DEFINITION & STAGES
IDA = anaemia resulting from insufficient iron to support normal erythropoiesis , characterised by microcytic hypochromic red cells . The most common nutritional deficiency worldwide (affecting > 2 billion people ). Progresses through 3 stages: (1) Iron depletion (↓ stores, normal Hb); (2) Iron-deficient erythropoiesis (↓ serum iron, ↑ TIBC, normal Hb); (3) Iron deficiency anaemia (↓ Hb + microcytosis).
ETIOLOGY
- Inadequate intake — poor diet; vegetarians (non-haem iron less bioavailable); infants on cow's milk (low iron); poverty
- Increased demand — pregnancy (#1 cause in India); growth spurts; erythropoietin therapy
- Chronic blood loss (#1 cause globally) — GI bleeding (peptic ulcer, NSAID erosions, colorectal carcinoma — investigate all adults with IDA); menorrhagia (#1 cause in premenopausal women in India); hookworm (tropical countries); haematuria
- Malabsorption — coeliac disease; Crohn's; post-gastrectomy; H. pylori infection
CLINICAL FEATURES
- General anaemia symptoms: Fatigue, pallor, dyspnoea, palpitations, dizziness
- Specific IDA features:
- Koilonychia (spoon-shaped nails) — brittle, flat → concave nails; classic sign of chronic IDA
- Pica — craving for non-food substances (ice/pagophagia, clay/geophagia, starch/amylophagia)
- Plummer-Vinson syndrome (Paterson-Kelly) — post-cricoid web + IDA + dysphagia; risk of post-cricoid carcinoma
- Angular stomatitis (cheilosis) + Glossitis (atrophic, smooth tongue); pale conjunctivae + palmar creases; brittle hair
INVESTIGATIONS
Test IDA ACD (Anaemia of Chronic Disease) Thalassaemia trait MCV ↓ Microcytic ↓ or Normal ↓ Microcytic Serum Iron ↓ ↓ Normal TIBC ↑ (depleted stores → liver makes more transferrin) ↓ (liver makes less) Normal Transferrin Saturation ↓ < 16% ↓ Normal Serum Ferritin ↓ < 12 μg/L (best indicator of iron stores) Normal or ↑ (acute phase reactant) Normal/↑ Free Erythrocyte Protoporphyrin ↑ (iron unavailable for haem synthesis) ↑ Normal Blood film Microcytic hypochromic ; pencil cells; target cells; anisocytosis; poikilocytosis Normocytic or mildly microcytic Microcytic ; target cells; basophilic stippling Bone marrow (gold standard ): Absent iron stores (Prussian blue stain — no haemosiderin); ring sideroblasts absent (present in sideroblastic anaemia). NOT routinely needed — diagnosis made by serum iron studies.
MANAGEMENT
- Step 1 — Find and treat the cause (investigate GI tract in all adults — colonoscopy ± OGD; menorrhagia)
▶ Oral iron (first-line): Ferrous sulphate 200 mg TDS (= 65 mg elemental iron per tablet) — take on empty stomach (↑ absorption); with Vitamin C (ascorbic acid — reduces Fe³⁺ to Fe²⁺; ↑ absorption ); avoid with tea, milk, calcium, antacids. Reticulocyte response in 7–10 days; Hb rises at 2 g/dL per month; treat for 6 months after Hb normalises to replenish stores
- Side effects: constipation, nausea, black stools (benign )
▶ IV Iron (second-line) indications: intolerance to oral iron; malabsorption; non-compliance; severe anaemia needing rapid repletion; CKD on EPO therapy:
Ferric carboxymaltose (Ferinject) — single large dose; well-tolerated; preferred
Iron sucrose — multiple small doses; safe- Blood transfusion: Hb < 7 g/dL with symptoms; pre-operative with significant anaemia; cardiac compromise
OVERVIEW OF MEGALOBLASTIC ANAEMIA
Megaloblastic anaemia = macrocytic anaemia (MCV > 100 fL) caused by impaired DNA synthesis in rapidly dividing cells (erythroid precursors) → large, dysfunctional red cell precursors (megaloblasts) in bone marrow. Causes: Vitamin B12 deficiency ; Folate deficiency ; drugs (hydroxyurea, methotrexate, trimethoprim, phenytoin); congenital enzyme defects.
VITAMIN B12 (COBALAMIN) DEFICIENCY
B12 metabolism: Dietary B12 (animal products only — meat, fish, eggs, dairy) → bound to salivary R-protein → released in duodenum → binds Intrinsic Factor (IF) (produced by gastric parietal cells) → B12-IF complex absorbed in terminal ileum → stored in liver (3–5 year stores — hence deficiency takes years to manifest).
Cause of B12 Deficiency Mechanism Key Features Pernicious Anaemia (most common in developed world) Autoimmune destruction of gastric parietal cells → ↓ IF → ↓ B12 absorption; anti-parietal cell Ab (90%) + anti-IF Ab (50%) Middle-aged/elderly; Northern European; associated with autoimmune diseases (thyroid, T1DM, vitiligo ); Schilling test positive Dietary deficiency (most common in India ) Strict veganism (B12 only in animal products ) ↓ intake; responds to dietary change/supplements; no neurological features early Gastrectomy / gastric bypass Loss of parietal cells → ↓ IF Post-surgical; needs B12 replacement Terminal ileal disease Crohn's; ileal resection; tropical sprue; bacterial overgrowth Malabsorption of B12-IF complex Drugs Metformin (reduces B12 absorption); PPI (↓ gastric acid); nitrous oxide (inactivates B12) Monitor B12 on long-term metformin CLINICAL FEATURES
- Haematological: Fatigue; pallor; macrocytic anaemia; jaundice (mild — intramedullary haemolysis); glossitis (beefy red smooth tongue); angular stomatitis
- Neurological (B12-specific; NOT in folate deficiency ):
- Subacute Combined Degeneration (SACD) of Spinal Cord — bilateral symmetrical degeneration of posterior columns (sensory) + lateral corticospinal tracts (motor) + rarely anterior columns
- Posterior column: Loss of proprioception + vibration sense; Romberg +ve; sensory ataxia
- Lateral column (UMN): Spastic weakness; ↑ reflexes; extensor plantar
- Peripheral neuropathy: Glove-stocking sensory loss; ↓ reflexes (can coexist with UMN — creates mixed picture)
- Psychiatric: Dementia; psychosis; depression ('megaloblastic madness')
- KEY: Neurological manifestations precede and can exist WITHOUT anaemia (B12 must be given if any neurological signs even if Hb normal)
DIAGNOSIS
- CBC: Macrocytic anaemia (MCV > 100 fL); hypersegmented neutrophils (> 5 lobes; ≥ 1 neutrophil with 6 lobes = diagnostic ); thrombocytopenia; leucopenia (pancytopenia in severe)
- Blood film: Macroovalocytes (oval macrocytes ); hypersegmented neutrophils; anisocytosis; poikilocytosis
- Serum B12 < 200 pg/mL (normal 200–900); Serum folate ; RBC folate (more reliable than serum folate)
- MCV > 100 fL; Serum LDH ↑↑ (intramedullary haemolysis); indirect bilirubin ↑; haptoglobin ↓
- Bone marrow: Hypercellular; megaloblastic erythropoiesis (giant metamyelocytes, giant band cells; nuclear-cytoplasmic dyssynchrony — nucleus larger/less mature than cytoplasm — pathognomonic ); NOT routinely needed if B12/folate levels diagnostic
- Schilling test — tests B12 absorption: Stage 1: oral radiolabelled B12 without IF; Stage 2: repeat with IF. ↑ excretion with IF = Pernicious Anaemia. ↑ excretion after antibiotics = bacterial overgrowth. Not improved with IF = ileal disease. Rarely used now.
