Cold agglutinin disease (CAD) is autoimmune haemolytic anaemia mediated by IgM autoantibodies that bind red cells at low temperature and activate complement.

Primary CAD: clonal B cell lymphoproliferative disorder of the marrow (IgM kappa), median age 65, about 15% of AIHA.
Secondary cold agglutinin syndrome: infections (Mycoplasma pneumoniae, EBV), lymphoma.
Haemolysis is mainly extravascular via C3b opsonisation in the liver, with a thermal amplitude up to 30 C.
Complications: acrocyanosis, Raynaud, thrombosis, severe anaemia during cold or infection.

Anaemia, raised bilirubin, LDH, reticulocytes, low haptoglobin, red cell agglutination on film at room temperature, spurious macrocytosis and high MCHC.
Direct antiglobulin test positive for C3d only (IgG negative).
Cold agglutinin titre 1:64 or more at 4 C, thermal amplitude testing; samples kept warm at 37 C.
Serum protein electrophoresis with immunofixation (IgM kappa), bone marrow biopsy (clonal lymphoplasmacytic infiltrate, MYD88 usually wild type), CT, Mycoplasma and EBV serology.

Avoid cold exposure, warm clothing, warm blood products (use blood warmer).
Supportive: folic acid 5 mg daily, transfusion if needed.
Indications for therapy: symptomatic anaemia, transfusion dependence, severe cold symptoms.
First line: rituximab 375 mg/m2 weekly for 4 doses (response 50%), or rituximab with bendamustine 90 mg/m2 days 1 and 2 for 4 cycles (response 70 to 75%); fludarabine with rituximab.
Sutimlimab (anti C1s) 6.5 g (under 75 kg) or 7.5 g IV on days 0 and 7, then every 2 weeks, reduces haemolysis and transfusions; risk of infection with encapsulated organisms (vaccinate against meningococcus, pneumococcus, Hib).
Corticosteroids and splenectomy are ineffective.
Plasma exchange for severe haemolysis or perioperative preparation.
Secondary: treat infection and lymphoma.
Thromboprophylaxis in hospitalised patients.

Cold Agglutinin Disease

Overview

Clinical Features

Diagnosis

Management