Autoimmune Haemolytic Anaemia

Antibody-mediated destruction of red blood cells, classified by the thermal reactivity of the responsible antibody, which determines the pathophysiology, associations and treatment approach.

Warm autoimmune haemolytic anaemia: IgG antibodies reactive at body temperature (37°C), causing predominantly extravascular haemolysis via splenic macrophage Fc receptor-mediated phagocytosis (partial "bite" removal producing spherocytes). Idiopathic in roughly half; secondary causes include lymphoproliferative disorders (chronic lymphocytic leukaemia, lymphoma), autoimmune disease (systemic lupus erythematosus), drugs (methyldopa, penicillins, cephalosporins), and infections.

Cold agglutinin disease: IgM antibodies reactive at cold temperatures, causing complement fixation and predominantly intravascular haemolysis (and extravascular via complement receptor-mediated hepatic clearance) on rewarming. Idiopathic (often associated with an underlying clonal B-cell lymphoproliferative disorder even without overt lymphoma) or secondary to infection (Mycoplasma pneumoniae, Epstein-Barr virus) or lymphoproliferative disease.

Paroxysmal cold haemoglobinuria: rare, IgG (Donath-Landsteiner) biphasic haemolysin, classically post-viral in children, causing acute intravascular haemolysis on rewarming after cold exposure.

Mixed type: combined warm and cold antibody features.

• Warm type: gradual or acute onset fatigue, pallor, jaundice, splenomegaly; can be fulminant with rapid severe anaemia.
• Cold agglutinin disease: symptoms precipitated or worsened by cold exposure --- acrocyanosis of fingers, toes, nose and ears (reversible with warming, distinguishing from Raynaud phenomenon by the livedo/acrocyanotic pattern rather than triphasic colour change), haemolysis and haemoglobinuria on cold exposure, chronic mild-moderate anaemia.
• Paroxysmal cold haemoglobinuria: acute severe haemolysis, fever, abdominal/back pain and haemoglobinuria shortly after cold exposure, typically following a viral illness in a child.
• Features of the underlying/associated condition: lymphadenopathy or B symptoms suggesting lymphoproliferative disease, features of systemic lupus erythematosus, recent Mycoplasma or viral infection, relevant drug history.

• Direct antiglobulin (Coombs) test is central: positive for IgG (± complement C3d) in warm type; positive for complement C3d alone (IgG negative) in cold agglutinin disease, since IgM dissociates during sample processing leaving only bound complement detectable.
• Full blood count, reticulocyte count, LDH, haptoglobin, unconjugated bilirubin as for haemolysis generally.
• Blood film: spherocytes and polychromasia in warm type; red cell agglutination (clumping visible on the film, and sometimes macroscopically in the tube) in cold agglutinin disease.
• Cold agglutinin titre, and Donath-Landsteiner test for suspected paroxysmal cold haemoglobinuria.
• Investigate for underlying cause: CT imaging and lymphocyte immunophenotyping if lymphoproliferative disease is suspected, antinuclear antibody and complement levels for lupus, Mycoplasma/EBV serology, full drug history.
• Crossmatching difficulty is common (autoantibody reacts with all donor cells) --- liaise closely with the blood bank; transfusion should not be withheld for life-threatening anaemia while awaiting a perfect match.

Warm autoimmune haemolytic anaemia

• First-line: corticosteroids, prednisolone 1mg/kg/day, tapered over weeks to months once response is achieved (haemoglobin stabilisation, reticulocyte fall).
• Second-line for relapsed/refractory disease: rituximab (increasingly preferred second-line, often before splenectomy given comparable efficacy with less morbidity), splenectomy, or other immunosuppressants (azathioprine, mycophenolate, ciclosporin).
• Folic acid supplementation.
• Treat any identified secondary cause (stop the offending drug, treat underlying lymphoproliferative disorder or lupus).
• Transfusion for symptomatic/severe anaemia despite crossmatch difficulty.

Cold agglutinin disease

• Avoidance of cold exposure is the mainstay for mild disease --- keeping extremities warm, avoiding cold drinks/environments.
• Corticosteroids are generally ineffective (unlike warm type) given the complement-mediated rather than Fc-receptor mechanism; splenectomy is also typically ineffective since destruction is predominantly hepatic/intravascular.
• Rituximab (alone or with bendamustine/fludarabine) is effective, particularly given the frequent underlying clonal B-cell process.
• Complement inhibition (sutimlimab, a C1s inhibitor) is an emerging targeted therapy specifically for cold agglutinin disease.
• Treat any underlying infection or lymphoproliferative disorder.
• Warmed intravenous fluids and blood products (use a blood warmer) during transfusion.

Paroxysmal cold haemoglobinuria: supportive care, avoidance of cold, usually self-limiting in the post-viral paediatric setting; transfusion (warmed) if severe.