TREATMENT
▶ B12 deficiency (IM): Hydroxocobalamin 1 mg IM OD × 7 days → 1 mg IM every 3 months (lifelong in pernicious anaemia/ileal disease)
OR Cyanocobalamin 1000 μg IM × 6 doses over 2 weeks → monthly▶ Dietary deficiency (oral): Cyanocobalamin 1000 μg oral OD × 3–6 months → maintenance; oral B12 is effective even without IF (passive diffusion at high doses)
▶ Folate deficiency: Folic acid 5 mg OD × 4 months; CRITICAL: Always replace B12 FIRST if B12 low — giving folate alone can worsen or precipitate neurological B12 deficiency symptoms (accelerates haematological recovery without correcting neurological)
- Hypokalaemia — common complication of starting treatment (↑ K⁺ uptake by rapidly proliferating cells); monitor + replace K⁺
DEFINITION
CML = clonal myeloproliferative neoplasm originating in a pluripotent haematopoietic stem cell, characterised by the Philadelphia chromosome [t(9;22)] → BCR-ABL1 fusion gene → constitutively active tyrosine kinase → uncontrolled myeloid proliferation.
PHILADELPHIA CHROMOSOME
Philadelphia (Ph) chromosome = reciprocal translocation t(9;22)(q34;q11): BCR gene (chromosome 22) fuses with ABL1 gene (chromosome 9) → BCR-ABL1 fusion protein (p210 ) → constitutively active tyrosine kinase → uncontrolled cell proliferation + inhibition of apoptosis.
- Detection: Conventional cytogenetics (karyotype) — shows Ph chromosome; FISH — BCR-ABL1 fusion signals; RT-PCR — most sensitive; used to monitor minimal residual disease (MRD) and treatment response (BCR-ABL1 IS — International Scale)
CLINICAL FEATURES
- Splenomegaly — most prominent feature; massive splenomegaly (#1 cause of massive splenomegaly in India ); dull left hypochondrial fullness; splenic infarct → sharp LUQ pain
- Constitutional: Fatigue, weight loss, night sweats, low-grade fever (from high cell turnover)
- Gout (hyperuricaemia from cell turnover); priapism (WBC > 300 × 10⁹/L → increased blood viscosity → sludging)
- Hepatomegaly (less prominent than splenomegaly); anaemia; bleeding (if thrombocytopenia)
- Leucostasis (WBC > 100–200 × 10⁹/L) — headache, confusion, respiratory failure, retinal haemorrhage
INVESTIGATIONS
- CBC: WBC massively elevated (usually 50,000–200,000/μL ); all stages of myeloid cells on peripheral film (myelocyte bulge = characteristic of CML — blast% < 10% in chronic phase); basophilia + eosinophilia (distinctive); thrombocytosis (may be > 1000 × 10⁹/L)
- Peripheral blood film: Left shift (metamyelocytes, myelocytes, promyelocytes, blasts < 10%) + basophilia + eosinophilia
- LAP score (Leucocyte Alkaline Phosphatase) — LOW in CML (differentiates from leukaemoid reaction where LAP is HIGH ); measured by scoring 100 neutrophils
- BCR-ABL1 PCR — confirms diagnosis + baseline for monitoring; karyotype/FISH for Ph chromosome
- Bone marrow trephine — hypercellular (100%); myeloid hyperplasia; megakaryocytes; blast% for phase assessment
PHASES OF CML
Phase Blast% Features Survival Chronic Phase (CP) < 10% Most patients diagnosed here; responds well to TKI; asymptomatic or mild symptoms 3–5 years (→ longer with TKI) Accelerated Phase (AP) 10–19% Worsening symptoms; increasingly resistant; blasts rising; basophils > 20%; cytogenetic evolution 6–12 months Blast Crisis (BC) ≥ 20% (AML or ALL phenotype) Acute leukaemia-like; fever; bleeding; rapidly fatal; treat as acute leukaemia + TKI 3–6 months TREATMENT
▶ Imatinib (Gleevec) 400 mg OD — 1st generation TKI (Tyrosine Kinase Inhibitor) ; revolutionised CML treatment (IRIS trial ); BCR-ABL1 kinase inhibitor; 90% CCyR (Complete Cytogenetic Response — no Ph+ cells); 5-yr survival now > 90%; side effects: oedema, nausea, muscle cramps, hepatotoxicity, myelosuppression
▶ Nilotinib/Dasatinib (2nd generation TKIs) — for imatinib-resistant/intolerant; faster deeper responses; faster MMR (Major Molecular Response ); Nilotinib: QTc prolongation + AVN; Dasatinib: pleural effusion
▶ Bosutinib/Ponatinib (3rd generation) — for T315I mutation (gatekeeper mutation — resistant to all 1st/2nd gen TKIs except ponatinib)
- Treatment-free remission (TFR) — patients with sustained deep molecular response (MR4.5 for ≥ 2 years) can try stopping TKI; 50% maintain remission
- HSCT (Allogeneic stem cell transplant) — curative; reserved for blast crisis, TKI failure, T315I mutation; no longer first-line
DEFINITION & EPIDEMIOLOGY
ALL = clonal malignant proliferation of lymphoid progenitor cells (lymphoblasts) in bone marrow, peripheral blood, and lymphoid tissues. Most common childhood cancer (peak 2–5 years ); also occurs in adults (worse prognosis). Two types: B-ALL (85%) and T-ALL (15%).
CLINICAL FEATURES
- Bone marrow failure:
- Anaemia — pallor, fatigue, dyspnoea
- Thrombocytopenia — petechiae, purpura, bruising, mucosal bleeding, epistaxis
- Neutropenia — recurrent/severe infections; fever (can be presenting feature)
- Organ infiltration:
- Lymphadenopathy — generalised; painless; firm; mediastinal widening in T-ALL (superior vena cava syndrome)
- Hepatosplenomegaly — common; leukaemic infiltration
- CNS involvement — headache, vomiting, CN palsies, papilloedema; prophylactic CNS treatment mandatory
- Bone pain — marrow expansion; 'bone tenderness on palpation'; very common in children
- Testicular infiltration — painless testicular enlargement (sanctuary site — requires local irradiation)
INVESTIGATIONS
- CBC: WBC variable (may be low, normal, or high); anaemia + thrombocytopenia; lymphoblasts on peripheral film
- Bone marrow biopsy (essential): > 20% lymphoblasts (diagnostic threshold); ALL classified by morphology (L1/L2/L3), immunophenotype (B vs T), cytogenetics
- Immunophenotyping (flow cytometry): CD10 (CALLA — common ALL antigen; B-ALL); CD19, CD20 (B-cell); CD3, CD7 (T-cell); TdT (terminal deoxynucleotidyl transferase — expressed in lymphoblasts)
- Cytogenetics: t(9;22) = Ph+ ALL (poor prognosis; add TKI to chemotherapy ); t(12;21)/ETV6-RUNX1 (good prognosis); hyperdiploidy > 50 (good prognosis); hypodiploidy (very poor)
- CXR (mediastinal widening in T-ALL ); LP + CSF cytology (CNS staging)
TREATMENT
◆ ALL Treatment Phases — ICDI ▸ I = Induction (4–6 weeks): Achieve complete remission (CR)
Vincristine + Prednisolone + Asparaginase + Daunorubicin (VPAD )▸ C = CNS prophylaxis: IT Methotrexate (intrathecal) ± cranial irradiation (no longer used routinely)
Prevents CNS relapse (sanctuary site )▸ D = Consolidation/Intensification (4–6 months): Kill residual disease
High-dose Methotrexate + AraC + Asparaginase combinations▸ I = Maintenance (2–3 years ): Prevent relapse — 6-Mercaptopurine daily + weekly Methotrexate + monthly vincristine + prednisolone - Ph+ ALL: Add Imatinib/Dasatinib (TKI) to chemotherapy → dramatically improved outcomes
- CAR-T cell therapy (Tisagenlecleucel/Brexucabtagene) — for relapsed/refractory B-ALL; 80% CR rate; curative potential
- Blinatumomab (BiTE antibody — bispecific T-cell engager; anti-CD19/CD3) — for relapsed/refractory B-ALL; MRD-negative induction
- Allogeneic HSCT — consolidation after 2nd CR; Ph+ ALL after 1st CR; high-risk features
- Prognosis: Children 80–90% cure rate; Adults 40–50%; T-ALL intermediate; Ph+ ALL improved with TKI
GENETICS
Haemophilia A = X-linked recessive disorder caused by deficiency of Factor VIII (FVIII) . Gene locus: Xq28 . Haemophilia B (Christmas disease) = Factor IX deficiency. Haemophilia A: B ratio = 5:1 . Affects males only (XY); females are carriers (XX; may have mild bleeding if FVIII < 40%). Spontaneous mutations in 30% (no family history).
