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HAEMATOLOGY - COMPREHENSIVE NOTES

Reference: Harsh Mohan's Textbook of Pathology | Robbins Basic Pathology | Frameworks for Internal Medicine

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1. ANAEMIA - DEFINITION AND CLASSIFICATION

Definition

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Pathophysiological (Aetiological) Classification

1. Acute post-haemorrhagic anaemia
2. Chronic blood loss anaemia

1. Deficiency anaemias
   • Iron deficiency anaemia
   • Megaloblastic anaemia (B12/folate deficiency)
   • Anaemia of protein deficiency
   • Pyridoxine-responsive anaemia
2. Bone marrow failure
   • Aplastic anaemia
   • Pure red cell aplasia
   • Myelophthisic anaemia (marrow infiltration)
3. Anaemia of chronic disease/inflammation

1. Intracorpuscular (intrinsic) defects
   • Hereditary: Hereditary spherocytosis, G6PD deficiency, Sickle cell anaemia, Thalassaemia
2. Extracorpuscular (extrinsic) defects
   • Immune: AIHA, HDN
   • Non-immune: Microangiopathic HA, infections (malaria), hypersplenism

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Morphological Classification (Most Clinically Used)

• Megaloblastic macrocytic: oval macrocytes (macro-ovalocytes), hypersegmented neutrophils
• Non-megaloblastic macrocytic: round macrocytes (liver disease, hypothyroidism, alcohol)

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2. IRON DEFICIENCY ANAEMIA (IDA)

Causes

• Infants and children (rapid growth)
• Pregnancy and lactation
• Poor dietary intake (vegetarian diet, poverty)
• Prematurity

• Gastrectomy, achlorhydria
• Malabsorption syndromes (Coeliac disease, Crohn's disease)
• Chronic diarrhoea

• GI tract: Peptic ulcer, carcinoma, hookworm infestation (Ancylostoma duodenale - most common cause worldwide), haemorrhoids, ulcerative colitis, diverticulosis
• Genital tract: Menorrhagia, metrorrhagia
• Urinary tract: Haematuria
• Repeated blood donations

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Etiopathogenesis

• Bone marrow iron stores depleted
• Serum ferritin falls
• No anaemia; Hb, MCV, and serum iron normal

• Serum iron falls, TIBC rises, transferrin saturation falls (<16%)
• Serum ferritin <12 µg/L
• Free erythrocyte protoporphyrin (FEP) increases
• Still no overt anaemia but impaired erythropoiesis begins

• Haemoglobin synthesis impaired
• Microcytic hypochromic anaemia develops
• All iron indices markedly abnormal

• Iron (Fe²⁺) is essential for haem synthesis (incorporation into protoporphyrin IX)
• Iron deficiency → reduced haemoglobin synthesis per cell → cells divide more times → small (microcytic), pale (hypochromic) RBCs
• Insufficient iron also impairs myoglobin synthesis and cytochrome activity → systemic features (pica, koilonychia, glossitis)

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Laboratory Investigations

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Peripheral Blood Smear (PBS) Findings

1. Microcytes - RBCs smaller than the nucleus of a small lymphocyte
2. Hypochromia - central pallor >1/3 of cell diameter (normal is up to 1/3)
3. Anisocytosis - variation in cell size (elevated RDW)
4. Poikilocytosis - abnormal shapes:
   • Pencil cells (cigar cells) - elongated thin cells (characteristic of IDA)
   • Target cells (codocytes) - occasional
   • Elliptocytes/ovalocytes
5. Dimorphic picture - if partially treated or mixed deficiency (IDA + B12/folate)
6. Occasional thrombocytosis (elevated platelet count on smear)

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Bone Marrow Findings

1. Erythroid hyperplasia - normoblastic with slight shift to smaller forms
2. Micronormoblasts - small erythroblasts with scanty, ragged cytoplasm ("shaggy" cytoplasm due to deficient Hb)
3. Absent haemosiderin - absence of Prussian blue staining (stainable iron) - the hallmark; normally marrow macrophages contain abundant iron granules
4. Absent sideroblasts - iron granules absent in erythroid precursors
5. Myeloid:erythroid ratio is reduced (erythroid hyperplasia)
6. Megakaryocytes normal or increased

Key diagnostic test: Perl's Prussian Blue stain for iron on bone marrow trephine - absent stainable iron = diagnostic of IDA

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3. MEGALOBLASTIC ANAEMIA

Causes

1. Inadequate intake - strict vegans (B12 only in animal products)
2. Pernicious anaemia - autoimmune destruction of gastric parietal cells → absent intrinsic factor (IF) → no ileal B12 absorption (most common cause in Western countries)
3. Gastrectomy (total/partial) - loss of parietal cells → no IF
4. Ileal disease/resection - Crohn's disease, tropical sprue (site of B12-IF complex absorption)
5. Bacterial overgrowth (blind loop syndrome) - bacteria consume B12
6. Fish tapeworm (Diphyllobothrium latum) - competes for B12
7. Transcobalamin II deficiency (rare)
8. Nitrous oxide exposure (inactivates B12)

