Autoimmune Hemolytic Anemias

Autoimmune hemolytic anemia (AIHA) refers to a group of disorders where autoantibodies are directed against red blood cell (RBC) membrane antigens resulting in shortened RBC survival (normally 100–120 days) through activation of the complement system and/or RBC removal within the reticuloendothelial system (RES). Classification of AIHA includes warm autoimmune hemolytic anemia (WAIHA), cold agglutinin disease (CAD), mixed-type AIHA due to wide thermal amplitude of the autoantibodies, drug-induced hemolytic anemia, and paroxysmal cold hemoglobinuria (PCH). The causes may include medications, autoimmune disease, lymphoma, or hematopoietic malignancy associated with monoclonal gammopathy, or recent viral infection. AIHA is classified as idiopathic if no underlying cause is identified.

In the AIHAs, the degree of hemolysis depends on antibody class and characteristics, such as concentration, “antigen” affinity, ability to fix complement, and thermal amplitude. These antibodies typically react as “panagglutinins,” meaning they show in vitro reactivity with all tested RBCs. These antibodies bind to a ubiquitous antigen or have nonspecific binding. In WAIHA, IgG autoantibody most commonly reacts with Rh group proteins or glycophorins on the RBC surface as panagglutinin antibodies. These IgG autoantibodies “coat” RBCs, and these coated RBCs are removed by phagocytosis by Fcγ receptors primarily within the spleen, thus achieving extravascular hemolysis. Drugs most commonly implicated in AIHA include antibiotics, such as penicillin, ceftriaxone, cefotetan, and piperacillin, as well as certain nonsteroidal antiinflammatory drugs, quinine, purine nucleoside analogues (e.g., fludarabine), and platinums (e.g., cisplatinin).

In contrast to IgG alloantibodies, IgM molecules efficiently activate the complement cascade (starting with C1q) and can result in intravascular hemolysis. The degree of intravascular hemolysis is affected by antibody concentration, thermal amplitude, and amount of inactivation by complement regulatory proteins, such as decay-accelerating factor (DAF or CD55) and membrane inhibitor of reactive lysis (MIRL, HRF, or CD59). Cold agglutinins (CAs) are autoantibodies present in most individuals, but typically have no clinical significance, unless they are sufficiently reactive at peripheral body temperatures. Both benign and pathologic conditions are caused by IgM autoantibodies, usually of I or i antigen specificity. CAD is caused by autoantibodies that are of higher titer (>512 at 4°C and >128 at 22°C) and are associated with agglutination or complement fixation at 30–37°C. Patients undergoing cardiac surgery with CA, in the absence of CAD, can safely be managed by undergoing normothermic cardiopulmonary bypass (avoiding cold cardioplegia). In contrast, hematology should be consulted for patients with CAD before cardiac surgery, and additional laboratory testing should be performed, including CA titers. The underlying causes of CAD include Mycoplasma pneumoniae , Waldenstrom macroglobulinemia, and IgM monoclonal gammopathy. Severe cases of CAD often result in intravascular hemolysis due to complement activation, but can result in extravascular hemolysis because RBCs are in the cool peripheral circulation for a short time period, and when the RBCs are warmed in the central circulation, the IgM dissociates. The short time period may only be sufficient to activate the complement cascade to the C3b stage and not to the membrane attack complex stage. The C3b-coated RBCs are cleared by hepatic macrophages with receptors specific for C3b, if there is a sufficient quantity of C3b molecules on the RBCs (>500–800/RBC). C3b-coated RBCs, which are not removed from the hepatic circulation, are unharmed, and the C3b is degraded to C3dg; C3dg-coated RBCs have near-normal survival.

Clinical Presentation

The presence of erythrocyte autoantibodies does not always cause hemolysis and thus anemia. In fact, most patients with low concentrations of IgG autoantibodies will have laboratory findings such as a positive DAT but will not have anemia or related symptoms. Clinically significant hemolysis results in anemia, jaundice, and splenomegaly. Laboratory testing should include a complete blood count, reticulocyte count, serum bilirubin level, serum lactic dehydrogenase (LDH) level, serum haptoglobin value, and peripheral blood smear. Hemolytic anemia results in anemia, elevated reticulocyte count, increased bilirubin levels (especially the indirect fraction), elevated LDH level, and decreased haptoglobin level. The peripheral smear may demonstrate spherocytes (WAIHA) or RBC agglutination (CAD), which may aid in the diagnosis of hemolytic anemia. Urinalysis will show hemoglobinuria when intravascular hemolysis is present.

