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PA16.1-3 | Hemolytic Anemias — PBL Case

CLINICAL SETTING

Savitri, a 32-year-old school teacher from a small town in Rajasthan, is brought to the district hospital by her husband in late December. Over the past three weeks, she has been increasingly tired, struggling to climb one flight of stairs, and has noted that her eyes have turned yellow. Her husband mentions that her urine has become dark — 'like tea' — especially in the mornings. She reports that the jaundice worsens in cold weather and that her fingers turn bluish-white in winter, something she has learned to live with for years. She had a similar but milder episode two years ago during a chest infection. There is no prior history of liver disease, blood transfusion, or alcohol use. She was started on azithromycin for a respiratory tract infection ten days ago by a local practitioner. On examination: pallor, icteric sclerae, temperature 37.2°C, blood pressure 108/72 mmHg, pulse 102/min. The spleen is palpable 3 cm below the left costal margin. No lymphadenopathy. Investigations: Hb 7.4 g/dL, MCV 91 fL, reticulocyte count 14%, total bilirubin 5.8 mg/dL (indirect 5.1 mg/dL), LDH 870 U/L, haptoglobin undetectable, urine dipstick negative for bilirubin but positive for urobilinogen. CBC shows mild thrombocytosis (440 × 10⁹/L). Peripheral blood smear shows clumping of red cells that disperses on warming the slide to 37°C, with no sickle forms or bite cells.

Trigger 1: Initial Presentation

The junior resident reviews Savitri's presentation: a 32-year-old woman with worsening fatigue, jaundice, and dark morning urine for three weeks, worsening in cold weather. She has a history of similar episodes in cold and infection-prone situations. Examination reveals pallor, icterus, splenomegaly, and no lymph nodes. Lab results confirm anaemia (Hb 7.4 g/dL) with reticulocytosis (14%), elevated indirect bilirubin, and undetectable haptoglobin. Urine is free of bilirubin. The smear shows red cell clumping that disperses on warming.

DISCUSSION POINTS

What is the clinical triad that suggests haemolytic anaemia, and which of these features does Savitri demonstrate?
The urine is positive for urobilinogen but negative for bilirubin — what does this pattern tell you about the type of bilirubin being produced, and why?
Why do red cells clump on the peripheral smear at room temperature and disperse at 37°C? What is the name of this phenomenon, and what antibody type is responsible?
How does the cold exposure history and the pattern of recurrent episodes during winter/infections fit together mechanistically?

Click to reveal Trigger 2: Investigations (discuss previous trigger first!)

Trigger 2: Investigations

The attending orders a direct antiglobulin test (DAT) using polyspecific antiserum — positive. Monospecific repeat: strongly positive for C3d, negative for IgG. Cold agglutinin titre: 1:2048 (positive >1:64). A further history reveals that Savitri had a mild respiratory illness three weeks ago and her GP mentioned 'walking pneumonia'. Chest X-ray shows patchy right lower zone consolidation. Cold agglutinin disease secondary to Mycoplasma pneumoniae infection is suspected. A bone marrow biopsy is not performed, but CECT chest confirms the chest finding. Haemoglobin electrophoresis is sent to rule out concurrent haemoglobinopathy and returns normal (HbA 97%, HbA2 2.4%, HbF 0.6%).

DISCUSSION POINTS

Explain the pathogenesis of cold agglutinin disease step-by-step: how does IgM binding in the periphery lead to complement activation and red cell destruction?
Why is the DAT positive for C3d but negative for IgG in cold AIHA, whereas the reverse is expected in warm AIHA?
Mycoplasma pneumoniae infection triggers cold agglutinins — what is the antigen target (I antigen) and why is this clinically important when considering associations?
The haemolysis is predominantly hepatic in cold AIHA rather than splenic — what immunological mechanism explains this, and how does it differ from warm AIHA?

Click to reveal Trigger 3: Diagnosis & Management (discuss previous trigger first!)