1. Inadequate intake - alcoholics, elderly, poverty (folate in green leafy vegetables, liver)
2. Increased demand - pregnancy, haemolytic anaemia, malignancy
3. Malabsorption - Coeliac disease, tropical sprue, jejunal resection
4. Drugs: Methotrexate (DHFR inhibitor), Phenytoin, Trimethoprim, Pyrimethamine, Sulphonamides

• Cytotoxic drugs (hydroxyurea, cytosine arabinoside, 5-fluorouracil)
• Congenital enzyme defects (orotic aciduria)
• Copper deficiency

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Etiopathogenesis

1. Role of B12 and Folate:
   • Dietary folate (polyglutamate) → absorbed as monoglutamate → reduced to dihydrofolate (DHF) → tetrahydrofolate (THF) by DHFR
   • THF (as methylene-THF) is the cofactor for thymidylate synthase: dUMP → dTMP (thymidine synthesis)
   • B12 is needed to regenerate THF from methyl-THF ("folate trap" - B12 deficiency traps folate as methyl-THF, making it unavailable for DNA synthesis)
   • B12 also needed for: methionine synthesis (homocysteine → methionine via methionine synthase) and for neurological function (conversion of methylmalonyl-CoA to succinyl-CoA)
2. Consequences of impaired DNA synthesis:
   • Nuclear maturation lags behind cytoplasmic maturation (RNA and protein synthesis continue normally)
   • Cells grow large but nuclei fail to divide properly → large cells with immature-looking ("open", finely stippled) nuclei = megaloblasts
   • Ineffective erythropoiesis: most megaloblasts die in the bone marrow (intramedullary haemolysis) → elevated LDH, bilirubin (indirect), low haptoglobin
   • ALL rapidly dividing cells affected: GI epithelium (glossitis, stomatitis, diarrhoea), cervical epithelium
3. B12 deficiency - additional neurological effects:
   • Impaired methylmalonyl-CoA → succinyl-CoA conversion → accumulation of methylmalonic acid (MMA)
   • Abnormal fatty acids incorporated into myelin → Subacute Combined Degeneration of the Spinal Cord (posterior columns + corticospinal tracts)
   • NB: Folate deficiency does NOT cause neurological disease

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Laboratory Investigations

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Peripheral Blood Smear Findings

1. Macro-ovalocytes (oval macrocytes) - large, oval-shaped RBCs; MCV >115 fL; the hallmark finding
2. Hypersegmented neutrophils - most characteristic single finding: >5% with ≥5 lobes, OR any neutrophil with ≥6 lobes; often called "Hyperseg polys"
3. Anisocytosis and poikilocytosis - marked variation in size and shape
4. Teardrop cells (dacrocytes)
5. Pancytopenia picture - reduced all cell lines in severe disease
6. Macrothrombocytes - large platelets occasionally

The combination of macro-ovalocytes + hypersegmented neutrophils on PBS is virtually pathognomonic of megaloblastic anaemia.

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Bone Marrow Findings

1. Hypercellular marrow - marked erythroid hyperplasia
2. Megaloblasts - the pathognomonic cell: large erythroid precursors with:
   • Nuclear-cytoplasmic dissociation (asynchrony): nucleus looks immature (open, finely stippled, lacy chromatin) while cytoplasm is well-haemoglobinised (mature)
   • Nuclei appear "young-looking" in "old-looking" cytoplasm
3. Giant metamyelocytes and band cells - large myeloid precursors with horseshoe-shaped nuclei (highly characteristic)
4. Hypersegmented megakaryocytes
5. Ineffective erythropoiesis - many cells die before reaching peripheral blood
6. Erythroid:myeloid ratio increased
7. Iron stores abundant (increased - iron cannot be used effectively)

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4. MACROCYTIC ANAEMIA

Causes

1. B12 deficiency (pernicious anaemia, dietary, malabsorption)
2. Folate deficiency
3. Drugs: Methotrexate, Hydroxyurea, Cytarabine, 5-FU, Phenytoin, Trimethoprim

1. Liver disease (alcoholic or non-alcoholic) - excess membrane lipid incorporated into RBC membrane → round macrocytes; increased MCV from lipid accumulation
2. Alcoholism - direct toxic effect on erythroblasts; also associated folate deficiency
3. Hypothyroidism - reduced metabolic rate; also associated B12 deficiency (autoimmune association)
4. Haemolytic anaemia - reticulocytes are large; reticulocytosis causes elevated MCV
5. Aplastic anaemia - macrocytes from stress erythropoiesis
6. Myelodysplastic syndromes (MDS)
7. Post-splenectomy - target cells, acanthocytes, larger RBCs
8. Pregnancy (physiological - due to increased folate demand and plasma expansion)
9. Chronic obstructive pulmonary disease (COPD) with cor pulmonale

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Etiopathogenesis

• Megaloblastic: see Megaloblastic Anaemia section (impaired DNA synthesis → nuclear-cytoplasmic asynchrony → macro-ovalocytes)
• Non-megaloblastic (liver/alcohol): Excess cholesterol and phospholipids from plasma lipoproteins are incorporated into RBC membrane → membrane expands → round macrocytes (not oval). No nuclear-cytoplasmic asynchrony. Normal DNA synthesis.
• Reticulocytosis-induced: Reticulocytes are inherently larger than mature RBCs (still contain ribosomes, RNA). When reticulocyte count rises (e.g. haemolysis, B12 treatment), the average MCV rises.

