From the Guidelines
For a patient with a positive cold agglutinin test, further workup should include testing for cryoglobulins, serum protein electrophoresis, and immunofixation to rule out underlying lymphoproliferative disorders such as Waldenström Macroglobulinemia (WM) 1. When suspected, a cryocrit, a test for cryoglobulins, should be obtained to evaluate the presence of cryoglobulins, which may render falsely low serum IgM levels 1. Additional testing may include:
- Twenty-four–hour urine for total protein, creatinine clearance, urine protein electrophoresis, and urine immunofixation electrophoresis 1
- Serum anti-MAG antibodies in patients with sensory peripheral neuropathies 1
- Antiganglioside M1 antibodies in those with motor neuropathy 1
- Nerve conduction studies or electromyography to determine if neuropathy is related to the monoclonal process or other causes 1
- Frailty assessment should be considered before treatment of older adults with WM as per NCCN Guidelines for Older Adult Oncology 1
- Imaging studies, cerebrospinal fluid (CSF) analysis, or tissue biopsy if central nervous system (CNS) involvement is suspected 1 It is essential to identify the underlying cause of cold agglutinin disease, as treatment depends on etiology 1. Hematology consultation is recommended for management, and for symptomatic patients, avoiding cold exposure is crucial while addressing the underlying condition 1.
From the Research
Further Workup for Cold Agglutinin Disease
The further workup for a patient with a positive cold agglutinin test involves several steps:
- Confirming the diagnosis of cold agglutinin disease (CAD) through laboratory tests, including a direct antiglobulin test (DAT) and cold agglutinin titration 2, 3, 4
- Identifying the underlying cause of CAD, such as an underlying hematologic disorder or lymphoma 5, 6
- Evaluating the patient's symptoms and medical history to determine the best course of treatment 3, 4, 6
- Considering the use of rituximab, a monoclonal antibody that has been shown to be effective in treating CAD 3, 4, 6
- Monitoring the patient's response to treatment and adjusting the treatment plan as needed 3, 4, 6
Laboratory Tests
The following laboratory tests may be used to confirm the diagnosis of CAD:
- Direct antiglobulin test (DAT) to detect the presence of autoantibodies on the surface of red blood cells 2, 4
- Cold agglutinin titration to measure the level of cold agglutinins in the patient's blood 2, 4
- Indirect antiglobulin test (IAT) to detect the presence of autoantibodies in the patient's serum 2
Treatment Options
The treatment options for CAD include:
- Rituximab, a monoclonal antibody that targets the CD20 antigen on B cells 3, 4, 6
- Combination therapy with rituximab and other medications, such as fludarabine 4
- Complement inhibitors, such as eculizumab and sutimlimab, which are currently being studied as potential treatments for CAD 3, 4
- Supportive care, such as blood transfusions and warming measures to prevent hemolysis 2, 6