Trigger 3: Diagnosis & Management

Savitri is diagnosed with cold agglutinin disease secondary to Mycoplasma pneumoniae. She is treated with doxycycline for the underlying infection and advised strict cold avoidance — warm clothing, heated environment, and warming all IV fluids. The azithromycin is stopped (macrolide resistance in Mycoplasma being considered). Over 10 days, her Hb improves to 9.1 g/dL and the cold agglutinin titre begins to decline. The registrar explains that her long-standing cold intolerance suggests a chronic low-level cold agglutinin state, possibly on a background of a lymphoproliferative disorder, warranting serum protein electrophoresis and follow-up. On discharge, she is counselled about avoiding cold environments and the importance of follow-up.

DISCUSSION POINTS

Compare the peripheral smear morphology expected in cold AIHA versus warm AIHA versus MAHA — what cell forms would you look for specifically on the smear?
Savitri's cold agglutinin titre is very high — what classes of conditions should be ruled out in a patient with chronic cold agglutinin disease not triggered by an acute infection?
Design a stepwise diagnostic algorithm for a patient presenting with haemolytic anaemia: which tests confirm haemolysis first, and which distinguish the mechanism?
The resident asks whether a splenectomy would help Savitri — construct your answer using your understanding of where red cell destruction occurs in cold versus warm AIHA.

Group Task Assignments

Group 1: Classification and laboratory markers of haemolytic anaemia

Draw and label the three axes of haemolytic anaemia classification (site, cause, defect location) and place Savitri's case correctly on all three axes.
Create a table of haemolysis laboratory markers distinguishing intravascular from extravascular haemolysis, indicating which of Savitri's results fit each column.

Competencies: PA16.1

Group 2: Hereditary haemolytic anemias — contrast with Savitri's case

Construct a comparison table of sickle cell disease versus β-thalassaemia major covering: gene defect, pathogenesis, MCV, peripheral smear findings, haemoglobin electrophoresis pattern.
Explain why hereditary spherocytosis produces a DAT-negative haemolytic anaemia with spherocytes on smear — distinguish from warm AIHA which also shows spherocytes.

Competencies: PA16.2

Group 3: Acquired haemolytic anemias — mechanism-based classification

Build a mechanism-based classification table of acquired haemolytic anemias, placing cold AIHA, warm AIHA, MAHA (TTP, HUS), PNH, and malaria in their correct slots with one key distinguishing feature each.
Outline the principle and interpretation of the direct antiglobulin test (DAT), explaining why monospecific reagents (anti-IgG vs anti-C3d) allow you to distinguish warm from cold AIHA.

Competencies: PA16.3

Group 4: Clinical integration and smear morphology

Describe and sketch the expected peripheral blood smear findings in cold AIHA, noting how red cell agglutination appears and which cell forms are absent (contrasted with warm AIHA spherocytes and MAHA schistocytes).
Develop a short patient-counselling note for Savitri explaining why cold avoidance is therapeutic and what symptoms should prompt re-attendance.

Competencies: PA16.1, PA16.3

Group 5: Integrated diagnostic algorithm

Draw a step-by-step diagnostic flowchart: starting from 'suspected haemolytic anaemia', progressing through confirming haemolysis, classifying by DAT result, and reaching a specific diagnosis.
Apply the flowchart to three brief vignettes: (a) a young woman with SLE, spherocytes, and DAT-IgG positive; (b) a child with schistocytes, thrombocytopenia, and renal failure after bloody diarrhoea; (c) Savitri's presentation.

Competencies: PA16.1, PA16.3

Learning Issues

Research these questions and bring your findings to the discussion.

[PA16.1] What are the three axes of classifying haemolytic anaemia (site, cause, defect location), what are the general clinical features common to all haemolytic anemias, and what laboratory indices (reticulocyte count, bilirubin fractions, LDH, haptoglobin) confirm ongoing haemolysis?
[PA16.2] What is the molecular basis and pathogenesis of sickle cell disease and the thalassaemias, how do their peripheral blood smear appearances and haemoglobin electrophoresis patterns differ, and why is MCV normal in sickle cell disease but low in thalassaemia?
[PA16.3] What are the etiology, pathogenesis, and diagnostic features (smear morphology, DAT result, clinical context) of the main acquired haemolytic anemias — warm AIHA, cold AIHA, MAHA, and PNH — and how do infection-triggered and autoimmune triggers differ in their management approach?