Severity FVIII Level Bleeding Pattern Mild 6–40% Bleeding only with major trauma/surgery Moderate 1–5% Bleeding with minor trauma; occasional spontaneous bleeding Severe < 1% Spontaneous bleeds — haemarthroses, muscle haematomas; life-threatening haemorrhage CLINICAL FEATURES
- Haemarthroses — bleeding into joints; #1 manifestation of severe haemophilia; target joints (repeated bleeds → chronic synovitis); knees (most common ) > elbows > ankles
- Muscle haematomas — large, tense; iliopsoas haematoma (can compress femoral nerve → hip flexion + groin pain); forearm → Volkmann's ischaemic contracture
- Intracranial haemorrhage — most dangerous; can be fatal; even minor head trauma requires factor replacement + CT
- GI/GU bleeding ; excessive bleeding post-surgery; easy bruising
- NO risk of thrombosis (FVIII involved in intrinsic pathway only — PT normal )
LONG-TERM SEQUELAE
- Haemophilic arthropathy — repeated haemarthroses → synovial inflammation → cartilage damage → fibrosis → bony ankylosis → chronic debilitating joint destruction (knees, elbows, ankles)
- Inhibitor development — 30% of severe HA patients develop IgG antibodies against FVIII (inhibitors) → treatment refractory bleeding; use bypassing agents (activated PCC/aPCC = FEIBA; recombinant FVIIa = Novoseven)
- Blood-borne infections (historical — pre-1985 screened products) — HIV, HCV from clotting factor concentrates; now all products viral-inactivated or recombinant
- Pseudotumour (haemophilic pseudocyst) — chronic encapsulated haematoma with bony erosion; can be massive
DIAGNOSIS
- APTT prolonged (intrinsic pathway deficiency — FVIII is intrinsic); PT normal (extrinsic pathway intact); BT normal (platelet number and function normal)
- FVIII assay (specific factor assay) — confirms diagnosis; quantifies severity
- Mixing study — mix patient plasma 1:1 with normal plasma; if APTT corrects → factor deficiency; if NOT corrected (remains prolonged) → inhibitor present (Bethesda assay to quantify inhibitor)
TREATMENT
▶ Recombinant FVIII concentrate — treatment of choice; viral-safe; on demand OR prophylactic; dose: 25–50 IU/kg for major bleeds (target FVIII 100% for life-threatening )
▶ DDAVP (Desmopressin) 0.3 μg/kg IV/SC OR 150 μg intranasal — releases endogenous FVIII + vWF from Weibel-Palade bodies; effective ONLY in mild haemophilia A (FVIII > 5%); response wears off with repeated doses (tachyphylaxis)
▶ Emicizumab (Hemlibra) — bispecific monoclonal antibody; bridges FIXa + FX (mimics FVIII function); SC injection weekly/biweekly/monthly; works even in inhibitor patients ; game-changer drug; significantly reduces annual bleed rate
▶ Tranexamic acid — antifibrinolytic; adjunct for mucosal bleeds (oral cavity, menorrhagia); NOT for haematuria (can cause ureteral clots)
- Prophylaxis — regular factor infusions 3×/week (or emicizumab) to prevent target joint damage in severe HA; begin in young children before joint damage
- Inhibitor management: Low-titre: high-dose FVIII; High-titre: bypassing agents (FEIBA/rFVIIa) + Immune Tolerance Induction (ITI — daily high-dose FVIII × months to years to eradicate inhibitor)
DEFINITION
Anaemia = Hb < 13 g/dL in adult males ; < 12 g/dL in adult females ; < 11 g/dL in pregnant women (WHO). Results from: ↓ production of RBCs, ↑ destruction, blood loss, or sequestration.
CLASSIFICATION BY MCV
Type MCV Causes Microcytic (MCV < 80 fL) < 80 fL IDA (#1 overall); Thalassaemia ; ACD (mild); Sideroblastic anaemia; Lead poisoning Normocytic (MCV 80–100 fL) 80–100 fL Acute blood loss ; ACD (most common normocytic); Haemolytic anaemia; Aplastic anaemia; Hypothyroidism; Renal failure (↓ EPO) Macrocytic (MCV > 100 fL) > 100 fL B12 deficiency ; Folate deficiency ; Alcohol; Liver disease; Hypothyroidism; Myelodysplasia; Drugs (hydroxyurea, MTX); Reticulocytosis (shift macrocytosis) CLASSIFICATION BY PATHOGENESIS
Mechanism Causes Key Lab Findings Impaired Production IDA, megaloblastic, aplastic, renal (↓ EPO), ACD, myelophthisic ↓ Reticulocyte count; hypocellular/infiltrated marrow Increased Destruction (Haemolytic) G6PD, hereditary spherocytosis, sickle cell, autoimmune (Coombs+ ), malaria, TTP/HUS, PNH ↑ Reticulocyte count; ↑ LDH; ↑ indirect bili; ↓ haptoglobin; haemoglobinaemia/haemoglobinuria Blood Loss Acute (trauma, GI bleed) or Chronic (IDA) Acute: normocytic; Chronic: microcytic DIAGNOSTIC APPROACH
- History: Duration; dietary history; menstrual; GI blood loss; family history (thalassaemia, G6PD); drugs; symptoms of haemolysis (jaundice, dark urine)
- CBC + Reticulocyte count + Blood film
- Branch by MCV:
- Microcytic → serum iron/TIBC/ferritin (IDA vs ACD) + Hb electrophoresis (thalassaemia) + blood film
- Macrocytic → B12 + folate levels + LFT + TFT + reticulocyte count
- Normocytic + ↑ retics → haemolysis workup (Coombs, LDH, haptoglobin, PBS for spherocytes/sickle cells/fragments)
- Normocytic + ↓ retics → bone marrow biopsy (aplastic, infiltration, MDS)
- Bone marrow biopsy — when diagnosis unclear; to assess marrow cellularity, infiltration, iron stores
Component Indication Dose Packed RBC Symptomatic anaemia (Hb < 7 g/dL ); Hb < 8 if cardiac disease; pre-op (Hb < 8); sickle cell crisis; massive haemorrhage 1 unit ↑ Hb by ~1 g/dL; 10 mL/kg in children Fresh Frozen Plasma (FFP) Coagulopathy (↑ PT/APTT); DIC; massive transfusion; reversal of warfarin (if Vit K not fast enough); liver disease + bleeding 15 mL/kg; thaw before use Platelets < 10 × 10⁹/L (prophylactic); < 50 × 10⁹/L with active bleeding or pre-surgery; < 100 × 10⁹/L for neurosurgery/ophthalmic surgery; NOT in TTP/HIT (worsen thrombosis) 1 adult dose ↑ platelets by 20–30 × 10⁹/L Cryoprecipitate Fibrinogen < 1.5 g/L; DIC; haemophilia A (when FVIII concentrate unavailable); von Willebrand disease (emergency) Rich in fibrinogen, FVIII, vWF, XIII, fibronectin Transfusion Reaction Onset Mechanism Management Haemolytic (acute AHTxR) Minutes ABO incompatibility ; anti-A/anti-B intravascular haemolysis Stop transfusion; NS bolus; LFT/RFT; Coombs; treat shock Febrile Non-Haemolytic (FNHTR) 1–6 hrs Anti-WBC/platelet antibodies; cytokines Stop; paracetamol; restart if mild Allergic/Urticarial Minutes Anti-plasma protein IgE (IgA deficiency ) Antihistamine; continue if mild; stop if anaphylaxis Anaphylaxis Seconds IgA-deficient patient + anti-IgA IgE Stop; IM adrenaline Transfusion-associated circulatory overload (TACO) Minutes–hours Fluid overload (heart failure/renal failure) Slow rate; diuretic; CPAP TRALI (Transfusion-related ALI) < 6 hrs Anti-WBC antibodies (donor) → ARDS Stop; supportive; ARDS management - Pre-transfusion: group and crossmatch (or type and screen); verify patient identity and unit details at the bedside, since most serious reactions stem from clerical/ABO error; use leucodepleted blood and irradiated products in immunocompromised patients.
