From the Guidelines
For a patient with a positive cold agglutinin test, further workup should include testing for cryoglobulins, such as cryocrit, and serum protein electrophoresis, as well as evaluation for underlying lymphoproliferative disorders, like Waldenström Macroglobulinemia (WM) 1. When suspected, cryocrit, a test for cryoglobulins, should be obtained to rule out the presence of cryoglobulins that may affect determination of IgM levels 1. Additional testing may include:
- 24-hour urine for total protein, creatinine clearance, urine protein electrophoresis, and urine immunofixation electrophoresis to assess for kidney involvement 1
- Serum anti-MAG antibodies in patients with sensory peripheral neuropathies, and 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 to investigate Bing-Neel syndrome 1 It is essential to consider the potential for underlying comorbidities and to distinguish between primary cold agglutinin disease and secondary causes related to infections or malignancies, as treatment approaches differ significantly 1. For any blood draws or transfusions, samples and blood products should be kept warm to prevent in vitro agglutination that could affect test results or cause transfusion reactions. Hematology consultation is appropriate for management guidance to ensure the best possible outcome in terms of morbidity, mortality, and quality of life.
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 or other targeted therapies, such as complement inhibitors, to manage the disease 3, 4, 6
Laboratory Tests
Laboratory tests that may be used to confirm the diagnosis of CAD include:
- 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 serum 2, 4
- Indirect antiglobulin test (IAT) to detect the presence of autoantibodies in the patient's serum 2
Treatment Options
Treatment options for CAD may include:
- Rituximab, a monoclonal antibody that targets B cells and has been shown to be effective in managing CAD 3, 4, 6
- Complement inhibitors, such as eculizumab and sutimlimab, which may be used to manage hemolysis and improve anemia 3, 4
- Combination therapy, such as rituximab and fludarabine, which may be used to manage patients who do not respond to single-agent therapy 4