Hematology

Autoimmune hemolytic anemia (including Evans syndrome)

Autoimmune hemolytic anemia (including Evans syndrome)

What every physician needs to know about autoimmune hemolytic anemia:

Autoimmune hemolytic anemia (AIHA) is a rare condition with an incidence of 0.8 per 100,000 per year and a prevalence of 17 per 100,000. The median age at presentation is in the mid-50s and 60% of patients are women.

Primary AIHA is less common than secondary AIHA, and can be induced by "warm" or "cold" autoantibodies.

In secondary AIHA, diagnosis and treatment of the underlying disease is essential to the successful treatment of the hemolysis.

Evans syndrome is defined by the presence of more than two immune-mediated cytopenias, more commonly anemia and thrombocytopenia; they can occur concurrently or sequentially. The median age at presentation and sex distribution of Evans syndrome in adults is similar to AIHA.

This chapter will be focused primarily on warm AIHA. There are no published guidelines for AIHA, and there are no randomized controlled studies or standardized response criteria to define appropriate therapy. This makes recommendations for treatment difficult.

What features of the presentation will guide me toward possible causes and next treatment steps:

Depending on the acuteness or severity of hemolysis, patients can range from being essentially asymptomatic to being severely disabled. The level of distress should dictate the pace of treatment. Patients with AIHA usually present with acute onset shortness of breath, dyspnea on exertion, palpitations, dizziness, progressive weakness or tiredness. On physical examination, conjunctival, buccal and/or nailbed pallor can be seen, depending on the degree of anemia. Occasionally, conjunctival or generalized icterus can be seen. Patients are usually tachycardic, tachypneic, and may be hypotensive. The spleen can be moderately enlarged.

In patients with Evans syndrome presenting with concurrent thrombocytopenia, abnormal bleeding or bruising can be seen. In 30% of cases of Evans syndrome, thrombocytopenia can precede AIHA, and in 10% AIHA can precede thrombocytopenia. In 50% of the cases, Evans syndrome is secondary to lupus, antiphospholipid syndrome, Sjogren’s syndrome, CVID (common variable immunodeficiency), immunoglobulin (Ig) A deficiency, lymphomas, CLL, MGUS (monoclonal gammopathy of undetermined significance), or hepatitis C infection.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The first step is to confirm the presence of anemia and hemolysis, which can be accomplished by checking a complete blood count, reticulocyte count, LDH (lactate dehydrogenase level), bilirubin (total and direct, most laboratories do not provide indirect bilirubin levels), and haptoglobin. A diagnosis of hemolytic anemia is suggested by a combination of increased LDH and undetectable haptoglobin levels (90% specific for hemolysis), in the context of a low hemoglobin level. Reticulocyte counts are usually elevated, and an increased MCV (mean corpuscular volume) (greater than 100 fl) can be seen, due to the larger size of reticulocytes in comparison to mature red blood cells.

Reviewing a peripheral blood smear is helpful; AIHA is suggested by the presence of microspherocytes (Figure 1), which are smaller in size than normal RBCs and lack the central pallor. Other characteristic findings on the smear include polychromasia, macrocytosis, and nucleated red blood cells.

Once a diagnosis of hemolysis is made, ordering a direct Coombs test (also known as direct antibody test or DAT) should confirm the diagnosis of AIHA. Direct Coombs test is reported as IgG+, C3+ or IgG/C3+. IgG+ Coombs is associated with warm IgG autoantibodies. IgG/C3+ is seen with warm IgG autoantibodies that are able to fix complement. If Coombs is C3+ only, a cold agglutinin should be sought, since this may be indicative of cold agglutinin disease. Indirect Coombs test is usually not necessary in the work-up.

If a patient presents with Evans syndrome with concurrent thrombocytopenia, a work-up similar to ITP (idiopathic thrombocytopenic purpura) should be ordered, including HIV ELISA (enzyme-linked immunosorbent assay), HCV (hepatitis C virus) and HBV (hepatitis B virus) serologic tests, SPEP (serum protein electrophoesis) with immunofixation, quantification of immunoglobulins, antinuclear antibodies, and Helicobacter pylori antigen in stool or urea breath test.

What conditions can be confused with autoimmune hemolytic anemia?

  • Cold agglutinin disease

- Cold agglutinin disease is associated with cold IgM autoantibodies. This condition should be evaluated as the therapy differs greatly from warm AIHA.