- Other reactions: febrile non-haemolytic (commonest - cytokines; antipyretics, prevented by leucodepletion); allergic/urticarial (antihistamine); anaphylaxis (IgA-deficient recipients); TACO (circulatory overload - slow the rate, diuretics); TRALI (within 6 h, non-cardiogenic pulmonary oedema); delayed haemolytic; transfusion-transmitted infection; iron overload with chronic transfusion.
- Megaloblastic anaemia = macrocytic anaemia (MCV > 100 fL) from impaired DNA synthesis; causes: B12 or Folate deficiency ; drugs (MTX, hydroxyurea, TMP)
- Causes: B12 deficiency (pernicious anaemia, veganism, gastrectomy, terminal ileal disease, metformin) versus folate deficiency (poor diet, pregnancy/lactation, haemolysis, malabsorption, methotrexate, phenytoin, trimethoprim).
- Blood film: Oval macrocytes + hypersegmented neutrophils (> 5 lobes or ≥ 1 with 6 lobes = pathognomonic )
- Bone marrow: Megaloblasts; giant metamyelocytes; nuclear-cytoplasmic dyssynchrony
- B12 — neurological features (SACD ); pernicious anaemia; check serum B12 + anti-IF antibodies
- Folate — NO neurological features; common in pregnancy; check RBC folate
- Supporting labs: raised LDH and indirect bilirubin (ineffective erythropoiesis), low reticulocytes, often mild pancytopenia; anti-intrinsic-factor and anti-parietal-cell antibodies support pernicious anaemia.
- Neurological involvement: subacute combined degeneration (SACD) of the spinal cord occurs only in B12 deficiency, not folate; demyelination of the dorsal and lateral columns; presents with paraesthesiae, sensory ataxia, and spastic weakness; can occur before the anaemia develops and may be irreversible if untreated.
- Folate vs B12 - key differences: folate deficiency causes NO neurological features; folate body stores last only 3-4 months (vs B12 stores lasting 3-5 years); folate is found in green leafy vegetables; deficiency is common in pregnancy, alcohol excess, malabsorption, and with methotrexate, phenytoin or trimethoprim.
- Treatment: Replace B12 first then folate (giving folate alone in B12 deficiency → worsens SACD )
Leukemoid reaction = extreme reactive leucocytosis (WBC > 50,000/μL ) resembling leukaemia but due to benign causes . Differentiated from CML by LAP score.
Feature Leukemoid Reaction CML LAP score HIGH (↑) LOW (↓) — key differentiator Ph chromosome Absent Present (BCR-ABL1 ) Basophilia/Eosinophilia Absent Present Toxic granulation Present (in neutrophils) Absent Splenomegaly Mild Massive WBC 50,000–100,000 (usually) Often > 100,000 Cause Infection, trauma, burns, malignancy Malignant clone - Causes of leukemoid reaction: Severe infections (pneumococcal pneumonia, pertussis, meningococcal); severe burns/trauma; haemolysis; solid tumours (paraneoplastic); drug reactions (G-CSF )
- Differentiation from CML: leukaemoid reaction has a HIGH LAP (leucocyte alkaline phosphatase) score, no Philadelphia chromosome/BCR-ABL1, no basophilia, and shows toxic granulation; CML has a low LAP, the Ph chromosome and basophilia.
- Approach: identify and treat the underlying cause and the leucocytosis resolves; a leucoerythroblastic film (nucleated RBCs with immature white cells) instead suggests marrow infiltration and warrants a bone marrow biopsy.
- Types: neutrophilic (severe bacterial infection, burns, trauma, haemolysis, solid tumours); lymphocytic (pertussis, infectious mononucleosis, CMV - also called lymphocytosis); eosinophilic (parasitic infection, allergy, drug reactions); monocytic (TB, SBE, protozoan infections).
- Leucoerythroblastic film: if immature white cells are accompanied by nucleated red cells (normoblasts), this pattern is called leucoerythroblastic and suggests marrow infiltration (myelofibrosis, metastatic carcinoma, lymphoma) rather than a reactive process.
MPDs (WHO 2022: Myeloproliferative Neoplasms — MPNs) = clonal stem cell disorders with proliferation of ≥ 1 myeloid lineage (RBCs, WBCs, platelets) WITHOUT significant dysplasia.
MPN Dominant Proliferation Key Gene Key Features Polycythaemia Vera (PV) RBCs (all 3 lineages) JAK2 V617F (95%) ↑ Hb; ↑ RCM; splenomegaly; plethora; pruritus after hot bath; thrombosis; treat: venesection + hydroxyurea Essential Thrombocythaemia (ET) Platelets JAK2 V617F (55%); CALR (25%); MPL (10%) Platelets > 600 × 10⁹/L; paradoxical bleeding/thrombosis; aspirin + hydroxyurea Primary Myelofibrosis (PMF) Fibrosis of marrow JAK2/CALR/MPL Massive splenomegaly ; leukoerythroblastic blood film; 'dry tap' on BM aspirate; teardrop cells (dacrocytes) ; poor prognosis; ruxolitinib (JAK inhibitor) CML WBCs (myeloid) BCR-ABL1 imatinib curative intent - Common features: clonal expansion driven by JAK2 V617F (PV ~95%; ET/PMF ~50-60%), CALR or MPL mutations; shared features are splenomegaly, thrombosis and bleeding risk, hyperuricaemia/gout, and potential transformation to myelofibrosis or acute leukaemia.
- Investigations and management: FBC and film, JAK2/CALR/MPL testing, EPO level and bone marrow; manage with venesection and aspirin (PV), cytoreduction (hydroxyurea) for high-risk disease, and control of thrombotic risk factors.