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Laboratory Investigations

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Peripheral Blood Smear Findings

1. Oval macrocytes (macro-ovalocytes)
2. Hypersegmented neutrophils (≥5 lobes)
3. Marked anisocytosis and poikilocytosis
4. Teardrop cells

1. Round macrocytes (not oval)
2. Target cells (in liver disease - increased membrane lipids)
3. Stomatocytes (liver disease)
4. Acanthocytes/spur cells (severe liver disease)
5. No hypersegmented neutrophils

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Bone Marrow Findings

• Normoblastic erythropoiesis
• No megaloblasts, no giant metamyelocytes
• May show erythroid hyperplasia if haemolytic
• Dysplastic changes in MDS

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5. SICKLE CELL ANAEMIA

Causes / Genetic Basis

• Autosomal recessive disorder
• Mutation: Single nucleotide substitution in codon 6 of the β-globin gene (chromosome 11): GAG → GTG → Glutamic acid → Valine at position 6 of the β-chain
• Results in abnormal haemoglobin: HbS (α₂β²S) instead of HbA (α₂β₂)
• Homozygous (HbSS): Sickle cell disease (severe)
• Heterozygous (HbAS): Sickle cell trait (usually asymptomatic; protective against P. falciparum malaria)
• Other combinations: HbSC disease, HbS/β-thalassaemia (intermediate severity)

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Etiopathogenesis

• In the deoxygenated state, HbS molecules polymerize (stack up) into long, insoluble tactoids (polymer chains)
• Val at position 6 creates a hydrophobic "sticky patch" that interacts with complementary sites on adjacent HbS molecules
• Deoxy-HbS polymerization distorts the RBC into the characteristic sickle shape

• Deoxygenation (hypoxia, high altitude)
• Acidosis (lowers oxygen affinity of Hb)
• Dehydration (increases intracellular HbS concentration)
• Hypothermia
• Infection, surgery, strenuous exercise

• Initially reversible sickling → irreversible sickle cell as membrane becomes damaged
• Irreversibly sickled cells (ISCs) are rigid, non-deformable
• ISCs trapped and destroyed in spleen, liver → extravascular haemolysis
• Haemolysis also occurs intravascularly
• Shortened RBC survival: 10-20 days (normal: 120 days)

• Sickled cells occlude small vessels (capillaries, venules)
• Also: enhanced RBC adhesion to endothelium, leucocyte/platelet activation, abnormal nitric oxide metabolism → vasoconstriction
• Ischaemia and infarction in multiple organs

• Spleen: Repeated infarctions → progressive autosplenectomy by adolescence → susceptibility to encapsulated bacteria (Streptococcus pneumoniae, Haemophilus influenzae, Salmonella)
• Bone: Medullary infarction → avascular necrosis of femoral/humeral heads; periostitis → "hand-foot syndrome" (dactylitis) in infants; Salmonella osteomyelitis
• Lung: Acute chest syndrome (fever, chest pain, pulmonary infiltrates, hypoxia) - the leading cause of death in SCD
• CNS: Stroke (in ~10% of patients)
• Kidney: Haematuria, papillary necrosis, progressive renal failure
• Eye: Proliferative retinopathy, vitreous haemorrhage
• Liver: Sickle hepatopathy, gallstones (pigment stones from chronic haemolysis)
• Penis: Priapism (vascular occlusion)

• Parvovirus B19 infects erythroid progenitors → transient cessation of erythropoiesis → acute severe anaemia (reticulocytopenia)

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Laboratory Investigations

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Peripheral Blood Smear Findings

1. Sickle cells (drepanocytes) - elongated, crescent/sickle-shaped RBCs with pointed ends - pathognomonic
2. Irreversibly sickled cells (ISCs) - present even in oxygenated blood
3. Target cells (codocytes) - particularly common; thin cells with central "bull's-eye"
4. Polychromasia/reticulocytosis - indicates compensatory erythropoiesis
5. Nucleated RBCs (normoblasts) - due to hyposplenism and stress erythropoiesis
6. Howell-Jolly bodies - nuclear remnants, due to hyposplenism/autosplenectomy
7. Helmet cells and fragmented cells (during crises)
8. Anisocytosis and poikilocytosis

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Bone Marrow Findings

1. Marked erythroid hyperplasia - compensatory; M:E ratio reduced
2. Normoblastic erythropoiesis (though severely increased)
3. Expanded marrow cavity - "hair on end" appearance on X-ray (frontal bossing, crew-cut skull)
4. Bone marrow infarction during crises - areas of necrosis, fat emboli
5. Iron stores: normal to increased (haemolytic disease)

