Autoimmune hemolytic anemia

I. Problem/Condition.

Autoimmune hemolytic anemia (AIHA) is a relatively uncommon condition with a prevalence of 17:100,000 people. Autoimmune hemolytic anemia is characterized by an abnormal antibody response to red blood cells resulting in hemolysis. AIHA encompasses three categories: warm autoimmune induced hemolytic anemia (wAIHA), cold agglutinin disease (CAD), and drug induced hemolytic anemia.

II. Diagnostic Approach

A. What is the differential diagnosis for this problem?

AIHA must be distinguished from other causes of hemolytic anemia. Hemolysis can occur in a number of conditions including splenomegaly (from any cause), mechanical causes such as a mechanical valve, disseminated intravascular coagulation (DIC), or hemolytic uremic syndrome or thrombotic thrombocytopenic purpura (HUS/TTP).

These conditions, which show predominantly schistocytes, can be separated from autoimmune hemolytic anemia by peripheral smear, as spherocytes are often present in AIHA instead. Though spherocytes are seen in all types of AIHA they are less prevalent and sometimes absent in cold agglutinin disease.

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B. Describe a diagnostic approach/method to the patient with this problem

AIHA must be approached from both a clinical and laboratory perspective. The clinical history is determined by the degree of anemia induced by the hemolysis, which may include fatigue, dyspnea or abdominal fullness from splenomegaly. Most clinical history is non-specific except those that may be directed by a secondary cause of hemolytic anemia such as lymphoma, leukemia, lupus, ulcerative colitis, etc.

Laboratory findings are based on the severity of the patient’s hemolysis and may include varying degrees of anemia, reticulocytosis, elevated lactate dehydrogenase (LDH), indirect hyperbilirubinemia, low haptoglobin and in rare cases of intravascular hemolysis, hemoglobinuria. Autoimmune hemolysis is confirmed with the direct antiglobulin test, known as the direct Coomb’s test. The Coomb’s test will distinguish autoimmune hemolysis from other forms of hemolysis.

1. Historical information important in the diagnosis of this problem.

Patients will present with symptoms either specific to AIHA-induced hemolysis or a potential secondary cause of AIHA. If the anemia is severe enough, the patient will present with symptoms of fatigue, weakness, dizziness, and dyspnea. It is rare to see symptoms of bleeding.

WAIHA constitutes the majority of cases (70%). It usually affects women (2:1) and often manifests around age 40. The most commonly associated secondary conditions of wAIHA are the lymphoproliferative disorders (lymphoma, leukemia, Waldenstrom’s macroglobulinemia, myeloma). Autoimmune disorders have also been implicated including lupus, Sjogren’s syndrome and rheumatoid arthritis.

Since hematologic malignancies and lupus are the two most commonly associated secondary causes of AIHA (albeit rare), patients may present with symptoms specific to the condition such as weight loss, night sweats, fevers, abdominal fullness, or lymph node enlargement with lymphoma and the characteristics associated with lupus including facial rash, photosensitivity, oral ulcers, serositis (chest pain with pericarditis, pleuritis or peritonitis), etc.

There have been a number of other diseases rarely associated with AIHA including Evan’s syndrome (thrombocytopenia and hemolytic anemia), primary biliary cirrhosis, thyroid diseases, ovarian cysts, and myelofibrosis. In any case of AIHA, a detailed history is required to rule out a secondary cause of AIHA as secondary causes constitute about 50% of the cases.

Cold agglutinin disease (CAD) usually presents in the seventh decade of life and predominantly affects women. The two most common secondary conditions are infectious etiologies (Mycoplasma pneumonia or infectious mononucleosis), which occur at a younger age, or lymphoproliferative disorders (chronic lymphocytic leukemia (CLL), lymphomas and Waldenstrom’s macroglobulinemia). After CAD is established, patients should be evaluated for infections, underlying malignancies and autoimmune disease, with greater than 70% of the cases attributable to these etiologies.

When associated with an infection, hemolysis usually occurs 2 to 3 weeks after the illness. Episodes of acute hemolysis in CAD are more common in the winter months since cold temperatures exacerbate the condition. Patients may present with acrocyanosis, Raynaud’s or even vascular occlusion causing necrosis.