- Transformation and natural history: PV and ET can transform to post-PV or post-ET myelofibrosis (splenomegaly, bone marrow fibrosis, leukoerythroblastic blood film, teardrop cells); any MPN can transform to AML (blast crisis), which has a very poor prognosis; allogeneic stem cell transplant is the only curative option.
- Thrombosis risk: all MPNs carry a high thrombosis risk (arterial and venous) due to activated platelets and hyperviscosity; aspirin is given to all; cytoreduction with hydroxyurea reduces thrombosis risk in high-risk patients.
MDS = heterogeneous group of clonal haematopoietic stem cell disorders characterised by ineffective haematopoiesis (normal/hypercellular marrow yet peripheral cytopenias) + dysplasia of ≥ 1 myeloid lineage + risk of transformation to AML (30% ).
- Risk factors: Prior chemotherapy (alkylating agents ); radiation; benzene exposure; advancing age (> 60 years )
- Clinical features: Anaemia (transfusion-dependent); infections (neutropenia ); bleeding (thrombocytopenia ); may be asymptomatic (incidental CBC)
- Peripheral film: Hypogranular neutrophils; pseudo-Pelger-Huët cells (bilobed neutrophils — 'pince-nez' appearance ); dimorphic RBCs (mix of normal + dysplastic)
- Bone marrow (essential): Dysplasia (≥ 10% of cells in ≥ 1 lineage); blast% < 20% (≥ 20% = AML ); ring sideroblasts (MDS-RS subtype — excess iron in mitochondria of erythroblasts)
- Cytogenetics: del(5q) (isolated = good prognosis; Lenalidomide responsive ); monosomy 7 (poor); complex karyotype (very poor)
▶ Low-risk MDS: ESA (Erythropoiesis-stimulating agents — darbepoetin); Lenalidomide (del5q ); transfusion support; iron chelation (deferasirox if > 20 units RBC)
▶ High-risk MDS (IPSS-R high/very high): Hypomethylating agents — Azacitidine (5-AZA; SC injection × 7 days every 28-day cycle; extends survival vs best supportive care); Decitabine ; Allogeneic HSCT (only curative option )
- Prognosis - IPSS-R: the revised International Prognostic Scoring System uses cytogenetics, bone marrow blast %, haemoglobin, platelets, and neutrophil count to stratify into 5 risk groups (very low to very high); median survival ranges from < 1 year (very high risk) to > 8 years (very low risk).
- Supportive care: regular transfusions (target Hb 8-10 g/dL); iron chelation with deferasirox when ferritin > 1000 microgram/L after multiple transfusions; growth factors (G-CSF for recurrent infections); platelet transfusions for bleeding; avoid unnecessary blood transfusions in low-risk patients.
ITP (Immune Thrombocytopenic Purpura) = autoimmune disorder characterised by platelet destruction by IgG auto-antibodies (anti-platelet ) directed against platelet surface glycoproteins (GPIIb/IIIa, GPIb/IX) → macrophage-mediated phagocytosis in spleen → thrombocytopenia; also impaired thrombopoiesis.
- Clinical features: Petechiae; purpura; ecchymoses; mucosal bleeding (gum bleed, epistaxis); menorrhagia; NO lymphadenopathy/hepatosplenomegaly (distinguishes from haematological malignancy); ICH (rare but life-threatening — platelets < 10 × 10⁹/L)
- Children: Acute ITP — often post-viral (EBV, CMV, varicella ); spontaneous remission in 80% within 6 months
- Adults: Chronic ITP (> 12 months ); women > men; may be secondary (SLE, HIV, HCV, CLL, drugs)
- Diagnosis: Thrombocytopenia (platelets < 100 × 10⁹/L); normal/large platelets on film (megathrombocytes — young platelets); NORMAL PT + APTT; BM: ↑ megakaryocytes (increased production compensating for destruction); exclusion of secondary causes
▶ 1st line: Prednisolone 1 mg/kg/day × 4–6 weeks (most pts respond); IV methylprednisolone (1 g/day × 3 days) for severe/urgent; IV immunoglobulin (IVIg 1 g/kg × 2 days ) — rapid platelet rise (within 24–48 hrs ); anti-D immunoglobulin (Rh+ non-splenectomised patients)
▶ 2nd line: Rituximab (anti-CD20 ) 375 mg/m² weekly × 4 doses — 60% response; Romiplostim/Eltrombopag (TPO receptor agonists ) — stimulate platelet production; avoid splenectomy (reserved for refractory )
- Emergency/life-threatening bleeding: Platelet transfusion + IVIg + methylprednisolone + tranexamic acid
- Pathogenesis: IgG autoantibodies (primarily anti-GPIIb/IIIa and anti-GPIb/IX) bind platelet surface glycoproteins; sensitised platelets are destroyed by splenic macrophages (Fc receptor-mediated phagocytosis); T-cell mediated direct platelet cytotoxicity also contributes.
- H. pylori and ITP: test and treat H. pylori in all ITP patients - eradication leads to platelet response in 50% of H. pylori-positive patients; non-invasive testing with urea breath test or stool antigen preferred.
Aplastic anaemia (AA) = hypocellular bone marrow (< 25% cellularity) with pancytopenia (anaemia + neutropenia + thrombocytopenia) due to destruction or suppression of haematopoietic stem cells.
- Causes: Idiopathic (65% — T-cell mediated autoimmune destruction of HSCs); drugs (chloramphenicol, gold, NSAIDs, antithyroid drugs, sulfonamides, carbamazepine, phenytoin); chemicals (benzene ); viruses (EBV, CMV, hepatitis-associated AA — seronegative hepatitis); radiation; PNH (paroxysmal nocturnal haemoglobinuria — 15% AA)
- Clinical features: Anaemia (pallor, fatigue); neutropenia (fever, infections ); thrombocytopenia (bleeding, petechiae); NO splenomegaly/lymphadenopathy (unlike malignancy); 'empty marrow' clinically
- Diagnosis: Pancytopenia on CBC; Bone marrow biopsy — hypocellular marrow (< 25%) with fat spaces; absent haematopoietic cells; no infiltration, no fibrosis
Severity Criteria Severe AA (SAA) Hypocellular BM + 2 of 3: neutrophils < 0.5 × 10⁹/L, platelets < 20 × 10⁹/L, reticulocytes < 20 × 10⁹/L Very Severe AA (vSAA) Same as SAA but neutrophils < 0.2 × 10⁹/L Moderate (non-severe) AA Not meeting SAA criteria ▶ < 40 years + matched sibling donor: Allogeneic HSCT — curative; first-line in young patients with SAA + suitable donor; 80–90% long-term survival
▶ No donor / > 40 years: Horse ATG (anti-thymocyte globulin) + Ciclosporin + Eltrombopag (NIH protocol) — 90% response rate; horse ATG superior to rabbit ATG; response in 3–6 months
- Supportive: Transfusion support (irradiated blood products ); GCSF; antibiotics; eltrombopag 150 mg OD added to IST
- Pathogenesis: in idiopathic AA, autoreactive CD8+ T-cells destroy haematopoietic stem cells (HSC); these T-cells produce IFN-gamma and TNF-alpha which suppress HSC proliferation and induce apoptosis; the marrow becomes empty and replaced by fat.
- Differential diagnosis: distinguish from hypocellular MDS (dysplasia on biopsy, clonal cytogenetics), PNH (CD55/CD59-negative clones on flow cytometry - frequent concomitant finding in AA), and infiltrative causes (malignancy, granuloma).
