Hematology & Hematological Malignancies
1. What this chapter covers, and how NEET PG actually tests it
Haematology is the highest-yield block within pathology, and it is examined through numbers rather than descriptions.
A blood count, a peripheral smear finding, and one or two special tests are usually all a stem provides.
Three questions, asked in that order, resolve almost every one of them: which cell line, production or destruction, and where is the maturation block.
The framework works because the bone marrow is an assembly line. A disease either damages a line, removes finished product faster than it is made, or halts the line at a specific station.
| Area | The question actually being asked | Usual clue |
|---|---|---|
| Anaemia | Which maturation defect | Mean corpuscular volume |
| Iron disorders | Storage, transport or utilisation | Ferritin with transferrin saturation |
| Haemolysis | Intravascular or extravascular | Haptoglobin and urine findings |
| Bleeding | Platelet or coagulation phenotype | Site and timing of bleeding |
| Acute leukaemia | Myeloid or lymphoid | Cytochemistry and immunophenotype |
| Chronic myeloid disorders | Which driver mutation | A named translocation or JAK2 |
| Lymphoma | Hodgkin or non-Hodgkin | Reed-Sternberg cells, pattern of spread |
2. Anaemia: the maturation stage tells you the cause
2.1 Why mean corpuscular volume works
Red cell size is set by how many divisions the precursor completes before haemoglobin concentration triggers it to stop.
Too little haemoglobin means extra divisions and a small cell; impaired DNA synthesis means too few divisions and a large cell.
That single mechanism is why microcytosis always implies a haemoglobin production problem and macrocytosis always implies a nuclear maturation problem.
2.2 Microcytic anaemia
The four causes are iron deficiency, thalassaemia, anaemia of chronic disease, and sideroblastic anaemia.
Each fails at a different point in haemoglobin assembly: iron supply, globin chain synthesis, iron release from stores, and haem synthesis respectively.
| Test | Iron deficiency | Chronic disease | Thalassaemia trait |
|---|---|---|---|
| Serum iron | Low | Low | Normal |
| Ferritin | Low | High | Normal |
| Total iron binding capacity | High | Low | Normal |
| Transferrin saturation | Low | Low or normal | Normal |
| Red cell count | Low | Low | Normal or high |
Ferritin is the discriminator between the two commonest causes, because it is an acute phase reactant and rises in inflammation while stores are being withheld from the marrow.
Hepcidin is the mediator of that withholding: inflammation raises hepcidin, which degrades ferroportin and traps iron inside macrophages and enterocytes.
In thalassaemia trait, the red cell count is preserved or raised despite microcytosis, which no other cause reproduces.
Sideroblastic anaemia shows ring sideroblasts on Perls staining of marrow, and is caused by lead, alcohol, isoniazid, or a congenital delta-aminolaevulinate synthase defect.
2.3 Macrocytic anaemia
Megaloblastic causes show hypersegmented neutrophils and result from vitamin B12 or folate deficiency.
Both vitamins feed the same reaction, so the anaemias are indistinguishable haematologically. Only the neurology separates them.
Methylmalonic acid is raised in B12 deficiency and normal in folate deficiency, because only B12 serves the methylmalonyl-CoA mutase reaction.
Homocysteine is raised in both, since both are required for the methionine synthase reaction.
Subacute combined degeneration affects the dorsal columns and corticospinal tracts, and giving folate alone to a B12-deficient patient corrects the anaemia while the neurology progresses.
Non-megaloblastic macrocytosis occurs in alcohol, liver disease, hypothyroidism and reticulocytosis, and lacks hypersegmentation.
2.4 Normocytic anaemia
Here the reticulocyte count divides the group cleanly.
A high reticulocyte count means the marrow is responding, so the problem is haemolysis or blood loss.
A low reticulocyte count means the marrow is not responding, pointing to aplastic anaemia, marrow infiltration, renal failure or early chronic disease.
2.5 When all three lines fall
Pancytopenia narrows the differential sharply, because a disease must affect the stem cell or the marrow space itself to lower every line at once.
Aplastic anaemia gives a hypocellular marrow replaced by fat, with no abnormal cells and a low reticulocyte count.
Marrow infiltration by leukaemia, lymphoma, myeloma or carcinoma gives a cellular marrow with the normal elements crowded out, and often a leukoerythroblastic film.
Megaloblastic anaemia is the reversible cause worth remembering, since impaired DNA synthesis affects every dividing lineage, not only the red cells.
Hypersplenism lowers all three lines by sequestration while the marrow remains normal or hyperplastic.
3. Haemolysis
3.1 Locating the destruction
Intravascular haemolysis consumes haptoglobin and spills free haemoglobin into urine, giving haemoglobinuria and later haemosiderinuria.
