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Anaemia: Basic to Clinical

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1. Definition

"Anaemia is defined as blood counts below normal for a given population." - Harrison's Principles of Internal Medicine 22E, p.731

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2. Basic Physiology: Normal RBC & Oxygen Transport

RBC Production (Erythropoiesis)

• Occurs in the bone marrow (axial skeleton in adults)
• Stem cell → BFU-E → CFU-E → proerythroblast → erythroblast → reticulocyte → mature RBC
• Regulated by erythropoietin (EPO), produced by the kidneys in response to hypoxia
• EPO binds JAK2-STAT5 pathway → stimulates erythroid proliferation and differentiation

Key Components of Haemoglobin

• Each RBC contains ~280 million Hb molecules
• Each Hb = 4 globin chains + 4 haem groups (each haem = protoporphyrin ring + Fe²⁺)
• One haem binds one O₂ molecule → each Hb molecule carries 4 O₂
• Normal adult Hb = HbA (α₂β₂) - 97%, HbA₂ (α₂δ₂) - 2.5%, HbF (α₂γ₂) - <1%

RBC Life Span

• Normal RBC life span: 120 days
• Senescent RBCs are destroyed by macrophages in the spleen, liver, and bone marrow (extravascular haemolysis)
• Iron is recycled; porphyrin ring → bilirubin → excreted

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3. Classification of Anaemia

A. Morphological Classification (by MCV)

"Anemia classification by red cell size was pioneered by the hematologist Max Wintrobe." - Harrison's Principles of Internal Medicine 22E

B. Pathophysiological Classification (by mechanism)

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4. Pathophysiology - General

Compensatory Mechanisms:

1. Cardiovascular: increased heart rate, increased stroke volume → hyperdynamic circulation
2. Redistribution of blood flow: preferentially to heart and brain
3. Rightward shift of O₂-Hb dissociation curve: via increased 2,3-DPG → greater O₂ offloading to tissues
4. Increased EPO secretion: stimulates erythropoiesis → raised reticulocyte count
5. Increased respiratory rate: mild hyperventilation to increase O₂ delivery

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5. Types of Anaemia in Detail

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5A. Iron Deficiency Anaemia (IDA)

Causes:

• Inadequate intake: malnutrition, poor diet (especially in developing countries, vegetarians)
• Malabsorption: coeliac disease, post-gastrectomy, H. pylori gastritis
• Increased demand: pregnancy, lactation, rapid growth in infancy/adolescence
• Chronic blood loss: menorrhagia (most common in women), GI bleeding (ulcers, colorectal cancer - most common in men over 50), haematuria
• Intravascular haemolysis: haemoglobinuria (e.g., PNH)

Stages of Iron Deficiency:

1. Pre-latent: Iron stores depleted (↓ ferritin). No anaemia yet.
2. Latent: ↓ ferritin, ↑ TIBC, ↓ serum iron, ↓ transferrin saturation. No anaemia yet.
3. Iron deficiency anaemia: ↓ Hb, ↓ MCV, ↓ MCH → microcytic, hypochromic anaemia + symptoms

Iron Studies Interpretation:

"A low ferritin rules in iron deficiency anaemia. In general populations, the LR- for a serum ferritin > 100 ng/mL is very low (0.08)." - Symptom to Diagnosis 4th Edition

Blood Film:

• Microcytes, hypochromic cells, pencil cells (elliptocytes), target cells, thrombocytosis (reactive)

Clinical Features:

• General: fatigue, weakness, pallor, dyspnoea on exertion, palpitations
• Specific to iron deficiency:
  • Koilonychia (spoon-shaped nails)
  • Angular stomatitis (cheilitis)
  • Glossitis (smooth, painful tongue)
  • Pica (craving for non-food items - ice, clay, starch)
  • Plummer-Vinson syndrome (post-cricoid web + IDA + dysphagia)
  • Restless leg syndrome
  • Hair loss

Management:

