A 58-year-old man presents with 6–8 weeks of increasing tiredness and shortness of breath on exertion. On examination he appears icteric, and his spleen is enlarged. Laboratory investigations show:
Hb: 100 g/L
MCV: 90 fL
Direct antiglobulin (Coombs) test: positive
Further immunological testing confirms a diagnosis of warm autoimmune haemolytic anaemia.
Which class of immunoglobulin is most commonly responsible for this condition?
A. IgM
B. IgG
C. IgE
D. IgA
E. IgD
Answer
IgG
Detailed discussion for MRCP
Warm autoimmune haemolytic anaemia (warm AIHA) is the commonest form of autoimmune haemolytic anaemia and is mediated predominantly by IgG antibodies. These antibodies optimally bind to red blood cell antigens at normal body temperature (around 37°C). Once IgG coats the red cells, macrophages in the spleen recognise the Fc portion of IgG via Fc receptors, leading to partial phagocytosis of the red cell membrane. This results in the formation of spherocytes, which are less deformable and are subsequently destroyed in the spleen, explaining the predominantly extravascular haemolysis and splenomegaly.
This extravascular destruction leads to classical biochemical features of haemolysis: raised unconjugated bilirubin, elevated LDH, low haptoglobin, and reticulocytosis (unless marrow response is impaired). The direct Coombs (DAT) test is positive because it detects IgG (and sometimes complement C3) bound to the red cell surface in vivo.
Warm AIHA is most often idiopathic but has important secondary associations that MRCP candidates must remember, particularly autoimmune diseases such as systemic lupus erythematosus, lymphoproliferative disorders like chronic lymphocytic leukaemia and lymphoma, and certain drugs—classically methyldopa, which induces true autoantibody formation against red cells.
Management principles are also exam favourites. First-line treatment is corticosteroids, which reduce antibody production and macrophage-mediated destruction. Rituximab (anti-CD20) is commonly used in steroid-refractory disease. Splenectomy may be considered in resistant cases because the spleen is the primary site of red cell destruction. Blood transfusion, if needed, should not be delayed due to fear of crossmatch difficulty—this is a common exam trap.
In contrast, cold autoimmune haemolytic anaemia is mediated by IgM antibodies, which bind at lower temperatures (around 4°C), activate complement, and cause predominantly intravascular haemolysis or hepatic clearance via C3b. Recognising the immunoglobulin class helps immediately differentiate warm from cold AIHA in exam scenarios.
Cheat sheet (exam-focused)
- Warm AIHA: IgG-mediated
- Optimal binding temperature: 37°C
- Site of haemolysis: extravascular (spleen)
- DAT: positive for IgG ± C3
- Blood film: spherocytes
- Common causes: idiopathic, SLE, CLL, lymphoma, methyldopa
- First-line treatment: corticosteroids
- Second-line: rituximab
- Refractory cases: splenectomy
- Cold AIHA: IgM, complement-mediated, cold exposure related
Flash cards
- Q: What immunoglobulin mediates warm AIHA?
A: IgG
Explanation: IgG binds RBCs at body temperature and promotes splenic destruction. - Q: At what temperature does warm AIHA antibody binding occur?
A: Around 37°C
Explanation: This distinguishes warm from cold AIHA. - Q: Primary site of haemolysis in warm AIHA?
A: Spleen
Explanation: Fc receptor–mediated macrophage phagocytosis. - Q: Typical blood film finding in warm AIHA?
A: Spherocytes
Explanation: Partial phagocytosis of RBC membrane. - Q: Which test confirms autoimmune haemolysis in vivo?
A: Direct Coombs test
Explanation: Detects IgG or complement on RBCs. - Q: Is haemolysis in warm AIHA intravascular or extravascular?
A: Extravascular
Explanation: Occurs mainly in spleen. - Q: Most common cause of warm AIHA?
A: Idiopathic
Explanation: No underlying disease in many cases. - Q: Autoimmune disease commonly associated with warm AIHA?
A: Systemic lupus erythematosus
Explanation: Classic exam association. - Q: Lymphoproliferative disorder linked to warm AIHA?
A: Chronic lymphocytic leukaemia
Explanation: Common secondary cause. - Q: Drug classically causing warm AIHA?
A: Methyldopa
Explanation: Induces true autoantibody formation. - Q: First-line treatment for warm AIHA?
A: Corticosteroids
Explanation: Reduce antibody production and phagocytosis. - Q: Monoclonal antibody used in steroid-resistant AIHA?
A: Rituximab
Explanation: Targets CD20-positive B cells. - Q: Why does splenectomy help in warm AIHA?
A: Removes main site of RBC destruction
Explanation: Spleen is central to pathology. - Q: Is transfusion contraindicated in warm AIHA?
A: No
Explanation: Should not be withheld if clinically indicated. - Q: Which immunoglobulin mediates cold AIHA?
A: IgM
Explanation: Binds at low temperatures. - Q: Mechanism of haemolysis in cold AIHA?
A: Complement-mediated
Explanation: Leads to intravascular or hepatic clearance. - Q: Cold AIHA commonly follows which infections?
