From the Guidelines
For a patient with a positive cold agglutinin test, further workup should include a comprehensive evaluation to assess for hemolysis, identify potential monoclonal proteins, and investigate underlying causes.
Initial Evaluation
- Complete blood count with peripheral smear
- Reticulocyte count
- Direct antiglobulin test (Coombs)
- Comprehensive metabolic panel
- Lactate dehydrogenase to assess for hemolysis
Specific Testing
- Cold agglutinin titers
- Protein electrophoresis
- Immunofixation to identify potential monoclonal proteins
Underlying Causes
- Tests for Mycoplasma pneumoniae, Epstein-Barr virus, cytomegalovirus, and HIV
- Consider CT scans of chest, abdomen, and pelvis to rule out lymphoma or other malignancies
- Bone marrow biopsy may be necessary if lymphoproliferative disorder is suspected
Management
- Depends on the underlying cause - treating infections if present, or referring to hematology for primary cold agglutinin disease
- Cold agglutinins are antibodies that bind to red blood cells at low temperatures, potentially causing hemolytic anemia
- The severity of symptoms and hemolysis guides treatment decisions, which may include cold avoidance, rituximab, or other immunosuppressive therapies in severe cases, as recommended by recent guidelines 1.
Additional Considerations
- Testing for cryoglobulins should be performed at diagnosis, as the presence of cold agglutinins or cryoglobulins may affect determination of IgM levels 1
- Serum anti-MAG antibodies can be evaluated in patients with sensory peripheral neuropathies, and antiganglioside M1 antibodies may also be evaluated in those with motor neuropathy 1
- Referral for neurologic consultation should be considered in patients with peripheral neuropathy, and nerve conduction studies or electromyography may help determine if neuropathy is related to the monoclonal process or other causes 1
From the Research
Further Workup for Cold Agglutinin Disease
The diagnosis of Cold Agglutinin Disease (CAD) is typically confirmed by the presence of C3 positivity at direct Coombs test along with high titer agglutins 2.
Laboratory Testing
- A stepwise approach to laboratory testing can help confirm the diagnosis, including a direct antiglobulin test (DAT) and testing for cold-reactive autoantibodies 3.
- Nearly all cold agglutinins are positive for the C3d direct antiglobulin test (DAT), and a negative C3d DAT should prompt investigation of a possible warm AIHA 3.
- The titer, thermal amplitude, strength, and specificity of the Coombs test are correlated with cold agglutinin hemolytic activity 4.
Associated Diseases
- Cold agglutinin syndrome may serve as an early indicator of lymphoma, and patients with CAD should be closely monitored for the development of lymphoproliferative disorders 5, 4.
- Diseases associated with cold agglutinin are varied, with the highest frequency of autoimmune disorders, followed by lymphoproliferative disorders and infections 4.
Treatment
- Rituximab represents the frontline approach in patients with symptomatic anemia or disabling cold-induced peripheral symptoms and is effective in 50-60% of cases 2, 3.
- Refractory/relapsing patients may benefit from complement inhibitors, particularly the anti-C1s sutimlimab, effective in controlling hemolysis and improving anemia in >80% of patients 2.
- Combination therapy, including rituximab and fludarabine, has been shown to be effective in up to 76% of patients, but patients experience more mild side effects with this treatment 3.