From the Guidelines
Further workup for a patient with a positive cold agglutinin test should include testing for underlying causes such as Waldenström Macroglobulinemia (WM) or lymphoplasmacytic lymphoma, as well as evaluation for cryoglobulins and cold agglutinins, which can affect determination of IgM levels 1. When a patient presents with a positive cold agglutinin test, it is essential to consider the potential underlying causes, including WM or lymphoplasmacytic lymphoma, as cold agglutinin activity can be present in fewer than 10% of patients with WM 1.
Key Tests
- Cryocrit, a test for cryoglobulins, should be obtained to evaluate for the presence of cryoglobulins, which can render falsely low serum IgM levels 1.
- Twenty-four–hour urine for total protein, creatinine clearance, urine protein electrophoresis, and urine immunofixation electrophoresis may be useful in evaluating the patient's condition 1.
- Serum anti-MAG antibodies can be evaluated in patients with sensory peripheral neuropathies, and in those with motor neuropathy, antiganglioside M1 antibodies may also be evaluated 1.
Additional Considerations
- Patients with peripheral neuropathy should be considered for referral for neurologic consultation, and nerve conduction studies or electromyography may help 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.
- If central nervous system (CNS) involvement is suspected in individuals with WM, imaging studies, cerebrospinal fluid (CSF) analysis, or tissue biopsy are needed to investigate Bing-Neel syndrome 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