  • DIC (disseminated intravascular coagulation)and TTP (thrombotic thrombocytopenic purpura)

- DIC (disseminated intravascular coagulation)and TTP (thrombotic thrombocytopenic purpura) are usually associated with the presence of schistocytes or fragmented RBCs (red blood cells) in the peripheral blood smear (Figure 2). DIC will also present with decreased fibrinogen levels and prolonged INR (international normalized ratio) and APTT (activated partial thromboplastin time). TTP can present with renal dysfunction and fever

  • Drug-induced hemolysis

- Drug-induced hemolysis is common and the list of medications of each patient with AIHA should be reviewed carefully. Cephalosporins, penicillins and NSAIDs (non-steroidal anti-inflammatory drugs) are among the most common culprits. Medications causing hemolysis should be stopped immediately

  • Congenital hemolytic processes

- Congenital hemolytic processes are rarely acute; however, G6PD (glucose-6-phosphate dehydrogenase) deficiency can be precipitated by the use of trimethoprim/sulfamethoxazole or dapsone, or the ingestion of fava beans.

- In patients with Evans syndrome, a minimal work-up to evaluate for lymphomas, CLL (chronic lymphoid leukemia), APS (antiphospholipid syndrome), and other immunodeficiencies is strongly recommended.

Figure 1

Spherocyte

Figure 2

Schistocyte

What conditions can underlie autoimmune hemolytic anemia:

AIHA could be the initial manifestation of other systemic processes such as lymphoma, CLL, SLE (systemic lupus erythematosus) and APS (antiphospholipid antibody syndrome).

When do you need to get more aggressive tests:

A bone marrow biopsy might be necessary if no reticulocytosis is seen in the context of ongoing hemolysis, if cold agglutinin disease is suspected, or lymphoma or CLL are part of the differential diagnosis.

What imaging studies (if any) will be helpful?

CT (computed tomography) scans could be of value in a small subset of patients in whom a diagnosis of lymphoma or other malignancy is entertained. CT scans or abdominal ultrasound may also detect splenomegaly.

What therapies should you initiate immediately and under what circumstances – even if root cause is unidentified?

Patients with AIHA usually represent a challenge for blood banks as they react against multiple self-antigens, sometimes making matching difficult. However, if the patient is hemodynamically unstable, type O-negative packed red blood cells should be transfused.

If the patient is stable, prednisone at a dose of 1mg/kg PO daily should be started immediately. The goal of the treatment with steroids is to bring the hemoglobin to levels greater than 10g/dl, which should be obtained between a few days and 2 to 3 weeks. Once a hemoglobin greater than 10g/dl is reached, the dose of prednisone can be decreased to 20mg PO daily within a few weeks, followed by a slower taper (5mg PO drop every month) with careful monitoring for a few months. If a hemoglobin greater than 10g/dl is not reached in 3 weeks, second line treatments will be necessary.

Splenectomy and rituximab are second-line therapies with proven short-term efficacy. Beyond second line, there is anecdotal experience with IVIG (intravenous immunoglobulin), danazol, azathioprine, mycophenolate mofetil, cyclosporin, cyclophosphamide, and alemtuzumab.

The approach for patients with Evans syndrome should be similar to patients with AIHA, with steroids for first line treatment, followed by rituximab or splenectomy.

What other therapies are helpful for reducing complications?

During steroid therapy, patients should receive folic acid, bisphosphonates, vitamin D, and calcium. It is also advisable to consider Pneumocystis jirovecci prophylaxis. Glucose should be monitored for steroid-related diabetes, and therapy with insulin instituted as appropriate.

For splenectomy, immunizations for pneumococcus, Haemophilus influenzae type B, and meningococcus can be administered 4 to 6 weeks prior, or 2 weeks after surgery. Patients should receive seasonal influenza vaccination annually. The mortality rate for laparoscopic splenectomy is 0.5%.

For rituximab, hepatitis B titers should be checked prior to therapy.

What should you tell the patient and the family about prognosis?

The initial response rate to steroids is 80%m but the chance of complete remission after withdrawal of steroids has been estimated to be about 20%. Fifty percent of responders will likely need long-term doses of prednisone greater than 15mg/day, which are associated with adverse events, necessitating second-line therapies.

Patients with Evans syndrome also experience a response rate of 80% with steroids but approximately 75% of initial responders will need some type of second-line therapy.