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6. MEGALOBLASTIC ANAEMIA (Already covered in detail above - Section 3)

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7. HAEMOLYTIC ANAEMIA

Definition

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Causes / Classification

A. INTRAVASCULAR vs. EXTRAVASCULAR HAEMOLYSIS

B. INTRINSIC (INTRACORPUSCULAR) DEFECTS

• Hereditary Spherocytosis (HS) - Autosomal dominant; defect in spectrin, ankyrin, or band 3 protein → loss of membrane lipid → spherocytes; splenomegaly; positive osmotic fragility test
• Hereditary Elliptocytosis (HE) - spectrin dimer-dimer interaction defect
• Stomatocytosis

• G6PD deficiency (Glucose-6-phosphate dehydrogenase) - X-linked; triggers: infection, drugs (primaquine, dapsone, nitrofurantoin), fava beans → oxidative stress → Heinz body formation → haemolysis; favism
• Pyruvate kinase deficiency - Autosomal recessive; impaired ATP production → rigid RBCs

• Sickle cell anaemia (HbSS)
• Thalassaemia (α and β)
• Unstable haemoglobin disorders

C. EXTRINSIC (EXTRACORPUSCULAR) DEFECTS

• Autoimmune haemolytic anaemia (AIHA):
  • Warm AIHA: IgG antibodies (react at 37°C); idiopathic or secondary (SLE, CLL, drugs - methyldopa, penicillin)
  • Cold AIHA (Cold agglutinin disease): IgM antibodies (react at 4°C); Mycoplasma pneumoniae, EBV infections
• Alloimmune: Haemolytic Disease of the Newborn (HDN - Rh/ABO incompatibility), transfusion reactions

• Mechanical fragmentation of RBCs through damaged small vessels
• Causes: TTP (Thrombotic Thrombocytopenic Purpura), HUS (Haemolytic Uraemic Syndrome), DIC, pre-eclampsia/HELLP syndrome, malignant hypertension, prosthetic heart valves

• Malaria (Plasmodium falciparum - direct invasion and lysis)
• Clostridium perfringens (lecithinase destroys RBC membrane)
• Bartonellosis
• Babesiosis

• Burns (thermal damage to RBCs)
• March haemoglobinuria (foot-strike haemolysis in runners)
• Snake venom

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Etiopathogenesis

1. RBCs with abnormal morphology (spherocytes, sickle cells) or antibody-coated RBCs are trapped in splenic cords (low O₂, low pH, low glucose, slow transit)
2. Macrophages recognize:
   • Abnormal shape (loss of deformability)
   • Bound IgG (Fc receptors on macrophages)
   • Bound C3b (complement receptors)
3. Partial phagocytosis → spherocytosis; complete phagocytosis → extravascular haemolysis
4. Haemoglobin released → bilirubin (unconjugated) → jaundice
5. Bone marrow compensates with erythroid hyperplasia

1. Direct RBC lysis within vessels (complement activation, mechanical trauma, toxins)
2. Free haemoglobin released into plasma
3. Haptoglobin binds free Hb → haemoglobin-haptoglobin complexes → cleared by liver → haptoglobin levels fall
4. Excess free Hb → haemoglobinaemia, haemoglobinuria (urine becomes dark red/brown)
5. Hb oxidized to methaemoglobin → haematin → haemosiderin deposited in renal tubules → haemosiderinuria

• Bone marrow erythroid hyperplasia (up to 6-8x normal)
• Extramedullary haemopoiesis (liver, spleen)
• Reticulocytosis

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Laboratory Investigations

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Peripheral Blood Smear Findings

1. Reticulocytosis and polychromasia - most consistent finding; polychromatic (bluish-tinged) cells = reticulocytes
2. Nucleated RBCs (normoblasts) - in severe haemolysis
3. Specific morphological clues by cause:
   • Spherocytes (dense, small, no central pallor) - HS, AIHA, ABO incompatibility
   • Sickle cells (drepanocytes) - Sickle cell anaemia
   • Target cells - Thalassaemia, HbC, liver disease
   • Schistocytes (fragmented RBCs) - MAHA (TTP, HUS, DIC) - characteristic finding
   • Bite cells (blister cells, degmacytes) - G6PD deficiency (Heinz bodies removed by spleen)
   • Heinz bodies (with supravital staining, e.g. crystal violet) - G6PD deficiency, unstable Hb
   • Elliptocytes - HE
   • Burr cells (echinocytes) - uraemia
   • Acanthocytes (spur cells) - abetalipoproteinaemia, liver disease
4. Thrombocytopenia - in TTP, HUS, DIC

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Bone Marrow Findings

1. Marked erythroid hyperplasia - M:E ratio reversed (normally 3:1; becomes 1:1 or even 1:3 in severe haemolysis)
2. Normoblastic erythropoiesis (increased polychromatic normoblasts)
3. Extramedullary haematopoiesis in severe/chronic cases
4. Erythrophagocytosis - macrophages engulfing RBCs (in immune haemolytic anaemia)
5. Iron stores: Increased (from haemoglobin breakdown; accumulates as haemosiderin in macrophages)
6. In G6PD deficiency: Heinz bodies visible on supravital stain of marrow
7. In aplastic crisis (parvovirus B19): Giant pronormoblasts (lantern cells), absent erythroid hyperplasia

