Haemolytic Anaemia — SAQ

Stem

A 56-year-old woman presents to the emergency department with a two-week history of progressive fatigue, breathlessness on exertion, and yellowing of her eyes. Over the past 24 hours she has noticed dark urine. She has a history of rheumatoid arthritis for which she takes methotrexate. On examination she is pale with scleral icterus, a lemon-yellow skin tinge, and a palpable spleen 4 cm below the left costal margin. Hb 58 g/L, MCV 104 fL, reticulocytes 9 percent (corrected), LDH 980 U/L, unconjugated bilirubin 68 µmol/L, haptoglobin under 10 mg/dL. Blood film shows spherocytes and polychromasia. DAT is strongly positive for IgG and C3d. Renal function is normal.^[3]

Questions

a) What is the diagnosis, and what two features in the stem most strongly support haemolysis? (2 marks)

Diagnosis: warm autoimmune haemolytic anaemia (AIHA). Two features supporting haemolysis: (1) raised reticulocytes (9 percent corrected — marrow response to premature red-cell destruction); (2) the biochemical signature of raised LDH, raised unconjugated bilirubin, and low/absent haptoglobin. The positive DAT for IgG +/- C3d and spherocytes on film confirm the immune, extravascular mechanism.^[1][3]

b) Outline the investigation strategy that distinguishes immune from non-immune haemolysis and gives the specific cause. (3 marks)

1. Confirm haemolysis — raised reticulocytes (corrected count / production index raised), raised LDH, raised unconjugated bilirubin, low/absent haptoglobin (a level of 25 mg/dL or less is 83 percent sensitive and 96 percent specific for haemolysis — Marchand 1980).
2. Localise site on film — spherocytes (extravascular — warm AIHA, HS), schistocytes/haemoglobinuria (intravascular — MAHA, PNH, G6PD, cold agglutinin).
3. DAT (direct Coombs) is THE discriminator — positive = immune (this patient: IgG + C3d = warm AIHA); negative = non-immune (HS, G6PD, PNH, MAHA, sickle, thalassaemia).
4. Cause-specific tests — cold agglutinin titre (cold agglutinin disease), Donath-Landsteiner (PCH), EMA-binding flow cytometry / osmotic fragility (HS), G6PD assay (G6PD — BewarE falsely normal during attack), Hb electrophoresis/HPLC (sickle/thal), FLAER/CD55-CD59 flow cytometry (PNH), ADAMTS13 (TTP).
5. Underlying cause screen — autoimmune (ANA, anti-dsDNA — rheumatoid arthritis here is a clue), lymphoproliferative (immunoglobulins, serum electrophoresis, blood film for lymphoma/CLL, marrow), viral serology (HIV, hepatitis, EBV, mycoplasma).^[3][4]

c) Detail the stepwise management of this patient. (3 marks)

1. Resuscitation — Hb under 70 g/L with symptoms warrants transfusion. In AIHA the antibody reacts with all donor cells so full crossmatch is impossible; request least-incompatible blood, inform the laboratory, and transfuse cautiously under observation. IV crystalloid to maintain urine output and protect the kidneys from haemoglobinuria. Folic acid supplementation to support compensatory erythropoiesis. Stop any offending drug.^[1]
2. First-line definitive — high-dose oral prednisolone (weight-based dosing per local protocol); response is usually prompt, and the 2020 international consensus is to add rituximab early when it is not. Add gastroprotection (PPI), bone protection (calcium/vitamin D +/- bisphosphonate), and monitor blood glucose. Investigate for underlying cause (rheumatoid arthritis is a clue to autoimmune aetiology; screen for lymphoma/CLL).
3. Second-line if steroid-dependent or refractory — rituximab (often preferred in older/frail patients), splenectomy (after vaccination; effective in approximately 2 of 3 cases), immunosuppressants (azathioprine, cyclophosphamide, ciclosporin, mycophenolate).

d) What are the key complications of her disease and its treatment? (2 marks)

• Disease complications — pigment (calcium bilirubinate) gallstones from chronic bilirubin load; folate deficiency (megaloblastic crisis); aplastic crisis from parvovirus B19 (sudden reticulocytopenia); acute kidney injury from haemoglobinuria; thromboembolism (a leading cause of death in AIHA).
• Treatment complications — steroids (osteoporosis, diabetes, hypertension, infection); rituximab (hepatitis B reactivation, infusion reactions); splenectomy — overwhelming post-splenectomy infection (OPSI) from encapsulated organisms (pneumococcus, meningococcus, Haemophilus influenzae), case-fatality 40–54 percent (narrative literature review) — prevented by pre-splenectomy vaccination at least 2 weeks before surgery (optimal 4–6 weeks): pneumococcal, meningococcal ACWY and B, annual influenza (additional Hib is no longer recommended in the UK Green Book 2020), antibiotic prophylaxis with phenoxymethylpenicillin 250 mg twice daily (lifelong for continued high risk; shared decision for others), a patient alert card, and counsel that any fever is an emergency requiring immediate empirical IV antibiotics — do not wait for cultures.^[5][6]

References6ShowHide

1. [1]Jäger U, Barcellini W, Broome CM, et al. Diagnosis and treatment of autoimmune hemolytic anemia in adults: Recommendations from the First International Consensus Meeting Blood Rev, 2020.PMID 31839434
2. [2]Zanella A, Barcellini W. Treatment of autoimmune hemolytic anemias Haematologica, 2014.PMID 25271314
3. [3]Phillips J, Henderson AC. Hemolytic Anemia: Evaluation and Differential Diagnosis Am Fam Physician, 2018.PMID 30215915
4. [4]Marchand A, Galen RS, Van Lente F. The predictive value of serum haptoglobin in hemolytic disease JAMA, 1980.PMID 7365971
5. [5]Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states Lancet, 2011.PMID 21474172
6. [6]Taniguchi LU, Correia MD, Zampieri FG. Overwhelming post-splenectomy infection: narrative review of the literature Surg Infect (Larchmt), 2014.PMID 25318011