“What if” scenarios.

  • Concurrent or sequential thrombocytopenia and/or neutropenia could represent Evans syndrome

  • Lymphadenopathy could indicate the presence of chronic lymphocytic leukemia or other lymphoproliferative disorder

  • A malar rash and/or arthritis might suggest systemic lupus erythematosus

  • A history of chronic sinorespiratory infections could indicate common variable immunodeficiency

  • Reticulocyte counts

- These can be normal or decreased if there is concurrent folate, cobalamin, and/or iron deficiency, or the patient has underlying parvovirus B19 infection, anemia of chronic disease, or myelodysplasia.

  • Approximately 1 to 5% of AIHA patients will have a negative Coombs test

- Such patients usually carry a low-affinity antibody, which is below the level of detection of a standard Coombs test, or can have IgA or IgM antibodies, which are not detected by standard Coombs. In such cases, a more sensitive Coombs test (also known as mini Coombs or super Coombs) can be ordered.

Pathophysiology

Red blood cell destruction in AIHA can be extravascular or intravascular, although the former is more common with warm autoantibodies. Warm IgG autoantibodies attach to red blood cell surface antigens. However, the etiology of the antibody production is unknown in most cases. IgG-coated red blood cells are partially ingested by the macrophages of the spleen through a process facilitated by immunoadherence. This partial ingestion leaves microspherocytes, the characteristic cells of AIHA (Figure 1). Microspherocytes, which have decreased deformability compared with normal red blood cells, are trapped in the splenic sinusoids and removed from circulation.

In patients with Evans syndrome, the mechanism of destruction of erythrocytes is thought to be similar to AIHA. In addition, the mechanism of platelet destruction should be similar to ITP.

What other clinical manifestations may help me to diagnose autoimmune hemolytic anemia?

It is important to ask about recent respiratory infections or viral illnesses, as in a few cases AIHA can be triggered by infection by Mycoplasma pneumoniae, Epstein-Barr virus, and other infectious agents.

What other additional laboratory studies may be ordered?

Immunoglobulin levels may be checked to evaluate for common variable immunodeficiency or a plasma cell dyscrasia.

Serum protein electrophoresis and immunofixation should be performed if a plasma cell dyscrasia is suspected.

Lupus anticoagulant and anticardiolipin antibodies may be checked to evaluate for antiphospholipid syndrome, mainly in patients with history of deep vein, thrombosis, pulmonary embolism, or pregnancy loss.

Peripheral blood flow cytometry may be ordered if a patient presents with lymphocytosis.

What’s the evidence?

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

[Review of treatment options for AIHA.]

Eaton, WW, Rose, NR, Kalaydijan, A, Pedersen, MG, Mortensen, PB. "Epidemiology of autoimmune diseases in Denmark". J Autoimmun. vol. 29. 2007. pp. 1-9.

[General review of autoimmune disease.]

Michel, M, Chanet, V, Dechartres, A. "The spectrum of Evans syndrome in adults: new insight into the disease based on the analysis of 68 cases". Blood. vol. 114. 2009. pp. 3167-3172.

[Review of Evans syndrome.]

Gehrs, BC, Friedberg, RC. "Autoimmune hemolytic anemia". Am J Hematol. vol. 69. 2002. pp. 258-271.

[Review of AIHA.]

King, KE, Ness, PM. "Treatment of autoimmune hemolytic anemia". Semin Haematol. vol. 42. 2005. pp. 131-136.

[Summary of treatment options for AIHA.]

Coon, WW. "Splenectomy in the treatment of hemolytic anemia". Arch Surg. vol. 120. 1985. pp. 625-628.

[Role and outcome of splenectomy in AIHA.]

Shanafelt, TD, Madueme, Hl, Wolf, RC, Teffer, A. "Rituximab for immune cytopenia in adults: idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia and Evans syndrome". Mayo Clin Proc. vol. 78. 2003. pp. 1340-1346.

[Review of efficacy of rituximab in treatment of AIHA.]

Garratty, G. " Immune hemolytic anemia associated with negative routine serology". Semin Haematol. vol. 42. 2005. pp. 156-164.

[Evaluation of suspected AIHA with negative Coombs' test.]

Dhaliwal, G, Cornett, PA, Tierney, LM. "Hemolytic anemia". Am Fam Physician. vol. 69. 2004. pp. 2599-2606.

[General review of hemolytic anemia.]
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