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SUMMARY TABLE: DIFFERENTIATING THE ANAEMIAS

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What's Covered (Navigation Guide)

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• IDA: pencil cells + absent Prussian blue iron on BM - pathognomonic; ferritin is the earliest and most sensitive test
• Megaloblastic: macro-ovalocytes + hypersegmented neutrophils on PBS; giant metamyelocytes + megaloblasts on BM; MMA elevated in B12 deficiency only
• Sickle Cell: GAG→GTG (Glu→Val) in β-globin codon 6; HbSS on electrophoresis; Howell-Jolly bodies = autosplenectomy
• Haemolytic: elevated reticulocytes + low haptoglobin = hallmark; schistocytes = MAHA; spherocytes = HS/AIHA; Heinz bodies = G6PD
• Morphological classification: Microcytic hypochromic (IDA, thalassaemia), Normocytic normochromic (aplastic, haemolytic), Macrocytic (megaloblastic, liver disease)

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COMPLICATIONS OF ANAEMIAS

Reference: Harsh Mohan's Textbook of Pathology | Robbins Basic Pathology

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1. COMPLICATIONS OF IRON DEFICIENCY ANAEMIA (IDA)

A. Haematological Complications

1. Severe microcytic hypochromic anaemia - Hb may fall to <5 g/dL in chronic neglected cases
2. Thrombocytosis - reactive; can predispose to thromboembolic events
3. Impaired immune function - iron is required for lymphocyte proliferation and neutrophil killing; increased susceptibility to infections
4. Thrombocytopenia - in very severe, long-standing IDA (rare)

B. Cardiovascular Complications

1. High-output cardiac failure - compensatory increased cardiac output to maintain O₂ delivery → eventually leads to:
   • Cardiomegaly
   • Palpitations, tachycardia
   • Cardiac failure (especially in elderly or those with pre-existing cardiac disease)
2. Angina pectoris - reduced O₂-carrying capacity worsens ischaemia in those with coronary artery disease

C. Neurological / Neuromuscular Complications

1. Fatigue, weakness, lethargy - due to reduced O₂ to muscles
2. Reduced cognitive function and poor concentration - iron required for dopamine synthesis and myelination
3. In children: impaired psychomotor development and intellectual disability - most significant long-term complication in paediatric IDA
4. Headache, dizziness, tinnitus, syncope
5. Restless legs syndrome (RLS) - iron deficiency in CNS dopaminergic pathways
6. Breath-holding spells in infants

D. Epithelial/Mucosal Complications (Specific to IDA)

1. Koilonychia (spoon-shaped nails) - flattening and concavity of nails; brittle nails
2. Angular cheilitis (angular stomatitis) - painful cracks at corners of mouth
3. Glossitis (atrophic glossitis) - smooth, beefy red, painful tongue; loss of papillae
4. Pharyngeal/oesophageal web - Plummer-Vinson syndrome (Patterson-Kelly syndrome): triad of IDA + glossitis + postcricoid web → dysphagia; premalignant (predisposes to postcricoid carcinoma)
5. Gastric atrophy - reduced gastric acid secretion (further impairs iron absorption - vicious cycle)
6. Pica - craving for non-food substances (ice = pagophagia; clay = geophagia; starch = amylophagia)

E. Pregnancy Complications

1. Intrauterine growth restriction (IUGR)
2. Preterm labour and low birth weight
3. Increased maternal mortality (especially peripartum haemorrhage in severe anaemia)
4. Post-partum depression
5. Impaired foetal brain development

F. Growth and Development (Paediatric)

1. Poor growth and short stature
2. Reduced exercise tolerance and physical performance
3. Increased susceptibility to lead poisoning (pica behaviour + increased GI lead absorption in iron deficiency)

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2. COMPLICATIONS OF MEGALOBLASTIC ANAEMIA

A. Haematological Complications

1. Pancytopenia - severe anaemia + leucopenia + thrombocytopenia in advanced disease
2. Increased bleeding tendency - thrombocytopenia → purpura, mucosal bleeding, menorrhagia
3. Increased infection risk - leucopenia + impaired neutrophil function
4. Ineffective erythropoiesis → haemolysis → pigment gallstones (bilirubin stones)
5. Haemolytic component - intramedullary destruction

B. Neurological Complications (B12 Deficiency ONLY)

1. Subacute Combined Degeneration (SCD) of the Spinal Cord - the most serious complication:
   • Demyelination of posterior columns (dorsal columns) → loss of vibration sense, proprioception, sensory ataxia, positive Romberg's sign
   • Demyelination of lateral (corticospinal) columns → upper motor neurone signs - spasticity, hyperreflexia, extensor plantar response (Babinski sign)
   • Demyelination of peripheral nerves → glove-and-stocking sensory loss, absent ankle jerks (mixed UMN+LMN picture)
   • Can occur without anaemia (neurological disease may precede haematological changes, especially if folate supplementation given)
2. Cognitive impairment and dementia - "megaloblastic madness": memory loss, confusion, psychosis, depression; reversible if treated early
3. Optic atrophy - rare; tobacco-alcohol amblyopia
4. Peripheral neuropathy - paresthesiae (pins and needles), numbness in hands and feet
5. Autonomic neuropathy - postural hypotension, impotence, bladder/bowel dysfunction

Critical: Folate treatment in undiagnosed B12 deficiency will correct anaemia but allow neurological damage to progress - the most dangerous pitfall. Always test B12 before prescribing folate.