• Identify and treat the underlying cause (this is key - never just treat without finding the cause)
• Oral ferrous sulphate 200mg TDS (provides 60mg elemental iron per dose) for 3-6 months after Hb normalises (to replenish stores)
• Response: reticulocytosis in 7-10 days, Hb rises 1-2 g/dL per week
• IV iron if: malabsorption, intolerance to oral iron, ongoing blood loss exceeding oral replacement, pre-operative optimisation
• Dietary advice: increase haem iron (red meat, liver), vitamin C with meals (enhances non-haem iron absorption), avoid tea/coffee with meals

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5B. Megaloblastic Anaemia (B12/Folate Deficiency)

Pathophysiology:

• B12 and folate are required for DNA synthesis (specifically thymidylate synthesis)
• Deficiency → impaired DNA synthesis → cells fail to divide but continue to grow → large cells (megaloblasts)
• All rapidly dividing cells affected: RBCs, WBCs, platelets, GI mucosa

B12 Deficiency - Causes:

• Pernicious anaemia (most common): autoimmune destruction of gastric parietal cells → loss of intrinsic factor (IF) → failure of B12 absorption in terminal ileum
• Strict vegetarian/vegan diet (B12 only in animal products)
• Terminal ileum disease (Crohn's, surgical resection)
• Fish tapeworm (Diphyllobothrium latum)
• Prolonged metformin use (reduces B12 absorption)

Folate Deficiency - Causes:

• Poor dietary intake (commonest cause - elderly, alcoholics)
• Malabsorption (coeliac disease)
• Increased demand (pregnancy, haemolytic anaemia)
• Drugs: methotrexate, phenytoin, trimethoprim (inhibit dihydrofolate reductase)

Blood Film:

• Macro-ovalocytes (large oval red cells) - hallmark
• Hypersegmented neutrophils (≥5 lobes in >5% of neutrophils OR any cell with ≥6 lobes) - pathognomonic
• Pancytopenia in severe cases

Clinical Features:

• Symptoms of anaemia (fatigue, pallor, dyspnoea)
• Glossitis (beefy-red, smooth tongue)
• Jaundice (mild, due to ineffective erythropoiesis → intramedullary haemolysis)
• B12-specific neurological features (NOT seen with folate deficiency):
  • Subacute combined degeneration of the spinal cord: demyelination of posterior columns (loss of vibration sense, proprioception) + lateral corticospinal tracts (upper motor neuron signs, weakness, spasticity)
  • Peripheral neuropathy
  • Cognitive impairment, dementia
  • IMPORTANT: Never give folate alone to a B12-deficient patient - it can precipitate or worsen neurological damage

Investigations:

• ↓ Hb, ↑ MCV, macro-ovalocytes, hypersegmented neutrophils
• ↓ Serum B12 (<200 pg/mL), ↓ serum folate (<3 ng/mL), ↓ RBC folate
• ↑ Serum LDH and bilirubin (ineffective erythropoiesis)
• ↑ Homocysteine (seen in both B12 and folate deficiency)
• ↑ Methylmalonic acid (MMA) - specific for B12 deficiency (not elevated in folate deficiency)
• Anti-intrinsic factor antibodies (positive in ~60% of pernicious anaemia)
• Anti-parietal cell antibodies (positive in ~90% of pernicious anaemia, less specific)
• Schilling test (now rarely done)

Management:

• B12 deficiency: Hydroxocobalamin IM injection 1mg on alternate days for 2 weeks, then every 3 months for life (if pernicious anaemia or irreversible cause). Oral cyanocobalamin if dietary deficiency.
• Folate deficiency: Folic acid 5mg daily for 4 months. Prophylactic folic acid 400mcg daily in all women planning pregnancy (or 5mg if high risk) to prevent neural tube defects.

