What is the workup for Autoimmune Hemolytic Anemia (AIHA)?

From the Guidelines

The workup for autoimmune hemolytic anemia (AIHA) should include a comprehensive diagnostic evaluation, as outlined in the American Society of Clinical Oncology clinical practice guideline, which recommends a thorough history and physical examination, blood chemistry, CBC with evidence of anemia, and other specific tests to confirm the diagnosis and identify underlying causes 1. The diagnostic work-up for AIHA should comprise the following key components:

• History and physical examination, with special consideration of new drugs, insect, spider, or snake bites
• Blood chemistry, CBC with evidence of anemia, macrocytosis, and evidence of hemolysis on peripheral smear
• LDH, haptoglobin, bilirubin, reticulocyte count, and free hemoglobin tests to assess hemolysis severity
• Disseminated intravascular coagulation panel, including Prothrombin Time and International Normalized Ratio (PT/INR), to rule out other causes of hemolysis
• Autoimmune serology, paroxysmal nocturnal hemoglobinuria screening, and direct and indirect bilirubin tests to identify underlying autoimmune conditions
• Evaluation for viral or bacterial causes of hemolysis, including mycoplasma, and protein electrophoresis, cryoglobulin analysis to assess for other potential causes
• Work-up for bone marrow failure syndrome, including B12, folate, copper, parvovirus, iron, thyroid, and infection testing, if refractory
• Glucose-6-phosphate dehydrogenase testing to rule out other causes of hemolysis
• Assessment of common drug causes, such as ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, quinine/quinidine, fludarabine, ciprofloxacin, lorazepam, diclofenac, and methemoglobinemia evaluation 1. In contrast to other studies, such as the one published in the Journal of the National Comprehensive Cancer Network 1, which provides a more limited approach to AIHA diagnosis, the American Society of Clinical Oncology guideline provides a more comprehensive framework for evaluating AIHA, which is essential for confirming the diagnosis and identifying underlying causes.

From the Research

Diagnostic Workup for Autoimmune Hemolytic Anemia (AIHA)

The diagnostic workup for AIHA involves several steps, including:

• Direct antiglobulin test (DAT) or Coombs test, which is the cornerstone of AIHA diagnosis 2, 3, 4, 5, 6
• Identification of the type of antibody involved, as symptoms, course of disease, and therapeutic management relate to the type of antibody 2
• Monospecific direct antiglobulin test is considered mandatory in the diagnostic workup 2
• Any causes of secondary AIHA have to be diagnosed 2
• Additional investigations, such as cold washes and low ionic salt solutions, identification of auto-Ab specificity and thermal range, study of the eluate, and Donath-Landsteiner test, may be necessary 5

Importance of Accurate Diagnosis

Accurate diagnosis of AIHA is crucial, as different types of AIHA require different therapies:

• Warm AIHA is typically treated with corticosteroids as first-line therapy, while rituximab is considered for severe cases or if no prompt response to steroids is achieved 2, 4, 6
• Cold agglutinin disease (CAD) is typically treated with rituximab, either as monotherapy or combined with bendamustine 2, 3, 6
• Complement inhibitors, such as sutimlimab, may be used in cases of acute severe hemolysis 6

Challenges in Diagnosis

Diagnosis of AIHA can be challenging, particularly in cases of:

• DAT-negative AIHA, which can be difficult to diagnose and may require experimental techniques, such as dual-DAT, flow cytometry, ELISA, immuno-radiometric assay, and mitogen-stimulated DAT 5
• Mixed or atypical forms of AIHA, which can require specialized testing and expertise 3, 4
• Underlying conditions, such as lymphoproliferative disorders, immunodeficiencies, neoplasms, transplants, and drugs, which can affect the diagnosis and treatment of AIHA 5, 6