C. Gastrointestinal Complications

1. Glossitis - smooth, sore, beefy-red tongue (Hunter's glossitis / atrophic glossitis)
2. Angular cheilitis
3. Anorexia, weight loss, malabsorption - GI epithelial cell DNA synthesis impaired
4. Diarrhoea - malabsorption due to villous atrophy
5. Increased risk of GI malignancy - pernicious anaemia patients have 2-3x increased risk of gastric carcinoma (due to chronic atrophic gastritis + achlorhydria + bacterial overgrowth → carcinogenic N-nitroso compounds)
6. Gastric carcinoid tumours - elevated gastrin in pernicious anaemia → ECL cell hyperplasia → carcinoid

D. Cardiovascular Complications

1. Hyperhomocysteinaemia - B12/folate deficiency → elevated homocysteine → endothelial damage → increased risk of atherosclerosis, coronary artery disease, stroke, DVT/PE
2. Cardiac failure from severe anaemia
3. High-output state

E. Obstetric Complications (Folate Deficiency in Pregnancy)

1. Neural tube defects (NTDs) - most important: anencephaly, spina bifida, encephalocele (folate required in first 28 days of neural tube closure - often before pregnancy recognised)
2. Spontaneous abortion and recurrent miscarriage
3. Placental abruption and pre-eclampsia
4. Preterm birth and low birth weight
5. Cleft palate

F. Associated Autoimmune Complications (Pernicious Anaemia)

1. Associated with other autoimmune diseases: Hashimoto's thyroiditis, Addison's disease, Type 1 diabetes, vitiligo
2. Gastric carcinoma risk (as above - 2-3x increased)

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3. COMPLICATIONS OF MACROCYTIC ANAEMIA

A. From Macrocytic Anaemia Itself

1. Cardiovascular: High-output cardiac failure, tachycardia, cardiac failure
2. Neurological: Fatigue, dizziness, syncope, poor concentration
3. If megaloblastic: All neurological and GI complications of megaloblastic anaemia (see above)

B. Complications Specific to Alcoholic Macrocytosis

1. Alcoholic liver disease (hepatitis → cirrhosis → liver failure) - the macrocytosis here is a marker of alcohol excess
2. Alcoholic cardiomyopathy
3. Wernicke-Korsakoff syndrome (thiamine deficiency from alcoholism)
4. Peripheral neuropathy
5. Pancreatitis (acute and chronic)
6. Portal hypertension → oesophageal varices → GI haemorrhage (worsens anaemia)

C. Complications Specific to Hypothyroid Macrocytosis

1. Myxoedematous coma (if untreated hypothyroidism progresses)
2. Associated autoimmune B12 deficiency (Hashimoto's + PA association)
3. Cardiovascular: Pericardial effusion, atherogenic dyslipidaemia

D. MDS-Associated Macrocytosis

1. Transformation to Acute Myeloid Leukaemia (AML) - the most feared complication; 10-40% of MDS cases transform
2. Progressive pancytopenia → life-threatening infections, bleeding

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4. COMPLICATIONS OF SICKLE CELL ANAEMIA

A. Acute Complications (Crises)

1. Vaso-occlusive (Painful) Crisis - Most common crisis

• Acute ischaemic pain in bones, joints, chest, abdomen
• Hand-foot syndrome (dactylitis) - swelling and pain in hands/feet; often the first manifestation in infants (6 months-2 years)
• Precipitated by infection, dehydration, cold, hypoxia, stress, acidosis

2. Acute Chest Syndrome (ACS) - Leading cause of death

• Fever + chest pain + pulmonary infiltrate + hypoxia + new chest X-ray opacity
• Caused by: fat embolism (from bone marrow infarction), infection (Chlamydia, Mycoplasma, Streptococcus pneumoniae, viruses), in-situ sickling in pulmonary vasculature
• Can progress to acute respiratory failure
• Single most common cause of death in SCD

3. Aplastic Crisis

• Caused by Parvovirus B19 infection → infects erythroid progenitors → transient arrest of erythropoiesis for ~7-10 days
• Severe, sudden-onset anaemia with reticulocytopenia (absence of reticulocytes - distinguishes from haemolytic crisis)
• Life-threatening in SCD (already anaemic baseline); may require transfusion
• Self-limiting; confers lifelong immunity