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5C. Anaemia of Chronic Disease (ACD) / Anaemia of Inflammation

Pathophysiology:

• Chronic inflammatory conditions (rheumatoid arthritis, cancer, TB, HIV, renal failure) trigger cytokines (IL-1, IL-6, TNF-α)
• IL-6 → stimulates liver to produce hepcidin
• Hepcidin binds and degrades ferroportin (the iron exporter on enterocytes and macrophages) → traps iron inside macrophages → iron unavailable for erythropoiesis
• Cytokines also suppress EPO production and impair erythroid precursor response to EPO
• Result: normocytic normochromic anaemia (can be mildly microcytic)

Features distinguishing ACD from IDA:

• Ferritin is elevated in ACD (acute phase reactant) - even when true iron stores are low
• TIBC is low in ACD (opposite of IDA)
• Serum transferrin receptor (sTfR) is normal in ACD but elevated in IDA - useful marker
• sTfR/log ferritin ratio >2 suggests IDA coexisting with ACD

Management:

• Treat the underlying condition
• IV iron and/or EPO in selected patients (e.g., pre-dialysis CKD)

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5D. Haemolytic Anaemias

Classification:

• Causes: complement activation (ABO incompatibility, PNH), mechanical trauma (prosthetic valves), G6PD in severe cases
• Features: haemoglobinuria (red/brown urine), haemoglobinaemia, haemosiderinuria, ↓↓ haptoglobin

• Most common pattern
• Causes: hereditary spherocytosis, autoimmune, sickle cell
• Features: splenomegaly, jaundice (unconjugated bilirubin), no haemoglobinuria

Lab Features of Haemolysis:

• ↑ LDH (released from lysed RBCs)
• ↑ Indirect (unconjugated) bilirubin → jaundice
• ↓ Haptoglobin (binds free Hb - consumed)
• ↑ Reticulocyte count (bone marrow compensating)
• Urine urobilinogen ↑

Key Haemolytic Conditions:

• AD inheritance; defect in spectrin, ankyrin, or band 3 protein → loss of RBC membrane → spherical, less deformable cells → trapped and destroyed in spleen
• Anaemia + jaundice + splenomegaly (classic triad)
• Blood film: spherocytes, ↑ MCHC
• Osmotic fragility test: increased; EMA binding test (flow cytometry) - more sensitive
• Rx: folate supplementation; splenectomy in severe cases (prevents destruction, not the underlying defect)

• X-linked recessive; G6PD protects RBCs from oxidative stress via NADPH
• Precipitants: infections, oxidant drugs (dapsone, primaquine, nitrofurantoin), fava beans
• Episodes of acute intravascular haemolysis: Heinz bodies (denatured Hb) on blood film, bite cells
• Between episodes: blood film is normal
• Rx: avoid triggers; supportive during acute episodes; transfusion if severe

• Warm AIHA (IgG, 37°C): idiopathic, SLE, CLL, drugs (methyldopa, penicillin). Extravascular.
• Cold AIHA (IgM, <37°C): Mycoplasma infection, EBV, lymphoma. Intravascular + extravascular.
• Direct Coombs test (DAT): positive (antibodies/complement on RBC surface)
• Rx: Warm AIHA - steroids, IVIG, rituximab, splenectomy. Cold AIHA - keep warm, treat underlying, rituximab.

• Autosomal recessive; point mutation in β-globin gene (glutamate → valine at position 6)
• Deoxygenation → HbS polymerises → RBCs sickle → vaso-occlusion + haemolysis
• Vaso-occlusive crises: severe bone pain (most common), dactylitis in children, acute chest syndrome (most common cause of death), stroke, priapism
• Haemolytic anaemia: chronic + episodic, Hb 6-9 g/dL at baseline
• Aplastic crisis: parvovirus B19 infection → sudden drop in Hb
• Sequestration crisis: RBCs pooled in spleen (children) → sudden splenomegaly + shock
• Blood film: sickle cells, target cells, features of hyposplenism (Howell-Jolly bodies)
• Confirmatory test: Hb electrophoresis (HbS > 90%, no HbA)
• Rx: Hydroxycarbamide (hydroxyurea - ↑ HbF), folic acid, penicillin V prophylaxis (functional asplenia), vaccinations, analgesia during crises, transfusion, bone marrow transplant (curative)

