglobulin in the treatment of
autoimmune haemolytic anaemia. Clin Lab Haematol 1988; 10:391.
63. Dierickx D, Verhoef G, Van Hoof A, et al. Rituximab in auto-immune haemolytic
anaemia and immune thrombocytopenic purpura: a Belgian retrospective
multicentric study. J Intern Med 2009; 266:484.
64. Peñalver FJ, Alvarez-Larrán A, Díez-Martin JL, et al. Rituximab is an effective and
safe therapeutic alternative in adults with refractory and severe autoimmune
hemolytic anemia. Ann Hematol 2010; 89:1073.
65. Zhang X, Sun J. [Lower dose of rituximab in the treatment of elderly
autoimmune hemolytic anemia]. Zhonghua Xue Ye Xue Za Zhi 2014; 35:236.
66. D'Arena G, Laurenti L, Capalbo S, et al. Rituximab therapy for chronic
lymphocytic leukemia-associated autoimmune hemolytic anemia. Am J Hematol
2006; 81:598.
67. Gupta N, Kavuru S, Patel D, et al. Rituximab-based chemotherapy for steroid-
refractory autoimmune hemolytic anemia of chronic lymphocytic leukemia.
Leukemia 2002; 16:2092.
68. Bussone G, Ribeiro E, Dechartres A, et al. Efficacy and safety of rituximab in
adults' warm antibody autoimmune haemolytic anemia: retrospective analysis
of 27 cases. Am J Hematol 2009; 84:153.
69. Maung SW, Leahy M, O'Leary HM, et al. A multi-centre retrospective study of
rituximab use in the treatment of relapsed or resistant warm autoimmune
haemolytic anaemia. Br J Haematol 2013; 163:118.
70. Shanafelt TD, Madueme HL, Wolf RC, Tefferi A. Rituximab for immune cytopenia
in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic
anemia, and Evans syndrome. Mayo Clin Proc 2003; 78:1340.
71. Mantadakis E, Danilatou V, Stiakaki E, Kalmanti M. Rituximab for refractory
Evans syndrome and other immune-mediated hematologic diseases. Am J
Hematol 2004; 77:303.
72. Michel M, Chanet V, Dechartres A, et al. The spectrum of Evans syndrome in
adults: new insight into the disease based on the analysis of 68 cases. Blood
2009; 114:3167.
73. Michel M. [Warm autoimmune hemolytic anemias and Evans syndrome in
adults]. Rev Med Interne 2008; 29:105.
74. Rao A, Kelly M, Musselman M, et al. Safety, efficacy, and immune reconstitution
after rituximab therapy in pediatric patients with chronic or refractory
hematologic autoimmune cytopenias. Pediatr Blood Cancer 2008; 50:822.
75. Park CY, Chung CH. A patient with mixed type Evans syndrome: efficacy of
rituximab treatment. J Korean Med Sci 2006; 21:1115.
76. Chan AC, Sack K. Danazol therapy in autoimmune hemolytic anemia associated
with systemic lupus erythematosus. J Rheumatol 1991; 18:280.
77. Hantaweepant C, Pairattanakorn P, Karaketklang K, et al. Efficacy and safety of
second-line treatment in Thai patients with primary warm-type autoimmune
hemolytic anemia. Hematology 2019; 24:720.
78. Moyo VM, Smith D, Brodsky I, et al. High-dose cyclophosphamide for refractory
autoimmune hemolytic anemia. Blood 2002; 100:704.
79. Kotb R, Pinganaud C, Trichet C, et al. Efficacy of mycophenolate mofetil in adult
refractory auto-immune cytopenias: a single center preliminary study. Eur J
Haematol 2005; 75:60.
80. Howard J, Hoffbrand AV, Prentice HG, Mehta A. Mycophenolate mofetil for the
treatment of refractory auto-immune haemolytic anaemia and auto-immune
thrombocytopenia purpura. Br J Haematol 2002; 117:712.
81. Pirofsky B. Immune haemolytic disease: the autoimmune haemolytic anaemias.
Clin Haematol 1975; 4:167.
82. Worlledge SM, Brain MC, Cooper AC, et al. Immmunosuppressive drugs in the
treatment of autoimmune haemolytic anaemia. Proc R Soc Med 1968; 61:1312.
83. Pignon JM, Poirson E, Rochant H. Danazol in autoimmune haemolytic anaemia.
Br J Haematol 1993; 83:343.
84. Ahn YS, Harrington WJ, Mylvaganam R, et al. Danazol therapy for autoimmune
hemolytic anemia. Ann Intern Med 1985; 102:298.
85. Shinohara K, Okafuji K, Ayame H, Ueda N. [Idiopathic autoimmune hemolytic
anemia successfully treated with danazol]. Rinsho Ketsueki 1990; 31:256.
86. Cervera H, Jara LJ, Pizarro S, et al. Danazol for systemic lupus erythematosus
with refractory autoimmune thrombocytopenia or Evans' syndrome. J
Rheumatol 1995; 22:1867.