NHL = heterogeneous group of lymphoid malignancies (B-cell 85%; T-cell/NK-cell 15%); most common lymphoma (commoner than Hodgkin's); bimodal age distribution but predominately adults > 50 years.
Subtype Grade Features Treatment DLBCL (Diffuse Large B-Cell Lymphoma) High-grade, aggressive Most common NHL; rapidly growing mass; elevated LDH; extranodal involvement; B symptoms R-CHOP: Rituximab + Cyclophosphamide + Hydroxydaunorubicin + Vincristine + Prednisolone × 6 cycles; 60–70% cure Follicular lymphoma Low-grade, indolent Most common low-grade NHL; waxing/waning lymphadenopathy; incurable but prolonged survival (10–15 yrs) Watch and wait (asymptomatic); R-CVP; Rituximab maintenance; CAR-T for relapse Burkitt's lymphoma High-grade Starry-sky appearance on biopsy (macrophages engulfing apoptotic cells); jaw tumour (African Burkitt's — EBV-associated ); tumour lysis syndrome risk ; t(8;14) MYC translocation Intensive chemotherapy (CODOX-M/IVAC); highly curable (> 80%) with correct treatment Mantle Cell Lymphoma Intermediate aggressive Elderly males; cyclin D1 overexpression ; t(11;14); leukaemic phase; poor prognosis R-CHOP + HSCT; Ibrutinib (BTK inhibitor ) for relapse - Clinical features: painless lymphadenopathy, hepatosplenomegaly and B symptoms (fever, night sweats, weight loss); extranodal disease is common (GI, CNS, skin); high-grade types grow rapidly while low-grade types are indolent but often incurable.
- Investigations and staging: excisional lymph node biopsy is essential for diagnosis and subtyping (with immunohistochemistry and flow cytometry); CT/PET for Ann Arbor staging; bone marrow biopsy; LDH (prognostic, part of IPI); HIV and hepatitis B/C serology before treatment.
- Ann Arbor staging: Stage I - single lymph node region; Stage II - two or more regions on the same side of the diaphragm; Stage III - on both sides of the diaphragm; Stage IV - disseminated disease (bone marrow, liver, lung); suffix E (extranodal) and B symptoms.
- IPI score: International Prognostic Index for DLBCL; 5 adverse factors each score 1 point (age > 60, LDH elevated, ECOG PS >= 2, Stage III/IV, extranodal sites > 1); score 0-1 = low risk (5-year survival 73%); score 4-5 = high risk (5-year survival 26%).
PRV (Polycythaemia Vera) = MPN with clonal proliferation of all 3 myeloid lineages (predominantly erythroid); JAK2 V617F mutation (95% of cases). Defined as true erythrocytosis: Hb > 16.5 g/dL (M) / > 16 g/dL (F) OR RCM (red cell mass) > 25% above predicted.
- Clinical features: Plethora (ruddy complexion); aquagenic pruritus (itching after hot bath — histamine release from mast cells; pathognomonic of PRV ); headache/dizziness (hyperviscosity); thrombosis (Budd-Chiari — hepatic vein thrombosis; portal vein; stroke; DVT/PE); erythromelalgia (burning red hands/feet — platelet-mediated microcirculatory occlusion); splenomegaly ; gout
- Diagnosis: ↑ Hb/HCT + ↑ RBC mass + JAK2 V617F mutation ; normal SaO2 (distinguishes from secondary erythrocytosis); ↓ EPO (autonomous production; secondary erythrocytosis has ↑ EPO); ↑ WBC + platelets (panmyelosis)
▶ Venesection (phlebotomy) — first-line; target HCT < 45% (M) / < 42% (F); reduces thrombosis risk; 450 mL every 2–3 days initially; simple; cheap
▶ Aspirin 75–100 mg OD — all patients (reduces thrombosis + erythromelalgia)
▶ Hydroxyurea 500–1000 mg/day (cytoreduction) — for high-risk patients (age > 60 or previous thrombosis or platelets > 1500 × 10⁹/L); reduces thrombosis risk
▶ Ruxolitinib (JAK1/2 inhibitor) (Jakafi) — for hydroxyurea-resistant/intolerant PRV; dramatically improves splenomegaly + pruritus + constitutional symptoms; FDA approved
- Aquagenic pruritus: Antihistamines; SSRI (paroxetine ); aspirin; phototherapy; ruxolitinib most effective
- WHO 2022 diagnostic criteria: major criteria - raised Hb/HCT, bone marrow hypercellularity with trilineage proliferation (panmyelosis), JAK2 V617F or exon 12 mutation; minor criterion - subnormal EPO level; diagnosis requires all 3 major or 2 major + 1 minor.
- Complications: thrombosis (stroke, MI, Budd-Chiari syndrome - hepatic vein thrombosis in PV), haemorrhage (platelet dysfunction), gout (cell turnover), transformation to myelofibrosis (~15% at 15 years) or AML (~3%).
Thrombocytopenia = platelets < 150 × 10⁹/L. Significant bleeding risk if < 50 × 10⁹/L; life-threatening if < 10 × 10⁹/L.
Mechanism Examples Key Test ↓ Production Aplastic anaemia, MDS, leukaemia (marrow infiltration), B12/folate deficiency, alcohol, drug-induced (chemotherapy, valproate, heparin) Bone marrow biopsy ↑ Destruction — Immune ITP, SLE, HCV, HIV, drug-induced (heparin — HIT; quinine; vancomycin), post-transfusion purpura Anti-platelet antibodies; Coombs; PF4-heparin Ab (HIT) ↑ Destruction — Non-immune DIC, TTP, HUS, HELLP ADAMTS13 (TTP ); coagulation screen (DIC) Sequestration Hypersplenism (cirrhosis, lymphoma, myelofibrosis) Splenomegaly on imaging HIT (Heparin-Induced Thrombocytopenia) — life-threatening; thrombosis despite thrombocytopenia (paradox!); IgG antibody against PF4-heparin complex → platelet activation → arterial + venous thrombosis; onset 5–14 days after heparin; treat by immediate CESSATION of heparin + switch to alternative anticoagulant (argatroban or fondaparinux); platelet transfusion CONTRAINDICATED.
TTP (Thrombotic Thrombocytopenic Purpura) — Pentad:
- MAHA (Microangiopathic Haemolytic Anaemia) + Thrombocytopenia + Fever + Renal failure + Neurological symptoms (fluctuating — confusion, seizures)
- Cause: ↓ ADAMTS13 (cleaves ultra-large vWF multimers; absent/inhibited → ULvWF → platelet thrombi in microvasculature)
- Treatment: Plasma exchange (PEX) — removes inhibitor + replenishes ADAMTS13; START IMMEDIATELY (mortality without PEX > 90%); + Prednisolone; Rituximab for refractory/relapsed
- HIT diagnosis: use the 4T score (Thrombocytopenia magnitude, Timing of onset, Thrombosis, other cause); intermediate/high 4T score warrants anti-PF4 ELISA; stop heparin immediately; replace with a non-heparin anticoagulant (argatroban, fondaparinux, or danaparoid); do NOT transfuse platelets (worsens thrombosis).
- DIC: disseminated intravascular coagulation - activation of coagulation throughout the microvasculature; consumptive coagulopathy; low platelets, prolonged PT/APTT, low fibrinogen, elevated D-dimer and FDPs; causes: sepsis (#1), obstetric catastrophe, malignancy, trauma; treat the underlying cause.