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5E. Aplastic Anaemia

Definition:

Causes:

• Acquired (most common): autoimmune T-cell mediated destruction of HSCs (idiopathic ~70%)
• Drugs: chloramphenicol, NSAIDs, cytotoxics, gold
• Infections: EBV, CMV, hepatitis (seronegative hepatitis is strongly associated)
• Radiation exposure
• Inherited: Fanconi anaemia (AR; DNA repair defect; associated with congenital anomalies)

Blood film: Normocytic normochromic anaemia + absence of reticulocytosis (hypoproliferative)

Bone marrow biopsy: Hypocellular marrow replaced by fat cells - diagnostic

Severity:

• Severe AA: BM cellularity <25% AND two of: neutrophils <0.5×10⁹/L, platelets <20×10⁹/L, reticulocytes <20×10⁹/L

Management:

• Young patients: allogeneic bone marrow (stem cell) transplant - potentially curative
• Older patients/no matched donor: immunosuppression with anti-thymocyte globulin (ATG) + ciclosporin + eltrombopag
• Supportive: RBC transfusions, platelet transfusions, G-CSF, antibiotics for infections

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5F. Thalassaemia

• Thalassaemia = genetic disorders with reduced or absent synthesis of globin chains
• α-thalassaemia: deletion of α-globin genes (chromosome 16)
  • 1 gene deleted: silent carrier
  • 2 genes deleted: alpha-thal trait (mild microcytic anaemia)
  • 3 genes deleted: HbH disease (moderate haemolytic anaemia)
  • 4 genes deleted: Hb Bart's (hydrops fetalis - incompatible with life)
• β-thalassaemia: mutations in β-globin gene (chromosome 11)
  • β-thal minor (trait): mild anaemia, microcytic, ↑ HbA₂ (>3.5%) - diagnostic
  • β-thal major (Cooley's anaemia): severe transfusion-dependent anaemia from 6 months (when HbF switches to HbA); massive splenomegaly, bone marrow expansion (frontal bossing, "hair-on-end" skull X-ray)
• Management of β-thal major: regular blood transfusions + iron chelation (desferrioxamine/deferasirox), BMT (curative), hydroxyurea

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6. Clinical Approach to a Patient with Anaemia

History:

• Duration, acuity of onset (acute = loss/haemolysis; chronic = nutritional/disease)
• Diet (vegan, poor diet → B12/folate/iron deficiency)
• Menstrual history, bleeding history (GI symptoms - PR bleeding, melaena, haematuria)
• Medications (NSAIDs, chemotherapy, metformin, PPIs)
• Family history (haemoglobinopathies)
• Ethnic background (sickle cell: West Africa, Caribbean; thalassaemia: Mediterranean, South/SE Asia)
• Systemic features: weight loss, night sweats (malignancy/lymphoma), jaundice (haemolysis)

Examination:

• General: pallor (conjunctivae, palmar creases, mucous membranes - most reliable)
• Nails: koilonychia (IDA), leukonychia (chronic disease)
• Mouth: glossitis, angular stomatitis, jaundice (sublingual), telangiectasia (hereditary haemorrhagic telangiectasia)
• Abdomen: splenomegaly (haemolysis, infiltration), hepatomegaly, lymphadenopathy
• Neurological: posterior column signs (B12 deficiency)
• CVS: tachycardia, flow murmur (ejection systolic), bounding pulse, cardiac failure signs (in severe anaemia)

Investigations:

• Full blood count (FBC) + blood film - the cornerstone
• Reticulocyte count - key for classifying (high = haemolysis/bleeding; low = hypoproliferative)
• MCV guides further workup

• Serum ferritin, serum iron, TIBC, transferrin saturation
• Hb electrophoresis (if thalassaemia suspected)

• Serum B12 and folate levels
• Liver function tests, TFTs
• Blood film for hypersegmented neutrophils, macro-ovalocytes