Warm Autoimmune Hemolytic Anemia

WAIHA represents 60%–80% of AIHA cases, including those that are drug-induced. WAIHA is secondary to IgG (rarely IgA or IgM) warm autoantibodies often with Rh specificity, which typically react at 37°C and results in primarily extravascular hemolysis. Extravascular hemolysis is when the hemolysis occurs in the RES, resulting in increased serum bilirubin, but not necessarily hemoglobinemia or hemoglobinuria. IgG-sensitized RBCs are destroyed or damaged within the RES, predominantly by splenic macrophages.

Pathogenesis

While many cases of WAIHA are primary (idiopathic), approximately 50% of WAIHAs are secondary to underlying disease states, including lymphoma and various lymphoproliferative disorders, autoimmune diseases, and drugs. For this reason, it is important to assess patients diagnosed with WAIHA for underlying disease, along with medication history. Lymphoma and other lymphoproliferative disorders are the most commonly associated condition, representing nearly half, while autoimmune diseases account for 27% in one study. The underlying clinical condition is frequently present preceding the diagnosis of WAIHA. Several studies have documented that the diagnosis of lymphoma is made subsequent to the clinical presentation of AIHA in a significant number of cases, which highlights the importance of evaluating patients for lymphoid malignancies at the time of presentation to avoid treatment delays and improve response. A detailed description of the pathogenesis and mechanisms of drug-induced hemolytic anemia follows at the end of this chapter. IgG-coated RBCs are detected serologically by a positive DAT with IgG; in addition, the RBCs may sometimes be coated with complement, and thus the DAT may also be positive for complement (see Chapter 21 ). IgG, when eluted from RBCs, typically reacts as a panagglutinin and does not demonstrate specificity. 80% of individuals with WAIHA have autoantibody present in the plasma as well as on the RBC membrane when sufficient antibody titers are present (see Chapter 20 ). The plasma-phase autoantibody usually reacts as a panagglutinin in the indirect antiglobulin test (i.e., antibody screen/antibody identification panel). Occasionally, antibody identification demonstrates specificity to antigens in the Rh system (usually c or e) or other RBC antigens and is said to have “apparent specificity.”

Treatment

Treatment for WAIHA depends on the clinical severity of the disease. First-line treatment is usually corticosteroids using high-dose prednisone, with or without rituximab, which may offer a higher rate of complete remission and relapse-free survival. Splenectomy is considered to be an effective second-line therapy. Other treatments may include IVIG and alternate immunosuppressive medications. A daily maintenance dose of prednisone is sometimes required to control hemolysis. Supplemental folic acid is also customary because chronic hemolysis may lead to folate deficiency. Rituximab has been found to be an effective treatment for both primary and secondary WAIHA, with favorable results in both adult and pediatric patients. It may also be useful in the treatment of cases of relapsed WAIHA. In secondary WAIHA, treatment should also target the underlying illness. For patients with chronic lymphocytic leukemia (CLL), AIHA often diminishes in parallel with response to therapy: treatment decisions are based on the International Workshop on CLL guidelines for active disease.

Severe anemia with cardiac or cerebral dysfunction requires urgent management, which may include RBC transfusion. Patients with severe disease, who are not responsive to RBC transfusion and other immunomodulatory treatments secondary to rapid RBC destruction, may occasionally benefit from plasma exchange for removal of the pathogenic antibodies (see below). Preliminary data suggest that hematopoietic stem cell transplantation may have a role in treatment of WAIHA; however, more data are required to assess its efficacy. The diagnosis of primary WAIHA may also precede the development of non-Hodgkin lymphoma, sometimes by many years, so it is important to follow these patients on a continuing basis after treatment of the AIHA.

Transfusion Management

During an acute presentation in a patient newly diagnosed with AIHA, finding the appropriate RBC product for transfusion can be a challenge and close communication between the transfusion service and the treating physician is necessary. Because of the presence of a strong autoantibody, both the direct and indirect antiglobulin tests (and thus the antibody screening tests and panels) will be positive as the autoantibody, reacting as a panagglutinin, will react with all tested cells. The presence of positive reactions (i.e., in vitro agglutinin) in all tested cells makes the serologic identification of coexisting allo antibodies difficult, as their identification typically requires patterns of differential reactivity. Absorption techniques using either donor or patient RBCs are available at some hospital laboratories, but usually reference laboratories perform these specialized time-consuming tests. As 12%–40% of patients with warm autoantibodies also have clinically significant alloantibodies, it is imperative that appropriate methods for determining the presence of coexisting alloantibodies be used. It is also helpful to recognize that the presence of a panagglutinin will create positive crossmatch results; thus, the crossmatch will not be helpful in determining compatibility with underlying alloantibodies.