DEFINITION & LAB HALLMARKS
- Haemolytic anaemia = premature RBC destruction (normal RBC survival 120 days) with anaemia + reticulocytosis + haemolysis markers
Parameter Intravascular Haemolysis Extravascular Haemolysis Site Blood vessels (complement activation) Spleen/liver macrophages LDH ↑↑ ↑ Haptoglobin ↓↓ (free Hb binds haptoglobin → saturated) ↓ (mild) Bilirubin ↑ indirect ↑↑ indirect Haemoglobinuria Yes (Hb in urine — dark) No Haemoglobinaemia Yes (pink plasma) No Causes PNH , G6PD + oxidant trigger, ABO incompatibility, MAHA (TTP/HUS) Spherocytosis , Autoimmune HA, Sickle cell, Thalassaemia, Hypersplenism - Coombs test (Direct Antiglobulin Test — DAT): Detects IgG or C3 on RBC surface → Positive in autoimmune HA (AIHA); negative in hereditary (spherocytosis, G6PD, sickle cell)
- G6PD deficiency: X-linked recessive; precipitated by oxidant stress (drugs: primaquine, dapsone, nitrofurantoin; infections; fava beans — favism ); Heinz bodies + bite cells on film; most common enzyme deficiency worldwide
- Hereditary spherocytosis: AD; spectrin/ankyrin defect → spherocytes (no biconcave disc) → splenic destruction; osmotic fragility test positive; treat with splenectomy (most benefit)
- Classification: inherited (membrane - hereditary spherocytosis; enzyme - G6PD, pyruvate kinase; haemoglobin - sickle cell, thalassaemia) versus acquired (immune - autoimmune/alloimmune/drug-induced; non-immune - MAHA, malaria, mechanical valves, PNH).
- Management: treat the cause and give folate; warm autoimmune haemolytic anaemia - corticosteroids, then rituximab or splenectomy; transfuse for symptomatic anaemia; avoid oxidant drugs in G6PD; splenectomy for severe hereditary spherocytosis.
- Hereditary spherocytosis features: jaundice (neonatal), anaemia and splenomegaly; MCHC raised (spherocytes are small, dense cells with no central pallor); osmotic fragility test positive (spherocytes lyse at higher NaCl concentrations); EMA (eosin-5-maleimide) binding test on flow cytometry is the most specific and sensitive.
- Sickle cell disease: HbSS (homozygous); vaso-occlusive crises (bone pain, acute chest syndrome, stroke); manage with hydroxyurea (increases HbF, reduces crises), regular transfusions for stroke prevention, and consider stem cell transplant; pneumococcal vaccine and penicillin prophylaxis essential (hyposplenism).
THALASSAEMIA
Thalassaemia = hereditary haemolytic anaemia from quantitative deficiency (reduced/absent synthesis) of alpha or beta globin chains → unmatched chains → ineffective erythropoiesis + haemolysis.
Type Genetics Clinical Features Management Beta-thalassaemia major Homozygous β⁰/β⁰ or β⁺/β⁰ Transfusion-dependent from 6 months; chipmunk facies (frontal bossing + malar prominence — marrow expansion); hepatosplenomegaly; growth retardation; jaundice; thalassaemic facies ; Xray: hair-on-end skull Regular transfusion (every 3–4 wks) + Desferrioxamine/Deferasirox (iron chelation) ; Allogeneic HSCT (curative ); Gene therapy (Zynteglo ) Beta-thalassaemia minor (trait) Heterozygous β/β⁰ Asymptomatic ; mild microcytic anaemia; basophilic stippling ; ↑ HbA2 > 3.5% (diagnostic); genetic counselling No treatment needed; genetic counselling Alpha-thalassaemia Gene deletion (α-thal-1 = --; α-thal-2 = -α) Silent carrier (1 gene); trait (2 genes — mild microcytic); HbH (3 genes — moderate haemolytic); Hb Barts/Hydrops fetalis (4 genes — fatal in utero ) Hydrops: incompatible with life PAROXYSMAL NOCTURNAL HAEMOGLOBINURIA (PNH)
PNH = clonal haematopoietic stem cell disorder caused by PIG-A gene mutation (somatic; X-linked) → deficiency of GPI-anchored proteins (CD55 + CD59 — complement regulatory proteins) → RBCs unprotected from complement → intravascular haemolysis + thrombosis + cytopenias.
- Clinical triad: Haemolytic anaemia + Thrombosis (especially unusual sites — hepatic vein/Budd-Chiari, sagittal sinus) + Cytopenias (pancytopenia in 30%)
- Classic: Haemoglobinuria — dark brown urine on waking (first morning urine darkest — nocturnal complement activation + urine concentration)
- Diagnosis: Flow cytometry — absent CD55 + CD59 on RBCs and granulocytes; Ham's acid lysis test (historical — haemolysis in acidified serum)
▶ Eculizumab (Soliris) — anti-C5 monoclonal antibody; blocks terminal complement; dramatically reduces haemolysis + thrombosis + improves QoL; meningococcal vaccine mandatory before eculizumab (↑ meningococcal risk); Ravulizumab (longer-acting C5 inhibitor)
HODGKIN'S LYMPHOMA (HL)
HL = lymphoma characterised by Reed-Sternberg (RS) cells ('owl-eye' nuclei — binucleate with prominent nucleoli); bimodal incidence (15–35 yrs + > 55 yrs); EBV association; predominantly B-cell origin; highly curable .
- Subtypes (WHO/Lugano ): Nodular sclerosis (most common, 70%); Mixed cellularity (EBV+; HIV); Lymphocyte-rich; Lymphocyte-depleted (worst prognosis); NLPHL (popcorn/LP cells, not RS cells)
- Clinical: Painless lymphadenopathy (cervical most common); B symptoms (fever > 38°C + night sweats + weight loss > 10% in 6 months — adverse prognosis ); Pel-Ebstein fever (cyclical fever); alcohol-induced pain in lymph nodes (classic feature ); mediastinal mass
- Staging (Ann Arbor + Cotswolds ): I (1 node region) → II (2+ same side diaphragm) → III (both sides) → IV (extranodal) + A/B symptoms + E (extranodal contiguous) + S (splenic involvement)
▶ ABVD: Adriamycin (Doxorubicin) + Bleomycin + Vinblastine + Dacarbazine — standard chemotherapy for most stages × 2–6 cycles
▶ Escalated BEACOPP — for advanced/unfavourable; more toxic; Brentuximab vedotin (anti-CD30 ) ADC for relapsed; PD-1 inhibitors (pembrolizumab/nivolumab) for refractory
- Prognosis: Stage I–II: 90–95% cure; Advanced: 70–80% cure with modern therapy
MULTIPLE MYELOMA
Multiple myeloma (MM) = clonal proliferation of malignant plasma cells in bone marrow producing monoclonal immunoglobulin (M-protein/paraprotein ) ± Bence-Jones proteins (free light chains ). Median age 65–70 years; incurable but manageable.