4. Haemolytic Crisis (Hyperhemolytic Crisis)

• Sudden acceleration of haemolysis → rapid fall in Hb
• Often precipitated by G6PD deficiency (common co-inheritance in same ethnic populations), infections
• Hyperhemolytic syndrome: can be transfusion-associated (transfused AND native RBCs destroyed)

5. Sequestration Crisis

• Sudden pooling/trapping of large volumes of blood in the spleen (in young children) or liver
• Rapidly enlarging, tender spleen/liver + sudden fall in Hb + hypovolaemic shock
• Most common in children aged 5 months-5 years (before autosplenectomy)
• Potentially fatal within hours - true haematological emergency
• Management: urgent blood transfusion; splenectomy after recurrence

B. Chronic/Systemic Organ Complications

1. Spleen

• Repeated infarctions → progressive autosplenectomy by age 5-10 years
• Resulting functional asplenia → high susceptibility to encapsulated bacteria:
  • Streptococcus pneumoniae (most common - risk of overwhelming sepsis = pneumococcal septicaemia)
  • Haemophilus influenzae
  • Neisseria meningitidis
  • Salmonella (unique to SCD - causes osteomyelitis unusually; Salmonella typhi bacteraemia)
• Requires prophylactic penicillin (from 2 months of age) and pneumococcal/meningococcal/Hib vaccinations

2. Bone and Joints

• Avascular necrosis (osteonecrosis) of femoral head (most common) and humeral head - due to medullary infarction
• Osteomyelitis - Salmonella spp. (uniquely common in SCD) and Staphylococcus aureus
• "Hair on end" appearance on skull X-ray (marrow hyperplasia eroding cortex)
• Frontal bossing - skull expansion due to marrow hyperplasia
• Pathological fractures
• Periostitis and cortical thinning
• Growth retardation in children

3. Neurological

• Stroke (cerebrovascular accident) - occurs in ~10% of patients by age 20; due to large vessel vasculopathy (intimal hyperplasia, thrombosis)
• Ischaemic stroke most common in children; haemorrhagic stroke in adults
• Silent cerebral infarcts - occur in ~35% and cause cognitive impairment
• Seizures
• Transient ischaemic attacks (TIAs)
• Management: chronic transfusion programme (maintains HbS <30%) reduces stroke risk

4. Lung (Chronic)

• Pulmonary hypertension - from repeated episodes of ACS, chronic haemolysis (free Hb scavenges NO → vasoconstriction), thromboemboli
• Progressive right heart failure (cor pulmonale)
• Chronic restrictive lung disease

5. Kidney

• Haematuria - papillary ischaemia; even in sickle cell trait
• Renal papillary necrosis - infarction of renal papillae → haematuria, renal colic, tubular dysfunction
• Hyposthenuria - inability to concentrate urine (ischaemia of renal medulla/vasa recta); early and universal finding; nocturia, enuresis
• Sickle nephropathy - progressive chronic kidney disease → ESRD (significant cause of mortality in adults)
• Nephrotic syndrome - membranoproliferative pattern

6. Eye

• Proliferative sickle retinopathy - neovascularization (sea-fan pattern), vitreous haemorrhage, retinal detachment → blindness
• Non-proliferative changes - salmon-patch haemorrhages, black sunburst lesions
• More common in HbSC than HbSS

7. Liver and Gallbladder

• Gallstones (cholelithiasis) - pigment (bilirubin) stones from chronic haemolysis; in >30% of adults with SCD
• Cholecystitis, ascending cholangitis
• Sickle cell hepatopathy - hepatomegaly from RBC sequestration, iron overload, hepatitis (from transfusions)
• Acute hepatic sequestration - sudden RBC trapping

8. Cardiovascular

• Cardiomegaly - chronic high-output state from anaemia
• Pulmonary hypertension → right ventricular failure
• Sudden cardiac death
• Iron overload cardiomyopathy in heavily transfused patients

9. Genitourinary

• Priapism - painful, prolonged, unwanted erection due to vascular occlusion in corpora cavernosa
  • Stuttering priapism: recurrent, brief (<3 hours) episodes
  • Major priapism (>4 hours): urological emergency; if untreated → erectile dysfunction (fibrosis of cavernosa)
• Risk of impotence is high in adult men

10. Dermatological

• Chronic leg ulcers (malleolar ulcers) - over medial and lateral malleoli; caused by ischaemia, venous stasis, poor healing; very painful, slow to heal, recurrent

11. Growth and Development

• Growth retardation and delayed puberty
• Nutritional deficiencies (zinc, folate)
• Psychosocial complications - depression, anxiety, school absenteeism, reduced quality of life

12. Transfusion Complications (in multiply-transfused patients)

• Iron overload (haemosiderosis) → cardiomyopathy, hepatic cirrhosis, endocrine failure (diabetes, hypogonadism, hypothyroidism)
• Alloimmunisation to RBC antigens → haemolytic transfusion reactions
• Infection transmission (HIV, hepatitis B/C - historical)

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5. COMPLICATIONS OF HAEMOLYTIC ANAEMIA