87. Liu H, Shao Z, Jing L. [The effectiveness of cyclosporin A in the treatment of
autoimmune hemolytic anemia and Evans syndrome]. Zhonghua Xue Ye Xue Za
Zhi 2001; 22:581.
88. Emilia G, Messora C, Longo G, Bertesi M. Long-term salvage treatment by
cyclosporin in refractory autoimmune haematological disorders. Br J Haematol
1996; 93:341.
89. Tsudo M, Moriguchi T. [Effective cyclosporine therapy to resistant-Evans
syndrome]. Rinsho Ketsueki 1996; 37:1289.
90. Kuter DJ, Piatek C, Röth A, et al. Fostamatinib for warm antibody autoimmune
hemolytic anemia: Phase 3, randomized, double-blind, placebo-controlled,
global study (FORWARD). Am J Hematol 2024; 99:79.
91. Silva VA, Seder RH, Weintraub LR. Synchronization of plasma exchange and
cyclophosphamide in severe and refractory autoimmune hemolytic anemia. J
Clin Apher 1994; 9:120.
92. Willis F, Marsh JC, Bevan DH, et al. The effect of treatment with Campath-1H in
patients with autoimmune cytopenias. Br J Haematol 2001; 114:891.
93. Robak T. Monoclonal antibodies in the treatment of autoimmune cytopenias.
Eur J Haematol 2004; 72:79.
94. Gómez-Almaguer D, Solano-Genesta M, Tarín-Arzaga L, et al. Low-dose
rituximab and alemtuzumab combination therapy for patients with steroid-
refractory autoimmune cytopenias. Blood 2010; 116:4783.
95. Fadlallah J, Michel M, Crickx E, et al. Bortezomib and dexamethasone, an
original approach for treating multi-refractory warm autoimmune haemolytic
anaemia. Br J Haematol 2019; 187:124.
96. Ratnasingam S, Walker PA, Tran H, et al. Bortezomib-based antibody depletion
for refractory autoimmune hematological diseases. Blood Adv 2016; 1:31.
 97. Schuetz C, Hoenig M, Moshous D, et al. Daratumumab in life-threatening
autoimmune hemolytic anemia following hematopoietic stem cell
transplantation. Blood Adv 2018; 2:2550.
98. Ma K, Caplan S. Refractory IgG Warm Autoimmune Hemolytic Anemia Treated
with Eculizumab: A Novel Application of Anticomplement Therapy. Case Rep
Hematol 2016; 2016:9181698.
99. Neave L, Wilson AJ, Lissack M, Scully M. Severe refractory idiopathic warm
autoimmune haemolytic anaemia responsive to complement inhibition with
eculizumab. BMJ Case Rep 2018; 11.
100. Rovira J, Cid J, Gutiérrez-García G, et al. Fatal immune hemolytic anemia
following allogeneic stem cell transplantation: report of 2 cases and review of
literature. Transfus Med Rev 2013; 27:166.
101. Galindo-Navarro P, Delgado-García A, Rodríguez-Gil MA, Puerta-Puerta JM.
Venetoclax for treating refractory autoimmune hemolytic anemia in chronic
lymphocytic leukemia: report of two cases in Spain. Haematologica 2023;
108:2261.
102. Yılmaz F, Kiper D, Koç M, et al. Clinical Features and Treatment Outcomes of
Warm Autoimmune Hemolytic Anemia: A Retrospective Analysis of 60 Turkish
Patients. Indian J Hematol Blood Transfus 2019; 35:523.
103. Sokol RJ, Hewitt S, Stamps BK. Erythrocyte autoantibodies, autoimmune
haemolysis and pregnancy. Vox Sang 1982; 43:169.
104. Lawe JE. Successful exchange transfusion of an infant for AIHA developing late
in mother's pregnancy. Transfusion 1982; 22:66.
105. Williamson TD, Liles LH, Blackall DP. A maternal warm-reactive autoantibody
presenting as a positive direct antiglobulin test in a neonate.
Immunohematology 1997; 13:6.
106. Fattizzo B, Michel M, Giannotta JA, et al. Evans syndrome in adults: an
observational multicenter study. Blood Adv 2021; 5:5468.
107. Norton A, Roberts I. Management of Evans syndrome. Br J Haematol 2006;
132:125.
108. Mathew P, Chen G, Wang W. Evans syndrome: results of a national survey. J
Pediatr Hematol Oncol 1997; 19:433.
109. Oyama Y, Papadopoulos EB, Miranda M, et al. Allogeneic stem cell
transplantation for Evans syndrome. Bone Marrow Transplant 2001; 28:903.
110. Prabhu R, Bhaskaran R, Shenoy V, et al. Clinical characteristics and treatment
outcomes of primary autoimmune hemolytic anemia: a single center study
from South India. Blood Res 2016; 51:88.
111. Alonso HC, Manuel AV, Amir CG, et al. Warm autoimmune hemolytic anemia:
experience from a single referral center in Mexico City. Blood Res 2017; 52:44.

Topic 7078 Version 59.0

© 2024 UpToDate, Inc. All rights reserved.