Drug-induced hemolytic anemia is most commonly associated with second and third generation cephalosporin but historically was associated with penicillins and alpha-methyldopa. Drug-induced hemolytic anemia can be either immune or non-immune characterized by a hapten reaction, immune complexes or autoantibodies.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

The physical examination will be specific only to the degree of anemia. With pronounced anemia, the patient may have pallor or jaundice which can be detected most readily by assessing the conjunctiva. Splenomegaly can be detected in about one third of patients with hemolytic anemia.

Otherwise, other physical exam findings may point to a secondary cause of AIHA. With lymphoma being the most common secondary cause of AIHA, the physical exam should be directed toward a complete lymph node exam including assessment of liver and spleen size. Another commonly associated condition with wAIHA is lupus and thus findings of lupus should be assessed (facial rash, photosensitivity, serositis, oral ulcers, etc.).

There are a number of other secondary conditions such as ulcerative colitis, Crohn’s, scleroderma, and multiple myeloma in which a targeted physical exam would be warranted.

In CAD, attention to the digits and peripheral areas such as the tip of the nose or the ears should be evaluated for cyanosis, Raynaud’s or necrosis. The patient should also be evaluated for evidence of an infection.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Assessment for AIHA must begin with a hemoglobin and hematocrit to assess for anemia. If present and in the correct clinical setting, work-up should include LDH, indirect bilirubin, haptoglobin, reticulocyte count, urinalysis (hemoglobinuria or myogloburia), peripheral smear (spherocytes), and a direct antiglobulin test (Coomb’s test).

In severe hemolysis, folate deficiency can occur, thus megaloblastosis with an elevated mean corpuscular volume (MCV) can be seen. Haptoglobin can be low in hemolysis but interpretation should be approached with caution in end stage liver disease as haptoglobin is produced by the liver and can be low in this state.

Diagnostic workup should include investigation to identify associated infections (Mycoplasma, mononucleosis), autoantibody profile for systemic autoimmune disease (ANA, anti dsDNA, lupus anticoagulant, anticardiolipin) and consideration of malignancy workup.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Warm induced autoimmune hemolytic anemia

Diagnosis is made by direct antiglobulin testing since 95% of wAIHAs have a positive direct antiglobulin test (DAT). The patient’s serum is incubated with antibodies to immunoglobulin (Ig) G and complement component 3 (C3) and if autoantibodies exist, the test will be positive for either IgG, C3 or both. If hemolysis is strongly suspected but the DAT is negative, the IgG autoantibodies may be below the level of detection of the test or the patient has the rare IgM or IgA autoantibodies.

Cold agglutinin disease

Ninety percent of cases are IgM-mediated. The diagnosis of CAD is established with a positive direct antiglobulin test (DAT) for anti-C3 and classically negative anti-IgG. IgM autoantibodies dissociate from the red blood cell after binding of C3 so IgM is usually not detected.

Drug induced autoimmune hemolytic anemia

The results of direct antiglobulin testing will appear similar to wAIHA with a positive IgG. However, drug induced hemolysis caused by a neoantigen formation or drug adsorption requires the presence of the drug to detect the antibody. Drug induced hemolytic anemia requires both a positive DAT and evidence of hemolysis.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

There is no over-utilized test for AIHA.

III. Management while the Diagnostic Process is Proceeding

A. Management of autoimmune hemolytic anemia.

Folic acid supplementation is recommended for all types of hemolysis.

Warm induced autoimmune hemolytic anemia

It is important to identify if there is an underlying secondary cause as treatment of the underlying cause can improve the hemolytic picture. If no underlying cause is identified, treatment is first defined by the degree of anemia. In case of severe symptom such as hypoxia, hemodynamic compromise or if the patient has underlying cardiovascular or cerebrovascular disease, transfusion should be considered. However, transfusion can worsen the underlying syndrome so it should be used with caution if symptoms do not warrant treatment.

First-line therapy for wAIHA is steroid therapy with either prednisone or methylprednisolone. Glucocorticoids have a response rate of about 70-80%. This therapy should be continued for 1-3 weeks until hemoglobin levels >10 g/dL are reached. Most patients will respond in this time but will require some lower dose of steroid therapy. After stabilization of the hemoglobin, prednisone should be gradually and slowly tapered off, over a period of at least 4-6 months, as patients receiving low doses of glucocorticoids for more than 6 months have a lower incidence of relapse and a longer duration of remission. If there is no or minimal response, second line therapy should either be splenectomy or rituximab therapy.

