76 HAEMATOLOGY

# 77 HAEMATOLOGY

Haematology in MRCS Part A is mostly pattern recognition. The exam will hand you a blood film, an MCV, a paraprotein band, a chromosomal translocation or a "punched-out lytic lesion" and expect you to land on the diagnosis in one step. This lesson is organised around exactly those pattern triggers.

👩‍⚕️ Three single-sentence facts that win marks: NHL = painless peripheral lymphadenopathy; myeloma = lytic bone lesions + M-spike + Bence Jones protein; give B12 before folate in megaloblastic anaemia to avoid precipitating subacute combined degeneration of the cord.

Detailed notes

1. Anaemia — classify by MCV first

The MCV is the single most useful exam clue. Decide microcytic, normocytic or macrocytic, then narrow within that group.

MCV	Range	Common causes	High-yield clues
Microcytic	< 80 fL	Iron deficiency, thalassaemia, anaemia of chronic disease, sideroblastic, lead poisoning	Mnemonic TAILS (Thalassaemia, Anaemia of chronic disease, Iron deficiency, Lead, Sideroblastic)
Normocytic	80–100 fL	Acute blood loss, anaemia of chronic disease, CKD (↓EPO), haemolytic, marrow failure	Reticulocyte count separates marrow failure (low) from haemolysis/bleeding (high)
Macrocytic	> 100 fL	Megaloblastic: B12, folate. Non-megaloblastic: alcohol, hypothyroidism, liver disease, myelodysplasia, drugs (methotrexate, hydroxycarbamide)	Hypersegmented neutrophils = megaloblastic

Iron studies — learn this table cold, it is the highest-yield haematology fact in Part A.

	Ferritin	Serum iron	TIBC	Transferrin saturation
Iron deficiency	↓	↓	↑	↓
Anaemia of chronic disease	↑ or normal	↓	↓	↓
Haemochromatosis / overload	↑↑	↑	↓	↑↑
Thalassaemia	Normal	Normal	Normal	Normal

The classic trap: ferritin is an acute-phase reactant, so in a septic or inflamed patient with iron deficiency it can be falsely normal. TIBC (transferrin) is the more reliable separator — high in iron deficiency, low in chronic disease.

2. Megaloblastic anaemia — B12 vs folate

Both cause macrocytosis and hypersegmented neutrophils. B12 deficiency additionally causes subacute combined degeneration of the cord (dorsal columns + corticospinal tracts → loss of vibration/proprioception with brisk reflexes and upgoing plantars). Folate deficiency does not.

If you give folate alone to a B12-deficient patient, the haematological picture improves but the neurology accelerates — sometimes irreversibly. Always replace B12 first, or replace both together. This is a guaranteed Part A question.

Common causes: B12 — pernicious anaemia (autoimmune anti-parietal cell / anti-intrinsic factor antibodies), terminal ileal resection or Crohn's, vegan diet. Folate — pregnancy, alcohol, methotrexate, phenytoin.

3. Haemolytic anaemia

Haemolysis = premature red cell destruction. Splits into hereditary (defective cell) and acquired (normal cell, hostile environment).

Category	Condition	Mechanism / inheritance	Exam clue
Hereditary — membrane	Hereditary spherocytosis	Autosomal dominant; spectrin/ankyrin defect	Spherocytes on film, ↑MCHC, splenomegaly, jaundice; Rx splenectomy
Hereditary — enzyme	G6PD deficiency	X-linked recessive (males)	Heinz bodies, bite cells; triggered by fava beans, sulfa drugs, primaquine, infection
Hereditary — haemoglobin	Sickle cell, thalassaemia	See below	—
Acquired — immune (warm)	Warm AIHA	IgG, optimal at 37°C	SLE, CLL, methyldopa; spherocytes; Rx steroids
Acquired — immune (cold)	Cold AIHA	IgM, optimal at < 37°C	Mycoplasma, EBV, lymphoma; agglutination on film
Acquired — membrane	PNH	Acquired PIG-A mutation → loss of CD55/CD59	Morning haemoglobinuria, thrombosis
Acquired — mechanical	MAHA (TTP, HUS, DIC)	Fibrin strands shear red cells	Schistocytes on film, thrombocytopenia
Acquired — mechanical	Prosthetic heart valve	Direct shear	Schistocytes, raised LDH

Laboratory signature of haemolysis: ↑ unconjugated bilirubin, ↑ LDH, ↑ reticulocytes, ↓ haptoglobin. Direct antiglobulin (Coombs) test is positive in autoimmune causes.

4. Sickle cell disease

Point mutation: glutamate → valine at position 6 of the β-globin chain (HbS). Homozygotes (HbSS) sickle when deoxygenated, dehydrated, acidotic or cold. Autosomal recessive; protective against falciparum malaria in heterozygotes.