- CRAB criteria (end-organ damage requiring treatment): Calcium ↑ (> 2.75 mmol/L); Renal failure (Cr > 177 μmol/L); Anaemia (Hb < 100 g/L); Bone disease (lytic lesions/fractures )
- Diagnosis: Serum + urine electrophoresis (SPEP + UPEP ) → M-spike; BJP (Bence-Jones Protein in urine — light chains ); BM biopsy > 10% plasma cells ; Skull X-ray: 'pepper-pot' lesions (punched-out lytic lesions); XR spine: fish-vertebrae ; β2-microglobulin (prognostic marker )
▶ Induction: VRD (Bortezomib + Lenalidomide + Dexamethasone ) × 4–6 cycles → response assessment
▶ High-dose Melphalan + ASCT (autologous stem cell transplant) — eligible patients (< 70 yrs, fit); extends remission; not curative
▶ Maintenance: Lenalidomide OD post-ASCT; extends PFS
- Daratumumab (anti-CD38 ) — now added to VRD (DaraVRD) for newly diagnosed transplant-eligible MM; dramatically improves outcomes
Tumour Marker Associated Cancer Notes PSA Prostate cancer Screening + monitoring; BPH also ↑ PSA slightly AFP HCC; non-seminomatous germ cell tumours Monitoring HCC in cirrhosis + screening; elevated in HCC + yolk sac tumours CEA Colorectal cancer; gastric; lung; breast Not specific; used for monitoring recurrence after surgery CA-125 Ovarian cancer Endometriosis also elevates; monitoring treatment response CA 19-9 Pancreatic cancer; cholangiocarcinoma; gastric Not specific; elevated in biliary obstruction even without cancer Beta-hCG Choriocarcinoma; seminoma (mild); hydatidiform mole Very sensitive; serial monitoring guides treatment LDH NHL; testicular cancer; any rapid cell turnover Non-specific; prognostic marker in lymphoma NSE (Neuron-Specific Enolase) SCLC; neuroblastoma Most useful for SCLC monitoring Paraneoplastic syndromes = symptoms caused by the tumour through remote (humoral/immunological) effects rather than direct invasion/metastasis. May precede cancer diagnosis.
- Paraneoplastic neurological syndromes: anti-Hu (sensory neuropathy, SCLC), anti-Yo (cerebellar degeneration, ovarian/breast), anti-NMDAR (encephalitis, ovarian teratoma), anti-Ri (opsoclonus-myoclonus, breast/SCLC); treat the underlying tumour; immunotherapy (steroids, IVIG, rituximab) for the neurological syndrome.
- Hypercalcaemia of malignancy: humoral (PTHrP from squamous cell carcinoma, RCC, breast) or osteolytic (myeloma, bone metastases) mechanisms; PTH is suppressed (distinguishes from primary hyperparathyroidism); manage with IV saline and bisphosphonate.
Syndrome Cancer Association Mechanism SIADH SCLC; brain tumours; lymphoma Ectopic ADH (AVP) secretion Hypercalcaemia Squamous cell lung; MM; breast PTHrP secretion; lytic bone metastases Cushing's SCLC; pancreatic neuroendocrine Ectopic ACTH secretion Lambert-Eaton myasthenic syndrome SCLC Anti-VGCC antibodies; proximal myopathy; ↑ EMG with repeated stimulation (opposite to MG ) Trousseau's syndrome Pancreatic/mucinous cancers Migratory superficial thrombophlebitis + hypercoagulability Acanthosis nigricans Gastric cancer; intra-abdominal malignancy ↑ Insulin-like growth factors TLS = metabolic emergency from massive lysis of tumour cells (spontaneous or treatment-induced) → release of intracellular contents into circulation. Most common with Burkitt's lymphoma , ALL, AML, aggressive NHL. Can be spontaneous or post-chemotherapy.
Feature Mechanism Consequence Hyperkalaemia K⁺ release from lysed cells Cardiac arrhythmias → death Hyperphosphataemia Phosphate release Hypocalcaemia (Ca × PO4 precipitation) Hypocalcaemia Ca-PO4 precipitation; ↓ PTH effect Tetany; seizures; arrhythmias Hyperuricaemia Nucleic acid breakdown → xanthine → uric acid AKI (urate crystals in tubules ); gout AKI Urate nephropathy + CaPO4 precipitation Oliguria → dialysis ◆ TLS Metabolic ABCD ▸ A = Acidosis (metabolic, from lactic acid + renal failure) ▸ B = Below-normal Ca (hypocalcaemia — tetany, seizures) ▸ C = Creatinine elevation (AKI) + cardiac arrhythmias (K⁺) ▸ D = Displaced uric acid ↑ + phosphate ↑ MANAGEMENT & PROPHYLAXIS
▶ Allopurinol — 300 mg OD (prophylaxis; inhibits xanthine oxidase → ↓ uric acid production); start 1–2 days before chemotherapy
▶ Rasburicase (recombinant urate oxidase) — converts uric acid to allantoin (soluble ); rapidly reduces uric acid levels; superior to allopurinol for high-risk TLS; CONTRAINDICATED in G6PD deficiency (produces H2O2 → haemolysis)
- Aggressive IV hydration — 3 L/m²/day; maintain UO > 100 mL/hr; prevents urate precipitation in tubules
- Urine alkalinisation — historically recommended; now controversial (may ↑ CaPO4 precipitation); use selectively
- Haemodialysis — for refractory hyperkalaemia + AKI; definitive management of severe TLS
- Cairo-Bishop definition: laboratory TLS requires >= 2 of: uric acid >= 476 umol/L, potassium >= 6 mmol/L, phosphate >= 1.45 mmol/L, or calcium <= 1.75 mmol/L, within 3 days before or 7 days after starting therapy; clinical TLS = laboratory TLS plus AKI, cardiac arrhythmia, or seizure.
- Risk stratification: high risk - Burkitt lymphoma, DLBCL, ALL with WBC > 100,000, AML with WBC > 100,000; intermediate risk - CML blast crisis, solid tumours with large burden; prophylaxis - all high-risk and intermediate patients should receive allopurinol and aggressive IV hydration before chemotherapy.
◆ 4T's of Anterior Mediastinal Masses ▸ T = Thymoma (most common anterior mediastinal mass in adults; associated with myasthenia gravis; pure red cell aplasia; hypogammaglobulinaemia) ▸ T = Teratoma/Germ Cell Tumours (mature/immature; ↑ AFP + beta-hCG; chemotherapy + surgery) ▸ T = Terrible Lymphoma (Hodgkin's and T-cell NHL most common mediastinal lymphoma; nodular sclerosis HL most common ) ▸ T = Thyroid/Parathyroid (retrosternal goitre; ectopic parathyroid) Compartment Contents Common Masses Anterior Thymus, lymph nodes, fat 4 T's (Thymoma, Teratoma, Terrible lymphoma, Thyroid); Ascending aorta aneurysm Middle Heart, pericardium, great vessels, trachea, main bronchi, lymph nodes Lymphoma; pericardial cysts; bronchogenic cysts; aneurysm (aortic arch) Posterior Oesophagus, descending aorta, vertebrae, neural foramina Neurogenic tumours (most common posterior mass — neurofibroma, schwannoma); oesophageal tumours; aortic aneurysm; vertebral lesions - Thymoma: Associated conditions: Myasthenia gravis (30–50% of thymoma patients have MG); pure red cell aplasia; hypogammaglobulinaemia; SLE; polymyositis
- Clinical features of mediastinal mass: SVC syndrome (facial oedema + arm oedema + engorged neck veins + dilated chest veins + venous pressure ↑); stridor/dyspnoea (airway compression); dysphagia (oesophageal compression); Horner's syndrome (sympathetic chain compression)
- Investigations: CXR localises the mass; contrast CT chest characterises it and the compartment; tumour markers (AFP and beta-hCG) for germ-cell tumours; biopsy for tissue diagnosis; check anti-AChR antibodies for myasthenia if a thymoma is found.
- Compartments: anterior - the 4 Ts (thymoma, teratoma/germ-cell, terrible lymphoma, thyroid); middle - lymphadenopathy, bronchogenic/pericardial cysts, vascular structures; posterior - neurogenic tumours (most common; schwannoma, neurofibroma, ganglioneuroma).