Extravascular haemolysis occurs in the spleen, so haptoglobin falls less, and splenomegaly with unconjugated hyperbilirubinaemia dominates.
Lactate dehydrogenase and unconjugated bilirubin rise in both.
3.2 The four mechanistic groups
| Group | Examples | Identifying test |
|---|---|---|
| Membrane | Hereditary spherocytosis | Osmotic fragility, EMA binding |
| Enzyme | G6PD deficiency, pyruvate kinase deficiency | Enzyme assay, Heinz bodies |
| Haemoglobin | Sickle cell disease, thalassaemia | Electrophoresis, HPLC |
| Immune or mechanical | Autoimmune haemolysis, microangiopathy | Coombs test, schistocytes |
The direct Coombs test is the single most useful branch point, separating immune from all non-immune causes.
Warm autoimmune haemolysis is IgG-mediated, extravascular, and associated with lupus, chronic lymphocytic leukaemia and methyldopa.
Cold agglutinin disease is IgM-mediated, complement-fixing, and associated with mycoplasma and infectious mononucleosis.
Hereditary spherocytosis is a defect of ankyrin or spectrin, giving spherocytes, raised mean corpuscular haemoglobin concentration and a negative Coombs test.
G6PD deficiency is X-linked, produces bite cells and Heinz bodies after oxidant stress, and the enzyme assay is falsely normal during an acute episode because the deficient old cells have already been destroyed.
3.3 The haemoglobinopathies
Sickle cell disease is a single point mutation replacing glutamate with valine at position six of the beta globin chain.
The valine is hydrophobic, so deoxygenated haemoglobin S polymerises into rigid fibres that deform the cell, and repeated sickling makes the deformity permanent.
Fetal haemoglobin inhibits polymerisation, which is why infants are protected until around six months and why hydroxyurea, which raises fetal haemoglobin, reduces crisis frequency.
Heterozygotes are protected against falciparum malaria, which explains the mutation's persistence at high frequency in endemic regions.
Autosplenectomy from repeated infarction leaves patients functionally asplenic, hence the vulnerability to encapsulated organisms and the need for pneumococcal vaccination.
Thalassaemias are quantitative rather than qualitative defects, with reduced synthesis of structurally normal chains.
Beta thalassaemia major presents after six months as fetal haemoglobin declines, with extramedullary haematopoiesis producing frontal bossing and a hair-on-end skull appearance.
Alpha thalassaemia severity depends on how many of the four genes are deleted, with three deletions giving haemoglobin H disease and four giving hydrops fetalis.
4. Haemostasis and bleeding disorders
4.1 Phenotype localises the defect
Platelet-type bleeding is mucocutaneous, immediate, and superficial: petechiae, epistaxis, menorrhagia.
Coagulation-factor bleeding is deep and delayed: haemarthrosis, muscle haematoma, rebleeding after initial haemostasis.
That distinction is often enough to answer without any laboratory value.
4.2 The screening tests
Prothrombin time tests the extrinsic and common pathways; activated partial thromboplastin time tests the intrinsic and common pathways.
An isolated prolonged prothrombin time points to factor VII, the shortest half-life factor, which is why it moves first in warfarin therapy and liver disease.
An isolated prolonged activated partial thromboplastin time points to factors VIII, IX, XI or XII, or to a lupus anticoagulant.
A mixing study separates deficiency from inhibitor: correction implies deficiency, failure to correct implies an inhibitor.
Both times prolonged suggests a common pathway defect, disseminated intravascular coagulation, or severe liver disease.
4.3 The named disorders
Haemophilia A is factor VIII deficiency and haemophilia B is factor IX deficiency; both are X-linked with a coagulation phenotype and a prolonged activated partial thromboplastin time.
Von Willebrand disease is the commonest inherited bleeding disorder, autosomal dominant, and produces a platelet phenotype because von Willebrand factor mediates platelet adhesion.
It may also prolong the activated partial thromboplastin time, since von Willebrand factor carries and stabilises factor VIII.
Immune thrombocytopenic purpura follows infection in children and is chronic in adults, with antiplatelet antibodies and increased marrow megakaryocytes.
Thrombotic thrombocytopenic purpura results from ADAMTS13 deficiency, so ultralarge von Willebrand multimers persist and cause microangiopathy.
Disseminated intravascular coagulation is the one condition where everything is abnormal at once: low platelets, prolonged times, low fibrinogen, and raised D-dimer.
Bernard-Soulier syndrome is a GPIb defect impairing adhesion, with large platelets; Glanzmann thrombasthenia is a GPIIb-IIIa defect impairing aggregation, with normal platelet size.