Clinical syndromes you must recognise:

- Vaso-occlusive (painful) crisis — bone pain, dactylitis in children. Management: Oxygen, Analgesia (opioids), IV Fluids, Antibiotics if febrile (mnemonic: think of it as resuscitation for the sickled red cell).

- Acute chest syndrome — fever, chest pain, hypoxia, new infiltrate on CXR. Leading cause of death; needs urgent transfusion ± exchange transfusion.

- Splenic sequestration — sudden splenic pooling of blood; hypotensive shock in children. After repeated infarction the spleen scars down → functional auto-splenectomy by adolescence.

- OPSI risk — auto-splenectomy means lifelong vulnerability to encapsulated organisms (Strep pneumoniae, H. influenzae, N. meningitidis). Vaccinate and give prophylactic penicillin.

- Aplastic crisis — parvovirus B19 shuts down erythropoiesis transiently; reticulocytes drop.

- Osteomyelitis — classically Salmonella in sickle cell (Staph aureus remains commonest overall; Salmonella is the trap).

- Avascular necrosis of the femoral head — chronic infarction.

5. Thalassaemia

Reduced synthesis of a globin chain → ineffective erythropoiesis and chronic haemolysis.

- α-thalassaemia — gene deletions on chromosome 16 (four α genes total). Loss of all four = HbBart's, incompatible with life (hydrops fetalis).

- β-thalassaemia — point mutations on chromosome 11. β-thalassaemia major (Cooley's anaemia) presents in infancy when HbF→HbA switch fails. Massive extramedullary haematopoiesis → hepatosplenomegaly, frontal bossing, "hair-on-end" skull X-ray, maxillary overgrowth ("chipmunk facies").

Transfusion-dependent patients accumulate iron → secondary haemochromatosis affecting heart, liver and endocrine organs. Requires lifelong iron chelation (desferrioxamine, deferasirox).

6. Leukaemia — pattern recognition table

	Age	Cell	Defining feature	Translocation / treatment
ALL	Children (peak 2–5)	Lymphoblast	Bone marrow failure + lymphadenopathy; CNS and testicular relapse	t(12;21) good prognosis; t(9;22) Ph+ poor
AML	Adults > 60	Myeloblast	Auer rods on blood film	M3 (APML) = t(15;17) → treat with all-trans retinoic acid (ATRA); high DIC risk at presentation
CLL	Elderly	Mature B-lymphocyte	Asymptomatic lymphocytosis, smudge cells, warm AIHA	Richter's transformation → high-grade NHL (DLBCL)
CML	Middle-aged	Myeloid lineage, all stages	Massive splenomegaly, high WCC with basophilia	Philadelphia chromosome t(9;22) BCR-ABL → imatinib (tyrosine kinase inhibitor)

Memory hook: ALL is for kids (A for A child), CLL is for grandparents. AML has Auer rods. CML has the Philadelphia chromosome.

7. Lymphoma — Hodgkin vs Non-Hodgkin

	Hodgkin lymphoma	Non-Hodgkin lymphoma
Hallmark cell	Reed–Sternberg ("owl-eye" binucleate) cell	Variable — most B-cell
Age	Bimodal (20s and 70s)	Increases with age
Spread	Contiguous lymph node groups	Non-contiguous, often extranodal
Distribution	Cervical / mediastinal, central	Peripheral lymphadenopathy common
Association	EBV	EBV, HIV, H. pylori, autoimmune
Classic clue	Pain in nodes after alcohol; pruritus; B symptoms	Painless peripheral lymphadenopathy
Prognosis subtypes	Lymphocyte-rich > nodular sclerosis > mixed cellularity > lymphocyte-depleted (worst)	DLBCL most common; Burkitt fastest growing

Non-Hodgkin subtypes worth knowing:

- DLBCL (diffuse large B-cell) — commonest NHL overall; aggressive but curable with R-CHOP.

- Burkitt lymphoma — c-myc translocation t(8;14); "starry sky" histology. Endemic African form linked to EBV + chronic malaria (classically jaw mass in a child); sporadic form presents as abdominal mass.

- MALT lymphoma of the stomach — driven by H. pylori; can regress with eradication therapy alone.

- Follicular lymphoma — t(14;18), BCL-2 overexpression, indolent.

8. Multiple myeloma

A malignant plasma cell proliferation producing a monoclonal immunoglobulin (most often IgG). Elderly patients.

