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Warm autoimmune hemolytic anemia (AIHA) in adults

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
Literature review current through: Dec 2022. | This topic last updated: May 09, 2022.

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.

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.)

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) [4,8,9]. 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 [10].

Cases of AIHA with SARS-CoV-2 (the virus that causes coronavirus disease 2019 [COVID-19]) have also been reported [11,12]. (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) [13].

Immunodeficiency – states including inherited immunodeficiencies, hematopoietic stem cell transplant (HCT), solid organ transplant, and hypogammaglobulinemia. The reported incidence of AIHA following allogeneic HCT is 4 to 6 percent [14].

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 pathogenetic titer, or that control of IgG autoreactivity by autologous IgM becomes defective [15].

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 [16]. 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) [17]. (See 'Evans syndrome' below.)

Spider bite – Brown recluse spider bites can rarely cause severe intravascular hemolysis and in some cases AIHA [18]. 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 'Solid organ transplant recipient' and "Kidney transplantation in adults: 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) [19,20]. A 2021 review cited an incidence of 5 to 10 per 1 million [9].

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 [1,21].

Prevalence of secondary warm AIHA – The approximate prevalence of warm AIHA in selected underlying conditions is as follows [14,22]:

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 [23].

CLINICAL MANIFESTATIONS — There is significant heterogeneity in presenting symptoms, ranging from mild to fulminant, as illustrated in several case series [4,8,24].

Findings include:

Anemia-related symptoms (dyspnea on exertion, fatigue, bounding pulse or palpitations) in at least three-fourths of individuals.

Jaundice or dark urine and splenomegaly in approximately one-third. In some cases, splenomegaly is due to an underlying lymphoproliferative disorder.

Chest pain in 7 percent.

Evans syndrome 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 [25]. 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) [24]. 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]) [24].

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 [24,26].

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 [8]. 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 [27].

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 [4,28]. Indirect bilirubin is in the range of 2 to 3 mg/dL (35 to 51 micromol/L) [28].

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 [8,29].

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 [30-32]. 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 [33]. (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 [14]. 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 [34,35]. 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 [2,36-41].

Testing using more sensitive methods such as flow cytometry can sometimes identify IgG bound to RBCs [42]. 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 [43].

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 [41].

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 — 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.

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 [44,45]. 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.

Emergency release blood may be used if there are challenges in identifying blood using the standard type and antibody screen protocol. (See "Pretransfusion testing for red blood cell transfusion", section on 'Emergency release blood for life-threatening anemia or bleeding'.)

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 [41]. 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 "Transfusion in individuals with complex serologies on pretransfusion testing", 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 [46,47]. 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 [47].

If transfusion-dependent hemolysis continues, we may add intravenous immune globulin (IVIG). (See 'IVIG' below.)

Treatment of the underlying disorder — Approximately 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 [1,41]. 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 [48].

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 [1,9]. 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 [49]. 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) [1,50]. 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 [8,51]. However, as many as half of individuals who have a response will experience a relapse within the first year [49]. 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 [14,52].

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 side 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)

IndicationsRituximab 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) [28]. 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) [53]. 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 [54,55]. Therapy was well tolerated.

Adverse effectsRituximab 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 [56]. 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 [57-60].

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 half of patients in two of the larger series) [4,8]. 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 [61-67].

Responses have been seen in some Evans syndrome case reports but not others [68-73]. (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 — A large number of 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 [74]. 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) [75]. 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 [49].

CyclophosphamideCyclophosphamide 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 [76]. 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 [77]. Another series that included four patients with AIHA reported responses in all four [78]. A starting dose is 500 to 1000 mg orally per day in two divided doses, increasing to 1000 to 2000 mg daily.

AzathioprineAzathioprine has been reported to result in responses, and toxicity may be less than with prolonged courses of cyclophosphamide [70,79,80]. 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 [74,81-83]. 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 [84].

Cyclosporin A – A series of 44 patients with AIHA and/or Evans syndrome reported responses to cyclosporin A in 89 percent [85]. Smaller series have reported similar response rates [86,87]. 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.

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 [88]. 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 [89-91].

Vinca alkaloids (vincristine, vinblastine).

Bortezomib [92,93].

Daratumumab [94].

Eculizumab [95-97].

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 are 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 [98].

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) [8]. 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 [9].

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 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 [99-101].

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) [102]. Less commonly, some patients will also have autoimmune neutropenia (15 percent in one series) [70].

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 [70].

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 [103-105]. In the series of 68 patients, responses were most likely with glucocorticoids, rituximab, and splenectomy [70]. (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 [106]. 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 [107]. 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.

We are saddened by the death of Stanley L Schrier, MD, who passed away in August 2019. The UpToDate editorial staff gratefully acknowledges Dr. Schrier's role as author on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.

The UpToDate editorial staff also acknowledges the extensive contributions of William C Mentzer, MD, to earlier versions of this and many other topic reviews.

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