Splenectomy can increase success of short-term remission of disease treatment by two-thirds and have a presumed curative effect in approximately 20% of cases. Preoperative vaccination for pneumococcus, meningococcus and Hemophilus should be done. Rituximab is increasingly preferred among second-line treatments with response rate of 70-80%. Median time to response is 4-6 weeks following the first rituximab dose, though later responses are not uncommon.

Prednisone therapy should continue at the same time given the delay in symptom improvement with rituximab. Other immunosuppressives should be considered third-line therapy (mycophenolate, cyclophosphamide, azathioprine). Aletuzumab is showing anecdotal efficacy particularly in CLL-associated AIHA.

Cold agglutinin disease

Nonpharmacologic measures are the cornerstone of management of CAD. Avoiding cold exposure and increasing use of warm clothing are recommended. Steroid therapy is not helpful in the treatment of CAD. Splenectomy should not be used to treat CAD because hemolysis occurs mostly outside the spleen.

Polyclonal antibodies seen in infections are self-resolving and require only supportive treatment. Treatment of the underlying infection may expedite the recovery. If transfusions are to be used, then warming of the blood, the patient and patient’s room is highly appropriate in order to avoid hemolysis at colder temperatures.

Monoclonal antibodies are seen in older adults and are often associated with underlying lymphoproliferative disorder or idiopathic CAD. The decision to treat CAD should be reserved for patients with symptomatic disease, severe anemia or transfusion dependence. Rituximab is now the preferred first-line treatment for CAD, although complete and sustained remissions are uncommon. Different series show a response rate ranging 45-83%.

Complement activation plays a definitive role in the pathogenesis of CAD. There are multiple case reports reporting the successful use of complement targeting agents (such as eculizumab) in the treatment of CAD.

Drug-induced autoimmune hemolytic anemia

Removal of the offending agent is the most important step in the treatment of this condition. Steroid therapy can also be used while splenectomy and Rituximab are not usually indicated.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem

Transfusions can worsen hemolysis and should be used with caution in AIHA unless symptoms related to the anemia or underlying cardiovascular or cerebrovascular disease warrant treatment.

IV. What's the evidence?

Dhaliwal, Gurpreet, Cornett, Patricia A, Tierney, Lawrence M. “San Francisco Veterans Affairs Medical Center/University of California–San Francisco School of Medicine, San Francisco, California: Hemolytic anemia”. Am Fam Physician. vol. 69. 2004 Jun 1. pp. 2599-2607.

Lechner, K, Jager, U. “How I treat autoimmune hemolytic anemias in adults”. Blood. vol. 116. 2010. pp. 1831-1838.

Gehrs, B, Friedberg, R. “Autoimmune hemolytic anemia”. Am J Hematol. vol. 69. 2002. pp. 258-271.

Blackall, D. “How do I approach patients with warm-reactive antibodies”. Transfusion. vol. 51. 2011. pp. 14-17.

Crowther, M, Chan, YL, Garbett, I, Lim, W, Vickers, M, Crowther, MA. “Evidence-based focused review of the treatment of idiopathic warm immune hemolytic anemia in adults”. Blood. vol. 118. 2011. pp. 4036-4040.

Swiecicki, PL, Hegerova, LT, Gertz, MA. “Cold agglutinin disease”. Blood. vol. 122. 2013. pp. 1114-1121. (Review article outlining the epidemiology, pathogenesis, diagnostic and treatment of cold agglutinin disease. Highly informative explaining the major differences in pathogenesis and treatment between wAIHA and CAD.)

Barcellini, W. “Immune hemolysis:diagnosis and treatment recommendations”. Semin Hematol. vol. 52. 2015. pp. 304-312. (Review article about diagnosis and treatment of various autoimmune hemolytic anemias, including a brief yet thorough explanation of the various laboratory tests available for diagnosis.)

Naik, R. “Warm autoimmune hemolytic anemia”. Hematol Oncol Clin North Am. vol. 29. 2015. pp. 445-453. (Review of the mechanism of wAIHA including a through and updated discussion about treatment.)