A. Complications Common to All Haemolytic Anaemias

1. Gallstones (Cholelithiasis)

• Chronic haemolysis → excess bilirubin production → precipitation as calcium bilirubinate (pigment) stones
• Can cause: biliary colic, acute cholecystitis, ascending cholangitis, pancreatitis, obstructive jaundice
• Even in children with HS, gallstones may form by age 10

2. Aplastic Crisis

• Parvovirus B19 - most common cause; infects erythroid progenitors → temporary cessation of erythropoiesis → sudden, severe anaemia with reticulocytopenia
• Life-threatening in chronic haemolytic anaemias (already compensating at maximum)
• Self-limiting (~10-14 days); managed with transfusion support

3. Folate Deficiency (Megaloblastic Change)

• Chronic high erythroid turnover demands large amounts of folate
• Folate stores depleted → superimposed megaloblastic anaemia → worsening of anaemia
• Prophylactic folic acid 5 mg/day is given routinely in chronic haemolytic anaemias

4. Iron Overload (Haemosiderosis)

• Mainly from repeated blood transfusions (each unit deposits ~250 mg iron)
• Also: increased intestinal iron absorption due to elevated erythropoiesis drive
• Target organs: Heart (cardiomyopathy - most lethal), liver (cirrhosis), pancreas (diabetes mellitus), endocrine glands (hypogonadism, growth failure, hypothyroidism)
• Management: iron chelation (desferrioxamine, deferasirox, deferiprone)

5. Extramedullary Haemopoiesis

• Chronic severe haemolysis → marrow hyperplasia overflows to extramedullary sites
• Spleen, liver (hepatosplenomegaly)
• Paravertebral masses (chest X-ray finding)
• Skull: "hair on end" radiological appearance (especially in thalassaemia and SCD)
• Facial deformity: frontal bossing, maxillary hyperplasia ("chipmunk facies") in severe thalassaemia

6. Splenomegaly and Hypersplenism

• Massive splenomegaly → hypersplenism → pancytopenia (RBC, WBC, platelet sequestration)
• Risk of splenic rupture (spontaneous or traumatic)
• Splenic infarction (in rapidly enlarging spleens)

7. Chronic Jaundice

• Persistent unconjugated hyperbilirubinaemia → jaundice, icteric sclerae
• Bilirubin may deposit in skin

B. Complications Specific to Autoimmune Haemolytic Anaemia (AIHA)

1. Life-threatening haemolysis - particularly in warm AIHA; Hb can fall precipitously
2. Steroid side effects - first-line treatment is corticosteroids; long-term use causes Cushing's syndrome, osteoporosis, diabetes, hypertension, cataracts
3. Splenectomy complications - second-line treatment; post-splenectomy sepsis from encapsulated organisms
4. Thromboembolic events - AIHA associated with hypercoagulable state; DVT, PE
5. Evans syndrome - simultaneous AIHA + immune thrombocytopenic purpura (ITP) → severe anaemia + thrombocytopenia + bleeding
6. Underlying disease progression - secondary AIHA (from SLE, CLL, lymphoma) - the primary disease may itself progress
7. Haemoglobinuria - renal tubular damage from free haemoglobin; acute tubular necrosis → acute kidney injury

C. Complications Specific to G6PD Deficiency

1. Neonatal jaundice - severe in neonates; can cause kernicterus (bilirubin encephalopathy → permanent brain damage, deafness, athetoid cerebral palsy)
2. Acute haemolytic episodes triggered by:
   • Drugs (primaquine, dapsone, nitrofurantoin, aspirin in large doses, chloroquine)
   • Favism (fava beans - Vicia faba)
   • Infections (any febrile illness)
   • Naphthalene (mothballs)
3. Haemoglobinuria → "Blackwater fever" (especially with primaquine + malaria)
4. Chronic non-spherocytic haemolytic anaemia in rare severe enzyme variants

D. Complications Specific to Hereditary Spherocytosis (HS)

1. Gallstones (in up to 50% of adults with HS)
2. Aplastic crisis (parvovirus B19)
3. Haemolytic crisis (during infections)
4. Megaloblastic crisis (folate depletion)
5. Post-splenectomy complications:
   • Post-splenectomy sepsis (encapsulated bacteria)
   • Thrombocytosis → thromboembolic risk
   • Atherosclerosis (cholesterol from excess Hb breakdown)
6. Leg ulcers (rare)

E. Complications Specific to MAHA (TTP/HUS)

1. Acute kidney injury (AKI) - hallmark of HUS (thrombotic microangiopathy in renal microvasculature); may progress to chronic renal failure
2. Neurological dysfunction - hallmark of TTP: confusion, seizures, focal deficits, stroke (from cerebral microthrombi)
3. Cardiac involvement - myocardial microinfarcts
4. Bowel ischaemia (in STEC-HUS from E. coli O157:H7 - bloody diarrhoea triggers)
5. DIC-related bleeding - in DIC-associated MAHA
6. Thrombotic microangiopathy → multi-organ failure if untreated

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SUMMARY TABLE: COMPLICATIONS AT A GLANCE

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