Performing RBC phenotyping/genotyping in patients with autoantibodies can be helpful because it focuses the antibody workup on the possible alloantibodies the patient is capable of forming. In addition, if a complete phenotype can be determined, then the transfusion service can provide phenotype-matched RBCs, which may prevent future alloimmunization and delayed hemolytic transfusion reactions as well as circumvent the need for exhaustive absorption studies (see Chapter 20 ). This is a worthwhile consideration to enhance transfusion safety, especially because individuals with WAIHA have higher rates of alloimmunization (12%–40%).

The Johns Hopkins Hospital published their approach to patients with warm autoantibodies (Shirey et al.). If possible, this included a phenotype for C, E, c, e, K, Jk ^a , Jk ^b , Fy ^a , Fy ^b , S, and s, allowing them to provide phenotype-matched, as well as antigen-negative units for any identified alloantibodies. During analysis of subsequent samples, if the serologic results were consistent with previous findings, phenotype-matched products were provided. Twelve of the 20 patients studied could be fully phenotyped and 8 patients could be partially phenotyped or phenotyping was indeterminate. The patients received between 2 and 39 products, and none developed new alloantibodies during the study period of 13 months.

Because of the presence of the warm, IgG autoantibody in these patients, it is typically not possible to identify crossmatch-compatible units. Restrictive transfusion strategies for hemodynamically stable patients should be followed per AABB RBC transfusion guidelines. Blood should not be withheld from patients if they are experiencing cardiopulmonary symptoms due to anemia. Because the autoantibodies target Rh or Rh-related antigens or glycophorin, which are nearly universally present on RBCs, administration of “incompatible” blood is often necessary. Most blood banks and clinicians will select so-called “least incompatible” blood, meaning that they will choose those units for which the crossmatch demonstrates the least reactivity after using special compatibility test procedures to rule out underlying alloantibodies. The predicative value of this approach for in vivo hemolysis is not known. When the autoantibody does demonstrate apparent specificity (e.g., anti-e), selection of antigen-negative units (e.g., e−) seems like an appropriate decision, although these antibodies will still react with the patient’s RBCs. Arguments against this approach include the following: there are scant data to support this approach, and this practice increases the likelihood that an alloantibody will be induced to the antithetical antigen (e.g., E), if it is not carried on the patient’s RBCs. In addition, the apparent antigen specificity is usually to a high-frequency antigen making it difficult to obtain antigen-negative RBCs (e.g., 98% of the population is e positive), which may delay transfusion while acquiring antigen-negative RBCs.

Risks of transfusion in patients with WAIHA are increased hemolysis, resulting from the increase in RBC mass or inability to recognize and respect underlying alloantibodies, and congestive heart failure secondary to circulatory overload. There are also risks to withholding transfusion when a patient has a justifiable need, even when the compatibility test is strongly positive, particularly in patients with cardiopulmonary symptoms or rapidly developing anemia with reticulocytopenia. It is recommended in severe cases that transfusion commence using small volumes of RBCs with close clinical observation.

Therapeutic plasma exchange (TPE) has been used in the management of WAIHA in severe cases unresponsive to RBC transfusion and other immunomodulatory therapies. WAIHA is an ASFA category III indication for TPE secondary to the rare and conflicting reports of its successfulness (see Chapter 75 ). Theoretically, TPE would be less effective in WAIHA because the IgG intravascular distribution is 45% (IgM is 80%). The pathogenic IgG antibody coating the RBCs is less available in the plasma resulting in inefficient antibody removal by TPE. However, in patients with severe hemolysis, TPE may be used as a temporizing measure until immunosuppressive therapy can take effect.

Autoimmune Hemolytic Anemia Associated With a Negative Direct Antiglobulin Test

A patient may have AIHA with a negative DAT secondary to either RBC-bound IgG being below the threshold of detection (standard DAT can detect >300–500 bound IgG molecules/RBC), RBC-bound IgA and IgM being responsible (these are not detected by most routine reagents), or low-affinity IgG, which is washed off the RBCs. This accounts for approximately 3%–11% of cases, and the typical clinical presentation is consistent with WAIHA. Because physicians may reject the diagnosis based on the negative DAT, it is important to recognize that this entity exists and perform additional diagnostic testing to minimize delays in treatment.

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