Remember the diagnostic tetrad with CRAB:

- C — hyperCalcaemia (osteoclast activation)

- R — Renal failure (light chain cast nephropathy)

- A — Anaemia (marrow infiltration; normocytic)

- B — Bone lesions (punched-out lytic lesions, vertebral collapse, pathological fractures)

Investigations: serum protein electrophoresis shows a monoclonal paraprotein band (M-spike); urine shows Bence-Jones protein (free light chains); bone marrow biopsy confirms ≥10% clonal plasma cells. ESR is markedly raised; ALP is usually normal because lesions are purely lytic (no osteoblastic response) — a classic exam trap distinguishing myeloma from bony metastases.

MGUS (monoclonal gammopathy of undetermined significance) is the asymptomatic precursor — paraprotein < 30 g/L, no CRAB features, ~1%/year progression to myeloma.

➡ Bone metastasis patterns: lytic — lung, myeloma, thyroid (follicular), renal, melanoma. Sclerotic — prostate, carcinoid. Mixed — breast, GI.

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Test yourself

A 70-year-old woman's blood film shows hypochromic microcytic anaemia. On examination, axillary and inguinal lymphadenopathy is noted. What is the most likely diagnosis?

• ((Bronchial cancer::Mediastinal nodes and lung mass — not widespread peripheral lymphadenopathy.))
• ((Non-Hodgkin's lymphoma::☑️ Painless peripheral lymphadenopathy + anaemia of chronic disease in an older adult.))
• ((Hodgkin's lymphoma::Contiguous central spread — cervical/mediastinal, rarely axillary + inguinal together.))
• ((Gastric cancer::Causes Virchow's node, not generalised peripheral lymphadenopathy.))
• ((Chronic lymphocytic leukaemia::Possible but lymphocytosis on FBC would be the giveaway, not microcytosis.))

👩‍⚕️ Painless, peripheral, multi-site lymphadenopathy in an elderly patient = NHL until proven otherwise.

A patient presents with dysphagia and is subsequently diagnosed with gastric lymphoma. What is the most likely cell type involved?

• ((T cell::Gastric T-cell lymphomas are rare.))
• ((NK cell::NK lymphomas of the GI tract are very uncommon.))
• ((Macrophage::Not a lymphoma lineage.))
• ((B cell::☑️ Gastric MALT lymphoma is a B-cell NHL driven by chronic H. pylori infection.))

👩‍⚕️ Early MALT lymphoma can regress with H. pylori eradication alone — a Part A favourite.

Lymph node biopsy confirms Hodgkin's lymphoma. Which subtype implies the worst prognosis?

• ((Nodular sclerosis::Commonest subtype, generally good prognosis.))
• ((Mixed cellularity::Intermediate prognosis.))
• ((Lymphocyte rich::Best prognosis of the four classical subtypes.))
• ((Lymphocyte depleted::☑️ Few lymphocytes, many Reed–Sternberg cells; advanced disease, worst prognosis.))

👩‍⚕️ Order best → worst: Lymphocyte rich > Nodular sclerosis > Mixed cellularity > Lymphocyte depleted.

A 70-year-old man presents with bone pain. Imaging reveals multiple lytic lesions in the pelvis. What is the most likely diagnosis?

• ((Osteosarcoma::Young patients, metaphysis of long bones, sunburst periosteal reaction.))
• ((Multiple myeloma::☑️ Elderly + bone pain + punched-out lytic lesions = myeloma until proven otherwise.))
• ((Metastatic prostate cancer::Prostate metastases are classically sclerotic (osteoblastic).))
• ((Paget's disease::Bone expansion and cortical thickening, raised ALP — not punched-out lesions.))
• ((Renal cell carcinoma::Can cause lytic mets but myeloma fits the demographic better.))

👩‍⚕️ Lytic: lung, myeloma, thyroid, renal, melanoma. Sclerotic: prostate, carcinoid.

A 68-year-old man presents with back pain. Laboratory tests show normocytic anaemia, elevated ESR, and hypercalcaemia. What is the most useful investigation to confirm the diagnosis?

• ((FBC::Confirms anaemia but does not diagnose myeloma.))
• ((Bone biopsy::Marrow biopsy is confirmatory but not the first-line investigation.))
• ((Serum protein electrophoresis::☑️ Reveals the monoclonal paraprotein (M-spike) band — diagnostic clue.))
• ((Bone scan::Misses purely lytic myeloma lesions because there is no osteoblastic uptake.))
• ((Alkaline phosphatase::Typically normal in myeloma — a classic exam trap.))

👩‍⚕️ CRAB features + raised ESR → electrophoresis first, then urine Bence-Jones and marrow biopsy.

A pregnant woman presents with macrocytic megaloblastic anaemia. What should be given first?

• ((Vitamin B12::☑️ Replace B12 first to avoid precipitating subacute combined degeneration of the cord.))
• ((Folic acid::Corrects anaemia but accelerates neurological damage if B12 is also low.))
• ((Iron::Treats microcytic anaemia — wrong MCV category.))
• ((Erythropoietin::Used in CKD anaemia, not megaloblastic anaemia.))

