What are the clinical features and recommended management for cold agglutinin disease?

Cold Agglutinin Disease: Clinical Features and Management

Clinical Features

Cold agglutinin disease (CAD) is a rare complement-mediated autoimmune hemolytic anemia caused by monoclonal IgM autoantibodies that bind red blood cells at temperatures below 37°C, resulting in chronic hemolysis with anemia, fatigue, and cold-induced circulatory symptoms. 1, 2

Hematologic Manifestations

• Chronic hemolytic anemia with elevated lactate dehydrogenase, low haptoglobin, elevated indirect bilirubin, and reticulocytosis 1
• Direct antiglobulin test (Coombs) positive for C3 complement with or without IgM 1, 3
• Cold agglutinin titer ≥1:64 at 4°C in 90% of cases 4
• Severe anemia events occur at a rate of 7.1 per patient-year, demonstrating the relapsing nature of disease 5

Cold-Induced Symptoms

• Raynaud phenomenon, acrocyanosis, and cold urticaria triggered by cold exposure 1, 2
• Symptoms affecting fingers, ears, and nose in elderly patients 4

Associated Conditions

• Underlying lymphoproliferative disorders (particularly Waldenström macroglobulinemia) in fewer than 10% of patients 1
• Secondary causes include infections and autoimmune diseases requiring exclusion 1, 3

Diagnostic Approach

Essential Laboratory Testing

• Complete blood count with reticulocyte count and hemolysis markers 2
• Direct antiglobulin test (monospecific for C3d) - a negative C3d DAT should prompt investigation for warm AIHA instead 4
• Cold agglutinin titer at 4°C (must be ≥1:64) 6, 4
• Serum protein electrophoresis and immunofixation to detect monoclonal IgM 2

Critical Collection Requirements

Blood samples must be maintained at 37°C during collection and processing to prevent in vitro agglutination and obtain reliable laboratory results. 1

Screening for Secondary Causes

• Viral serology for HBV, HCV, and HIV 1
• Evaluation for lymphoproliferative disorders through protein electrophoresis and cryoglobulin analysis 1

Treatment Algorithm

Indications for Treatment Initiation

Treatment should be initiated when patients have hemoglobin ≤10 g/dL with symptoms, symptomatic anemia affecting quality of life, hyperviscosity syndrome, or underlying lymphoproliferative disorder requiring therapy. 7, 2

First-Line Therapy

Rituximab-based regimens are the primary treatment for CAD, not corticosteroids. 1, 3, 2

Rituximab Monotherapy

• Response rate of 45-60% 2, 4
• Preferred in frail patients 8
• Time to response can be many months 8

Combination Regimens (Higher Efficacy)

• Bendamustine plus rituximab: Most efficacious first-line option with durable responses in most patients, though time to response can be many months 8
• Fludarabine plus rituximab: 75% response rate versus 50% with rituximab alone 1
• DRC (dexamethasone-rituximab-cyclophosphamide): 83% overall response rate 7, 1

Complement Inhibition (Emerging First-Line/Second-Line)

Sutimlimab, a humanized anti-C1s antibody that inhibits the classical complement pathway, is the only approved treatment for CAD and provides rapid hemolysis control within days. 6, 9, 8

• Rapidly acting with improvement in hemolysis parameters and fatigue 6, 9
• Does not improve cold-induced circulatory symptoms (these are not complement-mediated) 9
• Requires comprehensive vaccination against capsulated bacteria with bridging antibiotic prophylaxis until achieved 6
• May be considered first-line in specific situations requiring rapid response 8

Severe/Life-Threatening Disease Management

• Plasmapheresis for immediate relief in severe hyperviscosity or life-threatening hemolysis 7, 2
• Preemptive plasmapheresis before rituximab may be considered for patients with high IgM levels (>5000 mg/dL) to prevent IgM flare 7, 1
• Bortezomib induction before rituximab to rapidly reduce IgM levels in patients without symptomatic hyperviscosity 1

Supportive Care Measures

• Avoidance of cold exposure is essential as primary supportive measure 3, 6
• Adequate hydration during hemolytic crises 6
• Thrombosis prophylaxis (CAD carries risk of severe thromboembolic complications) 6
• RBC transfusion with minimum units necessary to achieve hemoglobin 7-8 g/dL, warming all blood products 1
• Folic acid 1 mg daily supplementation 1
• Vitamin B12 and iron supplementation if deficient 6

Critical Pitfalls to Avoid

Do not use corticosteroids as primary therapy for CAD - they are ineffective and should not be used. 3, 4, 8 Corticosteroids have response rates of only 10-60% in CAD compared to 70-80% in warm AIHA 1, 3

Do not rely on cold agglutinin titers alone to guide management decisions; clinical symptoms and hemolysis markers are more reliable indicators of disease severity. 1

Do not use splenectomy for CAD - rituximab is the preferred approach rather than splenectomy. 1, 3

Recognize that cold agglutinins can interfere with accurate IgM level determination, requiring testing at diagnosis when AIHA is suspected. 1

Distinguish CAD from warm AIHA early, as therapy differs substantially between the two entities. 4 A negative C3d DAT should prompt investigation for warm AIHA 4

Treatment of Underlying Causes

When autoimmune cytopenia does not respond to conventional therapy, treatment of the underlying lymphoproliferative disorder (such as Waldenström macroglobulinemia) is indicated 7, 3