4.4 Transfusion reactions
Transfusion reactions are separated by their timing and by one dominant feature each.
| Reaction | Timing | Mechanism |
|---|---|---|
| Acute haemolytic | Minutes | ABO incompatibility, usually clerical error |
| Febrile non-haemolytic | 1 to 6 hours | Recipient antibodies against donor leukocytes |
| Anaphylactic | Minutes | IgA deficiency with anti-IgA antibodies |
| Transfusion-related lung injury | Within 6 hours | Donor antibodies activating recipient neutrophils |
| Delayed haemolytic | Days to weeks | Anamnestic response to a minor antigen |
Fever with back pain and dark urine during a transfusion is an acute haemolytic reaction until proved otherwise, and the transfusion must be stopped immediately.
Transfusion-related acute lung injury and circulatory overload both present with breathlessness, and are separated by the jugular venous pressure, which is raised only in overload.
Leukodepletion has substantially reduced febrile non-haemolytic reactions, which were the commonest type before it became routine.
5. Acute leukaemias
5.1 The defining lesion
An acute leukaemia is a maturation block at the blast stage, so blasts accumulate while mature cells disappear.
The traditional threshold is 20 per cent blasts in blood or marrow.
Under the WHO 2022 classification the blast threshold has been removed for acute myeloid leukaemias with a defining genetic abnormality, with AML carrying BCR-ABL1 or a CEBPA mutation retained as the exceptions that still require 20 per cent.
The BCR-ABL1 exception exists specifically to avoid overlap with chronic myeloid leukaemia in blast crisis.
5.2 Separating myeloid from lymphoid
Myeloperoxidase positivity and Auer rods indicate myeloid lineage; periodic acid-Schiff block positivity and TdT indicate lymphoid lineage.
Acute lymphoblastic leukaemia is the commonest childhood malignancy, peaks at two to five years, and frequently involves the central nervous system and testis.
Its good prognostic markers are hyperdiploidy and the t(12;21) translocation; the t(9;22) Philadelphia translocation carries the worst prognosis.
Acute promyelocytic leukaemia carries t(15;17), fusing PML with the retinoic acid receptor alpha gene, and presents with disseminated intravascular coagulation from granule release.
All-trans retinoic acid overcomes the maturation block directly, which makes acute promyelocytic leukaemia the one acute leukaemia treated by forcing differentiation rather than by killing cells.
6. Chronic myeloid disorders
6.1 Chronic myeloid leukaemia
The Philadelphia chromosome, t(9;22), creates a BCR-ABL1 fusion with constitutive tyrosine kinase activity.
The blood shows marked leukocytosis with the full spectrum of maturation, basophilia, and a characteristically low leukocyte alkaline phosphatase.
Imatinib and its successors inhibit the fusion kinase, and the WHO 2022 classification has removed the accelerated phase, recognising two phases with defined blast phase criteria.
6.2 The JAK2-driven neoplasms
Polycythaemia vera, essential thrombocythaemia and primary myelofibrosis share activating JAK2 mutations, present in nearly all cases of polycythaemia vera.
Polycythaemia vera has a raised red cell mass with a low erythropoietin, which separates it from every secondary polycythaemia.
Aquagenic pruritus after a hot bath is its classic symptom, and thrombosis is the main cause of death.
Primary myelofibrosis shows marrow fibrosis, a leukoerythroblastic film with tear-drop cells, and massive splenomegaly from extramedullary haematopoiesis.
6.3 Chronic lymphocytic leukaemia
Chronic lymphocytic leukaemia is a mature B cell neoplasm, the commonest leukaemia of adults in Western populations, and is frequently found incidentally.
Smudge cells on the film are characteristic, and autoimmune haemolytic anaemia is a recognised complication.
Richter transformation to a high-grade lymphoma is the feared outcome.
Hairy cell leukaemia shows TRAP positivity, a dry tap on aspiration, and splenomegaly without lymphadenopathy.
7. Lymphoma and myeloma
7.1 Hodgkin versus non-Hodgkin
Hodgkin lymphoma spreads contiguously from one nodal group to the next; non-Hodgkin lymphoma spreads unpredictably and involves extranodal sites far more often.
Reed-Sternberg cells are the diagnostic cell of Hodgkin lymphoma, with an owl-eye binucleate appearance and CD15 and CD30 positivity.
Nodular sclerosis is the commonest subtype and affects young women; lymphocyte-rich carries the best prognosis and lymphocyte-depleted the worst.
Alcohol-induced nodal pain is an uncommon but highly specific Hodgkin feature.
7.2 The translocations worth knowing
| Lymphoma | Translocation | Gene |
|---|---|---|
| Follicular | t(14;18) | BCL2 |
| Burkitt | t(8;14) | MYC |
| Mantle cell | t(11;14) | Cyclin D1 |
Burkitt lymphoma has a starry-sky appearance from tingible body macrophages, the highest proliferation index of any tumour, and an endemic jaw form associated with Epstein-Barr virus.