👩‍⚕️ If uncertain which deficiency, give B12 first then folate. Pregnancy specifically requires folate supplementation pre-conception to prevent neural tube defects — but never alone if B12 status is unknown.

In splenomegaly, which mechanism best explains haemolysis?

• ((Secretion of autoimmune antibodies::Autoantibodies arise from lymphoid tissue, not splenic filtration.))
• ((Portal hypertension::Causes congestive splenomegaly but does not directly haemolyse cells.))
• ((Bone marrow hyperplasia::A compensatory response to haemolysis, not a cause.))
• ((Destruction by splenic sinusoids::☑️ Red pulp sinusoids over-filter and destroy red cells in hypersplenism.))

👩‍⚕️ The red pulp (cords of Billroth + sinusoids) culls aged or abnormal red cells; in hypersplenism this becomes pathological.

A 4-year-old boy of African descent presents with severe bone pain, fever and pallor. Reticulocyte count is markedly reduced. Which infection most likely precipitated his presentation?

• ((Salmonella::Causes osteomyelitis in sickle cell, but does not suppress reticulocytes.))
• ((Parvovirus B19::☑️ Causes aplastic crisis by transient red-cell aplasia — reticulocytes drop.))
• ((Streptococcus pneumoniae::Causes OPSI post-auto-splenectomy, not aplastic crisis.))
• ((Plasmodium falciparum::Triggers haemolysis with raised reticulocytes, not aplasia.))
• ((Mycoplasma pneumoniae::Triggers cold AIHA, not aplastic crisis.))

👩‍⚕️ Sickle cell + low reticulocytes = parvovirus B19 aplastic crisis. Sickle cell + osteomyelitis = Salmonella.

A 55-year-old man has a routine FBC showing WCC of 80 with massive splenomegaly. Cytogenetics confirm t(9;22). Which drug is first-line?

• ((Rituximab::Anti-CD20 monoclonal antibody — used in B-cell NHL, not CML.))
• ((All-trans retinoic acid::Treats acute promyelocytic leukaemia (AML M3, t(15;17)).))
• ((Imatinib::☑️ Tyrosine kinase inhibitor targeting the BCR-ABL fusion protein.))
• ((Cyclophosphamide::Part of CHOP regimens for lymphoma, not first-line CML.))
• ((Hydroxycarbamide::Used for cytoreduction but not the targeted first-line in CML.))

👩‍⚕️ Philadelphia chromosome = t(9;22) = BCR-ABL = imatinib. ATRA is for APML (t(15;17)).

Revision summary

- Anaemia by MCV: microcytic (TAILS — Thalassaemia, ACD, Iron def, Lead, Sideroblastic); normocytic (acute bleed, ACD, CKD, haemolysis); macrocytic (megaloblastic = B12/folate; non-megaloblastic = alcohol, hypothyroid, liver, MDS, drugs).

- Iron studies: IDA → ferritin ↓, TIBC ↑. ACD → ferritin ↑/normal, TIBC ↓.

- Give B12 before folate — folate alone in B12 deficiency worsens subacute combined degeneration.

- Haemolysis signature: ↑ unconjugated bilirubin, ↑ LDH, ↑ reticulocytes, ↓ haptoglobin. DAT positive = autoimmune.

- Sickle cell: Glu→Val at β6. Crisis = O₂, analgesia, fluids, antibiotics. Aplastic crisis = parvovirus B19. Osteomyelitis = Salmonella. Auto-splenectomy → OPSI from encapsulated organisms.

- Thalassaemia: α = deletions (HbBart's = hydrops); β = point mutations (Cooley's, extramedullary haematopoiesis, hair-on-end skull). Iron overload → chelation.

- Leukaemia: ALL (children, lymphoblasts); AML (Auer rods; M3 = APML, t(15;17), ATRA, DIC); CLL (smudge cells, Richter's → DLBCL); CML (Ph+ t(9;22) BCR-ABL → imatinib).

- Lymphoma: Hodgkin = Reed–Sternberg, contiguous spread, alcohol-induced pain, bimodal age; lymphocyte-depleted worst prognosis. NHL = painless peripheral nodes; DLBCL commonest; Burkitt = c-myc t(8;14), EBV + malaria (African); gastric MALT = H. pylori.

- Myeloma: CRAB (hyperCalcaemia, Renal failure, Anaemia, Bone lytic lesions). M-spike on electrophoresis, Bence-Jones in urine, normal ALP, raised ESR. MGUS = precursor.

- Bone mets: lytic — lung, myeloma, thyroid, renal, melanoma. Sclerotic — prostate, carcinoid.