❄️ Cold Agglutinin Disease (CAD) is a rare autoimmune haemolytic anaemia (AIHA) where autoantibodies target red blood cells at low temperatures, leading to haemolysis. Corticosteroids are not effective in severe cases. The commonest trigger is Mycoplasma pneumoniae infection.
🔎 About
- Rare cause of autoimmune haemolytic anaemia (AIHA) 🩸
- Cold-reactive IgM autoantibodies agglutinate RBCs
- First described in 1957
🧬 Aetiology (IgM-mediated)
- Agglutinates erythrocytes best at 0–4 °C ❄️
- Directed mainly against the I/i blood group system
- Fixes C3 complement → extravascular haemolysis (liver)
- High titres (>1:512) clinically significant
📌 Causes
- Primary CAD: Elderly (median age ~76), monoclonal IgM
- Secondary CAD:
- Infections: Mycoplasma pneumoniae, EBV, CMV, HIV, influenza, hepatitis C, syphilis, malaria
- Malignancies: Lymphoma, CLL, Waldenström’s, Myeloma
- Autoimmune: SLE
🩺 Clinical Features
- Anaemia: fatigue, jaundice, dark urine
- Cold-induced: acrocyanosis (blue hands/feet), Raynaud’s phenomenon ❄️🖐️
- Livedo reticularis (mottled skin), splenomegaly
🧪 Investigations
- Low Hb, red cell agglutination on smear 🔬
- Raised LDH & reticulocytosis (haemolysis)
- Direct Coombs test: positive for IgM & C3, negative for IgG
- Low complement levels (C3, C4)
💊 Management
- Avoid cold exposure ❄️ (gloves, warm environment)
- Transfuse via a blood warmer if required 🩸🔥
- Treat underlying cause (infection/malignancy)
- Rituximab (anti-CD20): effective in ~60% 💊
- Combination with cyclophosphamide or fludarabine in refractory cases
- Plasmapheresis: temporary removal of antibodies
- Steroids ineffective 🚫 (unlike warm AIHA)
📚 Reference
Cases — Cold Agglutinin Disease (CAD / AIHA)
- Case 1 — Elderly Patient with Anaemia & Acrocyanosis ❄️:
A 72-year-old woman presents in winter with fatigue, pallor, and dark-coloured urine after being outside. Exam: acrocyanosis of fingers, splenomegaly. Blood film: red cell agglutination. Direct antiglobulin (Coombs) test positive for C3d.
Diagnosis: Primary cold agglutinin disease.
Management: Keep warm, rituximab for severe anaemia, folate supplementation, transfuse with warmed blood if required.
- Case 2 — Post-Infectious CAD 🦠:
A 25-year-old man develops jaundice, anaemia, and dark urine 1 week after recovering from Mycoplasma pneumoniae infection. Exam: mild splenomegaly, acrocyanosis. Hb 85 g/L, reticulocytosis, raised LDH, indirect bilirubin elevated.
Diagnosis: Secondary cold AIHA triggered by Mycoplasma infection.
Management: Treat infection; supportive care; avoid cold; usually self-limiting.
- Case 3 — Lymphoma-Associated CAD 🧬:
A 60-year-old man with known low-grade lymphoma presents with progressive fatigue and cold-induced digital ischaemia. Labs: normocytic anaemia, positive DAT (C3d), serum protein electrophoresis shows monoclonal band.
Diagnosis: CAD secondary to lymphoproliferative disorder.
Management: Rituximab ± bendamustine for lymphoma; warming measures; avoid steroids (poor efficacy in CAD).
Teaching Commentary 🧠
Cold Agglutinin Disease is a form of autoimmune haemolytic anaemia mediated by IgM antibodies that bind RBCs at cold temperatures (<37°C).
- Primary CAD: idiopathic, chronic, older adults.
- Secondary CAD: triggered by infections (Mycoplasma, EBV) or lymphoproliferative disorders.
Features: anaemia, jaundice, acrocyanosis, haemoglobinuria in cold exposure.
Dx: DAT positive for complement (C3d), blood film shows agglutination.
Mx: Warming, avoid cold, rituximab for severe cases, treat underlying cause, transfuse with warmed blood.
Steroids usually ineffective (unlike warm AIHA).