7.3 Multiple myeloma
Myeloma is a plasma cell neoplasm producing a monoclonal immunoglobulin, and its features are captured by the CRAB criteria: hypercalcaemia, renal impairment, anaemia and bone lesions.
The bone lesions are punched-out and lytic with no osteoblastic reaction, which is why the isotope bone scan is characteristically negative.
Rouleaux formation, a raised erythrocyte sedimentation rate and Bence Jones proteinuria complete the picture.
The urine dipstick is negative in Bence Jones proteinuria because it detects albumin rather than light chains, so a negative dipstick with heavy proteinuria on quantitative testing is itself the clue.
8. Worked examples
Example 1
A 30-year-old woman has haemoglobin 9 g/dL, mean corpuscular volume 68 fL, red cell count 5.8 million, and a normal ferritin.
Microcytosis means a haemoglobin production problem, so the differential is the four microcytic causes.
The normal ferritin excludes iron deficiency, and chronic disease would show a raised ferritin with a low iron binding capacity.
The raised red cell count despite microcytosis is the decisive finding, since iron deficiency lowers the count while thalassaemia trait preserves or raises it.
The answer is beta thalassaemia trait, confirmed by a raised haemoglobin A2 on electrophoresis.
Example 2
A boy develops dark urine and jaundice two days after starting primaquine. The film shows bite cells.
Bite cells arise when splenic macrophages remove Heinz bodies, which are precipitated denatured haemoglobin.
That sequence requires oxidative stress in a cell that cannot regenerate reduced glutathione, which localises the defect to the pentose phosphate pathway.
The diagnosis is G6PD deficiency, and an enzyme assay taken now may be falsely normal because the most deficient cells have already been destroyed and the surviving young cells have higher enzyme levels.
Repeating the assay several weeks after recovery is what confirms it.
Example 3
A patient bleeds after dental extraction. Platelet count and prothrombin time are normal; the activated partial thromboplastin time is prolonged and corrects fully on mixing with normal plasma.
Correction on mixing means a factor is missing rather than inhibited.
An isolated prolonged activated partial thromboplastin time with a normal prothrombin time localises the defect to the intrinsic pathway: factors VIII, IX, XI or XII.
Factor XII deficiency prolongs the test but causes no bleeding, so it is excluded by the clinical history.
The bleeding phenotype and the isolated intrinsic prolongation point to haemophilia A or B, distinguished by specific factor assay.
9. Traps the exam sets repeatedly
Using ferritin alone to diagnose iron deficiency. Ferritin is an acute phase reactant, so a normal or raised value in an inflamed patient does not exclude iron deficiency; transferrin saturation is more reliable there.
Giving folate to a patient who may be B12 deficient. The anaemia corrects while subacute combined degeneration progresses, and the opportunity to recognise it is lost.
Reading a normal G6PD assay during an acute haemolytic episode as excluding the diagnosis. The deficient cells have already been removed.
Expecting a positive bone scan in myeloma. The lesions are purely lytic with no osteoblastic response, so plain radiography or whole-body imaging is used instead.
Assuming a prolonged activated partial thromboplastin time means bleeding risk. Factor XII deficiency and lupus anticoagulant both prolong it, and the lupus anticoagulant is associated with thrombosis rather than bleeding.
Summary
Three questions resolve most haematology: which cell line, production or destruction, and where is the maturation block.
Mean corpuscular volume reflects the number of precursor divisions, so microcytosis means a haemoglobin problem and macrocytosis a nuclear maturation problem.
Ferritin separates iron deficiency from anaemia of chronic disease, and a preserved red cell count identifies thalassaemia trait.
Methylmalonic acid separates B12 from folate deficiency, and only B12 deficiency causes subacute combined degeneration.
Haptoglobin and urine findings locate haemolysis, and the direct Coombs test separates immune from non-immune causes.
Platelet-type bleeding is mucocutaneous and immediate; factor-type bleeding is deep and delayed, and a mixing study separates deficiency from inhibitor.
Acute leukaemia is a blast-stage maturation block, and WHO 2022 has removed the 20 per cent threshold for genetically defined acute myeloid leukaemias apart from the BCR-ABL1 and CEBPA entities.
Acute promyelocytic leukaemia carries t(15;17), presents with disseminated intravascular coagulation, and is treated by forcing differentiation with all-trans retinoic acid.
Chronic myeloid leukaemia is defined by BCR-ABL1 with a low leukocyte alkaline phosphatase, while polycythaemia vera, essential thrombocythaemia and myelofibrosis are JAK2-driven.
Hodgkin lymphoma spreads contiguously and contains Reed-Sternberg cells; myeloma produces purely lytic lesions with a negative bone scan and a negative urine dipstick despite heavy light chain loss.