• Reticulocyte count: if high → haemolysis screen (LDH, haptoglobin, bilirubin, DAT/Coombs)
• U&E/creatinine (renal failure → ↓ EPO)
• TFTs (hypothyroidism)
• Consider bone marrow biopsy if unexplained

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7. Management Principles

General Approach:

1. Treat the underlying cause - always the primary goal
2. Correct deficiency (iron, B12, folate)
3. Blood transfusion if: acute haemodynamic compromise, severe symptomatic anaemia (Hb <7 g/dL generally, <8 g/dL in cardiac disease), pre-operative if expected major blood loss
4. EPO (erythropoiesis-stimulating agents): CKD-related anaemia, cancer chemotherapy anaemia
5. Specific therapies: hydroxycarbamide for sickle cell, ATG for aplastic anaemia, BMT as curative option

Transfusion triggers (general guidance):

• Hb <7 g/dL: transfuse most stable patients
• Hb <8 g/dL: transfuse in cardiac disease or perioperative setting
• Target Hb 7-9 g/dL post-transfusion (avoid over-transfusion)

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8. Special Situations

Anaemia in Pregnancy:

• Physiological dilutional anaemia (↑ plasma volume > ↑ RBC mass)
• Increased iron requirements (30mg/day in 3rd trimester)
• IDA most common cause; supplement all pregnant women with folic acid
• Treat with oral iron; IV iron if severe or intolerant

Anaemia of Renal Failure:

• ↓ EPO production by diseased kidneys → normocytic, normochromic, hypoproliferative
• Rx: EPO analogues (darbepoetin, epoetin) + IV iron to ensure adequate iron for erythropoiesis; target Hb 10-12 g/dL

Anaemia in Cancer:

• Multifactorial: ACD, chemotherapy (myelosuppression), tumour infiltration, bleeding, nutritional deficiency
• Rx: treat underlying, transfusion if symptomatic, ESAs (with caution - risk of thrombosis and tumour progression)

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9. Summary Table

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• Harrison's Principles of Internal Medicine, 22nd Edition - Chapters 66 (Anaemia)
• Park's Textbook of Preventive and Social Medicine - Nutritional Anaemia chapter
• Tietz Textbook of Laboratory Medicine, 7th Edition - RBC Parameters and Iron Studies
• Symptom to Diagnosis: An Evidence-Based Guide, 4th Edition - Ferritin diagnostic utility
• Bailey and Love's Short Practice of Surgery, 28th Edition - Perioperative anaemia, Thalassaemia, Haemolytic anaemia
• Quick Compendium of Clinical Pathology, 5th Edition - IDA vs ACD differentiation

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1. Definition & WHO cut-offs - exact Hb thresholds by age/sex/pregnancy status
2. Basic physiology - erythropoiesis, haemoglobin structure, RBC life cycle, EPO regulation
3. Classification - morphological (by MCV: micro/normo/macrocytic) and pathophysiological (reduced production / increased destruction / blood loss)
4. Compensatory mechanisms - 2,3-DPG shift, tachycardia, EPO surge, blood redistribution
5. Each major type in depth:
   • Iron Deficiency (stages, iron studies table, koilonychia, pica, Plummer-Vinson, treatment)
   • Megaloblastic (B12 vs folate, subacute combined degeneration, why never give folate alone in B12 deficiency)
   • Anaemia of Chronic Disease (hepcidin-ferroportin axis, differentiation from IDA)
   • Haemolytic (intra vs extravascular, spherocytosis, G6PD, AIHA warm/cold, sickle cell)
   • Aplastic anaemia (autoimmune HSC destruction, hypocellular marrow, ATG + BMT)
   • Thalassaemia (α vs β, Mentzer index, hair-on-end skull X-ray)
6. Clinical approach - history, examination, investigations algorithm guided by MCV + reticulocyte count
7. Management - transfusion triggers, specific therapies, EPO indications
8. Special situations - pregnancy, renal failure, cancer
9. Summary comparison table for exam/clinical use