What are cold agglutinins (Cold Agglutinin Disease)?

From the Guidelines

Cold agglutinins are a type of antibody that can cause chronic hemolytic anemia in patients with Waldenström Macroglobulinemia (WM), and their presence should be tested for at diagnosis, as they can affect the determination of IgM levels. In patients with WM, monoclonal IgM may present with cold agglutinin activity, where the monoclonal IgM interacts with specific red cell antigens below physiologic temperatures, producing chronic hemolytic anemia 1. The cold agglutinin titers are typically greater than 1:1,000 in most cases.

Key Points to Consider

• Cold agglutinins can cause retinal changes and hemorrhages, even at lower levels of serum viscosity, and may necessitate intervention 1.
• Testing for cold agglutinins and cryoglobulins should be performed at diagnosis, as their presence can affect the determination of IgM levels 1.
• When suspected, cryocrit, a test for cryoglobulins, should be obtained, and the presence of cryoglobulins may render falsely low serum IgM levels 1.
• Patients with WM and peripheral neuropathy may harbor antibodies against myelin-associated glycoprotein (MAG) or other glycoproteins or lipids, and serum anti-MAG antibodies can be evaluated in patients with sensory peripheral neuropathies 1.

Management and Treatment

• Management of cold agglutinins primarily focuses on avoiding cold exposure by wearing warm clothing and maintaining warm environments.
• For severe cases, medications like rituximab may be used to reduce antibody production, and plasmapheresis can provide temporary relief in acute severe hemolysis.
• Blood transfusions, if needed, must be given with blood warmers to prevent further hemolysis.

Underlying Mechanism

• The underlying mechanism involves IgM antibodies binding to red blood cell antigens at low temperatures, activating complement and causing hemolysis when blood recirculates to warmer areas of the body 1.
• Patients should be monitored regularly for anemia severity and complications, and referral for neurologic consultation should be considered in patients with peripheral neuropathy 1.

From the Research

Definition and Pathogenesis of Cold Agglutinins

• Cold agglutinin disease (CAD) is an uncommon autoimmune haemolytic anaemia characterized by a clonal low-grade lymphoproliferative disorder of the bone marrow, resulting in erythrocyte destruction mediated by the classical complement pathway 2.
• The disease is a well-defined clinicopathologic entity in which a specific, clonal lymphoproliferative B-cell bone marrow disorder results in autoimmune hemolytic anemia 3.

Clinical Features and Diagnostic Criteria

• Typical clinical features in CAD have diagnostic and therapeutic implications, including symptom-producing anemia or disabling circulatory symptoms 3.
• Approximately one-third of untreated patients have a haemoglobin level of ≤80 g/l, and about 50% have been considered transfusion dependent for shorter or longer periods 2.

Treatment Options

• Mild disease can be managed by avoidance of cold and adequate precautions in specific situations, without drug therapy 2.
• Corticosteroids should not be used to treat CAD 2, 3.
• Patients requiring pharmacological therapy should be considered for prospective trials, with rituximab-bendamustine combination or rituximab monotherapy recommended in the first line, depending on individual patient characteristics 2, 4, 5.
• Second-line options include rituximab-fludarabine in fit patients or a bortezomib-based regimen 2.
• Novel treatment options that target the classical complement pathway are under development, including the C1s inhibitor sutimlimab, which is currently being investigated in clinical trials 5.

Response to Treatment

• The combination of fludarabine and rituximab has been shown to be highly efficient in patients with CAD, with a response rate of 76% and a median response duration of more than 66 months 6.
• The bendamustine-rituximab combination therapy has also been shown to be highly efficient, with a response rate of 71% and a median increase in hemoglobin level of 4.4 g/dL in complete responders 4.