A: Mycoplasma, EBV
Explanation: Important exam triggers. - Q: Which haemolysis marker is reduced in AIHA?
A: Haptoglobin
Explanation: Consumed by free haemoglobin. - Q: Why is bilirubin raised in AIHA?
A: Increased breakdown of haemoglobin
Explanation: Leads to unconjugated hyperbilirubinaemia. - Q: Can SLE cause mixed-type AIHA?
A: Yes
Explanation: Rare but important MRCP fact.
MCQs to test yourself
- Warm autoimmune haemolytic anaemia is most commonly mediated by:
A. IgM
B. IgG
C. IgA
D. IgE
Answer: B – IgG binds at body temperature. - The primary site of red cell destruction in warm AIHA is:
A. Liver
B. Bone marrow
C. Spleen
D. Kidney
Answer: C – Extravascular haemolysis in spleen. - Which blood film feature is typical of warm AIHA?
A. Schistocytes
B. Target cells
C. Spherocytes
D. Bite cells
Answer: C – Due to partial phagocytosis. - A positive direct Coombs test indicates:
A. Circulating free antibodies
B. Antibodies bound to RBCs
C. Platelet antibodies
D. Complement deficiency
Answer: B – Detects in vivo RBC coating. - First-line therapy for warm AIHA is:
A. IVIG
B. Splenectomy
C. Corticosteroids
D. Plasmapheresis
Answer: C – Standard initial management. - Which of the following is false regarding warm AIHA?
A. IgG-mediated
B. Extravascular haemolysis
C. Commonly idiopathic
D. Primarily intravascular
Answer: D – Intravascular is incorrect. - Which drug is classically associated with warm AIHA?
A. Penicillin
B. Methyldopa
C. Rifampicin
D. Heparin
Answer: B – Classic association. - Warm AIHA antibodies bind best at:
A. 4°C
B. 20°C
C. 30°C
D. 37°C
Answer: D – Body temperature. - Which immunoglobulin is implicated in cold AIHA?
A. IgG
B. IgA
C. IgM
D. IgE
Answer: C – Cold agglutinin disease. - Complement-mediated haemolysis is typical of:
A. Warm AIHA
B. Cold AIHA
C. Hereditary spherocytosis
D. G6PD deficiency
Answer: B – IgM activates complement. - Which condition is most commonly associated with warm AIHA?
A. SLE
B. Thalassaemia
C. Iron deficiency
D. Aplastic anaemia
Answer: A – Autoimmune association. - A low haptoglobin level suggests:
A. Reduced erythropoiesis
B. Haemolysis
C. Iron overload
D. B12 deficiency
Answer: B – Consumed during haemolysis. - Which of the following is false in warm AIHA?
A. Raised LDH
B. Raised unconjugated bilirubin
C. Reticulocytosis
D. Low MCV
Answer: D – MCV is usually normal or high. - Rituximab works in AIHA by targeting:
A. T cells
B. Macrophages
C. Complement
D. B cells
Answer: D – Anti-CD20. - Which organ enlargement is typical in warm AIHA?
A. Hepatomegaly only
B. Splenomegaly
C. Lymphadenopathy only
D. Nephromegaly
Answer: B – Due to splenic destruction. - Cold AIHA commonly presents with:
A. Jaundice only
B. Acrocyanosis
C. Petechiae
D. Haematuria
Answer: B – Cold-induced symptoms. - Which infection is linked to cold AIHA?
A. HIV
B. Mycoplasma pneumoniae
C. Malaria
D. TB
Answer: B – Classic trigger. - In warm AIHA, haemolysis is best described as:
A. Complement-only mediated
B. Antibody-dependent cellular phagocytosis
C. Mechanical destruction
D. Osmotic lysis
Answer: B – Fc-mediated phagocytosis. - Which antibody fragment binds macrophage Fc receptors?
A. Fab
B. Fc
C. Light chain
D. J chain
Answer: B – Recognised by splenic macrophages. - Which statement about transfusion in warm AIHA is false?
A. It may be technically difficult
B. It should be avoided at all costs
C. It can be life-saving
D. It may be required in severe anaemia
Answer: B – Transfusion should not be withheld.
Summary for quick exam revision
Warm autoimmune haemolytic anaemia is the most common form of AIHA and is mediated by IgG antibodies that bind red blood cells optimally at body temperature. These IgG-coated cells are destroyed predominantly in the spleen via Fc receptor–mediated macrophage phagocytosis, leading to extravascular haemolysis, spherocytes on blood film, splenomegaly, and jaundice. The direct Coombs test is positive for IgG with or without complement. Biochemical features include raised LDH, elevated unconjugated bilirubin, low haptoglobin, and reticulocytosis. Most cases are idiopathic, but important associations include SLE, chronic lymphocytic leukaemia, lymphoma, and methyldopa use. First-line treatment is corticosteroids, with rituximab used in refractory disease and splenectomy reserved for resistant cases. Cold AIHA, in contrast, is IgM-mediated, complement-driven, cold-induced, and often associated with infections such as Mycoplasma or EBV.